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Aggressive Experience Increases Dendritic Spine Density within the Nucleus Accumbens Core in Female Syrian Hamsters
Abstract
Activity within the mesolimbic dopamine system is associated with the performance of naturally motivated behaviors, one of which is aggression. In male rats, aggressive behavior induces neurochemical changes within the nucleus accumbens, a key structure within the mesolimbic dopamine system. Corresponding studies have not been done in females. Female Syrian hamsters live as isolates and when not sexually responsive are aggressive toward either male or female intruders, making them an excellent model for studying aggression in females. We took advantage of this naturally expressed behavior to examine the effects of repeated aggressive experience on the morphology of medium spiny neurons in the nucleus accumbens and caudate nucleus, utilizing a DiOlistic labeling approach. We found that repeated aggressive experience significantly increased spine density within the nucleus accumbens core, with no significant changes in any other brain region examined. At the same time, significant changes in spine morphology were observed in all brain regions following repeated aggressive experience. These data are significant in that they demonstrate that repeated exposure to behaviors that form part of an animal's life history will alter neuronal structure in a way that may shift neurobiological responses to impact future social interactions.
... The winner effect has been extensively documented in male rodents, and although the number of encounters and the behavioral output (number of attacks, attack latency, and the percentage of time spent on aggression) may differ across studies, one thing is certain the successive winning and/or exposition to aggression increases the promptness of an animal to attack as well as the probability of winning (De Almeida et al. 2005;Miczek et al. 2013;Nordman et al. 2020;Oyegbile and Marler 2005;Staffend and Meisel 2012;Stagkourakis et al. 2020;Veenema et al. 2010). Importantly, only a few studies have attempted to describe how fighting experience and subsequent winning may affect aggressive behavior and neurobiology in females (Been et al. 2016(Been et al. , 2019Oliveira and Bakker 2022;Oliveira et al. 2021;Silva et al. 2010). ...
... F. Yang et al. 2013). Additionally, other studies have investigated how winning experiences affect plasticity in the NAcc of female hamsters (Been et al. 2016(Been et al. , 2019Staffend and Meisel 2012) and neuropeptide release in rats (Oliveira and Bakker 2022;Oliveira et al. 2021). ...
... In hamsters, successive winning experience was associated with escalated aggression (shorter attack latencies and higher number of attacks), those behavioral changes were accompanied by increased dendritic spines density in the NAcc (Staffend and Meisel 2012). The molecular mechanism underlying those morphological changes was further dissected in females. ...
... The winner effect has been extensively documented in male rodents, and although the number of encounters and the behavioral output (number of attacks, attack latency, and the percentage of time spent on aggression) may differ across studies, one thing is certain the successive winning and/or exposition to aggression increases the promptness of an animal to attack as well as the probability of winning (De Almeida et al. 2005;Miczek et al. 2013;Nordman et al. 2020;Oyegbile and Marler 2005;Staffend and Meisel 2012;Stagkourakis et al. 2020;Veenema et al. 2010). Importantly, only a few studies have attempted to describe how fighting experience and subsequent winning may affect aggressive behavior and neurobiology in females (Been et al. 2016(Been et al. , 2019Oliveira and Bakker 2022;Oliveira et al. 2021;Silva et al. 2010). ...
... F. Yang et al. 2013). Additionally, other studies have investigated how winning experiences affect plasticity in the NAcc of female hamsters (Been et al. 2016(Been et al. , 2019Staffend and Meisel 2012) and neuropeptide release in rats (Oliveira and Bakker 2022;Oliveira et al. 2021). ...
... In hamsters, successive winning experience was associated with escalated aggression (shorter attack latencies and higher number of attacks), those behavioral changes were accompanied by increased dendritic spines density in the NAcc (Staffend and Meisel 2012). The molecular mechanism underlying those morphological changes was further dissected in females. ...
Rodent models have been extensively used to study the neural underpinnings of aggression. Yet, the role of some external factors such as social experiences, or internal factors such as biological sex, have only recently gained attention. This chapter discusses how the composition of the social environment and/or the lack of social contact (social isolation) in different stages of development impact the display of aggressive behavior in rodents. Additionally, this chapter covers how biological sex interacts with changes in the composition of the social environment to affect the neuronal networks of aggression. From a neurobiological point of view, this chapter focuses particularly on the participation of neuroendocrine systems such as sex hormones, oxytocin, and vasopressin and on how social interactions shape brain plasticity within those systems.
... Aggressive interactions in female hamsters result in neuroplastic changes within the nucleus accumbens (NAc). These include long-term increases in mushroom-like dendritic spines on medium spiny neurons (MSNs) and an increase in postsynaptic density protein 95 (PSD-95), metabotropic glutamate receptor 5 (mGluR5), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) protein [9,11]. The activation of mGluR5 is required for both the increase in the expression of PSD-95 and the decrease in the latency to display aggression resulting from recurring aggressive interactions [10]. ...
... Aggressive interactions in female hamsters result in neuroplastic changes within the nucleus accumbens (NAc). These include long-term increases in mushroom-like dendritic spines on medium spiny neurons (MSNs) and an increase in postsynaptic density protein 95 (PSD-95), metabotropic glutamate receptor 5 (mGluR5), and α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) protein [9,11]. The activation of mGluR5 is required for both the increase in the expression of PSD-95 and the decrease in the latency to display aggression resulting from recurring aggressive interactions [10]. ...
... Thus, the transient increase in the phosphorylation of ERK1/2 in the nucleus accumbens and the decrease in the phosphorylation of mTOR in the medial prefrontal cortex may underlie the translational changes in these reward brain regions that drive the longterm morphological (mushroom-like spines) and thus electrical (glutamate release, PSD-95, mGluR5 and AMPARs) adaptations underlying aggressive experience [9][10][11]. Finally, these synaptic changes mediate the rewarding consequences of aggressive interactions and thus the corresponding decrease in the latency to display aggression with aggressive experience, i.e., the behavioral adaptations of reward encoding, in future encounters. ...
Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.
... These relationships can serve as a buffer to stress (Morrison et al., 2014;Smith and Wang, 2014) and reduce susceptibility to psychiatric and addictive disorders (Bodenmann and Randall, 2013;Nagy and Moore, 2017;Fett et al., 2019). Social interactions come in a variety of forms, including affiliation, aggression, parental and sexual behaviors, each with distinct molecular signatures (Young and Wang, 2004;Shahrokh et al., 2010;Albers, 2012;Staffend and Meisel, 2012;Staffend et al., 2014;Bredewold et al., 2015); yet due to the false belief that aggression is not a part of the normal repertoire of social behaviors displayed by females (Buss, 1961;Blanchard et al., 1988;Albers et al., 2002;Björkqvist, 2018), very little is known about the neural mechanisms mediating aggression in this sex . ...
... Changes in the electrical transmission of neurons in this region underlie reward processing (Schultz et al., 1997;Kourrich et al., 2007). Using female Syrian hamsters, a well validated animal model for studying aggression in this sex (Drickamer and Vandenbergh, 1973), our lab recently showed that aggressive experience results in an increase of mature mushroom-like head dendritic spines on NAc medium spiny neurons (MSNs) (Staffend and Meisel, 2012). Although the molecular and physiological mechanisms mediating these postsynaptic changes are unknown, follow-up studies from our lab suggest PSD-95 and mGluR5 play a functional role in this synaptic structural plasticity (Peterson et al., 2015;Been et al., 2016;Gross et al., 2016). ...
... Coronal sections (approximately 1 -2 mm) containing the NAc, caudate putamen (CPu) and medial prefrontal cortex (PFC) were taken with the aid of a brain matrix and bilateral tissue punches (1 mm diameter) were immediately collected from each area. NAc punches included the anterior commissure to bias the punches toward the NAc core, where we have previously found increases in dendritic spine density following aggressive experience (Staffend and Meisel, 2012). Dorsal medial CPu punches were taken to evaluate the regional specificity of the biochemical changes within the striatum following aggressive experience. ...
Our social relationships determine our health and well-being. In rodent models, there is now strong support for the rewarding properties of aggressive or assertive behaviors to be critical for the expression and development of adaptive social relationships, buffering from stress and protecting from the development of psychiatric disorders such as depression. However, due to the false belief that aggression is not a part of the normal repertoire of social behaviors displayed by females, almost nothing is known about the neural mechanisms mediating the rewarding properties of aggression in half the population. In the following study, using Syrian hamsters as a well-validated and translational model of female aggression, we investigated the effects of aggressive experience on the expression of markers of postsynaptic structure (PSD-95, Caskin I) and excitatory synaptic transmission (GluA1, GluA2, GluA4, NR2A, NR2B, mGluR1a, and mGluR5) in the nucleus accumbens (NAc), caudate putamen and prefrontal cortex. Aggressive experience resulted in an increase in PSD-95, GluA1 and the dimer form of mGluR5 specifically in the NAc 24 h following aggressive experience. There was also an increase in the dimer form of mGluR1a 1 week following aggressive experience. Aggressive experience also resulted in an increase in the strength of the association between these postsynaptic proteins and glutamate receptors, supporting a common mechanism of action. In addition, 1 week following aggressive experience there was a positive correlation between the monomer of mGluR5 and multiple AMPAR and NMDAR subunits. In conclusion, we provide evidence that aggressive experience in females results in an increase in the expression of postsynaptic density, AMPARs and group I metabotropic glutamate receptors, and an increase in the strength of the association between postsynaptic proteins and glutamate receptors. This suggests that aggressive experience may result in an increase in excitatory synaptic transmission in the NAc, potentially encoding the rewarding and behavioral effects of aggressive interactions.
... In the most widely studied rodent species (domestic mice and rats), maternal aggression is the main form of aggression in females. However, in other rodent species such as Syrian hamsters intrafemale aggression is more prevalent (Gutzler et al., 2010;Staffend and Meisel, 2012), which provides opportunities for examining neuroendocrine mechanism of female aggression outside of the context of reproduction. Another type of agonistic behavior commonly studied in the laboratory has been called fear-induced aggression, but this is more correctly termed 'defense' and is not strongly modulated by estrogens or androgens (Blanchard and Blanchard, 1989). ...
... However, femalefemale aggression is quite prevalent in other species. The Syrian hamster is a solitary species, and females are very aggressive toward other females (Solomon et al., 2007;Staffend and Meisel, 2012). In the California mouse, males and females form monogamous pairs, and females are also very aggressive toward other females (Davis and Marler, 2004;Silva et al., 2010;Trainor et al., 2010b). ...
... Interestingly, these motivational circuits are also altered by aggressive experience in female rodents. Female Syrian hamsters also become very aggressive with repeated aggressive encounters (Staffend and Meisel, 2012), and this behavioral change is mediated in part by glutamatergic synaptic plasticity in the nucleus accumbens (Been et al., 2016). ...
Aggressive behaviors range from lethal to subtle and typically arise whenever the interests of two or more individuals conflict. The relationship between the testes and aggression has been known since antiquity, but the relationship between testosterone and such behavior has some surprising twists. We review interactions between aggression, hormones, receptors, and brain structures in mammals. We examine the ontogeny of aggressive behavior and how hormones and experience shape the trajectory of adult sex differences in aggression. We compare rodent models with data on human aggression with the goal of emphasizing where further research is needed to understand pathological aggression.
... Using Syrian hamsters as our animal model, we have studied the neurobiology of aggression in females. In female hamsters, repeated aggressive experience leads to an escalated aggressive response to future encounters that is primarily manifested as a decrease in attack latency across repeated trials [12], modeling the short fuse seen in impulsive aggressive behavior. Escalated aggression in female hamsters is also coupled with an increase in mature dendritic spines on medium spiny neurons of the NAc core [12]. ...
... In female hamsters, repeated aggressive experience leads to an escalated aggressive response to future encounters that is primarily manifested as a decrease in attack latency across repeated trials [12], modeling the short fuse seen in impulsive aggressive behavior. Escalated aggression in female hamsters is also coupled with an increase in mature dendritic spines on medium spiny neurons of the NAc core [12]. This structural plasticity in the NAc presumably represents an increase in excitatory inputs [13] that could mediate a heightened response to future activation [14]. ...
... Coronal sections containing the NAc and caudate putamen (CP) were taken and bilateral tissue punches (1-mm diameter) were immediately collected from each area. NAc punches included the anterior commissure to bias the punches toward the NAc core, where we found increases in dendritic spine density following aggressive experience [12]. Dorsal medial CP punches were taken to evaluate the regional specificity of the biochemical changes within the striatum following aggressive experience. ...
Background:
Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on nucleus accumbens (NAc) neurons. We hypothesized that the activation of group I metabotropic glutamate receptor signaling though the fragile X mental retardation protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation.
Methods:
Female hamsters were given five daily aggression tests with or without prior treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)-pyridine. Following aggression testing, messenger RNA expression and protein levels were measured in the nucleus accumbens for postsynaptic density protein 95 (PSD-95) and SAP90/PSD-95-associated protein 3, as well as the levels of phosphorylated FMRP.
Results:
Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc, which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins PSD-95 and SAP90/PSD-95-associated protein 3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor.
Conclusions:
Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathologic aggression in both female and male subjects.
... When female hamsters are given brief repeated encounters with a non-aggressive intruder, their aggressive behavior escalates such that the onset of aggressive behavior is faster in future encounters, even in the absence of recent aggressive experience. This type of aggression escalation is marked by increased dendritic spine density in the nucleus accumbens (Staffend and Meisel, 2012). In contrast, female hamsters who experience repeated defeats show a long-term decrease in aggressive behavior, a phenomenon known as conditioned defeat (Huhman et al., 2003;Potegal et al., 1993). ...
... Across repeated days, females show a decrease in attack latency, indicating an experience-dependent escalation of aggression. This form of aggression is associated with increased dendritic spine density on medium spiny neurons in the nucleus accumbens (NAc) (Staffend and Meisel, 2012). Using a combination of pharmacology and molecular biology, it was demonstrated that this experiencedependent structural plasticity relies on mGluR5 receptors in the NAc, which regulate the Fragile X Mental Retardation Protein (FMRP) signaling pathway (See Fig. 2). ...
Although many people think of aggression as a negative or undesirable emotion, it is a normal part of many species’ repertoire of social behaviors. Purposeful and controlled aggression can be adaptive in that it warns other individuals of perceived breaches in social contracts with the goal of dispersing conflict before it escalates into violence. Aggression becomes maladaptive, however, when it escalates inappropriately or impulsively into violence. Despite ample data demonstrating that impulsive aggression and violence occurs in both men and women, aggression has historically been considered a uniquely masculine trait. As a result, the vast majority of studies attempting to model social aggression in animals, particularly those aimed at understanding the neural underpinnings of aggression, have been conducted in male rodents. In this review, we summarize the state of the literature on the neurobiology of social aggression in female rodents, including social context, hormonal regulation and neural sites of aggression regulation. Our goal is to put historical research in the context of new research, emphasizing studies using ecologically valid methods and modern sophisticated techniques.
This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’.
... Plasticity in the striatum, like many areas of the brain, is critical for adaptive responses to environmental stimuli at the molecular, cellular, and behavioral levels. Motivated behaviors, such as sex (Meisel & Mullins, 2006, Pitchers et al., 2010b, Wallace et al., 2008, aggression (Couppis & Kennedy, 2008, Staffend & Meisel, 2012, and wheel running (Greenwood et al., 2011, Vargas-Perez et al., 2003, Werme et al., 2002, as well as chronic exposure to drugs of abuse (Chen et al., 2010, Robinson & Kolb, 2004, Russo et al., 2010, result in activation of the mesolimbic dopamine system and long-lasting changes in the nucleus accumbens (NAc). Structural changes, particularly the formation of dendritic spines, are important components of this experience-based plasticity, which persists long after the motivated behavior or drug administration has ceased (Meisel & Mullins, 2006, Pitchers et al., 2010b, Robinson & Kolb, 2004. ...
... The ability of corecentered injections of ΔJunD to mitigate the rewarding consequences of sexual experience as measured in a conditioned place preference task is in agreement with previous research in our laboratory demonstrating that sexual experience increases c-Fos (Bradley & Meisel, 2001) and FosB expression (Meisel & Mullins, 2006) specifically within the NAc core. In addition, sexual experience (Meisel & Mullins, 2006) and another naturally rewarding behavior, aggressive experience (Staffend & Meisel, 2012), both increase dendritic spine density exclusively within the NAc core. Furthermore, the neural circuitry mediating the behavioral response to natural (e.g., sexual behavior) or synthetic (e.g., experience with drugs of abuse) rewards likely overlaps substantially, and recent evidence suggests that the NAc core may be particularly important for conditioning to social stimuli. ...
Motivated behaviors, including sexual experience, activate the mesolimbic dopamine system and produce long-lasting molecular and structural changes in the nucleus accumbens. The transcription factor ΔFosB is hypothesized to partly mediate this experience-dependent plasticity. Previous research in our laboratory has demonstrated that overexpressing ΔFosB in the nucleus accumbens of female Syrian hamsters augments the ability of sexual experience to cause the formation of a conditioned place preference. It is unknown, however, whether ΔFosB-mediated transcription in the nucleus accumbens is required for the behavioral consequences of sexual reward. We therefore used an adeno-associated virus to overexpress ΔJunD, a dominant negative binding partner of ΔFosB that decreases ΔFosB-mediated transcription by competitively heterodimerizing with ΔFosB before binding at promotor regions on target genes, in the nucleus accumbens. We found that overexpression of ΔJunD prevented the formation of a conditioned place preference following repeated sexual experiences. These data, when coupled with our previous findings, suggest that ∆FosB is both necessary and sufficient for behavioral plasticity following sexual experience. Furthermore, these results contribute to an important and growing body of literature demonstrating the necessity of endogenous ΔFosB expression in the nucleus accumbens for adaptive responding to naturally rewarding stimuli.
... Expression of the transcription factor FosB, known to be involved in reward-related behavioral change, is elevated in NAc D1-expressing cells after aggressive experience in male mice (Aleyasin et al., 2018). It is also the case that the increased NAc dendritic spine density after aggressive experience in female hamsters is specific to the NAc core (Staffend & Meisel, 2012). With regards to the bedding treatment, a recent study found increased NAc core D2 receptor immunoreactivity in adult male rats exposed to a Limited Bedding & Nesting paradigm (Laguna et al., 2022), while we found no change in NAc core D2 mRNA in our limited-bedding males. ...
Despite early‐life disadvantage (ELD) in humans being a highly heterogenous construct, it consistently predicts negative neurobehavioral outcomes. The numerous environmental contributors and neural mechanisms underlying ELD remain unclear, though. We used a laboratory rat model to evaluate the effects of limited resources and/or heavy metal exposure on mothers and their adult male and female offspring. Dams and litters were chronically exposed to restricted (1‐cm deep) or ample (4‐cm deep) home cage bedding postpartum, with or without lead acetate (0.1%) in their drinking water from insemination through 1‐week postweaning. Restricted‐bedding mothers showed more pup‐directed behaviors and behavioral fragmentation, while lead‐exposed mothers showed more nestbuilding. Restricted bedding‐raised male offspring showed higher anxiety and aggression. Either restricted bedding or lead exposure impaired goal‐directed performance in a reinforcer devaluation task in females, whereas restricted bedding alone disrupted it in males. Lead exposure, but not limited bedding, also reduced sucrose reward sensitivity in a progressive ratio task in females. D1 and D2 receptor mRNA in the medial prefrontal cortex and nucleus accumbens (NAc) were each affected by the early‐life treatments and differently between the sexes. Most notably, adult males (but not females) exposed to both early‐life treatments had greatly increased D1 receptor mRNA in the NAc core. These results illuminate neural mechanisms through which ELD threatens neurobehavioral development and highlight forebrain dopamine as a factor.
... This escalated aggression appears to be mediated through signaling via the metabotropic glutamate receptor, mGluR5 (Been et al. 2016). The hypothesis of glutamate enhancement of aggression is supported by structural changes in accumbens medium spiny neurons, with aggression promoting an increase in dendritic spine density in female hamsters (Staffend and Meisel 2012). A role for glutamate mediating this structural plasticity comes from observations (Sidorov et al. 2013) that glutamate can signal through mGluR5 receptors to modulate the phosphorylation of fragile X mental retardation protein (FMRP). ...
... Syrian golden hamsters (Mesocricetus auratus; hereafter referred to as hamsters) have been used as an alternative to mice in many disease models (1). They have shown advantages over mice in modelling diseases including diabetes, atherosclerosis, infectious diseases, neurology and cancer (2)(3)(4)(5)(6). The utility of hamsters has been notable in understanding the pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the development of vaccines and therapeutics against COVID-19 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). ...
Introduction
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but preclinical testing of hypotheses such as combination therapies has been complicated, in part due to species incompatibility issues. For example, one of few known permissive animal models for oncolytic adenoviruses is the Syrian hamster, for which an ICI, mainly an anti-PD-L1 monoclonal antibody (mAb) was not previously available. In this study, we developed an anti-Syrian hamster PD-L1 mAb to enable the evaluation of safety and efficacy, when combining anti-PD-L1 with an oncolytic adenovirus encoding tumour necrosis factor alpha (TNFα) and interleukin-2 (IL-2) (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2 or TILT-123).
Methods
Recombinant Syrian hamster PD-L1 was expressed and mice immunized for mAb formation using hybridoma technology. Clonal selection through binding and functional studies in vitro, in silico and in vivo identified anti-PD-L1 clone 11B12-1 as the primary mAb candidate for immunotherapy modelling. The oncolytic virus (OV) and ICI combination approach was then evaluated using 11B12-1 and TILT-123 in a Syrian hamster model of pancreatic ductal adenocarcinoma (PDAC).
Results
Supernatants from hybridoma parent subclone 11B12B4 provided the highest positive PD-L1 signal, on Syrian hamster PBMCs and three cancer cell lines (HT100, HapT1 and HCPC1). In vitro co-cultures revealed superior immune modulated profiles of cell line matched HT100 tumour infiltrating lymphocytes when using subclones of 7G2, 11B12 and 12F1. Epitope binning and epitope prediction using AlphaFold2 and ColabFold revealed two distinct functional epitopes for clone 11B12-1 and 12F1-1. Treatment of Syrian hamsters bearing HapT1 tumours, with 11B12-1 induced significantly better (p<0.05) tumour growth control than isotype control by day 12. 12F1-1 did not induce significant tumour growth control. The combination of 11B12-1 with oncolytic adenovirus TILT-123 improved tumour growth control further, when compared to monotherapy (p<0.05) by day 26.
Conclusions
Novel Syrian hamster anti-PD-L1 clone 11B12-1 induces tumour growth control in a hamster model of PDAC. Combining 11B12-1 with oncolytic adenovirus TILT-123 improves tumour growth control further and demonstrates good safety and toxicity profiles.
... This escalated aggression appears to be mediated through signaling via the metabotropic glutamate receptor, mGluR5 (Been et al. 2016). The hypothesis of glutamate enhancement of aggression is supported by structural changes in accumbens medium spiny neurons, with aggression promoting an increase in dendritic spine density in female hamsters (Staffend and Meisel 2012). A role for glutamate mediating this structural plasticity comes from observations (Sidorov et al. 2013) that glutamate can signal through mGluR5 receptors to modulate the phosphorylation of fragile X mental retardation protein (FMRP). ...
Syrian hamsters are a valuable, if underused, model system for studying the neurobiology of aggression. Male and female hamsters live in fields where they defend territories surrounding their individual burrows. With repeated aggressive experience, hamsters show an escalation of aggression as measured by a reduction in the time to initiate an attack. In contrast, defeated hamsters develop passivity and subordination. Both the escalation of aggression and development of submission activate the mesolimbic system, though through different circuits. Plasticity in the mesolimbic system mediates these changes in behavior, engaging synaptic transmission via both classic neurotransmitters and neuropeptides. At the same time that both male and female hamsters engage in territorial defense and aggression, there are sex differences in the underlying neurobiological control. These characteristics of hamsters make them an ideal model for studying normal and pathological aggression, along with developing therapeutics to treat pathological aggression separately in males and females.
... /2022 neuroplastic changes. Interestingly, acute estradiol treatment decreases dendritic spine density in the NACc, but not NAcSh, in rats (Peterson, Mermelstein, and Meisel 2015) and Syrian hamsters (Staffend and Meisel 2012). The impact of chronic estradiol treatment and/or estrogen withdrawal on NAcC spine density is unknown, but the current results would predict an increase in dendritic spine density following postpartum estrogen withdrawal. ...
In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an estrogen withdrawal state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estrogen withdrawal on several behavioral measures of anxiety and motivation. We found that estrogen withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estrogen withdrawal. In the social motivation test, estrogen withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ΔFosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ΔFosB expression in the nucleus accumbens core. Using transgenic reporter mice, we found that this increase in ΔFosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ΔFosB in the NAc core.
... Recent studies, however, have shown that girls and women exihibit disruptive aggression and can develop aggression disorders similarly to boys and men (Campbell, 1999;Mancke et al., 2015;Denson et al., 2018;Freitag et al., 2018;Ackermann et al., 2019), thereby negatively impacting their own quality of life and of their victims. Furthermore, studies in rodents indicated that females are able to show a considerable amount of aggression (Silva et al., 2010;Staffend and Meisel, 2012;Been et al., 2016Been et al., , 2019Hashikawa et al., 2017;Newman et al., 2019;Oliveira et al., 2019Oliveira et al., , 2021 and that the neurobiological mechanisms regulating aggressive behavior might be sex-dimorphic (Ho et al., 2001;Silva et al., 2010;Cordero and Sandi, 2013;Terranova et al., 2016;Hashikawa et al., 2017Hashikawa et al., , 2018Borland et al., 2019;Newman et al., 2019;Oliveira et al., 2019Oliveira et al., , 2021. Altogether, this highlights the need to learn more about the neurobiology of female aggression in order to identify possible targets of treatment for women and girls. ...
Exacerbated aggression is a high-impact, but poorly understood core symptom of several psychiatric disorders, which can also affect women. Animal models have successfully been employed to unravel the neurobiology of aggression. However, despite increasing evidence for sex-specificity, little is known about aggression in females. Here, we studied the role of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the central amygdala (CeA) on aggressive behavior displayed by virgin female Wistar rats using immunohistochemistry, receptor autoradiography, and neuropharmacology. Our data show that CeA GABAergic neurons are activated after an aggressive encounter in the female intruder test. Additionally, neuronal activity (pERK) negatively correlated with the display of aggression in low-aggressive group-housed females. Binding of OXT receptors, but not AVP-V1a receptors, was increased in the CeA of high-aggressive isolated and trained (IST) females. Finally, local infusion of either synthetic OXT or AVP enhanced aggression in IST females, whereas blockade of either of these receptors did not affect aggressive behavior. Altogether, our data support a moderate role of the CeA in female aggression. Regarding neuropeptide signaling, our findings suggest that synthetic, but not endogenous OXT and AVP modulate aggressive behavior in female Wistar rats.
... Our assessment and statistical analyses of dendritic spine densities is based upon a rigorous approach that we and others have previously used. 8,19,[34][35][36][37] With 9-10 animals/group, this equates to approximately 80-90 dendritic segments (and thousands of spines) per group per brain region. ...
Gonadal hormones affect neuronal morphology to ultimately regulate behavior. In female rats, estradiol mediates spine plasticity in hypothalamic and limbic brain structures, contributing to long‐lasting effects on motivated behavior. Parallel effects of androgens in male rats have not been extensively studied. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA), and medial preoptic nucleus (MPN). Intact and castrated (GDX) male rats were treated with dihydrotestosterone (DHT, 1.5mg) or vehicle (oil) in 3 experimental groups: intact‐oil, GDX‐oil and GDX‐DHT. Spine density and morphology, measured 24 hours after injection, were determined through 3D reconstruction of confocal z‐stacks of DiI‐labeled dendritic segments. We found that GDX decreased spine density in the MPN, which was rescued by DHT treatment. DHT also increased spine density in the MeA in GDX animals compared to intact oil treated animals. In contrast, DHT decreased spine density in the NAcSh compared to GDX males. No effect on spine density was observed in the NAcC or CPu. Spine length and spine head diameter were unaffected by GDX and DHT in the studied brain regions. In addition, immunohistochemistry revealed that DHT treatment of GDX animals rapidly increased the number of cell bodies in the NAcSh positive for pCREB, a downstream messenger of the androgen receptor (AR). These findings indicate that androgen signaling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviors.
... L. Robinson et al., 2001), feeding (Di Chiara et al., 1997), aggression (van Erp & Miczek, 2000), and exercising (Vargas-Pérez, Mena-Segovia, Giordano, & Díaz, 2003;Werme et al., 2002), as well as taking drugs of abuse (Volkow & Morales, 2015) all activate the nucleus accumbens (NAc). Further, repeated experience with motivated behaviors causes long-lasting structural changes in the NAc, including the formation of new dendritic spines on medium spiny neurons (Meisel & Mullins, 2006; T. E. Robinson & Kolb, 2004;Staffend & Meisel, 2012). These structural changes are important because they presumably reflect learning and can influence future behavior. ...
Motivated behaviors share the common feature of activating the mesolimbic dopamine system. Repeated experience with motivated behaviors can cause long-lasting structural changes in the nucleus accumbens (NAc). The molecular mechanisms underlying this experience-dependent plasticity in the NAc have been well described following experience with drugs of abuse. In particular, the transcription factor Delta FosB (ΔFosB) is a key regulator of drug-related neuroplasticity. Fewer studies have examined the molecular mechanisms underlying experience-dependent plasticity in the NAc following naturally motivated behaviors, but previous research has demonstrated that sexual experience increases the accumulation of ΔFosB in the NAc of female hamsters and male rats. Sex behavior is unique among motivated behaviors in that the expression of the behavior varies drastically between males and females of the same species. Despite this, a quantitative comparison of ΔFosB following sex experience in males and females of the same species has never been conducted. We therefore used Western blotting to test the hypothesis that sex experience increases ΔFosB in both male and female Syrian hamsters following repeated sexual experience. We found that sex experience significantly increases ΔFosB protein in male and female Syrian hamsters. Further, ΔFosB protein levels did not differ between males and females following sex experience. Interestingly, repeated sex experience only led to increased copulatory efficiency in female hamsters; male copulatory efficiency did not improve with repeated experience. Together, these data demonstrate that ΔFosB is increased following sexual reward in both males and females but may be uncoupled from behavioral plasticity in males. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
... One way that hormones can influence brain regions associated with reward is through modulating structural plasticity. In the nucleus accumbens (NAc), a primary component of the mesolimbic dopamine system, changes in dendritic spine density and morphology of medium spiny neurons (MSNs) occur in response to both natural rewards and drugs of abuse (Pitchers et al., 2010;Russo et al., 2010;Staffend and Meisel, 2012;Staffend et al., 2014). The structural changes induced by drugs of abuse in this region are incredibly persistent and have been found to correlate with aspects of drug-mediated behavior (Li et al., 2004;Robinson and Kolb, 2004), suggesting that they may be functionally relevant to long-lasting changes in synaptic signaling and behavior. ...
Gonadal hormones play a vital role in driving motivated behavior. They not only modulate responses to naturally rewarding stimuli, but also influence responses to drugs of abuse. A commonality between gonadal hormones and drugs of abuse is that they both impact the neurocircuitry of reward, including the regulation of structural plasticity in the nucleus accumbens (NAc). Previous hormonal studies have focused on the mechanisms and behavioral correlates of estradiol-induced dendritic spine changes in the female NAc. Here we sought to determine the effects of androgens on medium spiny neuron (MSN) spine plasticity in the male NAc. Following treatment with the androgen receptor agonist dihydrotestosterone (DHT), MSNs in castrated male rats exhibited a significant decrease in dendritic spine density. This effect was isolated to the shell subregion of the NAc. The effect of DHT was dependent on mGluR5 activity, and local mGluR5 activation and subsequent endocannabinoid signaling produce an analogous NAc shell spine decrease. Somewhat surprisingly, DHT-induced conditioned place preference remained intact following systemic inhibition of mGluR5. These findings indicate that androgens can utilize mGluR signaling, similar to estrogens, to mediate changes in NAc dendritic structure. In addition, there are notable differences in the direction of spine changes, and site specificity of estrogen and androgen action, suggesting sex differences in the hormonal regulation of motivated behaviors.
... On the other hand, hamsters, goats, monkeys, and pigs are better models for studying the pathogenesis of lung injury since their macrophages are more like human macrophages and produce lower levels of NO [86] where much higher amounts of NO is produced compared to human macrophages. Hamsters have been utilized widely for the development of vaccines and therapeutic approaches [109][110][111][112][113][114]. Other reported uses of hamster models include diabetes neural plasticity, atherosclerosis and cancer. ...
Smoke inhalation injury leads to various acute and chronic lung diseases and thus is the dominant cause of fire-related fatalities. In a search for an effective treatment and validation of therapies different classes of animal models have been developed, which include both small and large animals. These models have advanced our understanding of the mechanism of smoke inhalation injury, enabling a better understanding of pathogenesis and pathophysiology and development of new therapies. However, none of the animal models fully mirrors human lungs and their pathologies. All animal models have their limitations in replicating complex clinical conditions associated with smoke inhalation injury in humans. Therefore, for a correct interpretation of the results and to avoid bias, a precise understanding of similarities and differences of lungs between different animal species and humans is critical. We have reviewed and presented comprehensive comparison of different animal models and their clinical relevance. We presented an overview of methods utilized to induce smoke inhalation injuries, airway micro-/ macrostructure, advantages and disadvantages of the most commonly used small and large animal models.
... These advantages are why many consider hamsters a superior alternative to other small animals for use in research. For the development of vaccines and therapeutic approaches, some consider hamsters a higher standard as small animal model than mice and as such hamsters have been utilized in a wide range of models, from those examining diabetes, atherosclerosis, neural plasticity, to cancer (Table 1) (Bhathena et al. 2011;Dillard et al. 2010;Jové et al. 2013;Staffend and Meisel 2012;Woods et al. 2015;Vijayalingam et al. 2014). However, the use of hamsters for models of pathogenic human diseases may be the most valuable due to comparable disease progression seen in hamsters to that of humans for many infectious diseases including bacteria, viruses, and parasites (Dondji et al. 2008; da Silva-Couto et al. 2015;Kuehne et al. 2014;Safronetz et al. 2012). ...
The use of small animal models for the study of infectious disease is critical for understanding disease progression and for developing prophylactic and therapeutic treatment options. For many diseases, Syrian golden hamsters have emerged as an ideal animal model due to their low cost, small size, ease of handling, and ability to accurately reflect disease progression in humans. Despite the increasing use and popularity of hamsters, there remains a lack of available reagents for studying hamster immune responses. Without suitable reagents for assessing immune responses, researchers are left to examine clinical signs and disease pathology. This becomes an issue for the development of vaccine and treatment options where characterizing the type of immune response generated is critical for understanding protection from disease. Despite the relative lack of reagents for use in hamsters, significant advances have been made recently with several hamster specific immunologic methods being developed. Here we discuss the progress of this development, with focus on classical methods used as well as more recent molecular methods. We outline what methods are currently available for use in hamsters and what is readily used as well as what limitations still exist and future perspectives of reagent and assay development for hamsters. This will provide valuable information to researchers who are deciding whether to use hamsters as an animal model.
... The Syrian golden hamster has been used broadly in biomedical research for decades, especially as a model for cancer development. More recently, it has been served as models in research on diabetes (Bhathena et al., 2011), atherosclerosis (Dillard et al., 2010;Jove et al., 2013), and neural plasticity (Staffend and Meisel, 2012). Also, the Syrian hamster is frequently employed in studies of infectious disease, as it is highly susceptible to infection with a wide range of viruses, bacteria, and parasites (Espitia et al., 2010;Zivcec et al., 2011). ...
The Syrian golden hamster is an attractive animal for research on infectious diseases and other diseases. We report here the sequencing, assembly, and annotation of the Syrian hamster transcriptome. We include transcripts from ten pooled tissues from a naïve hamster and one stimulated with lipopolysaccharide. Our data set identified 42,707 non-redundant transcripts, representing 34,191 unique genes. Based on the transcriptome data, we generated a custom microarray and used this new platform to investigate the transcriptional response in the Syrian hamster liver following intravenous adenovirus type 5 (Ad5) infection. We found that Ad5 infection caused a massive change in regulation of liver transcripts, with robust up-regulation of genes involved in the antiviral response, indicating that the innate immune response functions in the host defense against Ad5 infection of the liver. The data and novel platforms developed in this study will facilitate further development of this important animal model.
... However, a similar increase was seen in non-manipulated NAB females tested twice in the FIT without surgery in between. These findings are consistent with multiple reports of increased aggression induced by fighting experience in male rats and house mice, and in male and female California mice and Syrian hamsters [61,[78][79][80][81][82]. ...
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.
... These cell lines are also used in the industrial production of recombinant therapeutic proteins (Dingermann, 2008;Jiang et al., 2002) as well as veterinary vaccines Radlett et al., 1985). The Syrian hamster is also an important animal model in the research of infectious disease (Paessler et al., 2004;Requena et al., 2000;Xiao et al., 2001), cardiomyopathy (Crespo and Escobales, 2008), diabetes (Bhathena et al., 2011;Popov et al., 2003), atherosclerosis (Dillard et al., 2010;Jové et al., 2012), and neural plasticity (Staffend and Meisel, 2012). ...
Baby Hamster Kidney (BHK) cell lines are used in the production of veterinary vaccines and recombinant proteins. To facilitate transcriptome analysis of BHK cell lines, we embarked on an effort to sequence, assemble, and annotate transcript sequences from a recombinant BHK cell line and Syrian hamster liver and brain. RNA-seq data were supplemented with 6,170 Sanger ESTs from parental and recombinant BHK lines to generate 221,583 contigs. Annotation by homology to other species, primarily mouse, yielded more than 15,000 unique Ensembl mouse gene IDs with high coverage of KEGG canonical pathways. High coverage of enzymes and isoforms was seen for cell metabolism and N-glycosylation pathways, areas of highest interest for biopharmaceutical production. With the high sequencing depth in RNA-seq data, we set out to identify single-nucleotide variants in the transcripts. A majority of the high-confidence variants detected in both hamster tissue libraries occurred at a frequency of 50%, indicating their origin as heterozygous germline variants. In contrast, the cell line libraries' variants showed a wide range of occurrence frequency, indicating the presence of a heterogeneous population in cultured cells. The extremely high coverage of transcripts of highly abundant genes in RNA-seq enabled us to identify low-frequency variants. Experimental verification through Sanger sequencing confirmed the presence of two variants in the cDNA of a highly expressed gene in the BHK cell line. Furthermore, we detected seven potential missense mutations in the genes of the growth signaling pathways that may have arisen during the cell line derivation process. The development and characterization of a BHK reference transcriptome will facilitate future efforts to understand, monitor, and manipulate BHK cells. Our study on sequencing variants is crucial for improved understanding of the errors inherent in high-throughput sequencing and to increase the accuracy of variant calling in BHK or other systems. Biotechnol. Bioeng. 2013;9999: 1-12. © 2013 Wiley Periodicals, Inc.
... We have developed a model of such experience based plasticity in which we discovered that repeated sexual experience produces augmented responsiveness, both pre-and postsynaptically, in the nucleus accumbens of female Syrian hamsters (Hedges et al., 2010;Meisel and Mullins, 2006). Besides female sexual behavior, other motivated behaviors such as male sexual behavior, aggression, and salt appetite induce similar patterns of plasticity in the nucleus accumbens (Pitchers et al., 2010a;Roitman et al., 2002;Staffend and Meisel, 2012), supporting a common neurobiological process across motivated behaviors. Here we add to that knowledge base with a detailed analysis of regional and phenotype specific structural plasticity following female sexual behavior experience. ...
Female sexual behavior is an established model of a naturally motivated behavior which is regulated by activity within the mesolimbic dopamine system. Repeated activation of the mesolimbic circuit by female sexual behavior elevates dopamine release and produces persistent postsynaptic alterations to dopamine D1 receptor signaling within the nucleus accumbens. Here we demonstrate that sexual experience in female Syrian hamsters significantly increases spine density and alters morphology selectively in D1 receptor-expressing medium spiny neurons within the nucleus accumbens core, with no corresponding change in dopamine receptor binding or protein expression. Our findings demonstrate that previous life experience with a naturally motivated behavior has the capacity to induce persistent structural alterations to the mesolimbic circuit that can increase reproductive success and are analogous to the persistent structural changes following repeated exposure to many drugs of abuse.
... The nucleus accumbens (NAc) is a key brain region for motivated behaviors, such as copulation [24,27,34], aggression [11,28,36], and wheel running [18,42,44], as well as in substance abuse and addiction [9,14,45]. NAc afferents are primarily comprised of two neurochemical phenotypes: dopamine (DA) and glutamate (GLU). ...
The nucleus accumbens (NAc) is an important brain region for motivation, reinforcement, and reward. Afferents to the NAc can be divided into two anatomically-segregated neurochemical phenotypes: dopaminergic inputs, primarily from the midbrain ventral tegmental area (VTA) and glutamatergic inputs from several cortical and sub-cortical structures. A population of glutamatergic neurons exists within the VTA and evidence from rats and mice suggests that these VTA axons may co-release dopamine and glutamate into the NAc. Our laboratory has used sexual experience in Syrian hamsters as a model of experience-dependent plasticity within the NAc. Given that both dopamine and glutamate are involved in this plasticity, it is important to determine whether these neurotransmitters are co-expressed within the mesolimbic pathway of hamsters. We therefore used immunofluorescent staining to investigate the possible co-localization of tyrosine hydroxylase (TH), a dopaminergic marker, and vesicular glutamate transporter 2 (VGLUT2), a glutamatergic marker, within the mesolimbic pathway. PCR analyses identified VGLUT2 gene expression in the VTA. No co-localization of TH and VGLUT2 protein was detected in NAc fibers, nor was there a difference in immunolabeling between males and females. Further studies are needed to resolve this absence of anatomical co-localization of TH and VGLUT2 in hamster striatal afferents with reports of functional co-release in other rodents.
In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an "estrogen withdrawal" state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.
Classically the neurobiology of aggression has been studied exclusively in males. Thus, females have been considered mildly aggressive except during lactation. Interestingly, recent studies in rodents and humans have revealed that non-lactating females can show exacerbated and pathological aggression similarly to males. This review provides an overview of recent findings on the neuroendocrine mechanisms regulating aggressive behavior in females. In particular, the focus will be on novel rodent models of exaggerated aggression established in non-lactating females. Among the neuromodulatory systems influencing female aggression, special attention has been given to sex-steroids and sex-steroid-sensitive neuronal populations (i.e., the core nuclei of the neural pathway of aggression) as well as to the neuropeptides oxytocin and vasopressin which are major players in the regulation of social behaviors.
Two expeditions were carried out during September 1997 and March 1999 to confirm the current existence of Mesocricetus auratus in northern Syria. Six females and seven males were caught at different sites near Aleppo. One female was pregnant and gave birth to six pups. Altogether, 30 burrows were mapped and the structures of 23 golden hamster burrows investigated. None of the inhabited burrows contained more than one adult. Burrow depths ranged from 36 to 106 cm (mean 65 cm). Their structure was simple, consisting of a single vertical entrance (gravity pipe) that proceeded to a nesting chamber and at least one additional food chamber. The mean length of the entire gallery system measured 200 cm and could extend up to 900 cm. Most burrows were found on agricultural fields preferentially on leguminous cultures. The distribution of golden hamsters is discussed in association with historical data, soil types, geography, climate and human activities. All 19 golden hamsters were transferred to Germany and, together with three wild individuals supplied by the University of Aleppo, form a new breeding stock.
Long-term synaptic plasticity requires postsynaptic influx of Ca²⁺ and is accompanied by changes in dendritic spine size. Unless Ca²⁺ influx mechanisms and spine volume scale proportionally, changes in spine size will modify spine Ca²⁺ concentrations during subsequent synaptic activation. We show that the relationship between Ca²⁺ influx and spine volume is a fundamental determinant of synaptic stability. If Ca²⁺ influx is undercompensated for increases in spine size, then strong synapses are stabilized and synaptic strength distributions have a single peak. In contrast, overcompensation of Ca²⁺ influx leads to binary, persistent synaptic strengths with double-peaked distributions. Biophysical simulations predict that CA1 pyramidal neuron spines are undercompensating. This unifies experimental findings that weak synapses are more plastic than strong synapses, that synaptic strengths are unimodally distributed, and that potentiation saturates for a given stimulus strength. We conclude that structural plasticity provides a simple, local, and general mechanism that allows dendritic spines to foster both rapid memory formation and persistent memory storage.
Fine neuronal morphology, such as dendritic spines, classically has been studied using the Golgi technique; however, Golgi staining is difficult to combine with other histological techniques. With the increasing popularity of fluorescent imaging, a number of fluorescent dyes have been developed that enable the coupling of multiple fluorescent labels in a single preparation. These fluorescent dyes include the lipophilic dialkylcarbocyanine, DiI; traditionally used for anterograde and retrograde neuronal tracing. More recently, DiI labeling has been used in combination with the Gene Gun for "DiOlistic" labeling of neurons in slice preparations. DiI sequesters itself within and diffuses laterally along the neuronal membrane, however once the cell is permeabilized, the DiI begins to leak from the cell membrane. A DiI derivative, Cell Tracker™ CM-DiI, increases dye stability and labeling half-life in permeabilized tissue, however at much greater expense. Here, the DiI and CM-DiI DiOlistic labeling techniques were tested in side-by-side experiments evaluating dye stability within dendritic architecture in medium spiny neurons of the dorsal stratum in both non-permeabilized and permeabilized tissue sections. In tissue sections that were not permeabilized, spine density in DiI labeled sections was higher than in CM-DiI labeling. In contrast, tissue sections that were permeabilized had higher spine densities in CM-DiI labeled neurons. These results suggest that for experiments involving non-permeabilized tissue, traditional DiI will suffice, however for experiments involving permeabilized tissue CM-DiI provides more consistent data. These experiments provide the first quantitative analyses of the impact of methodological permutations on neuronal labeling with DiI.
There is growing appreciation that social decision making in humans is strongly influenced by hedonic and emotional processing. The field of social neuroeconomics has shown that neural systems important for reward are associated with social choice and social preferences in humans. Here, we show that the neurobiology of social preferences in a monogamous rodent species, the prairie vole, is also regulated by neural systems involved in reward and emotional processing. Specifically, we describe how mesolimbic dopamine transmission differentially mediates the formation and maintenance of monogamous pair bonds in this species. Thus, reward processing exerts tremendous regulation over social choice behaviors that serve as the foundation of a rather complex social organization. We conclude that prairie voles are an excellent model system for the neuroscience of social choice and that complex social decision-making can be robustly explained by reward and hedonic processing.
Chronic cocaine treatment is associated with changes in dendritic spines in the nucleus accumbens, but it is unknown whether this neuroplasticity alters the effect of a subsequent cocaine injection on spine morphology and protein content. Three weeks after daily cocaine or saline administration, neurons in the accumbens were filled with the lipophilic dye, DiI. Although daily cocaine pretreatment did not alter spine density compared with daily saline, there was a shift from smaller to larger diameter spines. During the first 2 h after an acute cocaine challenge, a bidirectional change in spine head diameter and increase in spine density was measured in daily cocaine-pretreated animals. In contrast, no change in spine diameter or density was elicited by a cocaine challenge in daily saline animals during the first 2 h after injection. However, spine density was elevated at 6 h after a cocaine challenge in daily saline-pretreated animals. The time-dependent profile of proteins in the postsynaptic density subfraction elicited by a cocaine challenge in daily cocaine-pretreated subjects indicated that the changes in spine diameter and density were associated with a deteriorating actin cytoskeleton and a reduction in glutamate signaling-related proteins. Correspondingly, the amplitude of field potentials in accumbens evoked by stimulating prefrontal cortex was reduced for up to 6 h after acute cocaine in daily cocaine-withdrawn animals. These data indicate that daily cocaine pretreatment dysregulates dendritic spine plasticity elicited by a subsequent cocaine injection.
The frequency and sequencing of aggressive behaviors by naive female hamsters change during series of brief encounters, probably because of the lack of stable dominance relations. Such initial encounters seem most representative of interactions likely in free-ranging hamsters and have been emphasized in studies of the hormonal mediation of female aggression. Nonestrous females exhibit intense aggression toward conspecifics of either sex. Estrous females are not aggressive and spend much time in lordosis, indicative of sexual receptivity. The inhibition of fighting on estrous day depends on estrogen and progesterone. Whereas oil-injected adrenalectomized-ovariectomized females fight at high levels, comparable with intact nonestrous females, the combination of 17 beta-estradiol benzoate and progeterone suppresses fighting completely. In contrast, replacement of estradiol, progesterone, or testosterone propionate individually has on consistent effect. Hypophysectomized females also fight at high levels, indicating that pituitary hormones are not required for vigorous aggression. Further, individual anterior pituitary hormones did not produce marked changes in fighting. These results emphasize the roles of estrogen and progesterone in synchronizing aggression with current reproductive state.
Extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were examined concurrently, using in vivo microdialysis, in the nucleus accumbens and dorsal striatum of sexually active male rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually receptive female, and copulation. DA increased significantly in the nucleus accumbens when the males were presented with a sexually receptive female behind a screen and increased further during copulation. Although DA also increased significantly in the dorsal striatum during copulation, the magnitude of the effect was significantly lower than that observed in the nucleus accumbens. In contrast, forced locomotion on a rotating drum, exposure to a novel chamber, and exposure to sex odors did not increase DA significantly in either region, although both DOPAC and HVA increased significantly in both regions during the locomotion test. These results indicate that novelty or locomotor activity alone cannot account for the increased extracellular DA concentrations observed in the nucleus accumbens of male rats during the presentation of a sexually receptive female behind a screen, nor can they account for the increased DA concentrations observed in both the nucleus accumbens and dorsal striatum of male rats during copulation. The preferential increase in DA transmission in the nucleus accumbens, compared with that in the striatum, suggests that anticipatory and consummatory aspects of sexual activity may belong to a class of naturally occurring events with reward values that are mediated by DA release in the nucleus accumbens.
Five groups of ovariectomized rats were tested during in vivo microdialysis, and concentrations of dopamine (DA) and its metabolites were determined in dialysate. In striatum, DA increased more in hormone-primed ovariectomized female rats pacing copulation than in those engaging in sex that could not pace, those that were hormone primed but tested without a male present, or oil-treated groups (p < .02). Administration of estrogen before microdialysis resulted in enhanced striatal DA in response to a male rat relative to the animals tested without a male (p < .06). Female rats that were pacing sexual behavior also exhibited a greater increase in accumbens DA than did the no-male, estrogen-primed, or oil-treated groups (p < .015). Nonpacing animals displayed a significant decrease in DA from accumbens 30 min after introduction of the male rat (p < .05) but otherwise were not different from pacing animals. Estrogen-treated animals also had an enhanced increase in accumbens DA compared with oil-treated rats (p < .05). These data suggest that DA release in the striatum and accumbens is dependent on the context in which sexual behavior occurs and that estrogen may in part modulate these dopaminergic responses.
We investigated the influence of synaptically released glutamate on postsynaptic structure by comparing the effects of deafferentation, receptor antagonists and blockers of glutamate release in hippocampal slice cultures. CA1 pyramidal cell spine density and length decreased after transection of Schaffer collaterals and after application of AMPA receptor antagonists or botulinum toxin to unlesioned cultures. Loss of spines induced by lesion or by botulinum toxin was prevented by simultaneous AMPA application. Tetrodotoxin did not affect spine density. Synaptically released glutamate thus exerts a trophic effect on spines by acting at AMPA receptors. We conclude that AMPA receptor activation by spontaneous vesicular glutamate release is sufficient to maintain dendritic spines.
Dopamine (DA) and serotonin have been implicated in the regulation of aggressive behavior, but it has remained challenging to assess the dynamic changes in these neurotransmitters while aggressive behavior is in progress. The objective of this study was to learn about ongoing monoamine activity in corticolimbic areas during aggressive confrontations in rats. Male Long-Evans rats were implanted with a microdialysis probe aimed at the nucleus accumbens (NAC) or medial prefrontal cortex (PFC); next, 10 min samples were collected before, during, and after a 10 min confrontation. Rats continued to display aggressive behavior while being sampled, and they performed two to six attack bites as well as 140 sec of aggressive acts and postures. Dopamine levels in NAC were significantly increased up to 60 min after the confrontation. Peak levels of 140% were achieved approximately 20-30 min after the confrontation. No concurrent changes in accumbal serotonin levels were seen during or after the confrontation. Dopamine and serotonin levels in PFC changed in the opposite direction, with a sustained decrease in serotonin to 80% of baseline levels during and after the confrontation and an increase in dopamine to 120% after the confrontation. The temporal pattern of monoamine changes, which followed rather than preceded the confrontation, points to a significant role of accumbal and cortical DA and 5-hydroxytryptamine in the consequences as opposed to the triggering of aggressive acts. The increase in accumbal DA in aggressive animals supports the hypothesis that this neural system is linked to the execution of biologically salient and demanding behavior.
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.
Dopamine in dialysate from the nucleus accumbens (NAcc) increases during sexual and feeding behavior and after administration of drugs of abuse, even those that do not directly activate dopaminergic systems (e.g., morphine or nicotine). These findings and others have led to hypotheses that propose that dopamine is rewarding, predicts that reinforcement will occur, or attributes incentive salience. Examining increases in dopamine in NAcc or striatum during sexual behavior in female rats provides a unique situation to study these relations. This is because, for the female rat, sexual behavior is associated with an increase in NAcc dopamine and conditioned place preference only under certain testing conditions. This experiment was conducted to determine what factors are important for the increase in dopamine in dialysate from NAcc and striatum during sexual behavior in female rats. The factors considered were the number of contacts by the male, the timing of contacts by the male, or the ability of the female to control contacts by the male. The results indicate that increased NAcc dopamine is dependent on the timing of copulatory stimuli, independent of whether the female rat is actively engaged in regulating this timing. For the striatum, the timing of copulatory behavior influences the magnitude of the increase in dopamine in dialysate, but other factors are also involved. We conclude that increased extracellular dopamine in the NAcc and striatum conveys qualitative or interpretive information about the rewarding value of stimuli. Sexual behavior in the female rat is proposed as a model to determine the role of dopamine in motivated behavior.
Dendritic spines serve as preferential sites of excitatory synaptic connections and are pleomorphic. To address the structure-function relationship of the dendritic spines, we used two-photon uncaging of glutamate to allow mapping of functional glutamate receptors at the level of the single synapse. Our analyses of the spines of CA1 pyramidal neurons reveal that AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors are abundant (up to 150/spine) in mushroom spines but sparsely distributed in thin spines and filopodia. The latter may be serving as the structural substrates of the silent synapses that have been proposed to play roles in development and plasticity of synaptic transmission. Our data indicate that distribution of functional AMPA receptors is tightly correlated with spine geometry and that receptor activity is independently regulated at the level of single spines.
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.
Drugs of abuse act on the brain circuits mediating motivation and reward associated with natural behaviors. There is ample evidence that drugs of abuse impact male and female sexual behavior. First, the current review discusses the effect of drugs of abuse on sexual motivation and performance in male and female humans. In particular, we discuss the effects of commonly abused drugs including psychostimulants, opiates, marijuana/THC, and alcohol. In general, drug use affects sexual motivation, arousal, and performance and is commonly associated with increased sexual risk behaviors. Second, studies on effects of systemic administration of drugs of abuse on sexual behavior in animals are reviewed. These studies analyze the effects on sexual performance and motivation but do not investigate the effects of drugs on risk-taking behavior, creating a disconnect between human and animal studies. For this reason, we discuss two studies that focus on the effects of alcohol and methamphetamine on inhibition of maladaptive sex-seeking behaviors in rodents. Third, this review discusses potential brain areas where drugs of abuse may be exerting their effect on sexual behavior with a focus on the mesolimbic system as the site of action. Finally, we discuss recent studies that have brought to light that sexual experience in turn can affect drug responsiveness, including a sensitized locomotor response to amphetamine in female and male rodents as well as enhanced drug reward in male rats.
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.
We examined the effects of prior sexual experience on extracellular concentrations of dopamine in the nucleus accumbens of female hamsters. Nucleus accumbens dopamine was measured by in vivo microdialysis during mating in female Syrian hamsters that had previously been given six prior sexual encounters with a male, three prior encounters, or were sexually naive. High levels of sexual behavior were observed in all three groups, which were accompanied by increases in dialysate dopamine during periods when the male was present. However, females that received six prior sexual encounters had significantly elevated and prolonged increases in dialysate dopamine compared with those of the sexually naive females or females with only three prior sexual encounters with a male. The data indicate that the mesolimbic system can be sensitized by repeated experiences associated with a motivated behavior.
The present study investigated hormonal mediation of maternal behavior and accumbal dopamine (DA) responses to pup-stimuli, as measured in microdialysis samples collected from the nucleus accumbens shell of female rats in non-homecage environment. In Experiment 1, samples were collected before and after continuous homecage pup experience from either intact postpartum or cycling females. In Experiment 2, samples were collected before and after responding maternally in homecage from ovariectomized females given either parturient-like hormone or sham treatments. After baseline sample collection in the dialysis chamber, pup and food stimuli were individually presented to females. Upon sampling completion, all animals were placed back into their homecage with donor pups for several days, and then the sample collection procedure was repeated. Prior to stimulus presentation, postpartum and hormone-treated females had decreased basal DA release compared to their controls. In response to pup stimuli, only postpartum and hormone-treated females had increased DA release compared to basal release (both sampling days). In response to food stimuli, all females had increased DA responses from basal; although there were group differences on the initial day of sampling. Findings suggest that hormones associated with inducing maternal behavior in the postpartum rat play a significant role in modifying accumbal dopaminergic responses on first exposure to pup stimuli in the rat. However, the postpartum experience provides further modifications to this brain region to promote DA responses to pup stimuli.
Spine morphogenesis is largely dependent on the remodeling of the actin cytoskeleton. Actin dynamics within spines is regulated by a complex network of signaling molecules, which relay signals from synaptic receptors, through small GTPases and their regulators, to actin-binding proteins. In this chapter, we will discuss molecules involved in dendritic spine plasticity beginning with actin and moving upstream toward neuromodulators and trophic factors that initiate signaling involved in these plasticity events. We will place special emphasis on small GTPase pathways, as they have an established importance in dendritic spine plasticity and pathology. Finally, we will discuss some epigenetic mechanisms that control spine morphogenesis.
Following Darwin's original insights regarding sexual selection, studies of intrasexual competition have mainly focused on male competition for mates; by contrast, female reproductive competition has received less attention. Here, we review evidence that female mammals compete for both resources and mates in order to secure reproductive benefits. We describe how females compete for resources such as food, nest sites, and protection by means of dominance relationships, territoriality and inter-group aggression, and by inhibiting the reproduction of other females. We also describe evidence that female mammals compete for mates and consider the ultimate causes of such behaviour, including competition for access to resources provided by mates, sperm limitation and prevention of future resource competition. Our review reveals female competition to be a potentially widespread and significant evolutionary selection pressure among mammals, particularly competition for resources among social species for which most evidence is currently available.
Sexual behavior in male rats is rewarding and reinforcing. However, little is known about the specific cellular and molecular mechanisms mediating sexual reward or the reinforcing effects of reward on subsequent expression of sexual behavior. This study tests the hypothesis that ΔFosB, the stably expressed truncated form of FosB, plays a critical role in the reinforcement of sexual behavior and experience-induced facilitation of sexual motivation and performance. Sexual experience was shown to cause ΔFosB accumulation in several limbic brain regions including the nucleus accumbens (NAc), medial prefrontal cortex, ventral tegmental area and caudate putamen but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of ΔFosB, was measured in sexually experienced and naïve animals. The number of mating-induced c-Fos-immunoreactive cells was significantly decreased in sexually experienced animals compared with sexually naïve controls. Finally, ΔFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with ΔFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of ΔJunD, a dominant negative binding partner of ΔFosB, attenuated sexual experience-induced facilitation of sexual performance and stunted long-term maintenance of facilitation compared to green fluorescence protein and ΔFosB overexpressing groups. Together, these findings support a critical role for ΔFosB expression in the NAc for the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.
Natural reward and drugs of abuse converge on the mesolimbic system, where drugs of abuse induce neuronal alterations. Here, we tested plasticity in this system after natural reward and the subsequent impact on drug responses.
Effects of sexual experience in male rats on behavioral sensitization and conditioned place preference associated with d-amphetamine (AMPH) and Golgi-impregnated dendrites and spines of nucleus accumbens (NAc) cells were determined. Moreover, the impact of abstinence from sexual behavior in experienced males on these parameters was tested.
First, repeated sexual behavior induced a sensitized locomotor response to AMPH compared with sexually naive control subjects observed 1, 7, and 28 days after last mating session. Second, sexually experienced animals formed a conditioned place preference for lower doses of AMPH than sexually naive males, indicative of enhanced reward value of AMPH. Finally, Golgi-Cox analysis demonstrated increased numbers of dendrites and spines in the NAc core and shell with sexual experience. The latter two alterations were dependent on a period of abstinence of 7-10 days.
Sexual experience induces functional and morphological alterations in the mesolimbic system similar to repeated exposure to psychostimulants. Moreover, abstinence from sexual behavior after repeated mating was essential for increased reward for drugs and dendritic arbors of NAc neurons, suggesting that the loss of sexual reward might also contribute to neuroplasticity of the mesolimbic system. These results suggest that some alterations in the mesolimbic system are common for natural and drug reward and might play a role in general reinforcement.
Repeated activation of the mesolimbic dopamine system results in persistent behavioral alterations accompanied by a pattern of neural plasticity in the nucleus accumbens (NAc). As the accumulation of the transcription factor Delta FosB may be an important component of this plasticity, the question addressed in our research is whether Delta FosB is regulated by sexual experience in females. We have shown that female Syrian hamsters, given sexual experience, exhibit several behavioral alterations including increased sexual efficiency with naïve male hamsters, sexual reward and enhanced responsiveness to psychomotor stimulants (e.g. amphetamine). We recently demonstrated that sexual experience increased the levels of Delta FosB in the NAc of female Syrian hamsters. The focus of this study was to explore the functional consequences of this induction by determining if the constitutive overexpression of Delta FosB by adeno-associated virus (AAV) vectors in the NAc could mimic the behavioral effects of sexual experience. Animals with AAV-mediated overexpression of Delta FosB in the NAc showed evidence of sexual reward in a conditioned place preference paradigm under conditions in which control animals receiving an injection of AAV-green fluorescent protein (GFP) into the NAc did not. Sexual behavior tests further showed that males paired with the AAV-Delta FosB females had increased copulatory efficiency as measured by the proportion of mounts that included intromission compared to males mated with the AAV-GFP females. These results support a role for Delta FosB in mediating natural motivated behaviors, in this case female sexual behavior, and provide new insight into the possible endogenous actions of Delta FosB.
Changes in dopamine release and metabolism during drinking in thirsty rats were studied using in vivo microdialysis. Animals were maintained on controlled water (1 h per day) and trained to lick for water in a behavioural box. Microdialysis probes were then inserted into the left nucleus accumbens and right caudate nucleus through previously implanted guide cannulae, and the following day animals were connected for dialysis perfusion, during which they were allowed 1 h free access to water. Dopamine, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased in both nucleus accumbens and caudate nucleus in association with drinking, but the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid, only increased in the caudate nucleus. There was a direct correlation between the maximum dopamine release in nucleus accumbens and the maximum licking rate per 10-min period, but the maximum increase in dopamine did not occur until after the period of maximum licking. Increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid were further delayed (by 20 and 30 min, respectively). In the caudate, changes in 5-hydroxyindoleacetic acid showed a very similar time-course to those of 3,4-dihydroxyphenylacetic acid. These data show that dopamine systems in both nucleus accumbens and caudate nucleus are activated in relation to drinking in thirsty rats. In addition, they indicate that 5-hydroxytryptamine systems in the caudate nucleus, but not in nucleus accumbens, may also be involved. The support that the results provide for the hypothesized connection between reward and limbic dopamine is discussed.
Dopamine (DA) release was simultaneously monitored in the nucleus accumbens (NAC) and ventral tegmental area (VTA) of conscious rats using in vivo microdialysis. During dialysis perfusion, rats were allowed access to food or water for 20 min following a 36 h food and water deprivation period. DA release increased significantly in the NAC and VTA in response to eating and drinking. The increases in both regions continued until 20-60 min after the end of the feeding or drinking session. These results show that the mesolimbic DA pathway is activated in response to ingestive behavior, and that DA release occurs in the cell body (A10) region as well as in the mesolimbic DA nerve terminals.
It has long been hypothesized that changes in dendritic spine structure may modify the physiological properties of synapses located on them. Due to their small size, large number, and highly variable shapes, standard light microscopy of Golgi impregnations and electron microscopy (EM) of single thin sections have not proved adequate to identify most spines in a sample or to quantify their structural dimensions and composition. Here we describe a new approach, the series sample, that was developed to classify by shape and subcellular composition all of the spines and synapses in a sample of neuropil by viewing them through serial EM sections. Spines in each class are then randomly selected for serial reconstruction and measurement in three dimensions. This approach was used to assess whether structural changes in hippocampal CA1 spines could contribute to the enhanced synaptic transmission and the greater endurance of long-term potentiation (LTP) that occur with maturation. Our results show a near doubling in the total density of synapses in the neuropil and along reconstructed dendrites between postnatal day 15 (PND 15) and adult ages. However, this doubling does not occur uniformly across all spine and synapse morphologies. Thin spines, mushroom spines containing perforated postsynaptic densities (PSDs) and spine apparatuses, and branched spines increase by about four-fold in density between PND 15 and adult ages. In contrast, stubby spines decrease by more than half and no change occurs in mushroom spines with macular PSDs or in dendritic shaft synapses. The stubby spines that remain are smaller in adults than at PND 15 and the mushroom spines are larger, while no change occurs in the three-dimensional structure of thin spines. Only a few spine necks at either age are constricted or long enough to attenuate charge transfer; therefore, the doubling in synapses should mediate the enhancement of synaptic transmission that occurs with maturation. In addition, LTP is not likely to be mediated by widening of spine necks at either age. However, the constricted spine necks could serve to concentrate specific molecules at activated synapses, thereby enhancing the specificity and endurance of LTP with maturation. These results demonstrate that the new series sample method combined with three-dimensional reconstruction reveals quantitative changes in the frequency and structure of spines and synapses that are not discernable by other methods and are likely to have dramatic effects on synaptic physiology and plasticity.
Extracellular dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (N. Acc.) were measured by in vivo microdialysis during male sexual activity. DA and DOPAC were significantly increased during copulation, but not during mild tail pinch. These results are consistent with studies showing increases in N. Acc. DA associated with positively reinforcing environmental stimuli.
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.
Projection neurons of nucleus accumbens (NAC) of the rat were identified by either antidromic activation from stimulation of midbrain ventral tegmental area-substantia nigra (VTA-SN) regions, or by tracing axons of intracellularly labeled NAC neurons into the ventral pallidum. The morphology of these NAC projection neurons were determined to be medium spiny neurons similar to those identified in the caudate-putamen.
To gain information on possible hormonal correlates, the aggressive behavior of intact female hamsters towards males was observed at various times during the estrous cycle, pseudopregnancy, pregnancy, and lactation. For methodological information, estrous cycle females also were tested after varying periods of social isolation. It was found that pregnant and especially lactating hamsters were more aggressive than pseudopregnant or estrous cycling females. Comparisons of days within each reproductive condition showed that aggression tended to be higher on certain days: the day preceding behavioral estrus of the estrous cycle, Day 10 of pregnancy, and the first 5 days of lactation. Except for pseudopregnancy, sexual behavior unaccompanied by aggression occurred at some time during all reproductive conditions, and both sexual behavior and aggression were found to occur together on Day 10 of pregnancy and Day 1 of lactation. The changes in aggressive behavior associated with reproductive states were attributed to increased male interest, inhibition by ovarian hormones, and facilitation by prolactin. Increasing periods of social isolation also were found to be associated with increased aggression. It was suggested that this effect, too. might have been due to increased prolactin levels.
Pairs of hamsters were housed in large enclosures that contained separate male and female living areas and observed over the 4-day estrous cycle and after ovariectomy. Agonistic elements exhibited frequently by females included on-back, boxing, lateral posturing, and biting, whereas males engaged frequently in boxing and on-back patterns of behavior. Furthermore, on-back and boxing by females were significantly higher on estrus than on any other day of the estrous cycle. Agonistic acts performed after ovariectomy did not differ in occurrence from those shown by animals on diestrus and proestrus. Vaginal marking increased during diestrus and attained a peak 24 hr prior to sexual receptivity. Both vaginal marking and mating occurred more frequently in the female's than male's home area suggesting that vaginal marking and mating occurred serve to attract males to the nest of females. Males also organized their marking patterns by location as shown by more flank marking in their own than their partner's area, albeit the significance for this difference in location is not known. The results demonstrate that when heterosexual pairs of hamsters are tested in large and partially familiar habitats, a wide range of behavior is exhibited and organized in a manner that is not observed in small and unfamiliar cages.
Limbic forebrain structures and the hypothalamus are essential in the initiation of food-seeking, escape from predators and other behaviors essential for adaptation and survival. Neural integrative activities subserving these behaviors initiate motor responses but the neural interface between limbic and motor systems has received relatively little attention. This neglect has been in part because of the emphasis on the motor control of the movements and on the contributions of the cerebral cortex, cerebellum, spinal cord and other components of the motor system, but more importantly, because of a lack of relevant anatomical evidence of connections. Anatomical findings obtained in recent years now make it possible to investigate the neural interface between limbic and motor systems—neural mechanisms by which “motivation” gets translated into “action”. It has been proposed that the nucleus accumbens is a key component of this neural interface since it receives inputs from limbic forebrain structures, either directly or indirectly via the ventral tegmental area of Tsai, and sends signals to the motor system via the globus pallidus.
A growing body of evidence suggests that an interference with dopamine (DA) transmission disrupts maternal behavior in the rat. The present brain microdialysis study was therefore conducted to investigate whether infants can modulate ventral striatal DA release in mother rats. There was a significant rise in the extracellular concentrations DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the ventral striatum when mothers were reunited with their litters following separation overnight. Nursing was the predominant behavior during this phase of the experiment. More active behaviors were elicited by soiling pups with flowerpot earth, and this was accompanied by further increases in DA, DOPAC, HVA, and 5-HIAA. It is suggested that pup-induced stimulation of ventral striatal DA release facilitates parental responses such as pup retrieval.
Microdialysis was used to study the effects of exposure to a male hamster on extracellular concentrations of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in the ventral striatum of ovariectomized female Syrian hamsters pretreated with either estradiol and progesterone, or a similar regimen of oil injections. The hormone-treated females showed high levels of lordosis throughout the hour of exposure to the male. In hormone-treated females, there was a rapid elevation of dialysate dopamine within the first 15 min of exposure to the male. Dialysate dopamine gradually declined over the next 45 min, though remaining significantly above baseline during the entire period of exposure to the male. None of the oil-treated females showed any indication of lordosis, and the addition of the male produced only a small increase in dopamine at 30 min, after which dopamine returned to pre-male basal levels. DOPAC, HVA, and 5-HIAA were all elevated following introduction of the male for both groups of females. These results suggest that ovarian hormones modulate the responsivity of ventral striatal dopamine to incentive stimuli associated with mating behavior in females, although extracellular levels of dopamine in the ventral striatum do not seem to be directly coupled to the display of lordosis.
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.
In vivo microdialysis was used to monitor extracellular concentrations of dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the nucleus accumbens of sexually naive male rats during their first exposure to sexually receptive or nonreceptive females. DA, DOPAC, and HVA increased progressively and significantly in males that copulated to ejaculation with receptive females. In contrast, DA, DOPAC, and HVA did not increase significantly in males exposed to non-receptive females, despite several attempts by these males to mount the non-receptive females. These results indicate that DA is released unconditionally in the nucleus accumbens of male rats by exposure to sexually receptive female rats, and that copulation with intromission, but not mounting alone, leads to further increases in DA release.
In vivo microdialysis was used to monitor extracellular concentrations of dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and dorsal striatum of sexually active female rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually active male rat, and copulation. DA increased slightly but significantly in the nucleus accumbens when a sexually active male was placed behind a wire-mesh screen, and further during copulation. DA also increased significantly in the dorsal striatum during copulation; however, the magnitude of this effect was significantly lower than that observed in the nucleus accumbens. The metabolites DOPAC and HVA generally followed DA with a delay, and increased significantly during copulation in both regions. In contrast, forced locomotion on a rotating drum, exposure to a novel testing chamber, and exposure to sex odors did not increase DA significantly in either region, although forced locomotion increased DOPAC significantly in both regions, and HVA significantly in the nucleus accumbens. The magnitude of DA release in the nucleus accumbens was significantly greater during copulation than running, whereas no significant difference was detected for striatal DA release between these two behavioral conditions. These results indicate that novelty or locomotor activity alone do not account for the increase in DA observed in the nucleus accumbens of female rats during copulation, and suggest that DA transmission in the nucleus accumbens is associated with anticipatory and consummatory aspects of sexual activity, as it is in male rats. In the dorsal striatum, however, DA release during copulation may reflect an increase in locomotor activity associated with active pacing of the male.
The mesolimbic dopaminergic system (MDS) has been shown to be activated by ingestive behaviors, and it has been suggested that this activation may be related to the rewarding properties of foods. Because rats eat more when given a more palatable diet, this study was undertaken to determine-the relationship between the amount of food ingested and DA release in the nucleus accumbens of freely moving rats. The extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by high-performance liquid chromatography with electrochemical detection on microdialysis samples from the nucleus accumbens. Each rat underwent three microdialysis sessions that differed in feeding conditions: on the first day they had access to a highly palatable diet (short cakes) ad lib; on the second day they were given half the amount consumed on the previous day of the same food; and on the third day they were deprived of food. In the absence of food, there were no significant alterations in extracellular levels of DA, DOPAC, and HVA. During feeding, levels of DA and its two metabolites rose. DA release in the nucleus accumbens was related to the amount of food ingested. As the amount ingested is a component of the reinforcement associated with food intake, this result is consistent with a direct relationship between MDS activity and food reward.
The extent to which glutamate receptors in the nucleus accumbens and ventral tegmental area regulate feeding-evoked increases in dopamine release in the nucleus accumbens was determined using in vivo brain microdialysis in the rat. In some animals a second dialysis probe was implanted in the ventral tegmental area ipsilateral to the nucleus accumbens probe. The feeding protocol involved access to standard rat chow after 18 h of food deprivation. Under these conditions rats began eating approximately 30 s after the introduction of food and consumed 7-8 g, resulting in a 50% increase in dopamine release. Application of the glutamate receptor antagonist kynurenate (1 mM) in the nucleus accumbens potentiated the feeding-evoked increase in dopamine release by 80%. Application of the metabotropic glutamate receptor agonist trans-1S,3R-1-amino-1,3-cyclopentanedicarboxylic acid (100 microM) in the nucleus accumbens blocked the feeding-evoked increase in dopamine release. Application of a combination of the ionotropic glutamate receptor antagonists 2-amino-5-phosphopentanoic acid (200 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (50 microM) through the dialysis probe in the ventral tegmental area reduced basal dopamine output in the nucleus accumbens by 20% and markedly attenuated (by 70%) the effect of feeding on dopamine release. None of the treatments affected the latency to eat or the volume of food consumed. These results indicate that glutamatergic afferents to the ventral tegmental area mediate feeding-induced increases in dopamine release in the nucleus accumbens. In contrast, at physiological concentrations, glutamate in the nucleus accumbens appears to decrease dopamine release via actions on ionotropic and metabotropic receptors.
To determine whether post-feeding increases in dialysate dopamine (DA) in the nucleus accumbens are associated with persisting increases in DA release, we examined the effect of Ca++-free perfusion on post-feeding dialysate concentrations of DA. Post-feeding dialysate DA is entirely Ca++-dependent, suggesting the existence of post-feeding increases in exocytotic DA release and the ability of microdialysis to monitor dynamic changes in DA release through behaviour.
We have previously shown in non-deprived rats that feeding of an unfamiliar palatable food (Fonzies(R)) phasically stimulates in vivo dopamine (DA) transmission in the medial nucleus accumbens (NAc) and this effect undergoes habituation after a previous (24 h) Fonzies meal (Bassareo & Di Chiara 1997, J. Neurosci., 17, 851-861). The present study shows that an unfamiliar food (Kinder(R)) with a taste and composition (milk chocolate) different from that of Fonzies, also induces a release of DA in the NAc subjected to one-trial habituation. Habituation was taste specific as no cross-habituation was observed between Fonzies and Kinder. In undeprived rats, a 40-min exposure to an intrinsic appetitive stimulus (food smell arising from a Fonzies-filled plastic box) also prevented the increase in dialysate DA associated with Fonzies feeding, and this effect was partially reversed by food deprivation. Food deprivation also prevented habituation of Fonzies-induced increase of dialysate DA in the NAc. Predictive association of an empty plastic box to Fonzies feeding resulted in the acquisition of appetitive properties by the box and in facilitation (rather than inhibition) of the phasic responsiveness of DA transmission to Fonzies feeding. A 10-min pre-exposure to appetitive olfactory stimuli intrinsic to Fonzies still prevented, like a 40-min pre-exposure, the NAc DA response to Fonzies feeding; however, a 5-min pre-exposure to these appetitive stimuli did not prevent the DA response in the NAc. These results show that the phasic responsiveness of NAc DA transmission to an unfamiliar palatable food is under strong modulatory control by primary (consummatory) and secondary (appetitive) stimuli, and that the sign and extent of this control depends on the nature of the appetitive stimulus, delay of reward and motivational state (deprivation).
We describe a technique for rapid labeling of a large number of cells in the nervous system with many different colors. By delivering lipophilic dye-coated particles to neuronal preparations with a "gene gun," individual neurons and glia whose membranes are contacted by the particles are quickly labeled. Using particles that are each coated with different combinations of various lipophilic dyes, many cells within a complex neuronal network can be simultaneously labeled with a wide variety of colors. This approach is most effective in living material but also labels previously fixed material. In living material, labeled neurons continue to show normal synaptic responses and undergo dendritic remodeling. This technique is thus useful for studying structural plasticity of neuronal circuits in living preparations. In addition, the Golgi-like labeling of neurons with many different colors provides a novel way to study neuronal connectivity.
Transfection and subsequent expression of DNA in living neuronal tissue is problematic and no technique has emerged that is completely non-damaging, efficient and reproducible. The Bio-Rad hand-held Gene Gun has overcome some of these problems by exploiting a biolistic method in which small gold particles carrying plasmid DNA are propelled into neurons whilst causing minimal detectable cell damage. In its current configuration, however, the Bio-Rad Gene Gun is optimised for transfecting cells in dispersed cultures, and therefore delivers particles superficially over a relatively wide area. Here we report modifications to the Bio-Rad Gene Gun that both enhance its accuracy by restricting its target area, and increase the depth penetration achieved by gold particles, thereby allowing smaller and deeper tissues to be transfected. These alterations make the modified Gene Gun more applicable for in vitro transfection of organotypic cultures and enhance its potential utility for in vivo gene delivery. Moreover, the modified configuration operates successfully at lower gas pressures, thereby reducing even further the degree of cell damage incurred during transfection.
Sensitization to drugs, such as amphetamine, is associated with alterations in the morphology of neurons in the nucleus accumbens, a brain region critical to motivation and reward. The studies reported here indicate that a strong natural motivator, sodium depletion and associated salt appetite, also leads to alterations in neurons in nucleus accumbens. Medium spiny neurons in the shell of the nucleus accumbens of rats that had experienced sodium depletions had significantly more dendritic branches and spines than controls. In addition, a history of sodium depletions was found to have cross-sensitization effects, leading to enhanced psychostimulant responses to amphetamine. Thus, neuronal alterations common to salt and drug sensitization may provide a general mechanism for enhanced behavioral responses to subsequent exposures to these challenges.
Male and female Long-Evans hooded rats were placed in the complex environments for 3 months either at weaning (22 days), in young adulthood (120 days), or in senescence (24 months). The dendritic morphology of both the apical and basilar fields of layer III pyramidal cells was analyzed in both parietal and visual cortex. There were two novel results. First, although spine density was increased significantly with complex-housing in adulthood, it was decreased significantly by the same housing during development. Second, dendritic length was increased in both parietal and occipital cortex at all ages in males and was increased in adult females as well, but juvenile females showed no change in dendritic length in the occipital cortex and only a small effect on the apical field in parietal cortex. Thus, there are qualitative differences in the changes in spine density at different ages and the dendritic changes in response to complex versus isolated housing vary with sex, and in females, the changes vary with age as well. These results may explain some of the apparent inconsistencies in reports of spine and dendrite changes in the literature.
Autonomic and limbic neural activities are linked to aggressive behavior, and it is hypothesized that activities in the cardiovascular and monoaminergic systems play a role in preparing for an aggressive challenge. The objective was to learn about the emergence of monoamine activity in nucleus accumbens before an aggressive confrontation that was omitted at the regular time of occurrence, dissociating the motoric from the aminergic activity. Dopamine, serotonin, heart rate and behavioral activity were monitored before, during and after a single 10-min confrontation in resident male Long-Evans rats fitted with a microdialysis probe in the n. accumbens and with a telemetry sender (experiment 1). DA, but not 5-HT efflux, was confirmed to increase in n. accumbens during and after a single aggressive episode. In aggressive males that confronted an opponent daily for 10 days (experiment 2) heart rate rose 1 h before the regularly scheduled encounter relative to control rats, as measured on day 11 in the absence of any aggression. Concurrently, DA levels increased by 60-70% over baseline levels and 5-HT levels decreased by 30-35% compared to baseline levels. These changes were sustained over 1 h, and contrasted with no significant changes in DA, 5-HT, heart rate or behavioral activity in control rats. The rise in mesolimbic DA appears to be significant in anticipating the physiological and behavioral demands of an aggressive episode, and the fall in 5-HT in its termination, dissociated from the actual execution of the behavior.
We used in vivo microdialysis to examine the responses to intraspecific social interactions in the striatal dopamine systems of females of two vole species displaying vastly different social structures. Both highly social prairie voles and asocial meadow voles had similar increases in extracellular dopamine associated with mating. There was a species-specific effect of social condition on extracellular dihydroxyphenylacetic acid (DOPAC). Exposure to a conspecific male significantly decreased extracellular DOPAC in female prairie voles isolated for approximately 18 h during surgical recovery. Such decrease in DOPAC was not seen if females experienced continued isolation or if they were housed with a sibling during surgical recovery. No changes in extracellular DOPAC were seen in meadow voles after manipulations of social environment. Together, our data indicate that mating-associated dopamine release is independent from mating systems. However, species-specific patterns of extracellular DOPAC suggest that social isolation may be a more stressful stimulus for the social prairie vole than for the asocial meadow vole.
Female rats engage in approach and avoidance behaviors directed toward the male to "pace" the rate of copulation. These pacing behaviors result in a pattern of vaginocervical stimulation that triggers a neuroendocrine reflex that is important for pregnancy to result from insemination. Each female rat has a preferred pacing interval, and females develop conditioned place preferences for paced sex versus nonpaced sex. Research from this laboratory has reported that extracellular dopamine concentrations in striatum and nucleus accumbens are greater in female rats that are engaging in paced sex compared with those engaging in nonpaced sex. Furthermore, females who have males removed at their preferred intervals during a copulatory bout show extracellular dopamine concentrations comparable to females engaging in paced sex. It is unclear, however, whether they would also develop a conditioned place preference for sex under such conditions. This experiment was designed to address this question. Female rats had six exposures each to a chamber in which they engaged in nonpaced sex and a chamber in which they engaged in paced or preferred pacing interval sex. Following conditioning trials, females were tested for a conditioned place preference. The findings indicate that female rats develop conditioned place preferences for paced sex and for sex in which the male is removed at her preferred interval. This suggests that sexual behavior is reinforcing to female rats when their preferred interval is achieved, whether or not they are actively controlling the rate of copulation.
Dendritic spines, which receive most of the excitatory synaptic input in the cerebral cortex, are heterogeneous with regard to their structure, stability and function. Spines with large heads are stable, express large numbers of AMPA-type glutamate receptors, and contribute to strong synaptic connections. By contrast, spines with small heads are motile and unstable and contribute to weak or silent synaptic connections. Their structure-stability-function relationships suggest that large and small spines are "memory spines" and "learning spines", respectively. Given that turnover of glutamate receptors is rapid, spine structure and the underlying organization of the actin cytoskeleton are likely to be major determinants of fast synaptic transmission and, therefore, are likely to provide a physical basis for memory in cortical neuronal networks. Characterization of supramolecular complexes responsible for synaptic memory and learning is key to the understanding of brain function and disease.
A brief exposure to social defeat in male Syrian hamsters (Mesocricetus auratus) leads to profound changes in the subsequent agonistic behavior exhibited by the defeated animals. Following defeat in the home cage of an aggressive conspecific, male hamsters will subsequently fail to defend their home territory even if the intruder is a smaller, nonaggressive male. This phenomenon has been called conditioned defeat. In Experiment 1, we examined the duration of conditioned defeat by repeatedly testing (every 3-5 days) defeated hamsters with a nonaggressive intruder. We found that conditioned defeat occurs in all defeated male hamsters and persists for a prolonged period of time (at least 33 days) in the majority of male hamsters tested despite the fact that these animals are never attacked by the nonaggressive intruders. In Experiment 2, we examined whether conditioned defeat could be induced in female Syrian hamsters. While conditioned defeat occurred in some females, they displayed only low levels of submissive/defensive behavior and, in contrast to males, the conditioned defeat response did not persist beyond the first test. These results suggest that in male hamsters conditioned defeat is a profound, persistent behavioral change characterized by a total absence of territorial aggression and by the frequent display of submissive and defensive behaviors. Conversely, social defeat in female hamsters does not appear to induce long-term behavioral changes. Finally, in Experiment 3, we determined that plasma adrenocorticotropin-like immunoreactivity increases in females following social defeat in a manner similar to that seen in males, suggesting that the disparate behavioral reactions of males and females are not due to sex differences in the release of, or response to, plasma adrenocorticotropin.