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Cell-Type Specific Increases in Female Hamster Nucleus Accumbens Spine Density following Female Sexual Experience
Abstract
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.
... 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 . ...
... Collectively, these results further provide evidence for an inverse role between mGluR1a and mGluR5 (Gross et al., 2016;Turner et al., 2018b), a reciprocal role between NR2A and NR2B in long-term potentiation and long-term depression (Massey et al., 2004;Bartlett et al., 2007), and differences in NMDAR function and learning and memory (Bar-Shira et al., 2015). In other words, these results provide support for the theory that mGluR1a and mGluR5 activation have opposite roles in NAc synaptic morphology, neuronal transmission and behavior (Dewing et al., 2007;Staffend and Meisel, 2012;Staffend et al., 2014;Been et al., 2016;Gross et al., 2016;Pitchers et al., 2016) through differences in their association with specific NMDAR subunits (Yashiro and Seki, 2017;Zoicas and Kornhuber, 2019). In agreement with previous literature, there was also a positive correlation in the expression of GluA1 and GluA2 (Diering and Huganir, 2018). ...
... There is evidence to suggest that there may be both conserved and divergent molecular mechanisms underlying aggression reward between males and females (Terranova et al., 2016;Borland et al., 2019a). There is also strong evidence that there are both conserved (Wallace et al., 2008;Hedges et al., 2009;Lobo et al., 2013;Pitchers et al., 2013;Aleyasin et al., 2018;Hamilton et al., 2018;Heshmati et al., 2018;Golden et al., 2019a) and divergent (Staffend and Meisel, 2012;Staffend et al., 2014) mechanisms underlying different social behaviors and animal species. We hypothesize that the recruitment of the glutamate system in the NAc for encoding social reward is conserved between males and females and across different species (Lei et al., 2020;Stagkourakis et al., 2020). ...
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 female hamsters, sexual experience (once a week for 6 weeks) increased spine density in D1 receptor expressing neurons in the NAcc core, a change that may facilitate reproductive success (Staffend, Hedges, Chemel, Watts, & Meisel, 2014). Given the dopaminergic activation that occurs in response to sexual behavior, Staffend et al. speculated that sexual experience may influence mesolimbic dopaminergic activity in a manner that leads to plastic changes. ...
... And sexual experience induces c-Fos expression in the NAcc of both males and females (Bradley & Meisel, 2001;Lopez & Ettenberg, 2002). Furthermore, sexually experienced female hamsters present increased D1 receptor responsiveness (Bradley et al., 2004), and increased spine density in D1 receptor expressing neurons of the NAcc core (Staffend et al., 2014). Together with the aforementioned microarray data demonstrating effects of sexual experience on the expression of a great variety of genes in the NAcc and dorsal striatum (see Gene expression section) (Bradley et al., 2005), these data suggest that the behavioral changes observed in sexually experienced female hamsters depend on plastic changes involving the mesolimbic dopaminergic system. ...
... Sexual behavior produces a variety of effects on brain and behavior, including altered sex hormone release (Exton et al., 1999;Gleason et al., 2009;Goldey & van Anders, 2011;Shulman & Spritzer, 2014;van Anders et al., 2007van Anders et al., , 2009; changes in neurogenesis in the hippocampus (Glasper & Gould, 2013;Leuner et al., 2010) and olfactory bulb (Arzate et al., 2013;Corona et al., 2011Corona et al., , 2016Portillo et al., 2012;Unda et al., 2016); changes in synaptic spine density in the medial prefrontal cortex (Glasper et al., 2015;Meisel & Mullins, 2006), hippocampus (Glasper et al., 2015;Leuner et al., 2010), NAcc (Staffend et al., 2014), and vlVMH (Flanagan-Cato et al., 2006); changes in the activation of intracellular signaling pathways in the hippocampus (Kim et al., 2013), MPOA (Meerts et al., 2016), VTA (Balfour et al., 2004), and NAcc (Bradley et al., 2004;Meisel & Mullins, 2006); changes in gene expression in the NAcc (Balfour et al., 2004;Bradley et al., 2005;Bradley & Meisel, 2001;Lopez & Ettenberg, 2002), VTA (Balfour et al., 2004), MPOA , cerebellum (Paredes-Ramos et al., 2011), andvlVMH (Flanagan-Cato et al., 2006); and changes in electrical activity in the cerebellum (Garcia-Martinez et al., 2010). Furthermore, sexual experience leads to behavioral changes, both related to sexual behavior (Meisel & Mullins, 2006;Woodson, 2002), and not directly related to it, such as changes in learning and memory performance (Glasper & Gould, 2013;Kim et al., 2013;Maunder et al., 2017) (Fig. 1). ...
Although sex drive is present in many animal species, sexual behavior is not static and, like many other behaviors, can be modified by experience. This modification relies on synaptic plasticity, a sophisticated mechanism through which neurons change how they process a given stimulus, and the neurophysiological basis of learning. This review addresses the main plastic effects of steroid sex hormones in the central nervous system (CNS) and the effects of sexual experience on the CNS, including effects on neurogenesis, intracellular signaling, gene expression, and changes in dendritic spines, as well as behavioral changes.
... Sexual experience increases dendritic spine density in medium spiny neurons of female hamsters, particularly in the core of the nucleus accumbens (Staffend et al., 2014). Dendritic spines receive excitatory, largely glutamatergic, inputs and have different morphologies which are thought to reflect biophysical properties impacting excitability of the neurons (Tonnesen and Nagerl, 2016). ...
... Knowing the phenotype of medium spiny neurons affected by sexual experience can be informative for developing hypotheses about the functional consequences of these changes in dendritic spines. Not only were the effects of sexual experience restricted to the core of the nucleus accumbens, but changes in spines were localized to the D1 containing medium spiny neurons (Staffend et al., 2014). These anatomical observations link observations of plasticity in neural pathways associated with intrinsic fixed-action behavioral sequences (Kalueff et al., 2016) to the control of female sexual motivation. ...
... This raises the question of how changes in dopamine-mediated intracellular signaling underlie structural and behavioral plasticities? Female sexual experience does not affect the levels of either D1 or D2 receptors in the nucleus accumbens, nor does it impact D1 or D2 receptor binding (Staffend et al., 2014), yet there must be an enhancement of dopamine receptor signaling since c-Fos production is sensitized. Stimulating dopamine D1 receptors produces a greater cAMP response in homogenates from the nucleus accumbens of sexually-experienced vs. inexperienced female hamsters (Bradley et al., 2004). ...
The hypothalamus is most often associated with innate behaviors such as is hunger, thirst and sex. While the expression of these behaviors important for survival of the individual or the species is nested within the hypothalamus, the desire (i.e., motivation) for them is centered within the mesolimbic reward circuitry. In this review, we will use female sexual behavior as a model to examine the interaction of these circuits. We will examine the evidence for a hypothalamic circuit that regulates consummatory aspects of reproductive behavior, i.e., lordosis behavior, a measure of sexual receptivity that involves estradiol membrane-initiated signaling in the arcuate nucleus (ARH), activating β-endorphin projections to the medial preoptic nucleus (MPN), which in turn modulate ventromedial hypothalamic nucleus (VMH) activity—the common output from the hypothalamus. Estradiol modulates not only a series of neuropeptides, transmitters and receptors but induces dendritic spines that are for estrogenic induction of lordosis behavior. Simultaneously, in the nucleus accumbens of the mesolimbic system, the mating experience produces long term changes in dopamine signaling and structure. Sexual experience sensitizes the response of nucleus accumbens neurons to dopamine signaling through the induction of a long lasting early immediate gene. While estrogen alone increases spines in the ARH, sexual experience increases dendritic spine density in the nucleus accumbens. These two circuits appear to converge onto the medial preoptic area where there is a reciprocal influence of motivational circuits on consummatory behavior and vice versa. While it has not been formally demonstrated in the human, such circuitry is generally highly conserved and thus, understanding the anatomy, neurochemistry and physiology can provide useful insight into the motivation for sexual behavior and other innate behaviors in humans.
... However, our recording paradigm would have biased against detection of these interneurons, and we believe that they are present. Although we characterize all of the recorded MSNs as a single class, MSN subtypes have been detected in other rodents (Gertler et al. 2008;Planert et al. 2013;Staffend et al. 2014), and these subtypes have subtle electrophysiological differences and there is likewise no reason to believe that they are absent from vole striatum. With that limitation acknowledged, we conclude it unlikely that the electrophysiological differences detected here are explained by differential sampling of D1 vs. D2 receptor-expressing MSNs. ...
... Thus any sexual experience gained by the voles over the 18-h partnering period would have been a novel stimulus and possibly reflected in MSN properties. It has been shown that male or female sexual experience increases the density of dendritic spines on NAc but not nucleus accumbens shell MSNs in hamsters and rats (Meisel and Mullins 2006;Pitchers et al. 2010;Staffend et al. 2014), a change normally associated with mEPSC frequency. However, mEPSC frequency did not associate with partner preference in voles, and no difference in mEPSC frequency was detected between voles and rats, despite differences in sexual experience. ...
Medium spiny neurons (MSNs) in the nucleus accumbens have long been implicated in the neurobiological mechanisms that underlie numerous social and motivated behaviors as studied in rodents such as rats. Recently, the prairie vole has emerged as an important model animal for studying social behaviors, particularly regarding monogamy due to their ability to form pair bonds. However, to our knowledge, no study has assessed intrinsic vole MSN electrophysiological properties, or tested how these properties vary with the strength of the pair bond between partnered voles. Here, we performed whole-cell patch clamp recordings of MSNs in acute brain slices of the nucleus accumbens core (NAc) of adult male voles exhibiting strong and weak preferences for his respective partnered female. We first document vole MSN electrophysiological properties and provide comparison to rat MSNs. Vole MSNs demonstrated many canonical electrophysiological attributes shared across species, but exhibited notable differences in excitability compared to rat MSNs. Second, we assessed male vole partner preference behavior and tested whether MSN electrophysiological properties varied with partner preference strength. Male vole partner preference showed extensive variability. We found that decreases in mEPSC amplitude and the slope of the evoked action potential firing rate to depolarizing current injection weakly associated with increased preference for the partnered female. This suggests that excitatory synaptic strength and neuronal excitability may be decreased in MSNs in males exhibiting stronger preference for a partnered female. Overall, these data provide extensive documentation of MSN electrophysiological characteristics, and their relationship to social behavior in the prairie vole.
... Moreover, we have demonstrated that D1R blockage in the NAcc during the conditioning phase reduced the olfactory preference of males toward female chemosignals more than 10 days later. The reinforcing effects of sexual stimuli are mediated by long-lasting neuroplasticity changes in the NAc (Beloate et al., 2016;Pitchers et al., 2012;Staffend et al., 2014), which are dependent on D1R signaling and its down-stream effects (Pitchers et al., 2013;Staffend et al., 2014). Our results suggest that blocking D1R signaling during the initial interactions with female chemosignals prevented the occurrence of female-induced neuroplasticity in the NAcc, and this altered the olfactory preference of males days later. ...
... Moreover, we have demonstrated that D1R blockage in the NAcc during the conditioning phase reduced the olfactory preference of males toward female chemosignals more than 10 days later. The reinforcing effects of sexual stimuli are mediated by long-lasting neuroplasticity changes in the NAc (Beloate et al., 2016;Pitchers et al., 2012;Staffend et al., 2014), which are dependent on D1R signaling and its down-stream effects (Pitchers et al., 2013;Staffend et al., 2014). Our results suggest that blocking D1R signaling during the initial interactions with female chemosignals prevented the occurrence of female-induced neuroplasticity in the NAcc, and this altered the olfactory preference of males days later. ...
Sexual preference for the opposite sex is a fundamental behavior underlying reproductive success, but the neural mechanisms remain unclear. Here, we examined the role of dopamine signaling in the nucleus accumbens core (NAcc) in governing chemosensory-mediated preference for females in TrpC2-/- and wild-type male mice. TrpC2-/- males, deficient in VNO-mediated signaling, do not display mating or olfactory preference toward females. We found that, during social interaction with females, TrpC2-/- males do not show increased NAcc dopamine levels, observed in wild-type males. Optogenetic stimulation of VTA-NAcc dopaminergic neurons in TrpC2-/- males during exposure to a female promoted preference response to female pheromones and elevated copulatory behavior toward females. Additionally, we found that signaling through the D1 receptor in the NAcc is necessary for the olfactory preference for female-soiled bedding. Our study establishes a critical role for the mesolimbic dopaminergic system in governing pheromone-mediated responses and mate choice in male mice.
... For example, removal of dopaminergic inputs into the nucleus accumbens of female rats attenuates the effect of female sexual experience on copulatory efficiency (Bradley et al., 2005). Relatedly, sexually experienced female hamsters (Mesocricetus auratus) also show greater D1-receptor dependent intracellular signaling (Bradley et al., 2004) and increased spine density on D1 receptor expressing neurons in the nucleus accumbens (Staffend et al., 2014). ...
Revealing the mechanisms underlying experience-dependent plasticity is a hallmark of behavioral neuroscience. While the study of social behavior has focused primarily on the neuroendocrine and neural control of social behaviors, the plasticity of these innate behaviors has received relatively less attention. Here, we review studies on mating-dependent changes to social behavior and neural circuitry across mammals, birds, and reptiles. We provide an overview of species similarities and differences in the effects of mating experiences on motivational and performative aspects of sexual behaviors, on sensory processing and preferences, and on the experience-dependent consolidation of sexual behavior. We also discuss recent insights into the neural mechanisms of and developmental influences on mating-dependent changes and outline promising approaches to investigate evolutionary parallels and divergences in experience-dependent plasticity.
RESEARCH HIGHLIGHTS
• Social experiences alter the performance and hormonal and neural control of social behavior
• Nonmammalian vertebrates can demonstrate similar types of experience-dependent changes as mammals
• Similarities and differences in brain mechanisms of behavioral plasticity between mammals and nonmammalian vertebrates are discussed
... Indeed, we found that both sexual experience and overexpression of ⌬FosB significantly increased the density of spines on IL pyramidal neurons, with sexual experience increasing mature mushroom spines and overexpression of ⌬FosB increasing thin and total spines. These results are consistent with previous work: sexual experience in female hamsters increases NAc spine density (Staffend et al., 2014); in other rodents, sexual experience in males increases mPfC pyramidal neuron spine density (Glasper et al., 2015), early-life stress reduces both social interaction and mPfC spines (Farrell et al., 2016), and antidepressant treatment increases both dendritic spine number and ⌬FosB expression in PfC (Li et al., 2010;Vialou et al., 2014). One intriguing potential explanation for these findings is that sexual experience increases ⌬FosB expression driving an initial increase in thin spines, while consolidation of memories encoding learned sexual behavior is accompanied by a return to basal ⌬FosB levels and a maturation of spines into a mushroom shape. ...
Acquisition of social proficiency entails behavioral adaptations to social experience, including both behavioral flexibility and inhibition of behaviors inappropriate in specific social contexts. Here, we investigated the contributions of testosterone and delta FosB, a transcription factor linked to experience-dependent neural plasticity, to the adolescent maturation of social proficiency in male-female social interactions. To determine whether pubertal testosterone organizes circuits underlying social proficiency, we first compared behavioral adaptations to sexual experience in male Syrian hamsters that were deprived of testosterone during puberty (prepubertal castration; NoT@P) to those of males deprived of testosterone for an equivalent period of time in adulthood (postpubertal castration; T@P). All males were given testosterone replacement in adulthood for two weeks before sexual behavior testing, where males were allowed to interact with a receptive female once per week for five consecutive weeks. T@P males showed the expected decrease in ectopic (mis-directed) mounts with sexual experience, whereas NoT@P males did not. In addition, sexual experience induced FosB gene products expression in the infralimbic cortex (IL) in T@P, but not NoT@P, males. Overexpression of delta FosB via an adeno-associated viral (AAV) vector in the IL of NoT@P males prior to sexual behavior testing was sufficient to produce a behavioral phenotype similar to that of experienced T@P males. Finally, overexpression of delta FosB in IL increased the density of immature spines on IL dendrites. Our findings provide evidence that social proficiency acquired through sexual experience is organized by pubertal testosterone through the regulation of delta FosB in the IL, possibly through increasing synaptic lability.
... 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.
... However, one could speculate that the factors underlying the neural response among higher sexual risk youth, including sensitivity to peer feedback or sexual desire arising from peer attractiveness, influence the function of reward and affective neural circuits, such that sexual risk evaluation is biased towards immediate sexual rewards over long-term health. As non-human primate studies have indicated, brain function changes as a result of sexual experiences and contact (Olsen, 2011;Staffend et al., 2014). The effects of sexual experience could have both adaptive and maladaptive consequences at many levels, including function in endocrine systems, development of brain structure, and sensitivity of brain function. ...
Adolescent sexual risk behavior can lead to serious health consequences, yet few investigations have addressed its neurodevelopmental mechanisms. Social neurocircuitry is postulated to underlie the development of risky sexual behavior, and response to social reward may be especially relevant. Typically developing adolescents (N=47; 18M, 29F; 16.3±1.4years; 42.5% sexual intercourse experience) completed a social reward fMRI task and reported their sexual risk behaviors (e.g., lifetime sexual partners) on the Youth Risk Behavior Survey (YRBS). Neural response and functional connectivity to social reward were compared for adolescents with higher- and lower-risk sexual behavior. Adolescents with higher-risk sexual behaviors demonstrated increased activation in the right precuneus and the right temporoparietal junction during receipt of social reward. Adolescents with higher-risk sexual behaviors also demonstrated greater functional connectivity between the precuneus and the temporoparietal junction bilaterally, dorsal medial prefrontal cortex, and left anterior insula/ventrolateral prefrontal cortex. The greater activation and functional connectivity in self-referential, social reward, and affective processing regions among higher sexual risk adolescents underscores the importance of social influence underlying sexual risk behaviors. Furthermore, results suggest an orientation towards and sensitivity to social rewards among youth engaging in higher-risk sexual behavior, perhaps as a consequence of or vulnerability to such behavior.
... Moreover, in male rats sexual experience causes sensitized conditioned place preference (CPP) for low doses of the psychostimulant, D-Amphetamine (Amph) (Pitchers et al., 2010a), which is dependent on a period of sexual abstinence and is longlasting (Pitchers et al., 2010a(Pitchers et al., , 2013. Sexual experience also causes neural alterations in the nucleus accumbens (NAc) and ventral tegmental area (VTA), including increased dendritic arborization and spine density in NAc medium spiny neurons (Pitchers et al., 2010a(Pitchers et al., , 2013Staffend et al., 2014), reduction of VTA dopamine cell soma size (Pitchers et al., 2014), and upregulation of the transcription factor deltaFosB, in both NAc and VTA (Meisel and Mullins, 2006;Pitchers et al., 2010bPitchers et al., , 2013. Hence, our laboratory has proposed that these neural alterations contribute to the effects of sexual experience on cross-sensitization to Amph reward. ...
An important factor that can modulate neuron properties is sex-specific hormone fluctuations, including the human menstrual cycle and rat estrous cycle in adult females. Considering the striatal brain regions, the nucleus accumbens (NAc) core, NAc shell, and caudate-putamen (CPu), the estrous cycle has previously been shown to impact relevant behaviors and disorders, neuromodulator action, and medium spiny neuron (MSN) electrophysiology. Whether the estrous cycle impacts MSN dendritic spine attributes has not yet been examined, even though MSN spines and glutamatergic synapse properties are sensitive to exogenously applied estradiol. Thus, we hypothesized that MSN dendritic spine attributes would differ by estrous cycle phase. To test this hypothesis, brains from adult male rats and female rats in diestrus, proestrus AM, proestrus PM, and estrus were processed for Rapid Golgi-Cox staining. MSN dendritic spine density, size, and type were analyzed in the NAc core, NAc shell, and CPu. Overall spine size differed across estrous cycle phases in female NAc core and NAc shell, and spine length differed across estrous cycle phase in NAc shell and CPu. Consistent with previous work, dendritic spine density was increased in the NAc core compared to the NAc shell and CPu, independent of sex and estrous cycle. Spine attributes in all striatal regions did not differ by sex when estrous cycle was disregarded. These results indicate, for the first time, that estrous cycle phase impacts dendritic spine plasticity in striatal regions, providing a neuroanatomical avenue by which sex-specific hormone fluctuations can impact striatal function and disorders.
Mating is essential for the reproduction of animal species. As mating behaviors are high-risk and energy-consuming processes, it is critical for animals to make adaptive mating decisions. This includes not only finding a suitable mate, but also adapting mating behaviors to the animal’s needs and environmental conditions. Internal needs include physical states (e.g., hunger) and emotional states (e.g., fear), while external conditions include both social cues (e.g., the existence of predators or rivals) and non-social factors (e.g., food availability). With recent advances in behavioral neuroscience, we are now beginning to understand the neural basis of mating behaviors, particularly in genetic model organisms such as mice and flies. However, how internal and external factors are integrated by the nervous system to enable adaptive mating-related decision-making in a state- and context-dependent manner is less well understood. In this article, we review recent knowledge regarding the neural basis of flexible mating behaviors from studies of flies and mice. By contrasting the knowledge derived from these two evolutionarily distant model organisms, we discuss potential conserved and divergent neural mechanisms involved in the control of flexible mating behaviors in invertebrate and vertebrate brains.
This chapter discusses the influence of the autonomic nervous system on sexual behavior, physiology, and human sexual dysfunction. We review the innervation of the male and female sexual organs, the role of the autonomic nervous system in sexual responses, neuroanatomical sex differences, and sexual function in patients with disorders of the nervous system.
Female sexual dysfunction is both a symptom of depression and exacerbated by treatments for depression. Ketamine, a novel treatment for depression, has been shown to enhance, whereas fluoxetine has been shown to impair sexual motivation. Sexual experience leads to more robust partner preference and paced mating behavior in female rats. Whether acute ketamine and fluoxetine similarly affect sexual motivation and mating behavior in sexually experienced female rats is unknown. Sexually experienced female rats received 10 mg/kg i.p. of ketamine or saline vehicle (Experiment 1) or 10 mg/kg i.p. of fluoxetine or water vehicle (Experiment 2) 30 min before a 10-min No-Contact partner preference test followed immediately by a 15-intromission paced mating test. Partner preference and paced mating behavior did not differ between ketamine- and saline-treated rats. In contrast, rats treated with fluoxetine spent significantly less time with either stimulus animal and were less active during the partner preference test than water-treated rats. Additionally, contact-return latency to ejaculation was significantly longer in fluoxetine-treated rats and they spent less time with the male during paced mating in comparison to water-treated rats. Thus, even with sexual experience, fluoxetine disrupts sexual function whereas ketamine has no detrimental effects on sexual behavior in female rats. A growing body of evidence suggests that ketamine is an encouraging new approach to treat depression particularly because it is not associated with sexual dysfunction.
Hormones and Behavior was first published 50 years ago including some articles related to the hormonal regulation of sexual behavior in different species. Since then, this research field has produced outstanding discoveries that have contributed to our understanding of the control of sexual behavior. The refinement of classical techniques and the development of new experimental tools has opened the door to a new era of research that will allow us to understand different aspects of sexual behavior. It would also expand the possible extrapolation from animal models to understand human sexuality and its dysfunctions. In this review, we summarize some of the most recent findings about sexual behavior in both sexes including the refinement of classical methods of study with new approaches and questions as well as the development of new methods trying to explain mechanisms of action on motivational and consummatory elements of mating behavior. We also reviewed other aspects that modulate sexual behavior such as attractivity, olfactory signals and learning which model mate selection. Additionally, we described studies demonstrating that sexual behavior induces permanent brain modifications in neuronal circuits. Finally, we briefly describe recent contributions on animal models of human sexuality dysfunctions which, although with their own limitations, are under continuous refining.
The striatal brain regions, including the caudate-putamen, nucleus accumbens core, and nucleus accumbens shell, mediate critical behavioral functions. These functions include but are not limited to motivated behavior, reward, learning, and sensorimotor function in both pathological and normal contexts. The phenotype and/or incidence of all of these behaviors either differ by sex or are sensitive to the presence of gonadal hormones such as 17β-estradiol and testosterone. All three striatal brain regions express membrane-associated estrogen receptors. Here we present a brief review of the recent literature reporting on sex differences and effects of the estrogenic hormone 17β-estradiol on behavioral and neural function across all three striatal regions, focusing upon the most prominent striatal neuron type, the medium spiny neuron. We emphasize recent findings in three broad domains: (1) select striatal-relevant behaviors and disorders, (2) striatal medium spiny neuron dendritic spine density, and (3), striatal medium spiny neuron electrophysiological properties including excitatory synaptic input and intrinsic cellular excitability. These recent advances in behavior, neuroanatomy, and electrophysiology collectively offer insight into the effects of sex and estrogen on striatal function, especially at the level of individual neurons.
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.
D1 and D2 receptor expressing striatal medium spiny neurons (MSNs) are ascribed to striatonigral ("direct") and striatopallidal ("indirect") pathways, respectively, that are believed to function antagonistically in motor control. Glutamatergic synaptic transmission onto the two types is differentially affected by Dopamine (DA), however, less is known about the effects on MSN intrinsic electrical properties. Using patch clamp recordings, we comprehensively characterized the two pathways in rats and mice, and investigated their DA modulation. We identified the direct pathway by retrograde labeling in rats, and in mice we used transgenic animals in which EGFP is expressed in D1 MSNs. MSNs were subjected to a series of current injections to pinpoint differences between the populations, and in mice also following bath application of DA. In both animal models, most electrical properties were similar, however, membrane excitability as measured by step and ramp current injections consistently differed, with direct pathway MSNs being less excitable than their counterparts. DA had opposite effects on excitability of D1 and D2 MSNs, counteracting the initial differences. Pronounced changes in AP shape were seen in D2 MSNs. In direct pathway MSNs, excitability increased across experimental conditions and parameters, and also when applying DA or the D1 agonist SKF-81297 in presence of blockers of cholinergic, GABAergic, and glutamatergic receptors. Thus, DA induced changes in excitability were D1 R mediated and intrinsic to direct pathway MSNs, and not a secondary network effect of altered synaptic transmission. DAergic modulation of intrinsic properties therefore acts in a synergistic manner with previously reported effects of DA on afferent synaptic transmission and dendritic processing, supporting the antagonistic model for direct vs. indirect striatal pathway function.
Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.
Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards. In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ΔFosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ΔJunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ΔFosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ΔFosB induction and prevented increased spinogenesis and sensitized amphetamine reward. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.
Recent work has advanced our knowledge of phasic dopamine reward prediction error signals. The error signal is bidirectional, reflects well the higher order prediction error described by temporal difference learning models, is compatible with model-free and model-based reinforcement learning, reports the subjective rather than physical reward value during temporal discounting and reflects subjective stimulus perception rather than physical stimulus aspects. Dopamine activations are primarily driven by reward, and to some extent risk, whereas punishment and salience have only limited activating effects when appropriate controls are respected. The signal is homogeneous in terms of time course but heterogeneous in many other aspects. It is essential for synaptic plasticity and a range of behavioural learning situations.
Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS(3)) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward.
Studies addressing behavioral functions of dopamine (DA) in the nucleus accumbens septi (NAS) are reviewed. A role of NAS DA in reward has long been suggested. However, some investigators have questioned the role of NAS DA in rewarding effects because of its role in aversive contexts. As findings supporting the role of NAS DA in mediating aversively motivated behaviors accumulate, it is necessary to accommodate such data for understanding the role of NAS DA in behavior. The aim of the present paper is to provide a unifying interpretation that can account for the functions of NAS DA in a variety of behavioral contexts: (1) its role in appetitive behavioral arousal, (2) its role as a facilitator as well as an inducer of reward processes, and (3) its presently undefined role in aversive contexts. The present analysis suggests that NAS DA plays an important role in sensorimotor integrations that facilitate flexible approach responses. Flexible approach responses are contrasted with fixed instrumental approach responses (habits), which may involve the nigro-striatal DA system more than the meso-accumbens DA system. Functional properties of NAS DA transmission are considered in two stages: unconditioned behavioral invigoration effects and incentive learning effects. (1) When organisms are presented with salient stimuli (e.g., novel stimuli and incentive stimuli), NAS DA is released and invigorates flexible approach responses (invigoration effects). (2) When proximal exteroceptive receptors are stimulated by unconditioned stimuli, NAS DA is released and enables stimulus representations to acquire incentive properties within specific environmental context. It is important to make a distinction that NAS DA is a critical component for the conditional formation of incentive representations but not the retrieval of incentive stimuli or behavioral expressions based on over-learned incentive responses (i.e., habits). Nor is NAS DA essential for the cognitive perception of environmental stimuli. Therefore, even without normal NAS DA transmission, the habit response system still allows animals to perform instrumental responses given that the tasks take place in fixed environment. Such a role of NAS DA as an incentive-property constructor is not limited to appetitive contexts but also aversive contexts. This dual action of NAS DA in invigoration and incentive learning may explain the rewarding effects of NAS DA as well as other effects of NAS DA in a variety of contexts including avoidance and unconditioned/conditioned increases in open-field locomotor activity. Particularly, the present hypothesis offers the following interpretation for the finding that both conditioned and unconditioned aversive stimuli stimulate DA release in the NAS: NAS DA invigorates approach responses toward `safety'. Moreover, NAS DA modulates incentive properties of the environment so that organisms emit approach responses toward `safety' (i.e., avoidance responses) when animals later encounter similar environmental contexts. There may be no obligatory relationship between NAS DA release and positive subjective effects, even though these systems probably interact with other brain systems which can mediate such effects. The present conceptual framework may be valuable in understanding the dynamic interplay of NAS DA neurochemistry and behavior, both normal and pathophysiological.
The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems--so-called direct and indirect pathways--form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D(1) and D(2) DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.
Identifying neuronal morphology is a key component in understanding neuronal function. Several techniques have been developed to address this issue, including Golgi staining, electroporation of fluorescent dyes, and transfection of fluorescent constructs. Ballistic delivery of transgenic constructs has been a successful means of rapidly transfecting a nonbiased population of cells within tissue or culture. Recently, this technique was modified for the ballistic delivery of dye-coated gold or tungsten particles, enabling a nonbiased, rapid fluorescent membrane labeling of individual neurons in both fixed and nonfixed tissue. This unit outlines a step-by-step protocol for the ballistic method of dye delivery ("DiOlistic" labeling) to fixed tissue, including optimal tissue fixation conditions. In addition, a protocol for coupling "DiOlistic" labeling with other immunofluorescent methods is detailed, enabling the association of neuronal morphology with a specific cellular phenotype.
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.
Cocaine induces plasticity at glutamatergic synapses in the nucleus accumbens (NAc). Withdrawal was suggested to play an important role in the development of this plasticity by studies showing that some changes only appear several weeks after the final cocaine exposure. In this study, the requirement for prolonged withdrawal was evaluated by comparing the changes in glutamatergic transmission induced by two different noncontingent cocaine treatments: a short treatment followed by prolonged withdrawal, and a longer treatment without prolonged withdrawal. Recordings were performed from mouse medium spiny neurons (MSNs) in the NAc at the same time after the first cocaine injection under both treatments. A similar increase in the frequency of glutamate-mediated miniature EPSCs was observed in D(1)-expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPA receptor-to-NMDA receptor ratios, higher spine density, and enlarged spine heads were observed in the absence of withdrawal after a long cocaine treatment. These synaptic adaptations expressed in D(1)-containing MSNs of the NAc core were not further enhanced by protracted withdrawal. In conclusion, a few repeated cocaine injections are enough to trigger adaptations at glutamatergic synapses in D(1)-expressing MSNs, which, although they take time to develop, do not require prolonged cocaine withdrawal.
Estradiol affects a variety of brain regions by modulating physiological and cellular functions as well as neuronal morphology. Within the striatum, estradiol is known to induce physiological and molecular changes, yet estradiol's effects on striatal dendritic morphology have not yet been evaluated. Using ballistic delivery of the lipophilic dye DiI to tissue sections, we were able to evaluate estradiol's effects on striatal morphology in female Syrian hamsters. We found that estradiol significantly decreased spine density within the nucleus accumbens core, with no effect in the nucleus accumbens shell or caudate. Interestingly, estradiol treatment caused a significant deconstruction of spines from more to less mature spine subtypes in both the nucleus accumbens core and shell regardless of changes in spine density. These results are significant in that they offer a novel mechanism for estradiol actions on a wide variety of nucleus accumbens functions such as motivation or reward as well as their pathological consequences (e.g. drug addiction).
INTRODUCTION
This protocol describes detailed procedures for rapid labeling of cells in a variety of preparations by means of particle-mediated ballistic (i.e., Gene Gun) delivery of fluorescent dyes. The method has been used for rapid labeling of cells with either lipid- or water-soluble dyes, in a variety of preparations at different ages. Tissue preparations include fixed mouse brain slices (described here), cell cultures, and tissue explants. This ballistic labeling technique is useful for studying neuronal connectivity, function, and pathology in the nervous system of living as well as fixed specimens.
Many of the brain's reward systems converge on the nucleus accumbens, a region richly innervated by excitatory, inhibitory, and modulatory afferents representing the circuitry necessary for selecting adaptive motivated behaviors. The ventral subiculum of the hippocampus provides contextual and spatial information, the basolateral amygdala conveys affective influence, and the prefrontal cortex provides an integrative impact on goal-directed behavior. The balance of these afferents is under the modulatory influence of dopamine neurons in the ventral tegmental area. This midbrain region receives its own complex mix of excitatory and inhibitory inputs, some of which have only recently been identified. Such afferent regulation positions the dopamine system to bias goal-directed behavior based on internal drives and environmental contingencies. Conditions that result in reward promote phasic dopamine release, which serves to maintain ongoing behavior by selectively potentiating ventral subicular drive to the accumbens. Behaviors that fail to produce an expected reward decrease dopamine transmission, which favors prefrontal cortical-driven switching to new behavioral strategies. As such, the limbic reward system is designed to optimize action plans for maximizing reward outcomes. This system can be commandeered by drugs of abuse or psychiatric disorders, resulting in inappropriate behaviors that sustain failed reward strategies. A fuller appreciation of the circuitry interconnecting the nucleus accumbens and ventral tegmental area should serve to advance discovery of new treatment options for these conditions.
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 transcription factor deltaFosB (DeltaFosB), induced in nucleus accumbens (NAc) by chronic exposure to drugs of abuse, has been shown to mediate sensitized responses to these drugs. However, less is known about a role for DeltaFosB in regulating responses to natural rewards. Here, we demonstrate that two powerful natural reward behaviors, sucrose drinking and sexual behavior, increase levels of DeltaFosB in the NAc. We then use viral-mediated gene transfer to study how such DeltaFosB induction influences behavioral responses to these natural rewards. We demonstrate that overexpression of DeltaFosB in the NAc increases sucrose intake and promotes aspects of sexual behavior. In addition, we show that animals with previous sexual experience, which exhibit increased DeltaFosB levels, also show an increase in sucrose consumption. This work suggests that DeltaFosB is not only induced in the NAc by drugs of abuse, but also by natural rewarding stimuli. Additionally, our findings show that chronic exposure to stimuli that induce DeltaFosB in the NAc can increase consumption of other natural rewards.
On the basis of behavioural evidence, dopamine is found to be involved in two higher-level functions of the brain: reward-mediated learning and motor activation. In these functions dopamine appears to mediate synaptic enhancement in the corticostriatal pathway. However, in electrophysiological studies, dopamine is often reported to inhibit corticostriatal transmission. These two effects of dopamine seem incompatible. The existence of separate populations of dopamine receptors, differentially modulating cholinergic and glutamatergic synapses, suggests a possible resolution to this paradox.
The synaptic enhancement which occurs in reward-mediated learning may also be involved in dopamine-mediated motor activation. The logical form of reward-mediated learning imposes constraints on which mechanisms can be considered possible. Dopamine D1 receptors may mediate enhancement of corticostriatal synapses. On the other hand, dopamine D2 receptors on cholinergic terminals may mediate indirect, inhibitory effects of dopamine on striatal neurons.
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.
The interactions among excitatory inputs arising from the prefrontal cortex, amygdala, and hippocampus, and innervating nucleus accumbens neurons were studied using in vivo intracellular recording techniques. Neurons recorded in the accumbens displayed one of three activity states: (1) silent, (2) spontaneously firing at low, constant rates, or (3) a bistable membrane potential, characterized by alternating periods of activity and silence occurring in concert with spontaneous transitions between two steady-state membrane potentials (average, -77.3 +/- 7.1 mV base, -63.0 +/- 7.4 mV plateau). These neurons also exhibited a high degree of convergence of responses elicited by stimulation of each of the three excitatory inputs tested. Activation of hippocampal afferents, but not cortical, amygdaloid, or thalamic afferents, induced bistable cells to switch to the depolarized (active) state. In contrast, no bistable cells were encountered in the nucleus accumbens following an acute transection of the fornix. Furthermore, microinjection of lidocaine in the vicinity of the hippocampal afferents at the level of the fornix caused a reversible elimination of the plateau phase in bistable cells. These data suggest that hippocampal input is necessary for accumbens neurons to enter a depolarized, active state. Furthermore, activation of prefrontal cortical inputs fail to evoke spike firing in accumbens neurons unless they are in this active state. Consequently, the hippocampus appears to be capable of gating prefrontal corticoaccumbens throughput.
Behavioral sensitization caused by repeated and intermittent administration of psychostimulants, such as cocaine and D-amphetamine, is accompanied by enhanced function in limbic-motor circuitry that is involved in the generation of motivated behavior. The present microdialysis study investigated the effect of D-amphetamine-induced sensitization on dopamine (DA) efflux in the nucleus accumbens (NAC) of male rats during sexual behavior. Male rats were given one injection of D-amphetamine (1.5 mg/kg, i.p.) or saline every other day for a total of 10 injections. Three weeks after discontinuation of drug treatment, rats were tested for sexual behavior during a test in which microdialysis was performed. There was an augmented efflux of DA in the NAC of D-amphetamine-sensitized rats compared with nonsensitized control rats when a receptive female was present behind a screen (35 vs 17%). Sensitized rats exhibited facilitated sexual behavior when the screen was removed, as indicated by a significantly shorter latency to mount and an overall increase in the amount of copulatory behavior. Although there was a significant increase in NAC DA concentrations from baseline in both sensitized and nonsensitized rats during copulation, there was a greater increase in DA efflux in the NAC of sensitized rats during the first 10 min copulatory sample (60 vs 37%). These results demonstrate that behavioral sensitization caused by repeated psychostimulant administration can "cross-sensitize" to a natural behavior, such as sex, and that increased NAC DA release may contribute to the facilitation of appetitive and consummatory aspects of this behavior.
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.
The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.
Synaptic modifications in nucleus accumbens (NAc) medium spiny neurons (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modification of NAc MSN synapses may occur in part via changes in the transcriptional potential of certain genes in a cell type-specific manner. The transcription factor FosB is one of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. Here, we demonstrate that overexpression of FosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor-expressing direct pathway MSNs in both the NAc shell and core. In contrast, FosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor-expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that FosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. To determine the behavioral consequences of cell type-specific actions of FosB, we selectively overexpressed FosB in D1 direct or D2 indirect MSNs in NAc in vivo and found that direct (but not indirect) pathway MSN expression enhances behavioral responses to cocaine. These results reveal that FosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.
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.
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 basal ganglia are often conceptualised as three parallel domains that include all the constituent nuclei. The ‘ventral domain’ appears to be critical for learning flexible behaviours for exploration and foraging, as it is the recipient of converging inputs from amygdala, hippocampal formation and prefrontal cortex, putatively centres for stimulus evaluation, spatial navigation, and planning/contingency, respectively. However, compared to work on the dorsal domains, the rich potential for quantitative theories and models of the ventral domain remains largely untapped, and the purpose of this review is to provide the stimulus for this work. We systematically review the ventral domain’s structures and internal organisation, and propose a functional architecture as the basis for computational models. Using a full schematic of the structure of inputs to the ventral striatum (nucleus accumbens core and shell), we argue for the existence of many identifiable processing channels on the basis of unique combinations of afferent inputs. We then identify the potential information represented in these channels by reconciling a broad range of studies from the hippocampal, amygdala and prefrontal cortex literatures with known properties of the ventral striatum from lesion, pharmacological, and electrophysiological studies. Dopamine’s key role in learning is reviewed within the three current major computational frameworks; we also show that the shell-based basal ganglia sub-circuits are well placed to generate the phasic burst and dip responses of dopaminergic neurons. We detail dopamine’s modulation of ventral basal ganglia’s inputs by its actions on pre-synaptic terminals and post-synaptic membranes in the striatum, arguing that the complexity of these effects hint at computational roles for dopamine beyond current ideas. The ventral basal ganglia are revealed as a constellation of multiple functional systems for the learning and selection of flexible behaviours and of behavioural strategies, sharing the common operations of selection-by-disinhibition and of dopaminergic modulation.
Exposure to addictive drugs causes changes in synaptic function within the striatal complex, which can either mimic or interfere with the induction of synaptic plasticity. These synaptic adaptations include changes in the nucleus accumbens (NAc), a ventral striatal subregion important for drug reward and reinforcement, as well as the dorsal striatum, which may promote habitual drug use. As the behavioral effects of drugs of abuse are long-lasting, identifying persistent changes in striatal circuits induced by in vivo drug experience is of considerable importance. Within the striatum, drugs of abuse have been shown to induce modifications in dendritic morphology, ionotropic glutamate receptors (iGluR) and the induction of synaptic plasticity. Understanding the detailed molecular mechanisms underlying these changes in striatal circuit function will provide insight into how drugs of abuse usurp normal learning mechanisms to produce pathological behavior.
Adenosine A(2A) and dopamine D(2) receptors (A(2A) and D(2)) associate in homo- and heteromeric complexes in the striatum, providing a structural basis for their mutual antagonism. At the cellular level, the portion of receptors engaging in homo- and heteromers, as well as the effect of persistent receptor activation or antagonism on the cell oligomer repertoire, are largely unknown. We have used bimolecular fluorescence complementation (BiFC) to visualize A(2A) and D(2) oligomerization in the Cath.a differentiated neuronal cell model. Receptor fusions to BiFC fluorescent protein fragments retained their function when expressed alone or in A(2A)/A(2A), D(2)/D(2), and A(2A)/D(2) BiFC pairs. Robust fluorescence complementation reflecting A(2A)/D(2) heteromers was detected at the cell membrane as well as in endosomes. In contrast, weaker BiFC signals, largely confined to intracellular domains, were detected with A(2A)/dopamine D(1) BiFC pairs. Multicolor BiFC was used to simultaneously visualize A(2A) and D(2) homo- and heteromers in living cells and to examine drug-induced changes in receptor oligomers. Prolonged D(2) stimulation with quinpirole lead to the internalization of D(2)/D(2) and A(2A)/D(2) oligomers and resulted in decreased A(2A)/D(2) relative to A(2A)/A(2A) oligomer formation. Opposing effects were observed in cells treated with D(2) antagonists or with the A(2A) agonist 5'-N-methylcarboxamidoadenosine (MECA). Subsequent radioreceptor binding analysis indicated that the drug-induced changes in oligomer formation were not readily explained by alterations in receptor density. These observations support the hypothesis that long-term drug exposure differentially alters A(2A)/D(2) receptor oligomerization and provide the first demonstration for the use of BiFC to monitor drug-modulated GPCR oligomerization.
Two-photon (2P) uncaging of caged neurotransmitters can efficiently stimulate individual synapses and is widely used to characterize synaptic functions in brain slice preparations. Here we extended 2P uncaging to neocortical pyramidal neurons in adult mice in vivo where caged glutamate was applied from the pial surface. To validate the methodology, we applied a small fluorescent probe using the same method, and confirmed that its concentrations were approximately homogenous up to 200 μm below the cortical surface, and that the extracellular space of the neocortex was as large as 22%. In fact, in vivo whole-cell recording revealed that 2P glutamate uncaging could elicit transient currents (2pEPSCs) very similar to excitatory postsynaptic currents (EPSCs). A spatial resolution of glutamate uncaging was 0.6-0.8 μm up to the depth of 200 μm, and in vivo 2P uncaging was able to stimulate single identified spines. Automated three-dimensional (3-D) mapping of such 2pEPSCs which covered the surfaces of dendritic branches revealed that functional AMPA receptor expression was stable and proportional to spine volume.Moreover, in vivo 2P Ca2+ imaging and uncaging suggested that the amplitudes of glutamate-induced Ca2+ transients were inversely proportional to spine volume. Thus, the key structure-function relationships hold in dendritic spines in adult neocortex in vivo, as in young hippocampal slice preparations. In vivo 2P uncaging will be a powerful tool to investigate properties of synapses in the neocortex.
The nucleus accumbens (NAc) is a brain region critically involved in psychostimulant-induced neuroadaptations. A major proportion of NAc neurons consists of medium spiny neurons (MSNs), commonly divided into two major subsets on the basis of their expression of D1 dopamine receptors (D1R-MSNs) or D2 dopamine receptors (D2R-MSNs). Although NAc MSNs are known to undergo extensive alterations in their characteristics upon exposure to drugs of abuse, the functional and structural changes specific to each type of MSN have yet to be fully resolved.
We repeatedly injected cocaine into transgenic mice expressing enhanced green fluorescent protein under the control of promoters for either D1R or D2R and then analyzed the physiological characteristics of each type of MSN by whole-cell recording. We also analyzed cocaine-induced changes of spine densities of individual MSNs with recombinant lentivirus in a cell type-specific manner and corroborated findings by use of a pathway-specific labeling using recombinant rabies virus.
The D1R-MSNs exhibited decreased membrane excitability but increased frequency of miniature excitatory postsynaptic currents after repeated cocaine administration, whereas D2R-MSNs displayed a decrease in miniature excitatory postsynaptic current frequency with no change in excitability. Interestingly, miniature inhibitory postsynaptic currents decreased in D1R-MSNs but were unaffected in D2R-MSNs. Moreover, morphological analyses revealed a selective increase in spine density in D1R-MSNs after chronic cocaine exposure.
This study provides the first experimental evidence that NAc MSNs differentially contribute to psychostimulant-induced neuroadaptations by changing their intrinsic, synaptic, and structural characteristics in a cell type-specific fashion.
Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.
Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior.
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.
There is an increasing awareness that adolescent females differ from males in their response to drugs of abuse and consequently in their vulnerability to addiction. One possible component of this vulnerability to drug addiction is the neurobiological impact that reproductive physiology and behaviors have on the mesolimbic dopamine system, a key neural pathway mediating drug addiction. In this review, we examine animal models that address the impact of ovarian cyclicity, sexual affiliation, sexual behavior, and maternal care on the long-term plasticity of the mesolimbic dopamine system. The thesis is that this plasticity in synaptic neurotransmission stemming from an individual's normal life history contributes to the pathological impact of drugs of abuse on the neurobiology of this system. Hormones released during reproductive cycles have only transient effects on these dopamine systems, whereas reproductive behaviors produce a persistent sensitization of dopamine release and post-synaptic neuronal responsiveness. Puberty itself may not represent a neurobiological risk factor for drug abuse, but attendant behavioral experiences may have a negative impact on females engaging in drug use.
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.
A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.
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.
Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorders (of which Parkinson's disease is the best-known example) at one extreme to the hyperkinetic disorders (exemplified by Huntington's disease and hemiballismus) at the other. Both extremes of this movement disorder spectrum can be accounted for by postulating specific disturbances within the basal ganglia-thalamocortical 'motor' circuit. In this paper, Mahlon DeLong describes the changes in neuronal activity in the motor circuit in animal models of hypo- and hyperkinetic disorders.
Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.
Intracellular recordings were made from neurons in the nucleus accumbens in situ to determine how dopamine produces the selective neuromodulatory action in the accumbens observed in previous studies. Electrical stimulation of the basolateral nucleus of the amygdala was found to produce monosynaptically evoked depolarizing and hyperpolarizing postsynaptic potential sequences in a large proportion of the accumbens neurons sampled. Dopamine applied iontophoretically or released endogenously by stimulation of the ventral tegmental area produced consistent membrane depolarization and an increase in membrane conductance but not an increase in spontaneous activity of the accumbens neurons. Stimulation of the ventral tegmental area with trains of 10 pulses at 10 Hz prior to stimulation of the amygdala produced 8–58% reduction in the amplitude of the depolarizing postsynaptic potential but no change in the late hyperpolarizing postsynaptic potential. Although attenuation of the depolarizing postsynaptic potential amplitude from ventral tegmental area stimulation was often accompanied by membrane depolarization, it appeared that the two responses were not causally related. The effect of ventral tegmental area stimulation on the evoked depolarizing postsynaptic potential and the membrane potential were blocked by haloperidol indicating the involvement of dopamine. Iontophoretically applied dopamine produced responses similar to ventral tegmental area stimulation with two exceptions:
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.
A majority of dopamine neurons are activated by phasically occurring, primary appetitive stimuli, such as foods and liquids, whereas the remaining neurons are not influenced by any stimulus tested. Responses are very phasic, occurring frequently in short spans, and are observed when animals touch a small morsel of hidden food during exploratory movements in the absence of other phasic stimuli or when receiving a drop of liquid at the mouth outside of any behavioral task or while learning a task. The responses do not discriminate between different rewards but distinguish rewards from nonreward objects. Neurons activated by primary rewards do not respond or are occasionally depressed in their activity when nonfood objects are touched, even when they are similarly shaped, or when a fluid valve is operated audibly without actually delivering liquid. A majority of dopamine neurons are also activated by conditioned visual and auditory stimuli that have become valid reward predictors. Responses do not discriminate between visual and auditory stimuli, the same neurons responding to both modalities. Conditioned stimuli are generally slightly less effective than primary rewards, both in terms of response magnitude in individual neurons and in terms of fractions of neurons activated. In most situations, dopamine responses show an all-or-none discrimination between appetitive and neutral or aversive stimuli. Taken together, dopamine neurons respond to a limited range of stimuli. Most of them are specifically appetitive in nature, namely primary rewards and conditioned, rewarding-predicting stimuli. The remaining effective stimuli are potentially appetitive, namely novel or appetitive-resembling stimuli. Dopamine neurons, thus, report nearly exclusively the positive motivational value of environmental events.
The nucleus accumbens, a site within the ventral striatum, is best known for its prominent role in mediating the reinforcing effects of drugs of abuse such as cocaine, alcohol, and nicotine. Indeed, it is generally believed that this structure subserves motivated behaviors, such as feeding, drinking, sexual behavior, and exploratory locomotion, which are elicited by natural rewards or incentive stimuli. A basic rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. It is likely, therefore, that the nucleus accumbens may serve as a substrate for reinforcement learning. However, there is surprisingly little information concerning the neural mechanisms by which appetitive responses are learned. In the present study, we report that treatment of the nucleus accumbens core with the selective competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol/0.5 microl bilaterally) impairs response-reinforcement learning in the acquisition of a simple lever-press task to obtain food. Once the rats learned the task, AP-5 had no effect, demonstrating the requirement of NMDA receptor-dependent plasticity in the early stages of learning. Infusion of AP-5 into the accumbens shell produced a much smaller impairment of learning. Additional experiments showed that AP-5 core-treated rats had normal feeding and locomotor responses and were capable of acquiring stimulus-reward associations. We hypothesize that stimulation of NMDA receptors within the accumbens core is a key process through which motor responses become established in response to reinforcing stimuli. Further, this mechanism, may also play a critical role in the motivational and addictive properties of drugs of abuse.
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.