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–Fos expression in female hamster brain following sexual and aggressive behaviors
Abstract
The goal of these experiments was to use c-Fos immunocytochemistry to determine areas of the female hamster brain that are active during lordosis and aggression. Ovariectomized hamsters were given (i) estradiol and progesterone, plus a lordosis test, (ii) estradiol and progesterone, but no lordosis test, (iii) oil, plus an aggressive behavior test, or (iv) oil, but no behavior test. Results showed that following lordosis, there was increased c-Fos expression in the medial bed nucleus of the stria terminalis, medial accumbens, medial preoptic nucleus, paraventricular nucleus and medial amygdala. Following a single aggression test, c-Fos was significantly increased only within the medial amygdala. There was no effect of lordosis or aggression on c-Fos expression within the lateral or central ventromedial hypothalamus, suprachiasmatic nucleus or dorsal midbrain central gray. In a second experiment, ovariectomized female hamsters were given (i) repeated aggressive experience, (ii) a single aggression test or (iii) no aggression test. Because some females were not aggressive towards males, they became a separate group post hoc. The number of cells expressing c-Fos was higher in the medial preoptic nucleus and medial amygdala of females given a single aggressive test and in non-aggressive females vs control females. Females given prior aggressive experience showed higher c-Fos expression only in the medial preoptic nucleus. These results demonstrate that increased neural activation in several forebrain nuclei is seen after sexual or aggressive behaviors in female hamsters. However, because the pattern of c-Fos staining in the non-aggressive females was similar to the pattern in aggressive females, this questions previous conclusions regarding the behavioral specificity of these effects and suggests instead that such activation is common to social interactions in general.
... Studies in molecular biology have begun to provide tools for studying how experiences in aggressive confrontations alter the activity of corticolimbic cells, via both genomic and nongenomic action (e.g., Caspi et al. 2002;Craig and Halton 2009;Day et al. 2011;Lesch and Merschdorf 2000;Taylor and Kim-Cohen 2007;Tecott and Barondes 1996). The link between a specific social experience and altered gene expression in the cells of discrete mesocorticolimbic pathways involves a cascade of events that ultimately leads to changes in translation and transcription (Joppa et al. 1995;Kollack-Walker et al. 1997;Martinez et al. 1998bMartinez et al. , 2002Nikulina et al. 1998;Young and Wang 2004). The study of social experience-dependent gene expression complements the traditional approaches of behavior genetics, namely to trace the genetic basis of a particular behavioral phenotype. ...
... Some of these genes encode for the synthesis of opioid peptides, and manipulations of opioid receptors shortly after their discovery demonstrated the importance of these neuropeptides in social attachment in both avian and mammalian species (Panksepp et al. 1978). Similarly, sexual experiences are of remarkable salience and readily engender transcriptional activation in discrete brain areas such as the extended amygdala (Baum and Everitt 1992;Joppa et al. 1995;Kollack-Walker and Newman 1995;Ogawa et al. 1997;Parfitt and Newman 1998;Potegal et al. 1996). In the following account, the focus is on behavior during social conflict, particularly on the individual who is the target of attack and threat behavior by aggressive opponents. ...
... The examples begin early in development when differential maternal care leads to the expression of hippocampal glucocorticoid receptors in adulthood (Liu et al. 1997). Mating and aggressive experiences engender c-fos expression in discrete limbic and mesencephalic regions in female hamsters (Joppa et al. 1995). By now, considerable evidence documents how social defeat stress modulates the expression of immediate early genes in the core of the neuroaxis, most frequently studied in voles, mice, rats and hamsters (Cooper et al. 2009;Day et al. 2011;Fekete et al. 2009; Kirkpatrick et al. 1994;Kollack-Walker et al. 1999;Kollack-Walker and Newman 1995;Martinez et al. 2002;Nikulina et al. 1998;Vivian and Miczek 1998). ...
In this review, we examine how experiences in social confrontations alter gene expression in mesocorticolimbic cells. The focus is on the target of attack and threat due to the prominent role of social defeat stress in the study of coping mechanisms and victimization. The initial operational definition of the socially defeated mouse by Ginsburg and Allee (1942) enabled the characterization of key endocrine, cardiovascular, and metabolic events during the initial response to an aggressive opponent and during the ensuing adaptations. Brief episodes of social defeat stress induce an augmented response to stimulant challenge as reflected by increased locomotion and increased extracellular dopamine (DA) in the nucleus accumbens (NAC). Cells in the ventral tegmental area (VTA) that project to the NAC were more active as indicated by increased expression of c-fos and Fos-immunoreactivity and BDNF. Intermittent episodes of social defeat stress result in increased mRNA for MOR in brainstem and limbic structures. These behavioral and neurobiological indices of sensitization persist for several months after the stress experience. The episodically defeated rats also self-administered intravenous cocaine during continuous access for 24 h ("binge"). By contrast, continuous social stress, particularly in the form of social subordination stress, leads to reduced appetite, compromised endocrine activities, and cardiovascular and metabolic abnormalities, and prefer sweets less as index of anhedonia. Cocaine challenges in subordinate rats result in a blunted psychomotor stimulant response and a reduced DA release in NAC. Subordinate rats self-administer cocaine less during continuous access conditions. These contrasting patterns of social stress result from continuous vs. intermittent exposure to social stress, suggesting divergent neuroadaptations for increased vulnerability to cocaine self-administration vs. deteriorated reward mechanisms characteristic of depressive-like profiles.
... As in males, a robust and remarkably consistent induction of Fos mRNA and protein has been observed following copulation with intromission or manual vaginocervical stimulation (VCS) within steroid concentrating brain regions of female rats and hamsters, including the MPOA, ventrolateral septum, BST, PVN, ventrolateral VMH (VMHvl), MeApd, arcuate nucleus, lateral habenula, PMV, VTA, mesencephalic central grey (MCG), and peripeduncular nuclei [22,23,27,35,53,85,88,92,97,100,[112][113][114]119]. Fos has also been induced by copulation with intromission or VCS in regions of the brain that do not contain ''classic'' intracellular steroid receptors, such as cortex, nucleus accumbens, and mediodorsal striatum. ...
... Although lordosis by itself does not induce Fos, [53,85], it is not yet known whether other sexual behaviors, such as solicitation, pacing, or proceptive behaviors, lead to selective induction of Fos in different brain areas. However, Fos induction in the cingulate cortex appears to occur in female rats when they copulate actively with male rats in bilevel chambers (where they show high levels of solicitation, pacing, and proceptive behaviors), but not when they receive manual VCS or flank stimulation [85]. ...
... Finally, other regions such as the cingulate cortex, striatum, posterior BNST, PVN, MEApd, ventral premammillary nuclei, and VTA are activated in female rats and hamsters [53,85,97]. Although the precise role of these regions in female sexual behavior is not known, the Fos induction observed in these regions following VCS or other aspects of copulation can be used to identify discrete locations for lesion studies. ...
Induction of immediate-early genes (IEGs), such as c-fos, has been widely used to mark the activation of brain regions following different types of sexual stimulation and behavior. A relatively common set of hormone-concentrating basal forebrain and midbrain structures in female and male rodents is activated by copulatory stimulation, in particular, stimulation of sensory nerves that innervate the penis or vagina/cervix, olfactory or pheromonal stimuli, and conditioned sexual incentives. These regions include the preoptic area, lateral septum, bed nucleus of the stria terminalis, paraventricular hypothalamus, ventromedial hypothalamus, medial amygdala, ventral premammillary nuclei, ventral tegmentum, central tegmental field, mesencephalic central gray, and peripeduncular nuclei. Regions that do not contain classic intracellular steroid receptors, such as the ventral and dorsal striatum or cortex, are also activated. IEGs have also been colocalized with cytoplasmic proteins like GnRH and oxytocin, and have been used in conjunction with retrograde tracers to reveal functional pathways associated with different sexual behaviors. Steroid hormones can also alter the ability of sexual stimulation to induce IEGs. Despite the many similarities, some differences in IEG induction between sexes have also been found. We review these findings and raise the question of what IEG induction in the brain actually means for sexual behavior, that is, whether it indicates the perception of sexual stimulation, commands for motor output, or the stimulation of a future behavioral or neuroendocrine event related to the consequences of sexual stimulation. To understand the role of a particular activated region, the behavioral or neuroendocrine effects of lesions, electrical stimulation, drug or hormone infusions, must also be known.
... While there is a commonality between the brain regions that regulate aggression between males and females (Joppa et al., 1995;Kollack-Walker and Newman, 1995), there may be differences in the roles of hormones and neuropeptides responsible for activation or inhibition of these regions. To add to this complexity, female aggression across species takes on many forms due to context, i.e. maternal aggression (Erskine et al., 1978;Mayer and Rosenblatt, 1987), and is subject to regulation by hormones released in response to parturition, i.e. oxytocin (for review, Leng et al., 2008), as well as fluctuations of ovarian hormones throughout the four-day rodent estrous cycle (Takahashi and Lisk, 1983;Ciaccio et al., 1979;Floody and Pfaff, 1977). ...
... and lateral portions of the periaqueductal gray (PAG). These brain regions were selected based on their roles in aggressive and sexual behaviors (Delville et al., 2000;Joppa et al., 1995). ...
Aggression is a feature of many clinical disorders including autism, Alzheimer's disease, bipolar disorder, and schizophrenia. The available treatment options act to prevent impulsive aggression through modulation of GABAergic and dopaminergic pathways which come with metabolic and dyskinetic side effects. The mechanism underlying aggressive motivation, however, has not been elucidated. In addition, previous studies have been heavily biased towards males of various species. Mimicking changes in day length, or photoperiod, in the laboratory is a natural manipulation used to examine seasonal changes in aggressive behavior in many species. In response to the reduction in the duration of light exposure, animals undergo gonadal regression and become reproductively quiescent. During this non-breeding season in male photoperiod- responsive animals, aggressive behavior increases significantly. Although studies have shown
... Thus, it would be interesting to determine the similarities between the pattern of brain activation in animals exposed to an acute defeat and when exposed to other types of social stimuli. Some studies have assessed c-fos expression in animals exposed to aggressive (Joppa et al., 1995;Potegal et al., 1996;Wang et al., 1997), sexual (Robertson et al., 1991;Baum and Everitt, 1992;Kollack-Walker and Newman, 1992;Fernandez-Fewell and Meredith, 1994;Flanagan-Cato and McEwen, 1995;Joppa et al., 1995;Bialy and Kaczmarek, 1996;Coolen et al., 1996;Wang et al., 1997), and maternal behavior (Calamandrei and Keverne, 1994;Fleming et al., 1994;Numan et al., 1998). In general, there are some common areas that are activated when animals are exposed to defeat and other social stimuli (e.g. ...
... Thus, it would be interesting to determine the similarities between the pattern of brain activation in animals exposed to an acute defeat and when exposed to other types of social stimuli. Some studies have assessed c-fos expression in animals exposed to aggressive (Joppa et al., 1995;Potegal et al., 1996;Wang et al., 1997), sexual (Robertson et al., 1991;Baum and Everitt, 1992;Kollack-Walker and Newman, 1992;Fernandez-Fewell and Meredith, 1994;Flanagan-Cato and McEwen, 1995;Joppa et al., 1995;Bialy and Kaczmarek, 1996;Coolen et al., 1996;Wang et al., 1997), and maternal behavior (Calamandrei and Keverne, 1994;Fleming et al., 1994;Numan et al., 1998). In general, there are some common areas that are activated when animals are exposed to defeat and other social stimuli (e.g. ...
Social defeat is an important event in the life of many animals, and forms part of the process of social control. Adapting to social defeat is thus an intrinsic part of social "homeostasis", and mal-adaptation may have pathological sequelae. Experimental models of social defeat (e.g. inter-male aggression) have existed for many years. However, very few studies have investigated the changes in brain activity in male animals exposed to the social stress of being defeated by another conspecific male, and in all these studies the expression of the immediate-early gene c-fos has been used as the marker of neuronal activity. In general, the results obtained inform that many areas of the brain, especially those involved in the general stress response, increase their activity when animals are exposed to an acute defeat. However, when animals are defeated repeatedly over many consecutive days, the level of activation of the brain shows different patterns of adaptation depending on the brain areas (varying from complete habituation to persistent activation). Discrepancies between studies may be due to differences in the experimental procedure. On the other hand, further research has to be conducted in order to understand what these changes in the brain activity mean in relation to the other stress responses to social defeat. Furthermore, knowing that the corresponding protein products of many immediate-early genes are transcription factors that can promote or inhibit the expression of target genes, research following this approach is also necessary.
... Importantly, the aggression-regulating circuitry of the MeA is not exclusive to males; females exhibit similar patterns. For instance, increased c-Fos expression in the MeA of aggressive female Syrian hamsters parallels the response seen in males [45]. In meadow voles, reducing estrogen receptor alpha (ERα) in the MeA decreased aggression and promoted prosocial behaviors. ...
Aggression is a fundamental behavior with essential roles in dominance assertion, resource acquisition, and self-defense across the animal kingdom. However, dysregulation of the aggression circuitry can have severe consequences in humans, leading to economic, emotional, and societal burdens. Previous inconsistencies in aggression research have been due to limitations in techniques for studying these neurons at a high spatial resolution, resulting in an incomplete understanding of the neural mechanisms underlying aggression. Recent advancements in optogenetics, pharmacogenetics, single-cell RNA sequencing, and in vivo electrophysiology have provided new insights into this complex circuitry. This review aims to explore the aggression-provoking stimuli and their detection in rodents, particularly through the olfactory systems. Additionally, we will examine the core regions associated with aggression, their interactions, and their connection with the prefrontal cortex. We will also discuss the significance of top-down cognitive control systems in regulating atypical expressions of aggressive behavior. While the focus will primarily be on rodent circuitry, we will briefly touch upon the modulation of aggression in humans through the prefrontal cortex and discuss emerging therapeutic interventions that may benefit individuals with aggression disorders. This comprehensive understanding of the neural substrates of aggression will pave the way for the development of novel therapeutic strategies and clinical interventions. This approach contrasts with the broader perspective on neural mechanisms of aggression across species, aiming for a more focused analysis of specific pathways and their implications for therapeutic interventions.
... Similarly, when adolescents are exposed to social isolation or to brief episodes of social stress ("bullying") long-lasting sequelae ensue at the neural and behavioral level (Skelly et al. 2015;Wommack and Delville 2003). Studies in several species of laboratory animals such as mice, voles, rats, and hamsters have begun to map immediate early gene expression in distinctive hypothalamic and limbic pathways as a consequence of displaying aggressive, defensive-submissive and sexual behavior during adulthood Joppa et al. 1995;Kollack-Walker et al. 1997;Nikulina et al. 2004). A regionally distinctive pattern of neural activation emerged with each social stressor being characterized by c-fos gene expression and increased immunoreactivity in brain stem, hypothalamic and limbic regions (vide infra). ...
The urge to seek and consume excessive alcohol is intensified by prior experiences with social stress, and this cascade can be modeled under systematically controlled laboratory conditions in rodents and non-human primates. Adaptive coping with intermittent episodes of social defeat stress often transitions to maladaptive responses to traumatic continuous stress, and alcohol consumption may become part of coping responses. At the circuit level, the neural pathways subserving stress coping intersect with those for alcohol consumption. Increasingly discrete regions and connections within the prefrontal cortex, the ventral and dorsal striatum, thalamic and hypothalamic nuclei, tegmental areas as well as brain stem structures begin to be identified as critical for reacting to and coping with social stress while seeking and consuming alcohol. Several candidate molecules that modulate signals within these neural connections have been targeted in order to reduce excessive drinking and relapse. In spite of some early clinical failures, neuropeptides such as CRF, opioids, or oxytocin continue to be examined for their role in attenuating stress-escalated drinking. Recent work has focused on neural sites of action for peptides and steroids, most likely in neuroinflammatory processes as a result of interactive effects of episodic social stress and excessive alcohol seeking and drinking.
... In rodents, several brain regions have been associated with estrogen-dependent modulation of aggression (Aleyasin et al., 2018;Joppa et al., 1995;Trainor and Nelson, 2012). Aggressive behaviours are controlled by a social behaviour network (SBN), which include the medial amygdala, BNST, LS, anterior hypothalamus (AHA), VMH and the PAG (Delville et al., 2000). ...
Habenula is an evolutionarily conserved structure in the brain of vertebrates. Recent reports have drawn attention to the habenula as a processing centre for emotional decision-making and its role in psychiatric disorders. Emotional decision-making process is also known to be closely associated with reproductive conditions. The habenula receives innervations from reproductive centres within the brain and signals from key reproductive neuroendocrine regulators such as gonadal steroids, gonadotropin-release hormone (GnRH), and kisspeptin. In this review, based on morphological, biochemical, physiological, and pharmacological evidence we discuss an emerging role of the habenula in reproduction. Further, we discuss the modulatory role of reproductive endocrine factors in the habenula and their association with socio-reproductive behaviours such as mating, anxiety and aggression.
... This view of the social brain was largely inspired by early research in hamsters, wherein lesions to different sub-regions of the MeA and BNST resulted in specific sexual behavior deficits (Lehman et al., 1980). Further, analysis of expression of the immediate early gene c-fos demonstrated that the sub-regions of the MeA and BNST in male and female hamsters are selectively active during both sexual behavior and aggressive encounters (Joppa et al., 1995;Kollack-Walker and Newman, 1995;Wood and Newman, 1993). Other research that contributed to the development of the SBN utilized discrete lesions, electrical stimulation, local hormonal or neuropharmacological manipulations, and immediate early gene (IEG) expression to demonstrate that interconnected limbic regions of the SBN (i.e., LS, mPOA, AH, and VMH), and the midbrain, mediate a range of sexual, parental, and territorial behaviors in mammals ). ...
... Reproductive behaviors are extremely diverse, and they are dependent not only species, but also on sex and gonadal steroid levels, as well as time of year [6]. In most female mammals, including Siberian hamsters (Phodopus sungorus), lordosis is used to determine the receptivity of a female, and is characterized by a fixed posture accompanied by a dorsiflexion of the back [7]. Male rodents mount shortly after being introduced to a receptive female, followed by intromission and ejaculation [8]. ...
Early-life environmental stressors, including sickness, have the potential to disrupt development in ways that could severely impact fitness. Despite what is known about the effects of sickness on reproduction, the precise physiological mechanisms have not yet been determined. The goal of this study was to investigate the effects of a neonatal immune challenge on adult reproductive physiology and opposite-sex social behavior. Male and female Siberian hamster (Phodopus sungorus) pups were administered lipopolysaccharide ([LPS]; a cell wall component of gram-negative bacteria) or saline injections on postnatal days 3 and 5 and body mass, food intake, and measures of reproductive maturity were taken throughout development. In adulthood, hamsters were placed in staged mating pairs with reproductively mature individuals of the opposite sex, during which a series of behaviors were scored. We found that although males and females showed no change in food intake, body mass, or reproductive behaviors, LPS-treated females had abnormal estrous cycles and smaller ovaries. Females also showed increased investigation of and increased aggression towards males in a reproductive context. In contrast, LPS-treated males showed no change in any physiological measures, nor did they show any changes in behavior. The present findings demonstrate that females may be more robustly affected by neonatal sickness than males and that these effects could have potential impacts on reproductive success. Collectively, the results of this study can be used to expand upon what is already known about sickness and reproduction, specifically the importance of social behaviors involved in pre-copulation and information necessary to choose the appropriate mate.
... 10 The PFC and hippocampus have been identified as particularly important in the modulatory control of subcortical circuits that mediate aggressive and impulsive behaviors 11,12 ; the components of these circuits include the medial amygdala, hypothalamus and the periaqueductal grey. [13][14][15][16][17][18][19][20][21][22] Indeed, PFC lesions promote an increase in aggressive behavior in rats. 23 Similarly, lesions involving frontal and temporal brain areas have been demonstrated to dramatically increase aggressiveness in humans. ...
Introduction:
Agonistic behaviors help to ensure survival, provide advantage in competition, and communicate social status. The resident-intruder paradigm, an animal model based on male intraspecific confrontations, can be an ethologically relevant tool to investigate the neurobiology of aggressive behavior.
Objectives:
To examine behavioral and neurobiological mechanisms of aggressive behavior in male Swiss mice exposed to repeated confrontations in the resident intruder paradigm.
Methods:
Behavioral analysis was performed in association with measurements of plasma corticosterone of mice repeatedly exposed to a potential rival nearby, but inaccessible (social instigation), or to 10 sessions of social instigation followed by direct aggressive encounters. Moreover, corticotropin-releasing factor (CRF) and brain-derived neurotrophic factor (BNDF) were measured in the brain of these animals. Control mice were exposed to neither social instigation nor aggressive confrontations.
Results:
Mice exposed to aggressive confrontations exhibited a similar pattern of species-typical aggressive and non-aggressive behaviors on the first and the last session. Moreover, in contrast to social instigation only, repeated aggressive confrontations promoted an increase in plasma corticosterone. After 10 aggressive confrontation sessions, mice presented a non-significant trend toward reducing hippocampal levels of CRF, which inversely correlated with plasma corticosterone levels. Conversely, repeated sessions of social instigation or aggressive confrontation did not alter BDNF concentrations at the prefrontal cortex and hippocampus.
Conclusion:
Exposure to repeated episodes of aggressive encounters did not promote habituation over time. Additionally, CRF seems to be involved in physiological responses to social stressors.
... The anterior-dorsal MeA and posterior BNST have coordinated fos production both following mating and intermale aggression in Syrian hamsters (Kollack- Walker and Newman, 1995). Interestingly, similar patterns of fos expression in these nodes was observed in female hamsters after aggression (Potegal et al., 1996) or mating (Joppa et al., 1995). Syrian hamster females are as aggressive (and sometimes more aggressive) as males. ...
Sexual selection is based on differential investment in reproduction by males and females, and in most species of vertebrates females invest more energy in each individual offspring than males. Neurobiological systems controlling social behaviors have thus evolved under some form of sexual selection for millions of years. An evolutionarily conserved social behavior network consisting of hypothalamic and limbic brain nuclei contains several regions that are sexually dimorphic. Intriguingly, even nodes within this network that are not sexually dimorphic play a key role in mediating sex differences in behavior. In contrast, little anatomical sexual dimorphism is observed within the mesolimbic dopamine system. Nonetheless, important sex differences in dopamine functions have been identified. This chapter will review sex differences in the structure and function of these circuits and examine how social experience acting on these circuits induces long-term changes in behavior.
... Another study also found the medial amygdala to contain higher levels of Fos-IR in females during an aggressive encounter than in nontested controls. However, the same high levels of Fos-IR were observed in the medial amygdala of another group of females that did not display aggression during the social encounter (Joppa et al., 1995). So, activation of Fos-IR in the medial amygdala may be the result of some aspect of social interaction other than the display of aggression. ...
There is a substantial body of data on the interactions among hormones, reproductive behavior, and communicative behavior. However, significantly less is known about how hormones regulate social conflict and the communicative behaviors that are involved in influencing social relationships This chapter focuses on the hormonal regulation of social conflict and communication in Syrian (sometimes called golden) hamsters. Social behavior and its hormonal regulation have been studied in Syrian hamsters since the 1950s. Unlike many other species, both male and female hamsters are highly aggressive, and the behaviors engaged in during social conflict are readily observable and easily quantified. The severity of these encounters (in terms of bites or tissue damage) is usually quite low, and dominance relationships are often formed with relatively little overt aggression. These relationships are usually established very rapidly and remain stable over time. Hamsters also exhibit a variety of communicative behaviors that are easily quantified and that have been investigated extensively. As such, hamsters represent a comparatively simple animal model for the study of social conflict and communication.
... In addition, many brain areas that are implicated in both inter-male and inter-female aggression, including the lateral septum (LS), the bed nucleus of the stria terminalis (BST), the anterior and ventromedial hypothalamus (AHA, VMH), the amygdala and the paraventricular hypothalamic nucleus (PVN) [15,[27][28][29][30][31] are sexually dimorphic [32][33] and may control aggressive behavior in a sex-dependent manner. Due to the anticipated low levels of aggression in females from gregarious species, the (relatively rare) studies of female aggression have focused on lactating female rodents that show maternal defense [34][35][36][37][38], or on females from highly territorial rodent species such as Syrian hamsters (Mesocricetus auratus) and California mice (Peromyscus californicus) [39][40][41]. Although these studies have provided considerable knowledge on the neurobiology of aggression in lactating or territorial females, the extrapolation to non-maternal females of gregarious species is a priori limited: maternal aggression is under strong influence of parturition-associated neuroendocrine adaptations [42] and the neurobiological control of offensive behavior in highly territorial species may differ from that of gregarious, group-living species such as rats and humans [43]. ...
The costs of violence and aggression in our society have stimulated the scientific search for the predictors and causes of aggression. The majority of studies have focused on males, which are considered to be more aggressive than females in most species. However, rates of offensive behavior in girls and young women are considerable and are currently rising in Western society. The extrapolation of scientific results from males to young, non-maternal females is a priori limited, based on the profound sex differences in brain areas and functioning of neurotransmitters involved in aggression. Therefore, we established a paradigm to assess aggressive behavior in young virgin female rats, i.e. the female intruder test (FIT). We found that approximately 40% of un-manipulated adult (10-11 weeks old) female Wistar rats attack an intruder female during the FIT, independent of their estrous phase or that of their intruder. In addition, adolescent (7-8 weeks old) female rats selected for high anxiety behavior (HABs) displayed significantly more aggression than non-selected (NAB) or low-anxiety (LAB) rats. Intracerebroventricular infusion of oxytocin (OXT, 0.1 µg/5 µl) inhibited aggressive behavior in adult NAB and LAB, but not HAB females. Adolescent NAB rats that had been aggressive towards their intruder showed increased pERK immunoreactivity (IR) in the hypothalamic attack area and reduced pERK-IR in OXT neurons in the paraventricular hypothalamic nucleus compared to non-aggressive NAB rats. Taken together, aggressive behavior in young virgin female rats is partly dependent on trait anxiety, and appears to be under considerable OXT control.
... However, these studies were mostly conducted under long day photoperiods [i.e. 45,46]. There is emerging evidence that the relationship between the MPOA and male aggression may be contextdependent. ...
Photoperiodic regulation of aggression has been well established in several vertebrate species, with rodents demonstrating increased aggression in short day photoperiods as compared to long day photoperiods. Previous work suggests that estrogens regulate aggression via rapid nongenomic pathways in short days and act more slowly in long days, most likely via genomic pathways. The current study therefore examines the role of melatonin in mediating aggression and estrogen-dependent gene transcription. In Experiment 1, male California mice were housed under long day photoperiods and were treated with either 0.3 ug/g of melatonin, 40 mg/kg of the melatonin receptor antagonist luzindole, or vehicle for 10 days. We found that melatonin administration significantly increased aggression as compared to mice receiving vehicle, but this phenotype was not completely ameliorated by luzindole. In Experiment 2, male California mice were injected with either 1 mg/kg of the aromatase inhibitor letrozole or vehicle, and oxytocin receptor (OTR), estrogen receptor alpha (ERα), and c-fos gene expression was examined in the bed nucleus of the stria terminalis (BNST) and medial preoptic area (MPOA). In the BNST, but not MPOA, OTR mRNA was significantly downregulated following letrozole administration, indicating that OTR is an estrogen-dependent gene in the BNST. In contrast, ERα was not estrogen dependent in either brain region. In the MPOA, OTR mRNA was inhibited by melatonin, and luzindole suppressed this effect. C-fos and ERα did not differ between treatments in any brain region examined. These results suggest that it is unlikely that melatonin facilitates aggression via broad spectrum regulation of estrogen-dependent gene expression. Instead melatonin may act via regulation of other transcription factors such as extracellular signal regulated kinase.
... In this figure, HAA includes the anterior, ventromedial, and lateral hypothalamic nuclei. (Kollack-Walker and Newman 1995;Joppa et al. 1995;Potegal et al. 1996;Wang et al. 1997Wang et al. , 2011Delville et al. 2000;Gammie and Nelson 2001;Halász et al. 2002Halász et al. , 2006van der Vegt et al. 2003;Davis and Marler 2004;Haller et al. 2005bVeening et al. 2005;Gobrogge et al. 2007;Pan et al. 2010;Nehrenberg et al. 2012;Wall et al. 2012;Konoshenko et al. 2013) hypothalamic area represents abnormal or pathological aggression. One of the neuromodulators in the hypothalamus with a strong link to the level of aggression is arginine vasopression (AVP) (Donaldson and Young 2008). ...
Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals' survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression species-typical aggression ) and maladaptive violence (escalated aggression escalated aggression ) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques, e.g., immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here, we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), excitatory and inhibitory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie individual differences in aggression, using the so-called forward genetics approach.
... In rodents, intromissions induce expression of FOS in a number of neural loci implicated in the regulation of female sexual behavior (Erskine, 1993;Joppa et al., 1995;Shelley and Meisel, 2005). We sampled FOS expression in these regions and identified differential regulation in the mPOA, MeA, and BnST. ...
Reproductive success is maximized when female sexual motivation and behavior coincide with the time of optimal fertility. Both processes depend upon coordinated hormonal events, beginning with signaling by the gonadotropin-releasing hormone (GnRH) neuronal system. Two neuropeptidergic systems that lie upstream of GnRH, gonadotropin-inhibitory hormone (GnIH; also known as RFamide related peptide-3) and kisspeptin, are potent inhibitory and excitatory modulators of GnRH, respectively, participate in the timing of the preovulatory luteinizing hormone (LH) surge and ovulation. Whether these neuropeptides serve as neuromodulators to coordinate female sexual behavior with the limited window of fertility has not been thoroughly explored. In the present study, either intact or ovariectomized, hormone-treated female hamsters were implanted for fifteen days with chronic release osmotic pumps filled with GnIH or saline. The effect of GnIH on sexual motivation, vaginal scent marking, and lordosis was examined. Following mating, FOS activation was quantified in brain regions implicated in the regulation of female sexual behavior. Intracerebroventricular administration of GnIH reduced sexual motivation and vaginal scent marking, but not lordosis behavior. GnIH administration altered FOS expression in key neural loci implicated in female reproductive behavior, including the medial preoptic area, medial amygdala and bed nucleus of the stria terminalis, independent of changes in circulating gonadal steroids and kisspeptin cell activation. Together, these data point to GnIH as an important modulator of female proceptive sexual behavior and motivation, independent of downstream alterations in sex steroid production.
... Further, , found that aggressive rats exhibited increased c-Fos expression in the LS, medial septum, BNST, anterior hypothalamus, MeA, and periaqueductal gray relative to controls. Some studies examining Fos expression in male hamsters following an aggressive encounter have found that male hamsters have increased Fos expression in the MeA, ventrolateral hypothalamus and the dorsalateral periaqueductal gray or central gray (Delville et al., 2000), while others that have examined Fos expression in female hamsters following an aggressive encounter have found greater activation in the corticomedial amygdala (Potegal et al., 1996) or MeA and MPOA (Meisel et al., 1995). ...
Following social defeat, male hamsters exhibit behavioral changes characterized by a breakdown of normal territorial aggression and an increase in submissive/defensive behaviors in the presence of a non-aggressive intruder (NAI). We have termed this phenomenon conditioned defeat (CD). By contrast, only a small subset of defeated females exhibit submissive/defensive behavior in the presence of a NAI. We hypothesized that fluctuations in gonadal hormones might contribute to differences in the display of submissive behavior in intact female hamsters. Following social defeat, proestrous females (higher endogenous estradiol) were more likely to display conditioned defeat compared with diestrous 1 (lower endogenous estradiol) females. This finding suggests that there is an estrous cycle-dependent fluctuation in the display of CD in female hamsters and suggests that increased estradiol might contribute to increased submissive behavior. We then demonstrated that ovariectomized females given estradiol prior to CD testing exhibited significantly higher submissive behavior in the presence of a NAI suggesting that estradiol increases the expression of CD in female hamsters. We have also shown that castrated males that were singly housed for four weeks displayed
... Meisel and Mullins (2006) demonstrated that the NAcc is part of a circuit that regulates incentive-motivated behavior, including sexual behavior, in this species. A single sexual encounter in a sexually naïve female activates NAcc neurons (Meisel, Camp & Robinson, 1993; Joppa, Meisel & Gardner, 1995; Kohlert & Meisel, 1999) and sexual behavior increases c-Fos expression in the NAcc core, but not the shell (Bradley & Meisel, 2001). The NAcc core has greater involvement in behavioral response activation based on reward-related information associated with conditioned reinforcers, as derived from information transmitted by limbic inputs, such as the basolateral amygdala (e.g., Ito, Robbins, & Everitt, 2004). ...
Behavioral activation that is associated with incentive-reward motivation increases in adolescence relative to childhood and adulthood. This quadratic developmental pattern is generally supported by behavioral and experimental neuroscience findings. It is suggested that a focus on changes in dopamine neurotransmission is informative in understanding the mechanism for this adolescent increase in reward-related behavioral activation and subsequent decline into adulthood. Evidence is presented to indicate that incentive-reward motivation is modulated by mesoaccumbens dopamine, and that it increases in adolescence before declining into adulthood because of normative developmental changes at the molecular level. Potential mechanisms of variation in functional mesoaccumbens dopamine transmission are discussed with a focus on the interplay between tonic and phasic modes of dopamine transmission in modulating both general incentive-motivational biases and the efficacy of reward learning during exposure to novel reward experiences. Interactions between individual difference factors and these age-related trends are discussed.
... The increased amygdalar BOLD activity recorded in the present study may be involved in the increased translational activity reported in previous studies. Previous research suggests that the medial, central and basolateral amygdala are activated during maternal aggression, as early growth response factors increase following the display of aggression in rats (Lonstein & Stern, 1997a,b), hamsters (Joppa et al., 1995) and mice (Gammie & Nelson, 2001). Increased BOLD activity in the dorsal striatum is indicative of a heightened auditory response to the male intruder, as this region is activated in human mothers in response to general auditory stimuli (Lorberbaum et al., 2002). ...
Lactating rats must continuously maintain a critical balance between caring for pups and aggressively responding to nest threats. We tested the neural response of lactating females to the presentation of their own pups and novel intruder males using blood oxygen level-dependent functional magnetic resonance imaging at 7 T. Dams were presented with a single sequence of a control stimulus, pups or a male intruder in one imaging session (n = 7-9). To further determine the selectivity of neural processing, dams were imaged for their response to a male intruder in both the absence and presence of their pups (n = 6). Several maternal cortical and limbic brain regions were significantly activated by intruder presentation but not by pups or a control stimulus. These included the nucleus accumbens, periaqueductal gray, anterior cingulate, anterior thalamus, basal nucleus of the amygdala, temporal cortex, prelimbic/orbital area and insula. The nucleus accumbens, periaqueductal gray, temporal cortex and mediodorsal thalamus still showed greater neural activity when compared with intruder presentation in the absence of pups. The present results suggest that the high emotional state generated by a threat to pups involves robust activation of classical limbic regions controlling emotional responses. This pattern of blood oxygen level-dependent activity may precede behavioral states upon which lactating rats initiate attacks against a potential threat to offspring.
... The time course for BOLD activation associated with aggressive motivation (black triangle) is markedly different with SRX251 and fluoxetine treatments. A solid line is shown demarking the maximal percent change in BOLD signal for aggressive motivation (mate/intruder, left column) in the drug free [27][28][29][205][206][207][209][210][211][212][213][214][215][216] 1 (0, 6) 3 (0, 9)* 2.7 ± 0.2 4.6 ± 0.2 bed n. stria terminalis refs [25,27,29,30,[205][206][207][208][211][212][213][214]217] 2 (0, 5) 6 (2, 16)* 3.4 ± 0. [205][206][207]211,213,214,217] 1 (0, 2) 3 (1, 5)* 2.0 ± 0.1 3.8 ± 0.1 ...
With the advent of functional magnetic resonance imaging (fMRI) in awake animals it is possible to resolve patterns of neuronal activity across the entire brain with high spatial and temporal resolution. Synchronized changes in neuronal activity across multiple brain areas can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviors. To this end, fMRI in conscious rats combined with 3D computational analysis was used to identifying the putative distributed neural circuit involved in aggressive motivation and how this circuit is affected by drugs that block aggressive behavior.
To trigger aggressive motivation, male rats were presented with their female cage mate plus a novel male intruder in the bore of the magnet during image acquisition. As expected, brain areas previously identified as critical in the organization and expression of aggressive behavior were activated, e.g., lateral hypothalamus, medial basal amygdala. Unexpected was the intense activation of the forebrain cortex and anterior thalamic nuclei. Oral administration of a selective vasopressin V1a receptor antagonist SRX251 or the selective serotonin reuptake inhibitor fluoxetine, drugs that block aggressive behavior, both caused a general suppression of the distributed neural circuit involved in aggressive motivation. However, the effect of SRX251, but not fluoxetine, was specific to aggression as brain activation in response to a novel sexually receptive female was unaffected.
The putative neural circuit of aggressive motivation identified with fMRI includes neural substrates contributing to emotional expression (i.e. cortical and medial amygdala, BNST, lateral hypothalamus), emotional experience (i.e. hippocampus, forebrain cortex, anterior cingulate, retrosplenial cortex) and the anterior thalamic nuclei that bridge the motor and cognitive components of aggressive responding. Drugs that block vasopressin neurotransmission or enhance serotonin activity suppress activity in this putative neural circuit of aggressive motivation, particularly the anterior thalamic nuclei.
... To date, only a limited number of studies have addressed the patterns of brain activity associated with aggressive encounters (Morton et al., 1984; Joppa et al., 1995; Kollack-Walker and Newman, 1995; Potegal et al., 1996a,b), with only two of these studies directly comparing the patterns of neuronal activity associated with winning or losing. In mice, aggressive males show enhanced metabolic activity within the habenula and locus coeruleus and reduced levels in the septum and dorsal central gray when compared with defensive animals (Morton et al., 1984). ...
During an agonistic encounter, subordinate male hamsters display defensive and submissive postures and show increased secretion of glucocorticoids, whereas dominant males do not. To determine whether specific neuronal pathways are activated during the behavioral and neuroendocrine responses of subordinate males, expression of c-fos mRNA within the brains of subordinate males was compared with the pattern in dominant males after fighting. After 1 week of handling, pairs of hamsters were either swapped between cages (handled control males), or were allowed to interact for 30 min [dominant (DOM) males and subordinate (SUB) males]. A second group of control animals that received no handling or social stimulation (unhandled control males) were also included. After testing, all animals were killed by decapitation, their brains were removed for c-fos in situ hybridization, and trunk blood was collected for analysis of plasma cortisol and corticosterone levels. Exposure of males to their partner's cage for 30 min resulted in increased expression of c-fos mRNA in multiple brain regions. In addition, fighting increased c-fos expression in the medial amygdaloid nucleus of both DOM and SUB males as well as having more selective effects. In DOM males, c-fos expression was elevated within the supraoptic nucleus of the hypothalamus. In SUB males, c-fos expression increased within a multitude of brain areas, including cingulate cortex, lateral septum, bed nucleus of the stria terminalis, medial preoptic area, several hypothalamic nuclei, central amygdaloid nucleus, amygdalohippocampal area, dorsal periaqueductal gray, dorsal raphe, cuneiform nucleus, and locus coeruleus. These findings are discussed in relation to neurocircuits associated with behavioral arousal and stress.
... Recent research using activation of the immediate early gene c-fos as a measure demonstrates that the POA is one of the brain regions that is particularly responsive to VCS. That is, the POA and bed nucleus of the stria terminalis show an increase of Fos immunoreactivity in female rats (Erskine, 1993;Insel, 1990;Pfaus, Kleopoulos, Mobbs, Gibbs, and Pfaff, 1993;Pfaus, Jakob, Kleopoulos, Gibbs, and Pfaff, 1994;Rowe and Erskine, 1993;Wersinger, Baum, and Erskine, 1993;Tetel, Getzinger, and Blaustein, 1993;, ferrets (Lambert, Rubin, and Baum, 1992), and hamsters (Joppa, Meisel, and Garber, 1995;Ramos and DeBold, 1995) that have selectively received VCS. This increase in Fos ir in the POA and other brain areas can be negated by pelvic nerve transection in rats (Wersinger et al., 1993). ...
Sexual receptivity in female hamsters potentially lasts for about 16 h. However, vaginal cervical stimulation (VCS) from a male during mating eventually reduces receptivity and can shorten the duration of behavioral estrus. The process by which this change in response to the male takes place is unknown. Recently, detection of the Fos protein has indicated that the medial preoptic area (POA) is one of the brain regions particularly responsive to VCS. Additionally, the POA may have an inhibitory effect on sexual receptivity. To determine if protein synthesis in the POA is required to initiate the VCS-induced decrease in estrus duration, a protein synthesis inhibitor (anisomycin, 0.50 microg) or a control substance (cholesterol) was applied bilaterally to the POA of steroid-primed ovariectomized female hamsters. Females were tested with a sexually active male at five time points following the initial test for sexual receptivity (hour 1, 2, 6, 12, and 24). Half of the females tested were allowed to receive VCS from a male, while half were fitted with vaginal masks to prevent penile intromission. Each group receiving VCS showed a significant decrease in lordosis duration evident between hour 2 and hour 6, except the group which received anisomycin in the POA. In this respect the POA anisomycin group was similar to animals which did not receive VCS. Hamsters with vaginal masks and the anisomycin/POA animals allowed to receive VCS exhibited their first decrease in lordosis duration between hour 6 and hour 12. These results indicate that protein synthesis is important for VCS-induced decrease in estrus duration in the POA.
... Sexual behavior testing increased c-Fos expression in the core, but not the shell, of the nucleus accumbens, supporting previous research showing that a single sexual encounter can activate neurons in the nucleus accumbens in female rodents (Meisel et al., 1993; Joppa et al., 1995; Mermelstein and Becker, 1995; Pfaus et al., 1995; Kohlert et al., 1997; Kohlert and Meisel, 1999). Literature addressing the functional dichotomy of the nucleus accumbens is composed of numerous reports of differential changes in dopamine transmission within the shell and core of the nucleus accumbens in response to pharmacological and physiological stimuli. ...
Dopamine transmission in the nucleus accumbens can be activated by drugs, stress, or motivated behaviors, and repeated exposure to these stimuli can sensitize this dopamine response. The objectives of this study were to determine whether female sexual behavior activates nucleus accumbens neurons and whether past sexual experience cross-sensitizes neuronal responses in the nucleus accumbens to amphetamine. Using immunocytochemical labeling, c-Fos expression in different subregions (shell vs core at the rostral, middle, and caudal levels) of the nucleus accumbens was examined in female hamsters that had varying amounts of sexual experience. Female hamsters, given either 6 weeks of sexual experience or remaining sexually naive, were tested for sexual behavior by exposure to adult male hamsters. Previous sexual experience increased c-Fos labeling in the rostral and caudal levels but not in the middle levels of the nucleus accumbens. Testing for sexual behavior increased labeling in the core, but not the shell, of the nucleus accumbens. To validate that female sexual behavior can sensitize neurons in the mesolimbic dopamine pathway, the locomotor responses of sexually experienced and sexually naive females to an amphetamine injection were then compared. Amphetamine increased general locomotor activity in all females. However, sexually experienced animals responded sooner to amphetamine than did sexually naive animals. These data indicate that female sexual behavior can activate neurons in the nucleus accumbens and that sexual experience can cross-sensitize neuronal responses to amphetamine. In addition, these results provide additional evidence for functional differences between the shell and core of the nucleus accumbens and across its anteroposterior axis.
... Received 21 August 2001, revised 11 December 2001, accepted 12 December 2001European Journal of Neuroscience, Vol. 15, pp. 561±569, 2002 ã Federation of European Neuroscience Societies largely con®rmed these ®ndings (intruder rats and mice: Martinez et al., 1998; Matsuda et al., 1996; resident hamsters: Joppa et al., 1995; Kollack-Walker et al., 1997; Delville et al. 2000). Noteworthy, data on aggression-induced brain c-Fos activation in resident (i.e. ...
Glucocorticoid hypofunction is associated with persistent aggression in some psychologically disordered human subjects and, as reported recently, induces abnormal forms of aggression in rats. Here we report on the effects of glucocorticoid hypofunction on aggression-induced neural activation. Rats were adrenalectomized, and implanted with low-release glucocorticoid pellets. After one week recovery, they were challenged by an unfamiliar intruder in their home-cage. Neural activation was studied by c-Fos protein immunocytochemistry. Aggressive encounters in controls induced c-Fos activation in all brain areas relevant for the control of aggression (cortex, amygdala, septum, hypothalamus, periaqueductal grey and the locus coeruleus). Very intense c-Fos activation was observed in the medial amygdala, the hypothalamic attack area and the periaqueductal grey matter which constitute a downward stimulatory stream that activates attack behaviour. The experimentally induced glucocorticoid hypofunction dramatically increased attacks targeted towards vulnerable parts of the opponent's body (mainly the head). This abnormal behaviour was not associated with changes in the activation of brain centres involved in the control of aggression. However, the activation of brain centres involved in both the stress response (the parvocellular part of the hypothalamic paraventricular nucleus) and fear reactions (central amygdala) were markedly increased. An acute glucocorticoid treatment abolished both behavioural and neural consequences of glucocorticoid hypofunction. Our data suggest that glucocorticoid hypofunction-induced abnormal forms of aggressiveness are related to increased sensitivity to stressors and fear-eliciting stimuli. This assumption is supported by the finding that fearful situations induce attack patterns in intact rats that are similar to those induced by glucocorticoid hypofunction.
... As is well recognized, the control issues are truly enormous in such studies evaluating complex behavior patterns. Some investigators have tried to deal with such issues by exposing different groups of animals to various sensory, motor and motivational aspects of the complex behaviors that they have analyzed [9,12,15,18], but the c-fos results have not been especially illuminating in those studies. In general, these researchers have observed only modest differences among the active and "non-active" control groups. ...
Rough and tumble (R&T) play is an intrinsic behavior in most mammals. However, unlike sex and aggression, play has not been well characterized in terms of neuronal circuitry. We employed in situ hybridization to explore the differences of c-fos mRNA activation in juvenile rats that had been allowed R&T play for a total of 30 min before sacrifice contrasted to animals with comparable histories that had received no play. Densitometric estimates of c-fos gene activation revealed that the deep and dorsolateral tectum, inferior colliculus, dorsal periaquaductal gray, ventromedial hypothalamus, dorsal and ventral striatum, and somatosensory cortex were significantly more activated in animals that had played than those that had not. Prior play dominance and amount of social experience had no clear effects on the levels of c-fos gene expression. This provides a variety of new hypotheses concerning the role of various brain areas in the elaboration of R&T play behavior, but the important role of other types of motor arousal in the differential effects were not evaluated in this study.
Parenting behavior comprises a variety of adult-infant and adult-adult interactions across multiple timescales that require an extensive reorganization of individual priorities and physiology. The state transition from non-parent to parent is facilitated by combinatorial hormone action on specific cell types that are integrated throughout interconnected and brain-wide neuronal circuits. In this review we take a comprehensive approach to integrate historical and current literature on each of these topics across multiple species, with a focus on rodents. New and emerging molecular, circuit based and computational technologies have recently been used to address outstanding gaps in our current framework of knowledge on infant-mediated behavior, mainly in murine models. This work is raising fundamental questions about the interplay between instinctive and learned components of parenting and the mutual regulation of parenting and anti-parenting behaviors in health and disease. Whenever possible, we point to how these technologies have helped gain novel insights, while opening new avenues of research into studies of parenting. We hope this review will serve as an introduction for those new to the field, a comprehensive resource for those already studying parenting, and a guidepost for designing future studies.
In many animal species, males and females exploit different mating strategies, display sex-typical behaviors, and use distinct systems to recognize ethologically relevant cues. Mate selection thus requires mutual recognition across diverse social interactions based on distinct sensory signals. These sex differences in courtship and mating behaviors correspond to differences in sensory systems and downstream neural substrates engaged to recognize and respond to courtship signals. In many rodents, males tend to rely heavily on volatile olfactory and pheromone cues, while females appear to be guided more by a combination of these chemosensory signals with acoustic cues in the form of ultrasonic vocalizations. The mechanisms by which chemical and acoustic cues are integrated to control behavior are understudied in mating but are known to be important in the control of maternal behaviors. Socially monogamous species constitute a behaviorally distinct group of rodents. In these species, anatomic differences between males and females outside the nervous system are less prominent than in species with non-monogamous mating systems, and both sexes engage in more symmetric social behaviors and form attachments. Nevertheless, despite the apparent similarities in behaviors displayed by monogamous males and females, the circuitry supporting social, mating, and attachment behaviors in these species is increasingly thought to differ between the sexes. Sex differences in sensory modalities most important for mate recognition in across species are of particular interest and present a wealth of questions yet to be answered. Here, we discuss how distinct sensory cues may be integrated to drive social and attachment behaviors in rodents, and the differing roles of specific sensory systems in eliciting displays of behavior by females or males.
The brain control of aggression has been studied for nearly a hundred years with a number of technologies that have become increasingly sophisticated. During this long period, there were several phases when the issue seemed to have been solved: aggression control appeared to have been revealed; however, novel research methodologies have refuted this feeling time and time again. Today, we are witnessing an advance in research technologies that we would have thought unimaginable only a decade ago. As usual, these new technologies put a question mark on what was thought true and reliable earlier; however, there also is a consistency in knowledge. New discoveries did not entirely invalidate previous ones but added new details, explored unknown mechanisms, and incorporated the approaches from other fields. The purpose of this chapter is to integrate old and new discoveries into a single concept that accounts for, on the one hand, the complexity of neurons and network architectures and, on the other, the complexity of aggressive behavior. The created template will be used in subsequent chapters to understand what goes wrong with neural control in models of abnormal aggression and how normal and abnormal human aggression is controlled.
The involvement of the amygdala in aggression is supported by overwhelming evidence. Frequently, however, the amygdala is studied as a whole, despite its complex internal organization. To reveal the role of various subdivisions, here we review the involvement of the central and medial amygdala in male rivalry aggression, maternal aggression, predatory aggression, and models of abnormal aggression where violent behavior is associated with increased or decreased arousal. We conclude that: (1) rivalry aggression is controlled by the medial amygdala; (2) predatory aggression is controlled by the central amygdala; (3) hypoarousal-associated violent aggression recruits both nuclei, (4) a specific upregulation of the medial amygdala was observed in hyperarousal-driven aggression. These patterns of amygdala activation were used to build four alternative models of the aggression circuitry, each being specific to particular forms of aggression. The separate study of the roles of amygdala subdivisions may not only improve our understanding of aggressive behavior, but also the differential control of aggression and violent behaviors of various types, including those associated with various psychopathologies.
In this chapter we cross-check current concepts by making use of all the available information starting from accidental brain lesions to brain imaging studies, from animals to humans, and from normal manifestations to abnormal forms of aggression. The analysis focuses on four brain regions, namely the prefrontal cortex, amygdala, hypothalamus, and periaqueductal gray. While the number of brain regions involved in aggression is considerably larger, current views suggest that these four have critical roles and can be considered focal points of aggression control. The ultimate aim is to map the possibility of building a comprehensive neural theory of aggression control and of identifying brain alterations that result in dysfunctional aggression.
Mechanisms controlling aggressive behavior started to be identified from late 20's of the 20th century and subsequent research described such mechanisms in great detail. While the findings are of great relevance for the understanding of aggression per se, they provide limited insights into the mechanisms of abnormal aggression i.e. those mechanisms that underlie aggression-related psychopathologies. While basic phenomena and mechanism of aggression are presented, this book is the first that comprehensively describes ultimate and proximate mechanisms that transform normal (laboratory animals) or tolerable (humans) manifestations of aggressiveness into abnormal patterns in laboratory animals and aggression-related psychopathologies in humans. This book is written for behavioral neurobiologists and neuroscientists, interested in emotional control in general and aggression research in particular. The book will also offer important information to neurologists and psychiatrists dealing with aggressive behavior in the clinic and ultimately, may provide means to understand and on the long run to discover novel approaches to the treatment of abnormal human aggression.
Extracellular concentrations of dopamine in the nucleus accumbens were monitored using microdialysis in ovariectomized female Syrian hamsters hormonally primed with estradiol and progesterone or with a similar regimen of oil injections. Some females in each of these groups had their vaginas occluded with tape, whereas the remaining females' vaginas stayed unoccluded. When exposed to a male, both groups of hormonally primed females showed high levels of lordosis. However, only in the hormone-primed, unoccluded females were there significant elevations of dialysate dopamine during the sexual interactions with the male. There were no significant elevations in dopamine levels in the oil-treated females during interactions with the male. These data suggest that nucleus accumbens dopamine is responsive to stimuli associated with the vaginocervical stimulation received by the female during intromissions by the male. Histological analyses were based on Fluoro-Gold efflux through the probes combined with immunocytochemistry for tyrosine hydroxylase. Probe placements in the rostral accumbens, caudal accumbens, or rostral bed nucleus of the stria terminalis were not distinguishable based on analyses of basal dopamine levels, volume of Fluoro-Gold injection sites, or Fluoro-Gold labeling of midbrain, tyrosine hydroxylase-stained neurons. The number of midbrain neurons containing Fluoro-Gold was positively related to basal dopamine levels, indicating that the amount of dopamine recovered from the nucleus accumbens in microdialysis studies is a function of the number of neurons contributing to the terminal field in the region of the probe.
Copulation in rabbits provokes behavioral and neuroendocrine changes in both sexes. To investigate if the activity of particular brain regions is modified accordingly we quantified, by the reverse transcription-polymerase chain reaction method, c-fos expression in the preoptic area, hypothalamus, hippocampus, and frontal cortex of male and female rabbits before mating, immediately afterwards, and 1 h later. Mating immediately increased c-fos expression in the hypothalamus of both sexes, the frontal cortex of females, and the preoptic area of males. c-fos expression did not change in the hippocampus after mating in either sex but decreased in the preoptic area of females following mating. Results show that mating provokes changes in brain activity, in a gender- and region-specific manner, which may underlie the behavioral and endocrine consequences of copulation in rabbits.
Monogamous prairie voles (Microtus ochrogaster) show mating-induced aggression towards conspecific strangers. This behavior is both selective and enduring. The present study was designed to investigate the behavioral conditions for the emergence of selective aggression (by varying prior experience with a female and identity of intruders) and the limbic activation in response to an intruder (by mapping regional staining for c-fos) in male prairie voles. In a first experiment, males that mated with a female for 24 h exhibited aggression towards a male intruder and had more Fos-immunoreactive (Fos-ir) cells in the medial amygdala (AMYGme) and medial preoptic area (MPO) relative to males that cohabited with a female without mating or that had no prior exposure to a female. Cohabited males did not become aggressive. However, these males along with mated males had an increased number of Fos-ir cells in the lateral septum (LS) and the bed nucleus of the stria terminalis (BST) relative to males without prior exposure to a female. In a second experiment, mated males exhibited more offensive aggression to a male intruder but more defensive aggression to a female intruder. Both types of aggression, however, induced an increase in the number of Fos-ir cells in the AMYGme. In addition, Fos-ir staining in the BST was induced selectively in response to a male intruder and a similar trend was found in the LS. Exposure to a male or female intruder did not increase Fos-ir staining in the MPO. Taken together, our data suggest the neural substrates activated by social/sexual activity and involved in response to intruders. The AMYGme was involved in processing intruder-related cues and/or in the regulation of aggressive response to both male and female intruders. The BST and LS were modulated by social experience with a female (mating or cohabitation) and were responsive to male-related cues even in the absence of aggression. Finally, the MPO was activated at different magnitudes by social or sexual experience but did not respond to intruder-related cues as measured by Fos-ir.
The medial preoptic nucleus (MPN) of the medial preoptic area (MPOA) and the medial amygdala are two brain regions in which male rat sexual behavior increased Fos-like immunoreactivity (Fos-Li). Dopamine is released in the MPOA during male rat sexual behavior and facilitates copulation. Psychostimulants, which increase dopamine levels, induce Fos-Li in the striatum through D1 receptors. We examined whether copulation-induced Fos-Li in the MPN was also mediated through D1 receptors. In Experiment 1, sexually inexperienced male rats that received the D1 antagonist Schering 39166 prior to their first sexual experience had fewer Fos-Li cells in the MPN than did those that received vehicle. In Experiment 2, no significant effect of the D1 antagonist was observed on copulation-induced Fos-Li in male rats that had received repeated sexual experiences prior to the drug test day. Sexual experience increases copulatory efficiency; the mechanisms by which this improvement occurs are unclear. In Experiment 3, copulation by highly experienced male rats led to greater Fos-Li in the MPN than did copulation by sexually naive males. Although there were no differences between groups in amygdala Fos-Li in these studies, in several groups Fos-Li in the medial amygdala was positively correlated with the post-ejaculatory interval. These experiments indicate that (1) stimulation of D1 receptors may contribute to the transient copulation-induced increase in Fos-Li in the MPN, and (2) repeated sexual experiences enhanced copulation-induced Fos-Li in the MPN, which may represent a marker of altered responsiveness of neurons in the MPN to sexual or conditioned stimuli.
Nucleus taeniae (Tn) is a prominent cell group within the medial archistriatum of birds. Based upon similarities in sex-steroid binding sites, this nucleus has been hypothesized to be homologous to the medial nucleus of the amygdala (Me) in mammals, which is known to modulate the expression of sexual behavior in rodents. We therefore tested whether or not Tn likewise plays a role in the expression of sexual behavior in male Japanese quail. We found that bilateral damage to Tn produced deficits in several components of male responses toward female stimuli that were indicative of decreased sexual arousal, including goal-oriented responses, vocalizations associated with courtship, and motor reflexes that precede copulation. Our results suggest that Tn influences a wide range of behavioral functions in response to sexual stimuli, and they indicate a function for this nucleus similar to that subserved by the Me in mammals. These results strengthen the argument that these sex-steroid accumulating cell groups are homologous and suggest a conservation of function for them despite the vastly divergent evolutionary histories separating birds and mammals.
Evidence from lesion and inactivation studies suggests that the hippocampus (HPC) and dorsal striatum compete for control over navigation behavior, and there is some evidence in males that the structure with greater relative activation controls behavior. Estradiol has been shown to enhance HPC-dependent place learning and impair dorsal striatum-dependent response learning in female rats, possibly by increasing hippocampal activation and/or decreasing striatal activation. We used Fos-immunoreactivity (Fos-IR) to examine the activation of several subregions of the HPC and striatum in ovariectomized female rats with or without estradiol replacement 30 min after place or response learning. In 4-month-old rats, neither task nor estradiol increased Fos-IR above explore control levels in any subregion analyzed, even though estradiol impaired response learning. In 12-month-old rats, estradiol increased Fos-IR in the dentate gyrus, dorsal medial striatum, and dorsal lateral striatum in place task learners, while the absence of estradiol increased Fos-IR in these regions in response task learners. However, learning rate was not affected by estradiol in either task. We also included a group of long-term ovariectomized 12-month-old rats that displayed impaired place learning and altered Fos-IR in CA1 of the HPC. These results suggest that task-specific effects of estradiol on hippocampal and striatal activation emerge across age but that relative hippocampal and striatal activation are not related to learning rate during spatial navigation learning.
Whereas the adolescent brain is a major target for gonadal hormones, our understanding of hormonal influences on adolescent neural and behavioral development remains limited. These experiments investigated how variations in the timing of testosterone (T) exposure, relative to adolescence, alters the strength of steroid-sensitive neural circuits underlying social behavior in male Syrian hamsters. Experiment 1 simulated early, on-time, and late pubertal development by gonadectomizing males on postnatal d 10 and treating with SILASTIC brand T implants for 19 d before, during, or after adolescence. T treatment before or during, but not after, adolescence facilitated mating behavior in adulthood. In addition, preadolescent T treatments most effectively increased mating behavior overall, indicating that the timing of exposure to pubertal hormones contributes to individual differences in adult behavior. Experiment 2 examined the effects of preadolescent T treatment on behavior and brain regional volumes within the mating neural circuit of juvenile males (i.e. still preadolescent). Although preadolescent T treatment did not induce reproductive behavior in juvenile males, it did increase volumes of the bed nucleus of the stria terminalis, sexually dimorphic nucleus, posterodorsal medial amygdala, and posteroventral medial amygdala to adult-typical size. In contrast, juvenile anterodorsal medial amygdala and ventromedial hypothalamus volumes were not changed by preadolescent T treatment yet differed significantly in volume from adult controls, suggesting that further maturation of these brain regions during adolescence is required for the expression of male reproductive behavior. Thus, adolescent maturation of social behavior may involve both steroid-independent and -dependent processes, and adolescence marks the end of a postnatal period of sensitivity to steroid-dependent organization of the brain.
Prior studies have demonstrated the utility of conditioned place preference procedures for examining the motivational or rewarding properties of behavior. The purpose of this experiment was to assess whether female Syrian hamsters would show evidence of conditioned place preference for aggression or sexual behaviors. Weekly conditioning sessions were conducted for three groups of female hamsters for 5 weeks. One group of female hamsters engaged in sexual activity with a male hamster in the gray compartment of a place preference apparatus. A second group of females experienced aggressive interactions with a male when placed together also in the gray compartment. Females in each of these conditioning groups were placed alone in the white compartment within 1 h of the behavioral interactions. A control group of hormone-treated females was placed alone in both compartments of the apparatus. Following the conditioning sessions, all females were given free access to the conditioning apparatus. Females with prior sexual or aggressive experience spent significantly more time in the gray compartment than they did before conditioning. Control females did not show any significant change in their preference for either compartment of the apparatus. The results suggest that female hamsters prefer an environment associated with the prior rewarding properties of sexual or aggressive interactions.
Immunocytochemical techniques were used to examine and compare the effects of intracerebroventricular administration of nerve growth factor (NGF) on Fos expression within identified cholinergic and non-cholinergic neurons located in different regions of the adult rat basal forebrain. Animals were killed 1, 3, 6, and 12 h after receiving NGF (0.5 or 5.0 microg) or vehicle into the left lateral ventricle and sections through the medial septum, diagonal band of Broca, nucleus basalis magnocellularis, and striatum were processed for the combined immunocytochemical detection of Fos and choline acetyltransferase (a marker for cholinergic neurons), or Fos and parvalbumin (a marker for gamma aminobutyric acid (GABA)-containing neurons). NGF produced a significant increase in the percentage of cholinergic neurons containing Fos-like immunoreactivity within all four regions examined. The largest increases were detected in the medial septum (47.8%) and the horizontal limb of the diagonal band of Broca (67.7%). In these areas, NGF-mediated induction of Fos-like immunoreactivity was detected as early as 3 h, peaked at 6 h, and was reduced by 12 h, postinfusion. Small but significant increases in the percentage of cholinergic neurons containing Fos-like immunoreactivity were also detected in the striatum (4.2%) and in the nucleus basalis magnocellularis (19.2%) 3-12 h following administration of the higher dose of NGF. No evidence for an NGF-mediated induction of Fos within parvalbumin-containing neurons was detected in any of the four regions at any of the time-points examined; however, evidence for an NGF-mediated induction of Fos within epithelial cells lining the lateral ventricle was observed. These data demonstrate that NGF induces Fos expression within cholinergic, and not parvalbumin-containing (GABAergic), neurons in the basal forebrain, and furthermore that intracerebroventricular administration of NGF influences the different subgroups of basal forebrain cholinergic neurons to different degrees.
In sheep maternal behaviour and the formation of the selective olfactory, ewe/lamb bond are induced by feedback to the brain from stimulation of the vagina and cervix during parturition. In the present study, we have used in situ hybridization histochemistry to quantify changes in cellular expression of two immediately-early genes, c-fos and zif/268, in order to identify activated brain regions during the induction of maternal behaviour and olfactory bonding as well as regions where plastic changes are occurring during with the formation of the olfactory memory associated with bonding. Three different treatment groups were used. One group gave birth normally, became maternal and were allowed to interact with their lambs for 30 min. A second group received exogenous treatment with oestradiol and progesterone to induce lactation and then received a 5-min period of artificial stimulation of the vagina and cervix (VCS) which reliably induces maternal behaviour but could not interact with lambs. A final control group received exogenous hormone treatment but no VCS or interaction with lambs. Compared to the control group, post-partum animals and animals that had received VCS showed increased c-fos expression in a number of cortical regions (cingulate, entorhinal and somatosensory), the mediodorsal thalamic nucleus and the lateral habenula, the limbic system (bed nucleus of the stria terminalis, lateral septum, medial arnygdala, dentate gyrus and the CA3 region of the hippocampus) and the hypothalamus (medial preoptic area, mediobasal hypothalamus, paraventricular nucleus, supraoptic nucleus and periventricular complex). The group that gave birth and had contact with their lambs for 30 min had significantly enhanced c-fos mRNA expression in the cingulate cortex compared to those receiving VCS and additionally showed significantly increased c-fos mRNA expression in olfactory processing regions (olfactory bulb, piriform cortex and orbitofrontal cortex). Expression of zif/268 was significantly increased in the entorhinal cortex, orbitofrontal cortex and dentate gyrus of the parturition group compared to either the control or the VCS alone groups. These results show a clear differentiation between neural substrates controlling the expression of maternal behaviour and those involved in the olfactory memory process associated with selective recognition of offspring although at the level of the hippocampus and cingulate cortex there may be some degree of overlap. Alterations in zif/268 at tertiary processing sites for olfactory information (orbitofrontal cortex) and the entorhinal cortex and dentate gyrus may reflect plastic changes occurring during the early stages of olfactory memory formation.
Central monoamines display a variety of activation patterns in different social groups, and among males and females. We addressed three social conditions for female lizards of the species Anolis carolinensis: Isolated, paired with a mate, and in a group of 5 competing for one mate. Among those in a group, only 1 or 2 females exhibited recrudescing ovaries. Individuals paired with a mate (for one month) exhibited ovarian growth, isolated animals (initial controls) had quiescent ovaries. Reproductively dominant females had significantly greater telencephalic 5-HIAA, and serotonergic activation, as indicated by the ratio of 5-HIAA to 5-HT. Telencephalic HVA as well as the HVA/DA ratio were also significantly greater in dominant females compared to all other groups. In contrast, serotonergic activation in brainstem was elevated in subordinate females only. These results suggest that serotonergic activation in telencephalon, found only in dominant females, not in other reproductively active females, is a function of the unique social role of a dominant female, possibly combining submissive behaviors toward a male with dominance over other females and competition for access to that male. Dopaminergic activation in telencephalon, also found only in dominant females, may be related to aggressive interactions with other females. Activation of serotonin in brainstem, found in this study in subordinate females and previously in males [C.H. Summers and N. Greenberg, Activation of central biogenic amines following aggressive interaction in male lizards, Anolis carolinensis, Brain Behav. Evol., 45 (1995) 339-349], may be associated with subordinate social status. Monoamines, involved in social behaviors, appear to be regionally specialized for dominant and subordinate social roles, in males [C.H. Summers and N. Greenberg, Activation of central biogenic amines following aggressive interaction in male lizards, Anolis carolinensis, Brain Behav. Evol., 45 (1995) 339-349][T.R. Summers, E.T. Larson, A.L. Hunter, K.J. Renner, N. Greenberg and C.H. Summers, Amygdalar serotonin mediates long-term social roles following aggressive interaction, Soc. Neurosci. Abs., 22 (1996) 1147] and females. Dominant females exhibit unique social position, behavior and monoamine profile whereas subordinate females and males have a similar serotonergic response in this species.
This study explored the possibility that reduced behavioral responsiveness to estradiol and progesterone in female Syrian hamsters exposed to a short photoperiod is associated with a reduction in the concentration of neural steroid receptors. The effects of long and short photoperiod (LP; SP) exposure on steroid receptor immunoreactivity were examined in the ventromedial hypothalamus (VMH), medial tuberal region (mTu), medial preoptic area (mPOA), medial nucleus of the amygdala (mAMYG), and the arcuate nucleus (ARC) of ovariectomized hamsters. In Experiment 1, exposure to SP for ten weeks attenuated the lordosis response following sequential treatment with estradiol and progesterone. In a separate group of animals not given hormones, SP decreased the staining intensity of estrogen receptor immunoreactive (ERIR) cells in the mPOA while increasing the number of detectable ERIR cells in part of the mAMYG. In Experiment 2, SP diminished the lordosis response as it did in Experiment 1. One week later, the same females were administered estradiol systemically to induce progestin receptors (PR). Animals housed in SP showed significantly reduced progestin receptor immunoreactivity (PRIR) in the VMH, mTu, mPOA, mAMYG, and ARC. Experiment 3 examined whether the results of Experiment 2 might have been influenced by photoperiodic effects on peripheral metabolism of estradiol. Among hamsters housed in LP or SP, PRs were induced by estradiol implanted unilaterally in the medial basal hypothalamus, thus bypassing possible photoperiodic effects on peripheral estradiol availability. This treatment resulted in significantly fewer cells with detectable PRIR in the VMH and mPOA of SP females, suggesting that the photoperiodic influences on PR induction observed in Experiment 2 do not depend on alterations in the peripheral availability of estradiol.
This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia-ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.
Hormonal and chemosensory signals regulate social behaviors in a wide variety of mammals. In the male Syrian hamster, these signals are integrated in nuclei of the medial extended amygdala, where olfactory and vomeronasal system transmission is modulated by populations of androgen- and estrogen-sensitive neurons. Evidence from behavioral changes following lesions and from immediate early gene expression supports the hypothesis that the medial extended amygdala and medial preoptic area belong to a circuit that functions selectively in male sexual behavior. However, accumulated behavioral, neuroanatomical, and neuroendocrine data in hamsters, other rodents, and other mammals indicate that this circuit is embedded in a larger integrated network that controls not only male mating behavior, but female sexual behavior, parental behavior, and various forms of aggression. In this context, perhaps an individual animal's social responses can be more easily understood as a repertoire of closely interrelated, hormone-regulated behaviors, shaped by development and experience and modulated acutely by the environmental signals and the hormonal milieu of the brain.
Sexual interactions can cause changes in plasma hormone levels and activate immediate early genes within the mammalian brain. There are marked anatomical differences between the regions activated that relate directly to the sexual specific behaviour and neuroendocrinology of each sex. The aim of this study was to determine if such a sexual dimorphism exists in birds by examining the brain regions stimulated in adult virgin female Japanese quail (Coturnix japonica) during sexual behaviour and comparing this to previously reported data concerning males. Female quail were allowed to freely interact with adult males and both female and male sexual behaviour was recorded. Contrary to previous findings in male quail, no significant induction of Fos-like immunoreactive (FLI) cells was observed following sexual interactions in the preoptic area of females; this area is fundamentally involved in the control of male-type copulatory behaviour. Sexual interactions significantly induced FLI cells in the hyperstriatum ventrale, the part of the archistriatum just lateral to the anterior commissure, and the nucleus intercollicularis. Moreover, prominent activation was detected throughout most of the ventromedial nucleus of the hypothalamus, a region reported to be rich in oestrogen receptors. FLI induction was not a consequence of sexual behaviour induced changes in luteinizing hormone (LH) as plasma LH levels were unaltered. Instead, brain activation must be a consequence of copulation-associated somatosensory inputs or direct stimuli originating from the male. Male quail, like the majority of other birds, lack an intromittant organ (penis) so that the somatosensory inputs to the female are rather different from those in mammals; the precise nature of these inputs is yet to be determined.
Previous studies have demonstrated that gustatory stimulation evokes expression of the immediate-early gene, c-fos in the rostral division of the nucleus of the solitary tract (rNST) (Harrer and Travers [1996] Brain Res. 711:125-137; DiNardo and Travers [1997] J. Neurosci. 17:3826-3839; King et al. [1999] J. Neurosci. 19:3107-3121). The present investigation further defined the phenotype of those neurons by determining their projections, by using immunohistochemistry for the Fos protein and retrograde tracing with Fluoro-Gold. Tracer injections were made into the two major extranuclear targets of rNST, the parabrachial nucleus (PBN) and medullary reticular formation (RF). These structures are thought to play differential roles in higher-order discriminative and homeostatic (PBN) versus reflexive function (RF). After PBN injections, approximately 18% of the Fos-like immunoreactive (FLI) neurons were double-labeled; after RF injections the proportion was 9%. Because only a minority of FLI neurons appear to project to targets outside NST, this suggests that most of these cells have local, intranuclear projections. Comparable proportions of cells were double-labeled after sucrose or quinine, consistent with roles for both tastants in higher-order and reflexive function. On the other hand, regardless of stimulus, twice as many FLI neurons projected to the PBN as to the RF. This could suggest that more FLI neurons contribute to functions mediated by the ascending pathway. However, the results of a recent study prompted a different hypothesis: Because glossopharyngeal nerve section similarly devastates quinine-induced FLI and oral rejection but leaves discriminative function unimpaired, it was proposed that FLI neurons are more important in driving oral motor behavior than discrimination (King et al. [1999] J. Neurosci. 19:3107-3121). A plausible hypothesis for reconciling this apparent discrepancy is that many FLI neurons make local projections in rNST, that in turn give rise to RF connections.
Detection of the expression of c-fos mRNA or its protein product, Fos, has been used to indicate differences in neuronal response to exogenous stimuli. Factors contributing to differences in Fos expression as a result of various stimuli associated with mating have been extensively studied in the female rat. Less is known about the factors that contribute to Fos expression in female hamsters. Female hamsters differ from female rats in several aspects of sexual behavior; therefore, it seems likely that Fos expression may also differ. The purpose of this study was to determine which factors associated with mating selectively affect Fos expression in the female hamster. Animals were ovariectomized, hormone treated, and then exposed to several behavioral conditions. Fos expression in several brain areas was then assessed via immunocytochemistry (ICC). As has been found by others, mating increases Fos immunoreactivity in a number of brain regions. Specifically, vaginal-cervical stimulation (VCS) was determined to be the salient factor contributing to Fos expression in the preoptic area (POA) and bed nucleus of the stria terminalis (BNST) of ovariectomized hormone primed female hamsters that received a mating interaction.
Dominant subordinate relationships are formed as the result of social conflict and are maintained at least in part by communication. At this time, little is known about the neural mechanisms that are responsible for coordinating the social behaviours (e.g. aggression) that occur in association with the formation and maintenance of these relationships. The purpose of the present study was to investigate the role of oxytocin (OXT) within the medial preoptic anterior hypothalamic continuum (MPOA-AH) in the control of aggression in female hamsters. OXT injected into the MPOA-AH immediately before testing significantly reduced the duration of aggression in a dose-dependent manner. Injection of an OXT antagonist 30 min before testing significantly increased the duration of aggression. In contrast, the duration of aggression was not altered when hamsters were tested either 30 min after injection of OXT or immediately following injection of an OXT-antagonist. These data support the hypothesis that OXT release within the MPOA-AH regulates social behaviours important in the formation and maintenance of dominant subordinate relationships in female hamsters.
Ovariectomized female hamsters received small unilateral implants of estradiol at a variety of anterior-posterior levels of the medial preoptic area and hypothalamus. The results of an initial experiment using 27-ga. implants showed that females with estradiol implants in the ventromedial hypothalamus (VMN) or nearby anterior hypothalamus consistently showed higher levels of sexual receptivity than did females with implants farther rostral, in the preoptic area, or farther caudal, in the posterior hypothalamus. A second experiment used smaller, 28-ga. implants to compare directly the two areas at which implants were effective in the first experiment. The results confirm the findings of other recent studies of hamsters and rats by identifying the VMN as the most effective hypothalamic site for the estrogen priming of sexual receptivity.
Used Fos immunocytochemistry to show that the medial preoptic area and ventral bed nucleus of the stria terminalis are activated in maternally behaving female rats. In Exp 1, virgin female rats that showed maternal behavior toward pups had more cells in these regions that expressed Fos-like immunoreactivity than did virgin females that were not maternally responsive. In Exp 2, postpartum rats that were exposed to pups and showed maternal behavior had more Fos-labeled cells in these regions than did postpartum rats exposed to candy. Evidence also indicated that functional modifications in the medial amygdala were related to the changes in Fos expression observed in the preoptic area and ventral bed nucleus of the stria terminalis. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The effects of intracranial implants of estradiol in the ventromedial hypothalamus (VMH), the anterior hypothalamus (AH), or the medial amygdala (AMG) on aggression, sexual behavior, and serum estradiol were examined in female Syrian hamsters. Estradiol implants in the VMH, followed by systemic progesterone, stimulated sexual behavior and inhibited aggression. Estradiol implants in other intracranial sites activated sexual behavior but did not reliably inhibit aggression. Intracranially implanted and systemically treated animals had equivalent peripheral estradiol concentrations at sacrifice. These results suggest that: (a) the VMH is an important neural site for estradiol actions on sexual and aggressive behavior, (b) the caudal AH and AMG also may be sites of estradiol action on sexual behavior, and (c) these intracranial implants may only be effective given systemic estradiol exposure or the concurrent stimulation of multiple brain areas.
Transcription of the proto-oncogene c-fos is stimulated by 17β-estradiol in estrogen responsive human and rat cells. To understand the molecular mechanisms of estrogen
regulation of c-fos gene transcription, the human c-fos gene promoter, with 2.25 Kb of 5′-flanklng DNA, was cloned upstream of the bacterial CAT gene and tested for estrogen regulation
by transient transfection in HeLa cells. When an expression vector coding for the human estrogen receptor was cotransfected
with the fos -CAT reporter, the promoter was found to respond to 17β-estradiol. An element responsible for estrogen induction was mapped
in a 240 bp region localized 1060 to 1300 bases upstream of the startsite of transcription of the gene. Sequence analysis
revealed, clustered in a 19 bp sub-region, a sequence corresponding to an imperfectly palindromic ERE: CGGCAGCGTGACC and two sequences: CTGAG and GTGAC, homologous to the core sequence of AP-1 transcription factor binding sites. A synthetic
oligonucleotide reproducing this sub-region binds ‘in vitro’ both the estrogen receptor and AP-1 factor(s) and confers estrogen-responsivity
to the HSV-tk gene promoter. Transcriptional activation by the estrogen receptor is prevented by mutations in the fos ERE that hamper binding of the receptor in vitro. Activation of the c-fos gene promoter in HeLa cells requires the DNA binding domain of the estrogen receptor, and can be achieved independently by
the TAF-1 and the TAF-2 transcriptional activation functions of this molecule. A receptor mutant lacking the hormone binding
domain can activate the c-fos gene promoter in the absence of estrogen.
Fos, the protein product of the c-fos gene, is induced in neurons in response to a variety of stimuli. In order to see if Fos could be used to map activity in the brain, the pattern of Fos staining was compared to the pattern of (14C) 2-deoxyglucose (2DG) uptake in the seventh and eighth lobules of the cerebellum during electrical stimulation of the cerebral cortex.
Electrical stimulation of hindlimb motor/sensory cortex of awake rats increased 2DG uptake in the contralateral and ipsilateral cerebellum. The largest increases occurred in granule cell patches in the contralateral copula pyramidis (Cop P) and pyramis (P), the hemispheric and vermal portions of the eighth cerebellar lobule, respectively. The granule cell patches formed parasagittal bands that extended short distances mediolaterally, and extended long distances anteroposteriorly over much of the Cop P.
Forelimb motor/sensory cortex stimulation increased 2DG uptake bilaterally in the seventh, paramedian (PM) cerebellar lobule. The greatest increases occurred in the granule cell layer contralateral to the stimulation. These and the above results generally agree with classical studies that localize forelimb on the seventh lobule anterior to the hindlimb on the eighth lobule. However, hindlimb cortical stimulation activated parts of the PM, and forelimb cortical stimulation activated portions of the rostral Cop P. In general, nonoverlapping portions of Cop P and PM were activated during the two types of cortical stimulation. These results are consistent with a fractured somatotopy (Welker and Shambes, '85) in which nonadjacent body parts are consistently represented in adjacent granule cell patches on each lobule, with the fractured somatotopy being different for every lobule.
No region of cerebellum expressed Fos in unstimulated, electrode implanted, control subjects. However, following 15 minutes of electrical stimulation of hindlimb cortex, Fos was expressed 4 hours later in patches of granule cell nuclei in Cop P and P. These patches of Fos immunostained granule cells occurred in similar locations in Cop P to the patches of highest glucose metabolism observed with the 2DG method.
Zones of Purkinje cell nuclei also expressed Fos. These Purkinje cell zones were often directly over similar sized granule cell patches in P. In the hemisphere however, the zones of Purkinje cells in ventrolateral Cop P expressing Fos only partially overlapped underlying granule cell patches that expressed Fos. Moreover, Fos was not induced in any Purkinje cells adjacent to the Fos-stained granule cell patch in dorsolateral Cop P. These results demonstrate that somatotopically organized granule cell patches representing activated cerebellar afferents may be congruent with somatotopically organized zones of Purkinje cells representing activated cerebellar efferents-particularly in the vermis (P). However, in the cerebellar hemisphere activated cerebellar affer- ents and efferents from the same body part often only partially overlap one another or do not overlap at all.
Nerve growth factor (NGF) causes the differentiation of PC12 cells to sympathetic neuron-like cells and also induces a rapid but transient expression of fos mRNA and protein. fos mRNA transcripts can be detected 5 min after the addition of NGF, are maximally abundant after 30 min, and then their levels decrease. fos protein synthesis parallels the expression of fos mRNA, and the induced fos proteins are located in the nucleus. cAMP, epidermal growth factor, the phorbol ester phorbol 12-myristate 13-acetate, and K+ depolarization also induce the fos gene. Growth of PC12 cells in the presence of dexamethasone, which induces differentiation into chromaffin-like cells, is not accompanied by fos expression. We propose that while fos gene induction is associated with the differentiation of PC12 cells to sympathetic nerve, its enhanced expression is primarily involved in the anabolic responses induced by NGF and many growth factors.
Three members of the Jun/AP-1 family have been identified in mouse cDNA libraries: c-Jun, Jun-B, and Jun-D. We have compared the DNA binding properties of the Jun proteins by using in vitro translation products in gel retardation assays. Each protein was able to bind to the consensus AP-1 site (TGACTCA) and, with lower affinity, to related sequences, including the cyclic AMP response element TGACGTCA. The relative binding to the oligonucleotides tested was similar for the different proteins. The Jun proteins formed homodimers and heterodimers with other members of the family, and they were bound to the AP-1 site as dimers. When Fos translation product was present, DNA binding by Jun increased markedly, and the DNA complex contained Fos. The C-terminal homology region of Jun was sufficient for DNA binding, dimer formation, and interaction with Fos. Our general conclusion is that c-Jun, Jun-B, and Jun-D are similar in their DNA binding properties and in their interaction with Fos. If there are functional differences between them, they are likely to involve other activities of the Jun proteins.
Two experiments were conducted to examine the behavioral effects of medial amygdaloid (M) lesions during the estrous cycle in female golden hamsters. In Experiment 1, males were paired with gonadally intact M-lesioned, sham-operated, or ovariectomized M-lesioned females and tested in large enclosures. Medial amygdaloid lesions reduced, significantly, the occurrence of precopulatory biting attack and vaginal scent-marking behavior in females. In contrast, M lesions produced a significant increase in the duration of copulation. Mating behavior was also observed for a brief period of time in 1 M-lesioned female during the diestrus period and in 2 ovariectomized animals. After copulation, M-lesioned females attacked their mating partner less frequently than did sham-lesioned animals, which suggests that M lesions may modulate the reduction of both pre- and postcopulatory aggressive behavior by common processes. The attenuation in aggressive responsiveness was further documented in Experiment 2, which shows that during intrasexual fights, M-lesioned females exhibited significantly fewer offensive agonistic responses than did sham-operated opponents. Collectively, the results demonstrate that M lesions produce significant alterations in both social and sexual response patterns and suggest that M may be a neural component of a forebrain inhibitory system regulating the display of feminine copulatory behavior.
Ultrasound production and lordosis were examined in ovariectomized, hormone-primed female hamsters before and after sham operations or bilateral electrolytic lesions in the lateral septum/bed nucleus, corticomedial amygdala, or lateral habenula. During 2-min exposures to synthetic ultrasounds and 1-min exposures to stimulus males, females with corticomedial amygdala lesions exhibited reduced ultrasound rates and lordosis durations. Following lesions in the lateral septum/bed nucleus, females showed significant increases in ultrasound rates with no pre- to postoperative change in lordosis. Ablations of the lateral habenula had no effect on calling but were associated with shorter lordosis durations. These results demonstrate that two reproductive behaviors, ultrasound production and lordosis, are differentially affected, depending on lesion placement within the limbic system. In turn, these differences demonstrate that the neural mechanisms for two elements of a single major class of behavior can be quite distinct, both in terms of the likelihood that particular brain areas will be involved and in the nature of their involvement.
The effects of intracranial implants of estradiol in the ventromedial hypothalamus (VMH), the anterior hypothalamus (AH), or the medial amygdala (AMG) on aggression, sexual behavior, and serum estradiol were examined in female Syrian hamsters. Estradiol implants in the VMH, followed by systemic progesterone, stimulated sexual behavior and inhibited aggression. Estradiol implants in other intracranial sites activated sexual behavior but did not reliably inhibit aggression. Intracranially implanted and systemically treated animals had equivalent peripheral estradiol concentrations at sacrifice. Results suggest that (1) the VMH is an important neural site for estradiol actions on sexual and aggressive behavior, (2) the caudal AH and AMG may also be sites of estradiol action on sexual behavior, and (3) intracranial implants may only be effective given systemic estradiol exposure or the concurrent stimulation of multiple brain areas. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
These experiments were designed to test the effects of chronic estradiol treatment on aggression and sexual behavior in female hamsters. Isolated female hamsters were ovariectomized and tested for their behavioral responses to a group-housed, ovariectomized female hamster (aggression test) and a group-housed, intact male hamster (sexual behavior test). Following these baseline tests, the experimental females were implanted sc with Silastic capsules containing different concentrations of estradiol (100, 25, 10, or 0%) diluted with cholesterol and retested 3, 7, 10, and 14 days after implantation. High levels of aggression were observed on the baseline test, with no changes in aggression toward an intruder female observed for any implant group on subsequent tests. Despite these high levels of aggression toward another female, most of the estradiol-treated females (80% at 14 days) were sexually responsive in the presence of a male. There was no effect of Silastic estradiol concentration on sexual behavior, even though a range of serum estradiol levels (39–105 pg/ml) resulted. Lordosis latencies decreased and lordosis durations increased over the extent of estradiol treatment. Seventeen days after Silastic implantation, all females were injected with progesterone and retested. Estradiol-treated females showed an extreme reduction in aggression toward a stimulus female, as well as a further stimulation of sexual behavior after progesterone treatment. High levels of aggression in cholesterol-treated females (0% estradiol) were maintained even after progesterone injection, and these females never displayed any sexual responsivity. These results suggest that sexual behavior in the female hamster is sensitive to estradiol alone, whereas the inhibition of aggression requires the combination of estradiol plus progesterone.
The surgically-induced lesion has traditionally been used to study the localization of functions in the brain. The basic tenets for its use are that (1) functions are represented in discrete brain structures such as nuclei and fiber tracts and that (2) lesions disrupt function by removal of functional tissue in circumscribed sites in the brain. Contrary to this traditional view, there is growing evidence that the secondary changes in the brain which are induced by a lesion, both directly (necrosis, anterograde and retrograde degeneration) and indirectly (transneuronal degeneration, regeneration and sprouting, denervation supersensitivity, alteration of neurochemical pools, vascular disruption, diaschisis), may comprise the more significant neurological changes which can account for alteration of behavior in a lesion experiment. This evidence is reviewed and a new strategy of research utilizing lesions is proposed, suggesting that greater emphasis be placed on the a posteriori assessment of secondary changes in the brain as they are correlated with changes in behavior. The implications of such considerations for establishing brain-behavior relationships are discussed.
Patterns of female sexual behavior in the hamster are qualitatively different from that observed in the rat. Hamsters demonstrate tonic immobility and a sustained lordotic response that can last for several minutes following minimal stimulation from the male while in rats, the lordotic response is highly dependent upon continued stimulation from the male and lasts for only a few seconds following a mount or intromission. Also, the hamster requires both estrogen and progesterone priming in order to display female sexual behavior but the rat can show lordotic behavior following treatment with estrogen alone. Electrolytic lesions in the lateral septal area of female rats produce a facilitation in female sexual behavior and increase behavioral sensitivity to estrogen. However, lesions in the lateral septal area of rats produced by the neurotoxin kainic acid (KA) result in deficits in female sexual behavior following estrogen and progesterone treatment. Given these species differences in sexual behavior, we have examined the effects of KA lesions in the lateral septal area of hamsters on female sexual behavior. Adult female golden hamsters were ovariectomized and tested for female sexual behavior prior to receiving brain surgery. For all behavior tests, animals were injected SC with 60 micrograms of estradiol benzoate/kg per day for two days and 0.5 mg of progesterone three hours prior to the behavior test on day three. Behavior tests consisted of placing the test animal in a male's home cage for 10 minutes and recording the latency to the first lordosis, length of the longest single bout of lordosis and total lordosis duration.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of gonadal steroids on fos expression in the adult rat ventromedial hypothalamus (VMH) and uterus were examined using molecular hybridization and immunocytochemical techniques. Adult, ovariectomized rats were treated with estrogen (E), progesterone (P), or estrogen followed 24 h later with progesterone (E + P) and sacrificed 1–24 h after treatment. Slot blots revealed an approximately twofold increase in uterine c-fos mRNA within 3 h after receiving 10 μg E. Likewise, an increase in fos-like immunoreactivity (IR) within lumenal and glandular epithelial cells was detected at 3 h, appeared maximal at 6 h and was much reduced by 24 h after E treatment. The induction was both steroid and dose dependent—no induction of fos-like IR was observed following administration of 1 mg P, in response to a low dose of E (0.25 μg/100 g body wt), or when the low dose of E was followed 24 h later with 1 mg P. In addition, the effect was cell-specific—in no case was induction of fos-like IR within stromal or myometrial cells observed. In contrast with the uterus, no effect of E on levels of c-fos mRNA (3 or 6 h after treatment) in the VMH was observed. Sections through areas of the mediobasal hypothalamus were examined for the expression and regulation of fos-like IR. No effects of E, P, or E + P on the number of fos-like IR cells within the ventromedial nucleus of the hypothalamus, tha arcuate nucleus of the hypothalamus, or the medial amygdala were observed. Furthermore, no effects of E, P, or E + P on the expression of fos-like IR within other areas of the forebrain included in these sections were readily apparent. Many fos-like IR cells were consistently detected, however, within several areas of the brain including the arcuate nucleus, the cingulate cortex, the pyriform cortex, the endopyriform nucleus, the suprachiasmatic nucleus, the medial amygdala, and the dorsomedial nucleus of the hypothalamus. Immunoreactive cells in the paraventricular nucleus of the thalamus and in the lateral habenula were also frequently observed. For comparison, intense fos-like IR in the hippocampal formation and in the paraventricular nucleus of the hypothalamus was observed following metrazol-induced seizure activity and water deprivation, respectively. These data are consistent with the hypothesis that estrogenic effects on uterine epithelial cells may be mediated via the induction of fos. In contrast, evidence that estrogenic effects on adult VMH neurons are mediated by fos was not observed.
The distribution of immediate early gene zif-268, c-fos, c-jun and jun-D mRNAs was investigated in the visual cortex, dorsal lateral geniculate nucleus and hippocampus of the adult cat brain with in situ hybridization. In area 17, zif-268, c-jun and jun-D were found predominantly in layers II–III and VI, while c-fos mRNA was abundant in layer VI. In area 18, the zif-268, c-fos and c-jun labelling pattern was identical to that of area 17, this was not true for jun-D. In area 19, only c-jun retained the lamination pattern of areas 17 and 18, while zif-268, c-fos and jun-D were homogeneously distributed. In the dorsal lateral geniculate nucleus, only c-fos and jun-D resulted in labelling. In the pyramidal layer of hippocampus, zif-268 was found in CA1–4, c-jun in CA1–3, and jun-D in CA2–4. In the dentate gyrus, c-jun was abundant, jun-D moderate and zif-268 faint. C-fos labelling was absent in the hippocampal formation.
The effects of intracranial implants of the synthetic progestin, promegestone (R5020), on aggression and sexual behavior were examined in female Syrian hamsters. Ovariectomized female hamsters showed high levels of aggression and no lordosis towards stimulus male and female hamsters, both prior to and after estradiol benzoate treatment. Forty-six hr after estradiol treatment (10 μg SC), 10% crystalline promegestone was applied bilaterally (27 ga cannulae) to the ventromedial hypothalamus. When tested 5–7 hr later, these animals had a significant reduction in the rate of attacks towards females, with no lordosis responding to a male. In contrast, promegestone in the caudal anterior hypothalamus activated low levels of lordosis, yet these females maintained high levels of aggression towards stimulus females. Females receiving promegestone in the rostral anterior hypothalamus, and control females receiving intracranial cholesterol, maintained high levels of aggression and no lordosis. Estradiol treatment alone enhanced pelvic movements in response to experimenter-applied perineal stimulation in a majority of females ( compared with prior to estradiol injection), with intracranial treatments having no further effect. These results indicate that progestins act on aggression and sexual behavior in female Syrian hamsters at different hypothalamic loci.
Recovery of function of social behavior, hoarding, nesting, and weight gain was investigated in the juvenile hamster following bilateral septal lesions. Hamsters receiving septal lesions during the juvenile period showed as much disruption in behavior as animals receiving septal lesions as adults. As compared to control animals, both septal lesioned groups were more aggressive, showed a reduction in hoarding behavior, lost the ability to build nests, and gained significantly more weight.
The properties of the viral and cellular fos proteins (Fos) were investigated as a first step toward understanding the function
of the fos gene. Treatment of nuclei with salt and nonionic detergents solubilized a complex that contained Fos together with
several other cellular proteins. The majority of the Fos protein complex was released from isolated nuclei incubated in the
presence of deoxyribonuclease I or micrococcal nuclease but not with ribonuclease A, suggesting that Fos is associated with
chromatin. This hypothesis is supported by the finding that Fos protein from native or denatured nuclear extracts exhibited
DNA-binding activity in vitro. These results suggest that Fos is involved in the regulation of gene expression.
Reproductive events in the female rat can be influenced by exposure to the odors of conspecific males. Much evidence indicates that these pheromonal effects are mediated by the accessory olfactory system (AOS); however, individual cells within the AOS that are stimulated following exposure to male odors have not yet been visualized. The present experiment was designed to determine the effect of exposure to conspecific males and male odors on signal transduction in central AOS neurons as measured by immunohistochemical detection of the induction of the fos-like protein. AOS structures examined included the accessory olfactory bulb (AOB), medial amygdala (mAMYG), and bed nucleus of the stria terminalis (BNST). Due to its importance in the control of reproductive activities and its direct link to the AOS, the ventromedial nucleus of the hypothalamus (VMH) was also examined. Adult, ovariectomized rats were injected with estradiol benzoate (EB) and 48 h later were placed in cages containing bedding material soiled by conspecific males or placed in cages containing clean bedding material. After exposure durations ranging from 10 to 180 min, the animals were sacrificed and the brains were immunohistochemically processed for detection of fos-like immunoreactivity. Another group of ovariectomized, EB-injected females was repeatedly paired with conspeciflc males for 15 min followed by 15 min of rest. Repeated matings were conducted over a 60-, 120-, or 180-min period while control animals were repeatedly exposed to clean bedding material. Quantitative analysis of the number of fos-immunopositive cells in the AOB revealed that continuous exposure to male-soiled bedding or repeated mating resulted in significant induction of foslike immunoreactivity compared to controls. Both treatments produced similar numbers of fos-like immunoreactive cells in the mitral and granule cell layers of the AOB. Fos induction was apparent after 60 min of treatment but was more prominent at 120 and 180 min. In the mAMYG, BLAST, and VMH, differences between the two treatments were noted. Exposure to male-soiled bedding for 60 min produced scattered staining in the mAMYG, BLAST, and VMH, whereas 60 min of repetitive mating resulted in a more dense distribution of fos-like immunoreactive cells in these areas. Strikingly distinct patterns of fos-like immunoreactive cells were observed in the mAMYG, BLAST, and VMH following 120 or 180 min of repetitive mating. These patterns were not present in animals exposed to male odors. The findings indicate that exposure of female rats to reproductively relevant stimuli resulted in induction of fos-like immunoreactivity within the AOS and that both olfactory and nonolfactory cues probably contributed to this effect.
Effects of gonadal steroids on fos expression in the adult rat ventromedial hypothalamus (VMH) and uterus were examined using molecular hybridization and immunocytochemical techniques. Adult, ovariectomized rats were treated with estrogen (E), progesterone (P), or estrogen followed 24 h later with progesterone (E + P) and sacrificed 1-24 h after treatment. Slot blots revealed an approximately twofold increase in uterine c-fos mRNA within 3 h after receiving 10 mug E. Likewise, an increase in fos-like immunoreactivity (IR) within lumenal and glandular epithelial cells was detected at 3 h, appeared maximal at 6 h and was much reduced by 24 h after E treatment. The induction was both steroid and dose dependent-no induction of fos-like IR was observed following administration of 1 mg P, in response to a low dose of E (0.25 mug/100 g body wt), or when the low dose of E was followed 24 h later with 1 mg P. In addition, the effect was cell-specific-in no case was induction of fos-like IR within stromal or myometrial cells observed. In contrast with the uterus, no effect of E on levels of c-fos mRNA (3 or 6 h after treatment) in the VMH was observed. Sections through areas of the mediobasal hypothalamus were examined for the expression and regulation of fos-like IR. No effects of E, P, or E + P on the number of fos-like IR cells within the ventromedial nucleus of the hypothalamus, tha arcuate nucleus of the hypothalamus, or the medial amygdala were observed. Furthermore, no effects of E, P, or E + P on the expression of fos-like IR within other areas of the forebrain included in these sections were readily apparent. Many fos-like IR cells were consistently detected, however, within several areas of the brain including the arcuate nucleus, the cingulate cortex, the pyriform cortex, the endopyriform nucleus, the suprachiasmatic nucleus, the medial amygdala, and the dorsomedial nucleus of the hypothalamus. Immunoreactive cells in the paraventricular nucleus of the thalamus and in the lateral habenula were also frequently observed. For comparison, intense fos-like IR in the hippocampal formation and in the paraventricular nucleus of the hypothalamus was observed following metrazol-induced seizure activity and water deprivation, respectively. These data are consistent with the hypothesis that estrogenic effects on uterine epithelial cells may be mediated via the induction of fos. In contrast, evidence that estrogenic effects on adult VMH neurons are mediated by fos was not observed.
The lordosis response in ovariectomized, hormone-primed females was measured in repeated weekly tests before and after bilateral lesions of various medial hypothalamic regions. Changes in body weight, frequency of vaginal marking, and agonistic behavior were also recorded. Forty-two females were divided into five groups based on lesion location: (1) medial preoptic (MPO), (2) medial anterior hypothalamus (MAH), (3) dorsomedial nucleus-dorsal premammillary nucleus (DM-DPM), (4) dorsal ventromedial nucleus (Dorsal VMN), (5) medial basal hypothalamus (MBH). Unoperated control females were tested in an identical manner. Only lesions in the region of the ventromedial nucleus eliminated lordosis. Lesions which disrupted lordosis also increased agonistic behavior in male-female pairs. The frequency of vaginal marking was reduced by lesions in the MPO, MAH, and Dorsal VMN groups. Rapid weight increases and obesity were also seen following certain medial hypothalamic lesions, however no significant correlations were found between degree of weight change and degree of lordosis deficit. A quantitative analysis of VMN damage revealed a relatively low, but statistically significant positive correlation between degree of VMN damage and lordosis deficits. There were no significant correlations between degree of VMN damage and weight change.
— A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2-deoxy-D-[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose-6-phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2-chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.The method has been applied to normal albino rats in the conscious state and under thiopental anesthesia. The results demonstrate that the local rates of glucose consumption in the brain fall into two distinct distributions, one for gray matter and the other for white matter. In the conscious rat the values in the gray matter vary widely from structure to structure (54-197 μmol/100 g/min) with the highest values in structures related to auditory function, e.g. medial geniculate body, superior olive, inferior colliculus, and auditory cortex. The values in white matter are more uniform (i.e. 33–40 μmo1/100 g/min) at levels approximately one-fourth to one-half those of gray matter. Heterogeneous rates of glucose consumption are frequently seen within specific structures, often revealing a pattern of cytoarchitecture. Thiopental anesthesia markedly depresses the rates of glucose utilization throughout the brain, particularly in gray matter, and metabolic rate throughout gray matter becomes more uniform at a lower level.
Bilateral radio-frequency lesions in the medial preoptic area (MPOA) were found to reduce aggressiveness and to increase the incidence of submissive responding in female hamsters that were paired against other females. The reduced aggressiveness of females with MPOA lesions appeared to be relatively independent of their hormonal state, since ovariectomy and subsequent replacement therapy with 200 μg a day of testosterone propionate (TP) had no influence on the low levels of aggression exhibited by these females. In contrast to females with lesions in the MPOA, females with lesions in anterior hypothalamus (AHA) exhibited increased aggressiveness in the postoperative tests preceding ovariectomy. Ovariectomy reduced the frequency with which AHA-lesioned females exhibited fights, attack-chase sequences, and low intensity aggressive acts, and TP injections failed to reinstate precastration levels of these behaviors.
The effect of mating behavior on the expression of Fos protein was analyzed within the chemosensory pathways of the male Syrian hamster brain. Following a single mating test, the number of Fos-immunoreactive (Fos-ir) neurons increased within the amygdala, bed nucleus of the stria terminalis and medial preoptic area. The mating-induced pattern of Fos expression within these brain regions shows a strong correlation with the sites of lesions that eliminate or alter mating behavior. In addition, Fos expression was increased within the paraventricular nucleus of the hypothalamus. These results provide the first demonstration of a dynamic and selective pattern of neuronal activity within specific nuclei known to be essential for mating behavior in the male Syrian hamster.
Immunocytochemical methods were used to localize the protein product of the immediate-early gene, c-fos, in male rats after exposure to, or direct physical interaction with, oestrous females. Increasing amounts of physical contact with a female, with resultant olfactory-vomeronasal and/or genital-somatosensory inputs, caused corresponding increments in c-fos expression in the medial preoptic area, the caudal part of the bed nucleus of the stria terminalis, the medial amygdala, and the midbrain central tegmental field. Males bearing unilateral electrothermal lesions of the olfactory peduncle showed a significant reduction in c-fos expression in the ipsilateral medial amygdala, but not in other structures, provided their coital interaction with oestrous females was restricted to mount-thrust and occasional intromissive patterns due to repeated application of lidocaine anaesthetic to the penis. No such lateralization of c-fos expression occurred in other males with unilateral olfactory lesions which were allowed to intromit and ejaculate with a female. These results suggest that olfactory inputs, possibly of vomeronasal origin, contribute to the activation of c-fos in the medial amygdala. However, lesion-induced deficits in this type of afferent input to the nervous system appear to be readily compensated for by the genital somatosensory input derived from repeated intromissions. Unilateral excitotoxic lesions of the medial preoptic area, made by infusing quinolinic acid, failed to reduce c-fos expression in the ipsilateral or contralateral medial amygdala or central tegmental field following ejaculation. By contrast, combined, unilateral excitotoxic lesions of the medial amygdala and the central tegmental field significantly reduced c-fos expression in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area after mating; no such asymmetry in c-fos expression occurred when lesions were restricted to either the medial amygdala or central tegmental field. This suggests that afferent inputs from the central tegmental field (probably of genital-somatosensory origin) and from the medial amygdala (probably of olfactory-vomeronasal origin) interact to promote cellular activity, and the resultant induction of c-fos, in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area. The monitoring of neuronal c-fos expression provides an effective means of studying the role of sensory factors in governing the activity of integrated neural structures which control the expression of a complex social behaviour.
The data reviewed here are compatible with the hypothesis that telencephalic dopamine activity is elicited by motivationally significant stimuli which in turn creates a neural state in which animals are more prepared to respond to significant stimuli in the environment. This analysis may be viewed as extensions of both the sensorimotor hypothesis, which depicts dopamine as potentiating the ability of stimuli to elicit responses (Clody and Carlton, 1980; Marshall et al., 1974; White, 1986) and of the incentive motivational hypothesis, which emphasizes the importance of dopamine in responding to stimuli that serve as signals of biologically significant events (Blackburn et al., 1989a; Crow, 1973; Mogenson and Phillips, 1976). In addition, we have sought to emphasize that not all responses are equally dependent upon the integrity of forebrain dopamine activity. Some responses, such as ingestion of standard foods by hungry animals, copulation, and escape, are relatively impervious to dopamine disruption. Further, once other behaviours, such as avoidance or appetitive operant responses, have been acquired, they can be maintained at an initially high rate despite perturbation of dopamine systems, although performance deteriorates with repeated testing. This analysis has emerged from the joint consideration of how both appetitive and defensive behaviours are influenced by dopamine antagonists, along with an examination of dopamine release during sequences of behaviour. The data reviewed suggest that dopamine is involved in fundamental psychological processes through which environmental stimuli come to exert control over certain aspects of behaviour. In the future, as knowledge in this field advances, there will have to be an integration of the literature on dopamine and motivation with the literature on dopamine and motor systems. We expect that dopamine release will be seen as a mechanism by which important environmental cues, of innate or learned significance, lead to a general enhancement of motor skeletal responses directed towards distal cues. We conclude with a caveat: Caution must be exercised when attempting to infer a general role of any neurotransmitter in motivated behaviour based on the study of a limited number of motivational systems. Although neurotransmitter pathways may figure prominently in the control of certain behaviours, it is incorrect to think of neurotransmitters as having a single role in behaviour. However, when comparative analyses reveal a common thread among different motivational systems, as is becoming apparent for the general role of mesotelencephalic dopamine pathways in behaviour, then the goal of generating coherent and comprehensive theory concerning a neurotransmitter's function in behaviour will begin to be realised.(ABSTRACT TRUNCATED AT 400 WORDS)
The protooncogene c-fos is induced in rat brain by various forms of physiological stimulation. In this study immunocytochemical staining for a peptide fragment of the c-fos protein was used to assess estradiol's effects on c-fos in rat brain. After estradiol benzoate (100 micrograms/kg) administration to ovariectomized rats, the number of cells staining for c-fos-like protein increased in the anterior medial preoptic area, the medial preoptic area, the medial amygdala nucleus, and the ventromedial nucleus of hypothalamus, all regions rich in estradiol-concentrating cells. This increase peaked between 12-48 h (depending on the region) after estradiol administration and was not observed in several areas with a lower density of estradiol-concentrating cells. In the most affected region, the anterior medial preoptic area, estradiol effects were dose dependent and not altered by progesterone administration. It is not yet clear whether estradiol induces c-fos expression in brain directly or whether c-fos is part of a cascade of mechanisms by which estradiol regulates gene expression.
The ability of a wide variety of pharmacological and physiological stimuli to increase neuronal expression of Fos has led to the suggestion that it might serve as a marker of neuronal activation. Psychomotor stimulants increase the release of dopamine from the terminals of nigrostriatal and mesolimbic neurons and enhance Fos immunoreactivity in the striatum and nucleus accumbens (NAc). Because sexual behavior also increases dopamine release in these and other forebrain regions, the present study examined the effect of copulation on Fos immunoreactivity in the forebrain of intact, sexually active male rats. Sexual behavior produced a striking increase in Fos immunoreactivity in the medial preoptic area (MPOA), NAc, bed nucleus of the stria terminalis and piriform cortex. However, no increase in Fos immunoreactivity was observed in the striatum. These results are consistent with neurochemical, physiological, and behavioral data suggesting that the MPOA and NAc are important substrates of sexual behavior.
The ventral mesencephalon appears to be one of the sites of progesterone action in the control of sexual receptivity in female hamsters. The behavioral response to systemic progesterone was assessed in female hamsters following electrolytic lesions of portions of the ventral mesencephalon. Adult female hamsters were ovariectomized and pretested for sexual receptivity, then were given bilateral lesions aimed at the region of the ventral mesencephalon where progesterone implants have been shown to facilitate receptivity. Lesions were produced by stereotaxically lowering an electrode and applying anodal direct current of 1-2 mA for 5-20 seconds. One week later the hamsters were injected with estrogen followed 44 h later by progesterone. They were then tested for sexual receptivity. After this test, their brains were removed and histologically prepared. Lesion location was determined and lesion size was quantified with a digitizing pad. Lesions which were centered in and destroyed much of the ventral tegmental area produced the greatest lordosis impairments. Mesencephalic lesions which did not bilaterally damage the ventral tegmental area had little effect. These results support the hypothesis that the ventral mesencephalon, particularly the ventral tegmental area, is an important site for the facilitative action of progesterone on sexual receptivity in estrogen-primed female hamsters.
Central dopamine transmission was examined in the nucleus accumbens and striatum of sexually experienced male rats during mating behaviour using in vivo brain microdialysis. Dopamine release increased significantly in the nucleus accumbens when males were placed in a novel mating chamber and when a receptive female was introduced behind a screen partitioning this chamber. Subsequently, during copulation dopamine transmission increased sharply, this being followed by a gradual decrease after the female was removed. In contrast, striatal dopamine transmission increased significantly only during copulation. These data provide a neurochemical basis for the well-known interactions between dopaminergic drugs and male sexual behaviour and demonstrate the feasibility of using brain microdialysis to elucidate the neurochemical correlates of motivated behaviour.
Experiments investigating the neural mechanisms underlying the expression of masculine sexual behaviour are discussed in the context of the hypothesis set out by Frank Beach that suggested the existence of separate sexual arousal and performance mechanisms. The results indicate that the medial preoptic area is crucially involved in consummatory aspects of sexual behaviour: lesions and chemical manipulations of the area profoundly affect mounts, intromissions and ejaculation, but tend not to alter appetitive sexual responses. By contrast, ventral striatal dopamine-dependent mechanisms primarily affect appetitive sexual responses, measured in a variety of paradigms, but tend not to alter copulatory behaviour itself. Finally, associative mechanisms, for example those by which arbitrary environmental stimuli come to control appetitive sexual responses through their predictive association with sexual reinforcement, are shown to depend at least in part on interactions between the basolateral amygdala and dopamine-dependent events in the ventral striatum. Thus, diverse neural and behavioural procedures have revealed that separable neural mechanisms appear to be involved more or less selectively with different components of the male rat's sexual response system. It may still be useful to conceptualize separate sexual arousal and intromission/ejaculatory mechanisms when studying the neuroendocrine basis of sexual behaviour. However, a major challenge is to understand the way in which elements of the telencephalic limbic system, the striatum and preoptic area, some of which are targets for the action of sex steroids, interact to produce an integrated pattern of sexual behaviour.
Intracranial implantation experiments have shown that the ventromedial hypothalamus (VMH) is the most sensitive site for the facilitation of female sexual behavior by progesterone in estrogen-primed rats. However, similar implantation techniques have been much less successful in hamsters. Several lines of evidence indicate that both hypothalamic and midbrain structures are important for hamster lordosis. Therefore we compared the effect of progesterone (P) implants administered simultaneously to VMH and ventral midbrain on opposite sides of the brain to the effects of bilateral implants to each of these sites separately. Ovariectomized female hamsters were stereotaxically implanted with 24-gauge thin-wall guide tubes according to one of five patterns. Bilaterally symmetrical cannulae were aimed at VMH or ventral mesencephalon (vMES) or asymmetrical implants were aimed at one of the following pairs of sites, on opposite sides of the brain: VMH-vMES, VMH-preoptic area (VMH-POA), or anterior hypothalamus-anterior mesencephalon (AH-aMES). After recovery from surgery, females were primed with 10 micrograms estradiol benzoate and given pellets of P or cholesterol through a 30-gauge injector in the targeted sites. Latency, frequency, and duration of lordosis were recorded in 10-min tests with sexually active male hamsters. Sexual receptivity was significantly facilitated by simultaneous contralateral P implants into the VMH-vMES. P implants in any other combination of sites did not significantly facilitate lordosis compared to cholesterol control implants, nor did bilateral administration of this dose of P in either VMH or vMES have a reliable effect. The results support the hypothesis that P action is required in both VMH and vMES to reliably stimulate receptivity in hamsters.
The hypothalamus is known to be critical for the neuroendocrine control of sexual behavior, but the neural effects of gonadal hormones on behavior-related activity of hypothalamic neurons has received little investigation. The present study examined the effects on single hypothalamic neurons of lordosis-inducing estrogen and progesterone administration to behaving golden hamsters. The lordosis-inducing action of the hormones was associated with rapidly emerging, cumulative changes in the activity level and somatosensory responsiveness of neurons throughout the hypothalamus, as well as the appearance in most neurons of lordosis-correlated firing. This functional reconfiguration of hypothalamic neuronal properties resembled, in time course and other aspects, effects of estrogen and progesterone previously observed in hamster midbrain neurons. Although the firing rates of the hypothalamic neurons were typically low, the lordosis-related activity of these neurons was compatible with a role in the control of individual episodes of lordosis as well as a state-related tendency to exhibit the lordosis response.
In the first experiment, ovariectomized female hamsters were stereotaxically implanted with bilateral guide cannulae aimed at the medial preoptic area (POA), ventromedial hypothalamus (VMH), or ventral tegmentum (VTA). The following week these females were injected SC with 10 micrograms estradiol benzoate (EB) and then had 27-gauge cannulae containing crystalline progesterone inserted through the guide tubes. Sexual receptivity was observed in 3 of 11 animals with VMH implants of progesterone, in 2 of 10 with VTA progesterone, but in none with POA implants. In the second experiment, the amount of intracranial progesterone was increased by mechanically expelling a 1.5 micrograms progesterone pellet from the tip of each cannula insert. This treatment facilitated receptivity in 10 of 20 hamsters with VTA implants and in 9 of 32 VMH-implanted animals. This induction of receptivity required approximately 2 hr. Progesterone pellets in the POA, mammillary region, and lateral mesencephalon were generally ineffective. In hamsters, progesterone into either the VMH or the VTA is sufficient to facilitate receptivity, although neither site is highly sensitive to progesterone. These results differ from those in recent studies in rats and this difference may reflect important species differences in the control of lordosis.
Semi-quantitative [14C]2-deoxyglucose (2DG) autoradiography was used to map the neural responses of female hamsters to lordosis-inducing flank stimuli. Specifically, manual stimulation of one flank was used to maintain estrous females in lordosis for 20 min after an IV injection of 200 muCi/kg of 2DG. Hemispheric differences in 2DG uptake then were sought in brain nuclei implicated in the programming of lordosis, or in the mediation of somatosensory or hormonal influences on this response. The responses to lateralized flank stimulation included reliable contralateral elevations in 2DG uptake in the ventral posterior lateral nucleus of the thalamus (VPL), the dorsal mesencephalic central gray (dCG), and the tectum. Elevated activity on the part of the VPL may not be crucial for lordosis. However, the effects of flank stimulation on 2DG uptake by the dCG and tectum confirm and extend much previous evidence implicating the dorsal midbrain in the mediation of tactile and hormonal effects on sexual responses. For example, these results suggest that somatosensory influences on hamster lordosis are mediated by both the dCG and tectum. In addition, they suggest that these influences are strongly lateralized until at least this stage of sensory processing, leaving for some subsequent element of neural circuitry the task of translating these lateralized inputs into the bilaterally symmetric outputs ultimately required to program the normal, bilaterally symmetric, lordosis response.
Subtypes of dopamine receptors involved in the mechanism of reinforcement were examined. Twenty-five rats were implanted with bipolar electrodes into the ventral tegmental area (VTA) and cannulae into the nucleus accumbens (NAc) or the caudate-putamen complex (CPu). The rats were trained to press a bar to receive VTA stimulation, and dopamine antagonists were injected into the brain while the animals were responding. SCH 23390 (D1-specific antagonist) injected into NAc ipsilateral to the electrode site suppressed responding, but injections into contralateral NAc or ipsilateral CPu had no effect. Haloperidol was less effective. Sulpiride (D2-specific antagonist) produced no effect when injected into NAc, though slightly suppressed responding when injected into CPu. The animals that have reduced their response rate after accumbens injection of SCH 23390 responded at a normal rate when the frequency of pulses in the tegmental stimulation was increased, indicating that they were not incapacitated by the D1 antagonist. These findings suggest that dopamine D1 receptors in the nucleus accumbens are critically involved in the reinforcement produced by ventral tegmental stimulation.
A dramatic and specific induction of c-fos was observed in identifiable neuronal populations in vivo after administration of the convulsant Metrazole. This effect was time- and dose-dependent and was abolished by prior treatment with the anticonvulsant drugs diazepam or pentobarbital. About 60 minutes after administration of Metrazole, c-fos messenger RNA reached a maximum and declined to basal levels after 180 minutes. A further decrease below that in normal brain was observed before a return to basal levels after 16 hours. While Metrazole still elicited seizures during this period, reinduction of c-fos was largely refractory. At 90 minutes, c-fos protein was observed in the nuclei of neurons in the dentate gyrus, and in the pyriform and cingulate cortices. Subsequently, c-fos protein appeared throughout the cortex, hippocampus, and limbic system. Thus, seizure activity results in increased c-fos gene expression in particular subsets of neurons.
It has been suggested that the proto-oncogenes c-fos and c-myc participate in the control of genetic events which lead to the establishment of prolonged functional changes in neurons. Expression of c-fos and c-myc are among the earliest genetic events induced in cultured fibroblast and phaeochromocytoma cell lines by various stimuli including growth factors, peptides and the intracellular second messengers diacylglycerol, cAMP and Ca2+. We report here that physiological stimulation of rat primary sensory neurons causes the expression of c-fos-protein-like immunoreactivity in nuclei of postsynaptic neurons of the dorsal horn of the spinal cord. Activation of small-diameter cutaneous sensory afferents by noxious heat or chemical stimuli results in the rapid appearance of c-fos-protein-like immunoreactivity in the superficial layers of the dorsal horn. However, activation of low-threshold cutaneous afferents results in fewer labelled cells with a different laminar distribution. No c-fos induction was seen in the dorsal root ganglia, gracile nucleus or ventral horn. Thus, synaptic transmission may induce rapid changes in gene expression in certain postsynaptic neurons.
The proto-oncogene c-fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters.
In order to determine whether the c-fos protein (Fos) and Fos-related proteins can be induced in response to polysynaptic
activation, rat hindlimb motor/sensory cortex was stimulated electrically and Fos expression examined immunohistochemically.
Three hours after the onset of stimulation, focal nuclear Fos staining was seen in motor and sensory thalamus, pontine nuclei,
globus pallidus, and cerebellum. Moreover, 24-hour water deprivation resulted in Fos expression in paraventricular and supraoptic
nuclei. Fos immunohistochemistry therefore provides a cellular method to label polysynaptically activated neurons and thereby
map functional pathways.
Dual ipsilateral, contralateral and bilateral 28-gauge estradiol (E2) filled cannulae were implanted in the medial preoptic area (MPO) and ventromedial hypothalamus (VMH) of ovariectomized female golden hamsters housed in large arenas with male partners. Twenty-four hours after implantation, vaginal scent-marking patterns were significantly and equally elevated in all groups. Forty-four hours after implantation, progesterone was administered and females were tested for sexual receptivity 4-5 h later. Bilateral E2 implants in the VMH as well as dual ipsilateral and contralateral MPO-VMH implants were significantly more likely to facilitate sexual responsiveness than bilateral MPO implants. More importantly, ipsilateral MPO-VMH implants produced significantly longer lordosis duration scores than bilateral VMH and contralateral MPO-VMH implants. After mating, females with bilateral MPO implants attacked their mates more frequently than females with bilateral VMH and dual MPO-VMH implants. Taken together, results suggest that: (1) although MPO and VMH regions are equally sensitive to the vaginal marking promoting effects of E2, these same regions require synergistic ipsilateral activation for the effective priming of sexual responsiveness; (2) the heightened duration of lordosis behavior after ipsilateral MPO-VMH E2 implantation may reflect an anterior diencephalic estrogenic removal of an inhibitory process occurring primarily in the ipsilateral VMH region; and (3) the difference in postcopulatory attacks may reflect variable actions of progesterone on E2-induced progestin receptors in the MPO and VMH.
Ovariectomized female hamsters received small unilateral implants of estradiol at a variety of anterior-posterior levels of the medial preoptic area and hypothalamus. The results of an initial experiment using 27-ga. implants showed that females with estradiol implants in the ventromedial hypothalamus (VMN) or nearby anterior hypothalamus consistently showed higher levels of sexual receptivity than did females with implants farther rostral, in the preoptic area, or farther caudal, in the posterior hypothalamus. A second experiment used smaller, 28-ga. implants to compare directly the two areas at which implants were effective in the first experiment. The results confirm the findings of other recent studies of hamsters and rats by identifying the VMN as the most effective hypothalamic site for the estrogen priming of sexual receptivity.
Ovariectomized female hamsters received unilateral implants of estradiol aimed at the mesencephalic central gray (MCG). Postoperative levels of lordosis and ultrasonic vocalization were used to evaluate implant effects on sexual receptivity and proceptivity. Females with large MCG implants showed higher levels of receptivity than females with similar implants at control sites. In addition, females with small MCG implants showed little receptivity while the implant served as the sole source of estrogen, but diverged from controls by showing elevated receptivity during supplemental treatment with low systemic doses of estradiol. These results suggest that estradiol implants in the MCG facilitate receptivity if, and only if, accompanied by exposure of other brain areas to low estrogen levels. In turn, this suggests that the MCG, though not a self-sufficient site for the hormonal priming of lordosis, does modulate sexual motivation by mediating facilitatory effects of estrogen on receptivity and mating.
Lordosis responses in naturally-estrous hamsters were elicited by unilateral manual stimulation. Response latencies were compared before and after unilateral lesions of medial and lateral tegmental areas located ventral and ventrolateral, respectively, to the midbrain central gray. The only significant effects were produced by the more lateral lesions. These caused slightly delayed lordosis responses to stimulation of the ipsilateral flank, but had much more pronounced effects on responsiveness to contralateral stimuli, which often entirely failed to elicit lordosis postlesion. This difference in the effectiveness of ipsi- and contralateral stimuli suggests a selective disruption of neural mechanisms involved in the somatosensory control of lordosis initiation. Its locus suggests that a similar mechanism previously identified in the hamster tectum extends ventrally into the dorsal tegmentum, where it overlaps areas implicated in the sensory control of lordosis in other rodents. Since unilateral lesions of the dorsomedial tegmentum failed to affect behavior, a second experiment tested the effects of bilateral medial lesions on male-stimulated lordosis responses in ovariectomized, hormone-primed hamsters. These lesions caused significant increases in body weight, but again failed to show direct effects on lordosis. This result helps to delimit a ventral tegmental system previously implicated in the control of lordosis maintenance in hamsters. In addition, it suggests species differences in the brain circuits involved in the motor control of lordosis.
Diencephalic and mesencephalic neural sites regulating the biphasic effect of progesterone (P) were investigated using the hormone implantation technique in ovariectomized female golden hamsters primed with estrogen. Double barreled cannulae were implanted unilaterally and bilaterally in the medial preoptic area, anterior hypothalamus, ventromedial hypothalamus (VMH), central gray, or interpeduncular nucleus. Testing was conducted using a sequential paradigm; facilitation tests commenced after 44 h of estrogen priming. P-filled cannulae placed in the VMH region facilitated lordosis behavior in 42% and 60% of unilaterally and bilaterally implanted females, respectively. In the anterior hypothalamus, only P implants adjacent to the VMH area effectively promoted receptivity. Lordosis behavior was also observed in 20-36% of females with P implants in the medial preoptic area. P implants in central gray and interpeduncular nucleus regions had no significant facilitating effect on sexual behavior. Tests for inhibition occurred 24 h after facilitation testing and consisted of a pretest, followed by systemic P administration and a behavioral test 4-5 h later. During the pretest for inhibition, females that were receptive in the facilitation test attacked males more rapidly than previously nonreceptive animals and showed decrements in lordosis scores after systemic P delivery. This biphasic effect of P completely inhibited receptivity among several animals in the VMH group. Additional experiments, however, investigating the biphasic effect of P implants in the VMH suggested that the occurrence of copulation in the facilitation test may have been involved in mediating the subsequent increase in aggressive behavior and the suppression of sexual responsiveness in the inhibition test. Nevertheless, a final experiment showed that when P was implanted sequentially in the VMH, facilitation and, more importantly, a later reduction in lordosis behavioral scores occurred even when copulation was eliminated in the facilitation test. P implants in mesencephalic regions exerted no significant inhibitory effect on receptivity. These findings demonstrate that the biphasic action of P in the female hamster is regulated by nerve cells located in the diencephalon, especially in the VMH region.
Changes in heterosexual patterns of agonistic, marking, and sexual behavior were examined in female hamsters over a three day period following implantation of either estrogen or cholesterol in the hypothalamus. Animals were habituated to large arenas that permit the display of a wide range of behavior. Estrogen implants located in the ventromedial (VMH) but not the anterior (AH) portion of the hypothalamus were effective in facilitating the occurrence of vaginal marking, over a two day estrogen priming period. During this two day period, the exhibition of agonistic behavioral patterns declined significantly. Systemic administration of progesterone elicited sexual receptivity in 75% of the females in the VMH group, in contrast to only 25% in the AH group. Females with hypothalamic implants of cholesterol remained unreceptive following progesterone injections. The results provide important information on the estrogen sites of action at the hypothalamus in mediating heterosexual interactions.
Diencephalic sites of action of progesterone (P) responsible for inhibiting aggression and facilitating sexual receptivity were examined in ovariectomized golden hamsters primed with Silastic capsules of estradiol. P was applied centrally by inserting a hormone-filled, 27-gauge cannula into a 22-gauge guide cannula that was implanted unilaterally in the medial preoptic area (MPO), the anterior hypothalamus (AH), or the ventromedial hypothalamus (VMH). Control implants consisted of cholesterol-filled cannulae placed within the same regions of the brain. Tests for sexual and aggressive behavior occurred 1, 2, 4, and 6 h after hormone implantation by introducing a sexually experienced male into the home cage of the female. Nine of 20 females with P in the VMH exhibited lordosis in comparison to 1 of 12 females in the MPO group and 5 of 16 animals in the AH group. The induction of sexual responsiveness after P implantation in the VMH was further demonstrated in 6 of 11 ovariectomized-adrenalectomized females, indicating that the observed receptivity was not contingent upon activation of the hypothalamic-pituitary-adrenal axis. In addition to the receptive promoting action of P in the VMH, P implantation in the MPO and VMH but not in AH regions was highly effective in inhibiting female biting attacks upon males. In summary, these findings indicate that P can both facilitate sexual receptivity and inhibit aggressive behavior and that P induces these changes in behavior at different locations in the diencephalon.
Previously, we found that single implants of estradiol (E2) placed in the ventromedial hypothalamus (VMH) but not the anterior hypothalamus (AH) facilitated precopulatory, i.e. vaginal scent marking, and copulatory, i.e. lordosis, behavior following progesterone administration. However, the duration of lordosis was markedly attenuated in comparison to the duration shown by intact cycling females. This study was designed to examine whether dual implantation of E2 in the diencephalon would facilitate patterns of precopulatory and copulatory behaviors similar to those shown by intact cycling females. One E2 implant was placed in either the medial preoptic area (MPO) or AH and a second E2 implant was placed in the VMH. Control females were tested following E2 application at only the MPO or AH region in conjunction with a cholesterol implant in the VMH. An additional control group was tested with females implanted with cholesterol at both MPO-AH regions and the VMH. During a 2-day postimplantation test period, vaginal marking scores were elevated for both single and dual E2 implanted females and agonistic response patterns toward males declined significantly. In addition, a significant inverse relationship was found between the number of vaginal marks and bites exhibited by females with single E2 implants in the MPO, whereas these two response patterns were positively correlated in females with E2 stimulation occurring only in the AH region. No significant relationship was found between vaginal marking and biting attack for females receiving dual E2 stimulation. Systemic progesterone administration on the third postimplantation day facilitated sexual receptivity in the majority of females with dual E2 implants (greater than 90%). These receptive females displayed lordotic responsiveness that closely matches the full display of sexual receptivity shown by intact cycling females. In contrast, only one female with a single E2 implant in the AH region showed sexual responsiveness. The results demonstrate that: precopulatory vaginal marking and biting attack are mediated by E2 action in the MPO and AH but in a different manner; additional action of E2 in the VMH diminishes the distinctive precopulatory behavioral effects of E2 in the MPO and AH suggesting an influential role of the VMH in regulating sociosexual activities; and E2 action in either the MPO or AH region in conjunction with E2 action in the VMH may be necessary in order to facilitate the species-typical display of lordotic responsiveness.
Following a period of estrogen priming, the spayeds hamster displays normal estrous behavior within 2–3 h after subcutaneous placement of progesterone. To determine the locus of the estrogen priming effect, a single midline implant of estradiol, fused within the lumen of a 27 or 23 gauge hypodermic tube, was stereotaxically implanted into various sites of the hypothalamus of females which had been spayed 9 days. At the time of lights out on the 3rd and on the 7th day following implantation, all females were injected with 200 μg of progesterone in 0.1 cm3 of propylene glycol. Females were tested for estrous behavior by placing them with experienced males for a period of 10 min prior to progesterone injection, and at 90 min, 2, 3, 4, 6 and 10 h thereafter. A 23 gauge estradiol implant provides a sufficient priming treatment if the hormone is placed in the anterior dorsal hypothalamus in an area including: the dorsal half of the anterior hypothalamic area, the ventral third of the filiform nucleus, and the area anterior to the dorsomedial nucleus; extending 0.5 mm laterally and 1.5 mm in the anterior-posterior plane and 1.0 mm in the dorsal-ventral plane. Implants containing radioactive estradiol indicated that the hormone did not diffuse to other areas of the hypothalamus. A 23 gauge estradiol tube was ineffective if implanted into other areas of the hypothalamus or if placed subcutaneously. A 27 gauge estradiol implant into the sensitive area did not constitute a sufficient priming treatment.Copyright © 1974 S. Karger AG, Basel