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The consolidation of newly acquired memories involves the temporal transition from a recent, less stable trace to a more permanent consolidated form. Opiates possess potent rewarding effects and produce powerful associative memories. The activation of these memories is associated with opiate abuse relapse phenomena and the persistence of compulsive opiate dependence. However, the neuronal, molecular and temporal mechanisms by which associative opiate reward memories are consolidated are not currently understood. We report that the consolidation of associative opiate reward memories involves a temporal and molecular switch between the basolateral nucleus of the amygdala (BLA) (early consolidation phase) to the medial prefrontal cortex (mPFC) (late consolidation phase). We demonstrate at the molecular, behavioral and neuronal levels that the consolidation of a recently acquired opiate reward memory involves an extracellular signal-related kinase (ERK)-dependent phosphorylation process within the BLA. In contrast, later-stage consolidation of a newly acquired memory is dependent upon a calcium-calmodulin-dependent (CaMKII), ERK-independent, mechanism in the mPFC, over a 12 hr temporal gradient. In addition, using in vivo multi-unit neuronal recordings in the mPFC, we report that protein synthesis within the BLA modulates the consolidation of opiate-reward memory in neuronal mPFC sub-populations, via the same temporal dynamic.

Runx2, a member of the family of runt-related transcription factors, is rhythmically expressed in bone and may be involved in circadian rhythms in bone homeostasis and osteogenesis. Runx2 is also expressed in the brain, but its function is unknown. We tested the hypothesis that in the brain, Runx2 may interact with clock-controlled genes to regulate circadian rhythms in behavior. First, we demonstrated diurnal and circadian rhythms in the expression of Runx2 in the mouse brain. Expression of Runx2 mRNA and protein mirrored that of the core clock genes, Period1 and Period2, in the suprachiasmatic nucleus (SCN), the paraventricular nucleus and the olfactory bulb. The rhythm of Runx2 expression was eliminated in the SCN of Bmal1(-/-) mice. Moreover, by crossbreeding mPer2(Luc) mice with Runx2(+/-) mice and recording bioluminescence rhythms, a significant lengthening of the period of rhythms was detected in cultured SCN of Runx2(-/-) animals compared to either Runx2(+/-) or Runx2(+/+) mice. Behavioral analyses of Runx2 mutant mice revealed that Runx2(+/-) animals displayed a significantly lengthened free-running period of running wheel activity compared to Runx2(+/+) littermates. Taken together, these findings provide evidence for clock gene-mediated rhythmic expression of Runx2, and its functional role in regulating circadian period at the level of the SCN and behavior.

KNDy (kisspeptin/neurokinin B/dynorphin) neurons of the arcuate nucleus (ARC) appear to mediate the negative feedback actions of estradiol and are thought to be key regulators of pulsatile LH secretion. In the ewe, KNDy neurons may also be involved with the positive feedback actions of estradiol (E2) to induce the LH surge, but the role of kisspeptin neurons in the preoptic area (POA) remains unclear. The goal of this study was to identify which population(s) of kisspeptin neurons is (are) activated during the LH surge and in response to the removal of E2-negative feedback, using Fos as an index of neuronal activation. Dual-label immunocytochemistry for kisspeptin and Fos was performed on sections containing the ARC and POA from ewes during the luteal phase of the estrous cycle, or before or after the onset of the LH surge (experiment 1), and from ovary-intact, short-term (24 h) and long-term (>30 d) ovariectomized (OVX) ewes in anestrus (experiment 2). The percentage of kisspeptin neurons expressing Fos in both the ARC and POA was significantly higher during the LH surge. In contrast, the percentage of kisspeptin/Fos colocalization was significantly increased in the ARC, but not POA, after both short- and long-term E2 withdrawal. Thus, POA kisspeptin neurons in the sheep are activated during, and appear to contribute to, E2-positive feedback, whereas ARC kisspeptin (KNDy) neurons are activated during both surge and pulsatile modes of secretion and likely play a role in mediating both positive and negative feedback actions of E2 on GnRH secretion in the ewe.

Orexin, also known as hypocretin, is a hypothalamic neuropeptide important for mediation of arousal and sleep as well as feeding and energy homeostasis. Recent studies have indicated that orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse. Based on those findings, it has been hypothesized that orexin is involved in control of other natural reward behaviors. This review will summarize studies that examine the role of orexin in motivation and reward associated with food intake, maternal behavior, and male sexual behavior. In particular for sexual behavior in male rats, we have recently shown that orexin cell-specific lesions do not impair sexual performance and motivation but disrupt conditioned responses associated with sexual reward.

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 naı¨ve 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 a-amino-3-hydroxy-5-methylisoxazole-4- propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS3 ) 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 experienceinduced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward.

Orexin, also known as hypocretin, is a hypothalamic neuropeptide important for mediation of arousal and sleep as well as feeding and energy homeostasis. Recent studies have indicated that orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse. Based on those findings, it has been hypothesized that orexin is involved in control of other natural reward behaviors. This review will summarize studies that examine the role of orexin in motivation and reward associated with food intake, maternal behavior, and male sexual behavior. In particular for sexual behavior in male rats, we have recently shown that orexin cell-specific lesions do not impair sexual performance and motivation but disrupt conditioned responses associated with sexual reward.

Methamphetamine (Meth) users report having heightened sexual pleasure, numerous sexual partners, and engaging in unprotected sex due to loss of inhibitory control. This compulsive sexual behavior contributes to increased prevalence of sexually transmitted infections, but the neural basis for this is unknown. We previously established a paradigm for compulsive sexual behavior in male rats in which visceral illness induced by lithium chloride was paired with sexual behavior (Davis et al., 2010; Frohmader et al., 2010a). The current study examined the effects of repeated Meth administration on sexual performance, compulsive sexual behavior, and sex or Meth reward. First, results demonstrated that seven daily administrations of 2 mg/kg, but not 1 mg/kg, Meth increased latencies to initiate mating. This impairment was evident 30 min after last Meth administration, but dissipated after 1 or 7 d of subsequent drug abstinence. Repeated 1 mg/kg Meth exposure resulted in compulsive sex-seeking behavior 2 weeks following last Meth administration. This effect was dependent on Meth administration being concurrent with sexual experience and was not observed in sexually experienced animals that received Meth alone. Moreover, concurrent Meth and sexual experience enhanced conditioned place preference (CPP) for Meth, and for concurrent Meth and mating compared with Meth or mating alone. In contrast, CPP for mating alone was decreased. Together, these data indicate that the association between drug use and mating may be required for expression of compulsive sexual behavior and is correlated with increased reward seeking for concurrent Meth exposure and mating.

The sexual reflex ejaculation is controlled by a spinal ejaculation generator located in the lumbosacral spinal cord. A population of spinothalamic (LSt) neurons forms a key component of this generator, as manipulations of LSt cells either block or trigger ejaculation. However, it is currently unknown which afferent signals contribute to the activation of LSt cells and ejaculation.The current study tested the hypothesis that glutamate, via activation of N-Methyl-D-aspartic acid (NMDA) receptors in LSt cells, is a key regulator of ejaculation.Expression of phosphorylated NMDA receptor subunit 1 (NR1) was investigated following mating, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intraspinal delivery of NMDA receptor antagonist AP-5 on DPN stimulation-induced ejaculation were examined. Moreover, the ability of intraspinal delivery of NMDA to trigger ejaculation was examined. Finally, the site of action of NMDA was determined by studying effects of NMDA in male rats with LSt cell-specific lesions.Expression of NR1 and phosphorylated NR1 in LSt cells was analyzed. Electromyographic recordings of the bulbocavernosus muscle (BCM) were recorded in anesthetized, spinalized rats following stimulation of the DPN and delivery of AP-5 or NMDA.Results indicate that the NR1 receptors are activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, NR1 activation in LSt cells is an essential trigger for rhythmic BCM bursting, as DPN stimulation-induced reflexes were absent following administration of NMDA receptor antagonist in the L3-L4 spinal area, and were triggered by NMDA. NMDA effects were dependent on intact LSt cells and were absent in LSt-lesioned males.These results demonstrate that glutamate, via activation of NMDA receptors in LSt cells, is a key afferent signal for ejaculation.

Recently, a subset of neurons was identified in the arcuate nucleus of the hypothalamus that colocalize three neuropeptides, kisspeptin, neurokinin B, and dynorphin, each of which has been shown to play a critical role in the central control of reproduction. Growing evidence suggests that these neurons, abbreviated as the KNDy subpopulation, are strongly conserved across a range of species from rodents to humans and play a key role in the physiological regulation of GnRH neurons. KNDy cells are a major target for steroid hormones, form a reciprocally interconnected network, and have direct projections to GnRH cell bodies and terminals, features that position them well to convey steroid feedback control to GnRH neurons and potentially serve as a component of the GnRH pulse generator. In addition, recent work suggests that alterations in KNDy cell peptides may underlie neuroendocrine defects seen in clinical reproductive disorders such as polycystic ovarian syndrome. Taken together, this evidence suggests a key role for the KNDy subpopulation as a focal point in the control of reproductive function in health and disease.

Reproduction is unique among physiological systems in that it can be shut down completely for prolonged periods. In females, the most common instances of such reversible infertility are the anovulation that occurs prior to puberty, during lactation, and annually in seasonally breeding species. Although the afferent signals inhibiting reproduction vary among these three conditions, the basic changes in hypothalamic function appear to be similar. Specifically two distinct, but not mutually exclusive, alterations in the control of gonadotrophin-releasing hormone (GnRH) secretion have been described. First, there is a change in responsiveness to the negative feedback actions of oestradiol (E2) so that during anovulatory periods E2 exerts a potent inhibition of GnRH secretion that wanes as ovulatory ovarian cycles begin. Second, there is a steroid-independent inhibition of GnRH that is evident as unexpectedly low levels of luteinising hormone (LH) concentrations in ovariectomised (OVX) animals and agonadal girls. Although such instances of physiological infertility occur in all species, the underlying alterations in hypothalamic function remain largely unknown. One exception to this generalization is the ewe, in which a testable hypothesis has been developed for specific hypothalamic alterations to account for the seasonal suppression of reproductive function. In this review, we will first briefly consider the mechanisms by which the external environment controls the timing of ovulation in the ewe, and then describe the neural circuitry that appears to be responsible for seasonal changes in GnRH secretion.

Background 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. Methods 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. Results 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. Conclusions 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.

Recent work in sheep has identified a neuronal subpopulation in the arcuate nucleus that coexpresses kisspeptin, neurokinin B, and dynorphin (referred to here as KNDy cells) and that mediate the negative feedback influence of progesterone on GnRH secretion. We hypothesized that sex differences in progesterone negative feedback are due to sexual dimorphism of KNDy cells and compared neuropeptide and progesterone receptor immunoreactivity in this subpopulation between male and female sheep. In addition, because sex differences in progesterone negative feedback and neurokinin B are due to the influence of testosterone (T) during fetal life, we determined whether prenatal T exposure would mimic sex differences in KNDy cells. Adult rams had nearly half the number of kisspeptin, neurokinin B, dynorphin, and progesterone receptor-positive cells in the arcuate nucleus as did females, but the percentage of KNDy cells colocalizing progesterone receptors remained high in both sexes. Prenatal T treatment also reduced the number of dynorphin, neurokinin B, and progesterone receptor-positive cells in the female arcuate nucleus; however, the number of kisspeptin cells remained high and at levels comparable to control females. Thus, sex differences in kisspeptin in the arcuate nucleus, unlike that of dynorphin and neurokinin B, are not due solely to exposure to prenatal T, suggesting the existence of different critical periods for multiple peptides coexpressed within the same neuron. In addition, the imbalance between inhibitory (dynorphin) and stimulatory (kisspeptin) neuropeptides in this subpopulation provides a potential explanation for the decreased ability of progesterone to inhibit GnRH neurons in prenatal T-treated ewes.

It is now clear that seasonal breeding in ewes is due to an increase in response to estradiol (E(2)) negative feedback in the nonbreeding season (anestrus) that is mediated by the A15 group of dopaminergic (DA) neurons. Because A15 cells do not contain estrogen receptors, we have postulated the presence of estrogen-responsive afferents and recently reported evidence that input from neurons containing gamma-aminobutyric acid (GABA) contribute to the control of A15 activity by E(2). However, GABAergic afferents account for only a fraction of A15 synaptic input and do not appear to vary with season. We therefore investigated the possible role of stimulatory glutamatergic input to A15 neurons. In experiments 1 and 2, local administration into the A15 of either a N-methyl-D-aspartate (NMDA) receptor or a kainate/alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist stimulated episodic LH secretion in a dose-dependent manner in ovary-intact anestrous ewes. In experiment 3, we examined the number of glutamatergic close contacts onto A15 neurons using dual immunocytochemistry in tissue from E(2)-treated ovariectomized anestrous and breeding season ewes. All A15 DA neurons were contacted by glutamatergic vesicles, and the number of close contacts was significantly higher in anestrus than the breeding season. Finally, using a triple-label immunocytochemistry procedure, we did not observe any colocalization of markers for GABA and glutamate in vesicles contacting A15 neurons. These results support the hypothesis that glutamatergic afferents actively stimulate A15 DA neurons in ovary-intact anestrous ewes and raise the possibility that alterations in this input may contribute to increased A15 neural activity during anestrus.

Using the chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord, and identified SIP30 as a gene whose expression was elevated after CCI. SIP30 was previously shown to interact with SNAP25, but whose function was otherwise unknown. We now show that in the spinal cord, SIP30 was present in the dorsal horn laminae where the peripheral nociceptive inputs first synapse, co-localizing with nociception-related neuropeptides CGRP and substance P. With the onset of neuropathic pain after CCI surgery, SIP30 mRNA and protein levels increased in the ipsilateral side of the spinal cord, suggesting a potential association between SIP30 and neuropathic pain. When CCI-upregulated SIP30 was inhibited by intrathecal antisense oligonucleotide administration, neuropathic pain was attenuated. This neuropathic pain-reducing effect was observed both during neuropathic pain onset following CCI, and after neuropathic pain was fully established, implicating SIP30 involvement in the development and maintenance phases of neuropathic pain. Using a secretion assay in PC12 cells, anti-SIP30 siRNA decreased the total pool of synaptic vesicles available for exocytosis, pointing to a potential function for SIP30. These results suggest a role of SIP30 in the development and maintenance of peripheral nerve injury-induced neuropathic pain.

Various behavioral models and studies have provided evidence suggesting that male rat sexual behavior has rewarding and reinforcing properties. However, there is little information regarding the rewarding values of the different components of sexual behavior. Therefore, this study used a conditioned place preference (CPP) paradigm to address whether ejaculation and intromissions differ in their rewarding incentive values. We also addressed whether the differential rewarding values were dependent on prior sexual experience. Sexually naïve and experienced males received one pairing of either intromissions or ejaculation with one of the chambers in the CPP box. The amount of time spent in each chamber of the CPP apparatus after conditioning was then measured. Both sexually naïve and sexually experienced males formed a CPP for ejaculation, while, only sexually naïve, and not sexually experienced, males formed a CPP for intromissions. Moreover, in sexually naïve males, multiple pairings of ejaculation with the designated chamber resulted in a CPP relative to the control chamber paired with display of intromissions. These data support the hypothesis that there is a hierarchy of rewarding sexual behavior, with ejaculation being the most rewarding component, and that the rewarding incentive value of other components of sexual behavior is dependent upon prior sexual experience.

Contains fulltext : 52598.pdf (Publisher’s version ) (Closed access) Apomorphine is a non-selective dopaminergic receptor agonist. Because of its pro-erectile effects, apomorphine is clinically used for treatment of erectile dysfunction. We investigated the effects of subcutaneous apomorphine administration (0.4 mg/kg rat) on sexual behavior and mating-induced Fos-expression following acute (day 1) or chronic apomorphine treatment (days 8 and 15) in sexually experienced male rats. Consistent facilitatory effects of apomorphine were observed in the reduced numbers of mounts and intromissions over time and an increased ejaculation frequency on day 1. The first post-ejaculatory interval, however, was lengthened, while other behavioral parameters were unaffected. Fos-immunoreactivity induced by acute apomorphine administration (barrel cortex, paraventricular hypothalamic nucleus, central amygdala and locus coeruleus) was strongly reduced after chronic administration. After mating, induction of Fos-immunoreactivity was observed in well-known areas like medial preoptic nucleus and the posterodorsal medial amygdaloid area. Apomorphine, however, reduced mating-induced Fos-immunoreactivity in the nucleus accumbens shell and prevented its occurrence in its core area. This remarkable apomorphine effect was not observed in any other brain area. We conclude that the behavioral (pro-erectile) effects of apomorphine are consistent over time, and that the diminished accumbens-Fos-immunoreactivity and the elongated post-ejaculatory interval may reflect a decreased response to remote cues from the estrus female.

Among young adults, 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular drug of abuse, and anecdotal evidence indicates that repeated use of MDMA may result in impairments in sexual function and decreased sex drive in human users. There has been little investigation of the effects of MDMA on sexual function in rodents. In the present study, the authors determined that in male rats (Rattus novegicus) tested in a sexually naive or a sexually experienced state, administration of a serotonin (5-HT)-depleting regimen of MDMA did not produce a change in mount, intromission, and ejaculation latency or in mount and intromission frequency compared with such latency and frequency in vehicle-treated control rats. In contrast to vehicle-treated rats, MDMA-treated rats did not form a conditioned place preference (CPP) to sex. Failure of MDMA-treated rats to form CPP to sex may be due to MDMA-induced impairments in circuits mediating sexual reward.

Ejaculation is controlled by a spinal ejaculation generator located in the lumbosacral spinal cord, consisting in male rats of lumbar spinothalamic (LSt) cells and their inter-spinal projections to autonomic and motor centers. LSt cells co-express several neuropeptides, including gastrin releasing peptide (GRP) and enkephalin. We previously demonstrated in rats that GRP regulates ejaculation by acting within the lumbosacral spinal cord. In the present study, the hypothesis was tested that enkephalin controls ejaculation by acting on mu (MOR) or delta opioid receptors (DOR) in LSt target areas. Adult male rats were anesthetized and spinalized and received intrathecal infusions of vehicle, MOR antagonist CTOP (0.4 or 4 nmol), DOR antagonist (TIPP (0.4, 4 or 40 nmol), MOR agonist DAMGO (0.1 or 10 nmol), or DOR agonist deltorphin II (1.3 or 13 nmol). Ejaculatory reflexes were triggered by stimulation of the dorsal penile nerve (DPN) and seminal vesicle pressure and rhythmic contractions of the bulbocavernosus muscle were analyzed. Intrathecal infusion of MOR or DOR antagonists effectively blocked ejaculatory reflexes induced by DPN stimulation. Intrathecal infusion of DAMGO, but not deltorphin II triggered ejaculation in absence of DPN stimulation. Both MOR and DOR agonists facilitated ejaculatory reflexes induced by subthreshold DPN stimulation in all animals. Overall, these results support the hypothesis that enkephalin plays a critical role in the control of ejaculation in male rats. Activation of either MOR or DOR in LSt target areas is required for ejaculation, while MOR activation is sufficient to trigger ejaculation in the absence of sensory stimulation.

Contains fulltext : 46863.pdf (Publisher’s version ) (Closed access) It is a common belief that male aggressive and sexual behaviour share many of the underlying neurobiological, neurological, pharmacological and neuroendocrine mechanisms. Therefore, we studied brain activation patterns in male rat after performance of aggressive and sexual behaviour and compared serotonergic pharmacology in the same paradigms to delineate possible similarities and differences. Patterns of Fos-immunoreactivity induced by aggressive and sexual encounters of Wild-type male Brown Norway rats were studied to localise the commonly activated (functionally shared) parts of the circuitry, and the specific (functionally different) parts of the neuronal circuitry. Some brain areas (caudal medial preoptic area and medial amygdala) were commonly activated, but other areas (e.g. posterodorsal parts of the medial amygdala, rostral preoptic and premammillary hypothalamus) showed remarkably specific differences in neural activation. 5-HT(1A) receptor agonists inhibit aggressive, but stimulate male sexual behaviour, whereas 5-HT(1B) receptor agonists inhibit both types of behaviour. Selective serotonin reuptake inhibitors share comparable inhibitory effects in aggression and sexual behaviour, although only at relatively high doses. We propose that separate hard-wired neural systems exist in the brain for aggressive and sexual behaviours, modulated via hierarchically 'higher-level' brain areas that are involved in the integration (gating) of the behavioural outcome of an organism.

The five dopamine receptor subtypes (D1–D5) are members of the superfamily of G protein-coupled receptors (see also Chapter 1). Dopamine receptors. have been known since 1978 to be divided between two families differing in biochemical and pharmacological properties (1). Although the G protein and second messenger systems affected by dopamine receptors in vivo have not been clearly established, in vitro D1-family receptors (D1 and D5) couple to Gs stimulatory proteins, activating adenylyl cyclase, whereas D2- family receptors (D2, D3, D4) couple to Gi inhibitory proteins, inhibiting adenylyl cyclase. Dopamine receptors couple effectively to a wide range of signaling cascades in vitro, including calcium channels, phospholipase C, potassium channels, arachidonic acid release, Na+/H+ exchangers, Na+-H+-ATPase, and cell growth and differentiation pathways (reviewed in ref. 2), suggesting that dopamine may mediate a complex array of neural signaling pathways in vivo. Dopamine systems are believed to exert functional effects through these second-messenger signaling pathways via modulation of the activity of more rapidly acting ionotropic glutamatergic, GABAergic, and nicotinic cholinergic neuronal systems (3).

Repeated exposure to female-related stimuli causes functional alterations in the neural circuitry mediating male rat sexual behavior. In a study published in the current issue of this journal, G. M. Lagoda, J. W. Muschamp, A. Vigdorchik, and E. M. Hull (2004) provide interesting new evidence as to the mechanisms responsible for this effect, namely via activity of nitric oxide (NO) in the medial preoptic area. Given the history of NO in mediating neural plasticity in other systems, the results point to common mechanisms of plasticity between the processes underlying acquisition of sexual experience and those involved in learning and memory.

Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. During intercourse, the spinal ejaculation generator integrates the sensory inputs that are necessary to trigger ejaculation. At the time of ejaculation, it coordinates the sympathetic, parasympathetic, and somatic outflow to induce the two phases of ejaculation, i.e. emission and expulsion. It also provides the brain with signals related to the occurrence of ejaculation. Experimental and clinical data evidenced that these functions were devoted to neurons located in the lumbosacral cord. We recently characterized a population of spinothalamic neurons in the lumbar spinal cord of male rats (LSt cells) that constitutes an integral part of the spinal ejaculation generator. LSt cells send projections to the autonomic nuclei and motoneurons involved in the emission and expulsion phase, and they receive sensory projections from the pelvis. LSt cells are activated with ejaculation, but not following other components of sexual behavior, and lesions of LSt cells completely ablate ejaculatory function. These data support a pivotal role for the LSt cells in the control of ejaculation.

Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. This spinal ejaculation generator coordinates sympathetic, parasympathetic and motor outflow to induce the two phases of ejaculation, i.e., emission and expulsion. In addition, the spinal ejaculation generator integrates this outflow with inputs that are related to the summation of sexual activity prior to ejaculation that are required to trigger ejaculation. Recently, a group of spinothalamic neurons in the lumbar spinal cord (LSt cells) were demonstrated to comprise an integral part of the spinal ejaculation generator. Specifically, lesions of LSt cells completely ablate ejaculatory function. Moreover, LSt cells are activated following ejaculation, but not following other components of sexual behavior. Furthermore, based on their relationship with autonomic nuclei, motoneurons and genital sensory inputs, LSt cells are also in the ideal anatomical position to integrate sensory inputs and autonomic and motor outflow. Additionally, the spinal ejaculation generator is under inhibitory and excitatory influence of supraspinal sites, including the nucleus paragigantocellularis (nPGi), the paraventricular nucleus of the hypothalamus (PVN) and the medial preoptic area (MPOA). Finally, sensory information related to ejaculation is processed in the spinal cord and brain, possibly contributing to the rewarding properties of ejaculation. One candidate pathway for relay of ejaculation-related cues consists of LSt cells and their projections to the parvocellular subparafascicular thalamic nucleus. Moreover, neural activation specifically related to ejaculation is observed in the brain and may reflect of processing of ejaculation-related sensory cues.

Endogenous opioid peptides (EOP) mediate progesterone-negative feedback in many species, but the specific EOP systems involved remain unresolved. We first addressed this question in sheep by determining the role of different EOP receptor subtypes in the medial basal hypothalamus (MBH) and preoptic area (POA). Local administration of EOP receptor antagonists to luteal phase ewes indicated that kappa-, but not micro- or delta-, receptors mediate the inhibition of LH secretion in the MBH. In contrast, both kappa- and micro-, but not delta-receptor, antagonists increased LH pulse frequency when placed in the POA. We next examined close appositions between dynorphin (kappa ligand) and beta-endorphin (micro ligand) containing varicosities and GnRH perikarya in luteal phase ewes using dual immunocytochemistry and light microscopy. Approximately 90% of MBH GnRH neurons had close associations by dynorphin-containing varicosities, but only 40-50% of GnRH perikarya elsewhere had such close associations. In contrast, the percentage of beta-endorphinergic varicosities close to GnRH neurons was similar among all regions. Electron microscopic analysis demonstrated both dynorphinergic synapses and beta-endorphinergic synapses onto GnRH perikarya. These and other data lead to the hypothesis that dynorphin neurons play a major role in progesterone-negative feedback in the ewe and that this inhibition may be exerted directly on GnRH perikarya within the MBH, whereas dynorphin and beta-endorphin input to GnRH neurons in the POA provide redundancy to this system or are involved in other actions of progesterone or estradiol in the control of the GnRH surge.

Recent evidence suggests that the ovine premammillary hypothalamic area (PMH) is an important target for the pineal hormone, melatonin, and its role in seasonal reproduction. In rodents, the PMH is a complex region consisting of several cell groups with differing neurochemical content and anatomical connections. Therefore, to obtain a better understanding of the potential neural targets for melatonin in this area of the sheep brain, we have undertaken a detailed anatomical characterization of the PMH, including its nuclear divisions and the location of neuropeptide/neurotransmitter cells within them. By combining immunocytochemistry for NeuN, a neuronal marker, with Nissl staining in anestrous, ovariectomized, estradiol-treated ewes, we identified three nuclei within the PMH: a caudal continuation of the hypothalamic arcuate nucleus (cARC), the ventral division of the premammillary nucleus (PMv), and the ventral tuberomammillary nucleus (TMv). The cARC contained neurons that were immunoreactive for tyrosine hydroxylase, dynorphin, estrogen receptor alpha, cocaine- and amphetamine-regulated transcript peptide (CART), and nitric oxide synthase (NOS). The PMv was also characterized by the presence of cells that contained NOS and CART, although the size of these cells was larger than that of their corresponding phenotype in the cARC. By contrast, in the TMv, of the markers examined in the present study, only fibers immunoreactive for orexin were seen. Thus, the ovine PMH is a heterogeneous region comprised of three subdivisions, each with distinct morphological and neurochemical characteristics. This anatomical map of the PMH provides a basis for future studies to determine the functional contribution of each component to the influence of melatonin on seasonal reproduction.

The current study tested the hypothesis that sexual behavior is a biological stimulus for release of endogenous opioid peptides. In particular, activation of μ opioid receptors (MOR) in the medial preoptic area (MPOA), a key area for regulation of male sexual behavior, was studied in male rats. MOR endocytosis or internalization was used as a marker for ligand-induced receptor activation, utilizing confocal, electron, and bright microscopic analysis. Indeed, mating including one ejaculation induced receptor activation in the MPOA, demonstrated by increased immunoreactivity for MOR, increased numbers of endosome-like particles immunoreactive for MOR inside the cytoplasm of neurons, and increased percentage of neurons with three or more endosome-like particles inside the cytosol. Moreover, it was demonstrated that MOR activation occurred within 30 min following mating and was still evident after 6 h. Mating-induced internalization was prevented by treatment with the opioid receptor antagonist naloxone before mating, suggesting that mating-induced receptor activation is a result of action of endogenous MOR ligands. I.c.v. injections of MOR ligand [ d -Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin resulted in internalization of the MOR in a similar manner observed following mating. Finally, mating induced Fos expression in MOR containing neurons in the MPOA. However, naloxone pretreatment did not prevent Fos activation of MOR neurons, suggesting that Fos induction was not the result of MOR activation. In summary, these results provide further evidence that endogenous opioid peptides are released in the MPOA during male sexual behavior.

Item does not contain fulltext The parvocellular subparafascicular nucleus of the thalamus (SPFp) consists of separate subdivisions, i.e., a medial portion containing galanin-immunoreactive (-IR) axons and a lateral portion containing calcitonin gene related peptide (CGRP)-IR neurons and fibers. These subdivisions appear to have distinct functional roles. In particular, ejaculation-induced Fos expression is expressed in the medial SPFp. Hence, it was hypothesized that medial SPFp is involved in relay of copulation-related information. In contrast, lateral SPFp is involved in the processing of auditory and visual signals involved in fear-conditioned responses. Here we tested the hypothesis that medial and lateral subdivisions of SPFp receive different sets of afferents and that these differences contribute to the separate functional roles of the two subdivisions. Inputs to medial and lateral SPFp were identified following injections of FG restricted to either division in male rats. The medial SPFp receives unique inputs from lumbar spinothalamic cells and brain regions involved in processing of visceral stimuli, supporting the hypothesis that the medial SPFp is involved in the relay of genitosensory information critical for the expression of male sexual behavior. The afferents of the lateral SPFp include brain regions involved in processing of visual and auditory signals and support a role for this subdivision in relay of visual and auditory information. Thus, the two subdivisions of SPFp are anatomically and functionally distinctive.

Item does not contain fulltext The parvocellular subparafascicular thalamic nucleus (SPFp) is located in the posterior thalamus, consists of horizontally oriented cells, and extends from rostromedial to caudolateral, fusing with the posterior intralaminar nucleus and the peripeduncular nucleus. The present study demonstrates a chemoarchitechtonic and functional parcellation of the rat SPFp. Analysis of the distributions of the neuropeptides galanin, calcitonin gene related peptide (CGRP), substance P, and calbindin revealed the existence of a medial and lateral subdivision within SPFp, and a possible intermediate subdivision. The medial subdivision contains a dense population of galanin-immunoreactive fibers, originating from galanin neurons in the lumbosacral spinal cord. In contrast, the lateral subdivision contains CGRP-positive fibers and neurons. The presence of substance P and calbindin immunoreactivity throughout the entire nucleus suggests that these are separate subdivisions of SPFp, rather than different subnuclei. The present study also investigated the functional association of the separate subdivisions of SPFp for male and female rat sexual behavior. In the medial subdivision, Fos-positive neurons were activated in males by display of ejaculation and in females by vaginocervical stimulation. Thus, Fos induction in medial SPFp appears to reflect processing of inputs related to those events. In contrast, sexual behavior did not induce Fos in the lateral SPFp. Taken together, the present results indicate the existence of separate subdivisions in SPFp that are involved in different behavioral functions. The medial SPFp may process inputs important for sexual behavior, whereas the lateral SPFp may be involved in convergence of auditory and nociceptive inputs important for conditioned fear responses.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.

The precise pathways that convey copulation-related information to forebrain regions activated during male and female sexual behavior are poorly understood. Previous work from our laboratory and others has demonstrated the existence of a spinothalamic pathway that is a candidate to relay information to these areas. This pathway originates from a population of spinothalamic neurons in the lumbar spinal cord containing several neuropeptides including galanin, located in laminas 7 and 10 of the lumbar segments 3 and 4. To investigate the involvement of these lumbar spinothalamic neurons in conveying copulation-related information, we tested the hypothesis that these cells are activated after ejaculation in male rats and vaginocervical stimulation in female rats. This was assessed using galanin or cholecystokinin as a marker for this subset of spinothalamic neurons and Fos-immunoreactivity as a marker for neuronal activation. The results demonstrated that activation of these spinothalamic neurons is triggered by stimuli associated with ejaculation. Fos induction was specifically associated with ejaculation, because mounts or intromissions did not trigger expression. Moreover, these spinothalamic neurons were not activated by vaginocervical stimulation in female rats. Spinothalamic neurons have generally been associated with signaling pain and temperature information. The present findings demonstrate that a specific subpopulation of spinothalamic neurons signals information associated with ejaculation.

Recent evidence suggests that the dynorphin-kappa receptor opioid system acts to mediate the inhibitory effect of progesterone (P) on GnRH pulse frequency during the luteal phase of the ovine estrous cycle. It is known that progesterone receptors (PRs) are required for the actions of P on GnRH secretion. Therefore, if P acts directly on dynorphin (DYN) neurons, then these neurons should contain PRs. To test this hypothesis, we used a dual-label immunoperoxidase procedure to visualize PRs and DYN in the preoptic area (POA) and hypothalamus of ovary-intact ewes killed during the luteal phase of the estrous cycle. The PR was colocalized in more than 90% of parvicellular DYN neurons in the POA, anterior hypothalamus (AHA), and arcuate nucleus (ARC). By contrast, none of magnocellular DYN cells of the paraventricular and supraoptic nuclei coexpressed immunoreactive PRs. The high percentage of colocalization of PRs in parvicellular DYN cells of the POA, AHA, and ARC suggests that these cells are prime targets of P. In addition, DYN cells in the ARC, but not the POA or AHA, were found to receive synaptic inputs from DYN-positive axon terminals. This observation raises the possibility that an ultrashort feedback loop controls the release of DYN from ARC neurons.

We tested the significance of a population of lumbar spinothalamic cells for male sexual behavior in rats. These cells are positioned to relay ejaculation-related signals from reproductive organs to the brain, and they express neurokinin-1 receptors. Ablation of these neurons by the selective toxin SSP-saporin resulted in a complete disruption of ejaculatory behavior. In contrast, other components of sexual behavior remained intact. These results suggest that this population of spinothalamic cells plays a pivotal role in generation of ejaculatory behavior and may be part of a spinal ejaculation generator.

The middle-age decline in reproductive function is manifested by reduced LHRH release, resulting in a decreased magnitude and delay of onset of the LH surge. Earlier studies suggested that the reductions in LHRH neural activation in middle-aged rats resulted from deficits in the afferent drive to the LHRH neurons. One critical afferent to the LHRH neurons lies in the anteroventral periventricular preoptic area (AVPv) nucleus. The neurons of the medial AVPv are synchronously activated to express Fos with LHRH neurons at the time of an LH surge in young adult animals. The present study examined whether, in middle age, reductions in the activation of AVPv neurons accompany the reduction in Fos activation in LHRH neurons. Young (3- to 4-month-old) and middle-aged (10- to 12-month-old) spontaneously cycling and ovariectomized steroid-replaced rats were killed during peak and early descending phase of the LH surge, and their brains were examined for Fos in LHRH and AVPv neurons. Young animals had a characteristic increase in Fos expression in both LHRH and AVPv neurons. In middle-aged rats, the proportion of LHRH neurons expressing Fos at the time of an LH surge was reduced by approximately 50%, irrespective of whether surges were spontaneous or induced by exogenous steroids. A similar reduction in the number of Fos+ cells (by approximately 50%) was noted in the medial AVPv. Linear regression analysis of the relationship between the extent of Fos activation in LHRH and AVPv neurons revealed a strong positive correlation (r2 = 0.66; P < 0.01), suggesting that changes in the AVPv’s drive to LHRH neurons underlie the decrease in LHRH activity in middle age. A second series of experiments examined whether decreased input from the AVPv could account for reduced Fos activation in LHRH neurons seen in middle-aged animals. When the medial AVPv was lesioned, LHRH neurons failed to express Fos on the side ipsilateral to the lesion. Animals with lesioned medial AVPv also had significantly lower LH values than animals with an intact medial AVPv. Taken together, these data suggest that a principal deficit in middle-aged rats is the ability of the medial AVPv to stimulate LHRH neurons.

The GnRH neurosecretory system undergoes marked structural and functional changes throughout life. The initial goal of this study was to examine the neuroanatomical relationship between GnRH neurons and a glycoprotein implicated in neuroplasticity, the polysialylated form of neural cell adhesion molecule (PSA-NCAM). Using dual label immunocytochemistry in conjunction with confocal microscopy, we determined that fibers, terminals, and perikarya of GnRH neurons in adult ovariectomized ewes are intimately associated with PSA-NCAM. In the preoptic area, intense PSA-NCAM immunoreactivity was evident around the periphery of GnRH cell bodies. The second goal of this study was to determine whether PSA-NCAM expression associated with GnRH neurons varies in conjunction with seasonal changes in the activity of the GnRH neurosecretory system in ovariectomized ewes treated with constant release implants of estradiol. During the breeding season when reproductive neuroendocrine activity was enhanced, the expression of PSA-NCAM immunoreactivity associated with GnRH neurons was significantly greater than that during anestrus when GnRH secretion was reduced. This difference, which occurred despite an unchanging ovarian steroid milieu, was not observed in preoptic area structures devoid of GnRH immunoreactivity, suggesting that the seasonal change is at least partially specific to the GnRH system. The close association between PSA-NCAM and GnRH neurons and the change in this relationship in conjunction with seasonal alterations in GnRH secretion provide anatomical evidence that this molecule may contribute to seasonal remodeling of the GnRH neurosecretory system of the adult.

Fluvoxamine is a selective serotonin (5-HT) reuptake inhibitor (SSRI) with a broad spectrum of behavioral and therapeutic effects, e.g. in depressive illness. We used the expression of c-fos, after both acute and chronic oral administration of fluvoxamine in the rat, to study its immediate and long-term effects, in relation to the distribution of Galanin (GAL) and Vasoactive Intestinal Polypeptide (VIP). After acute oral administration, most consistent increases were apparent in (parts of); the nucleus of the solitary tract, medial part; the lateral parabrachial nucleus, external part; the bed nucleus of the stria terminalis, dorsolateral part; and the central nucleus of the amygdala, lateral part. After chronic administration, distribution of Fos-IR was similar to acute administration, although numbers of Fos-IR neurons were no longer significantly different from control values. It is concluded that activation of 5-HT3-receptors in the caudal brainstem or gastro-intestinal afferents of the vagal nerve may play a role in the observed pattern of Fos-IR after fluvoxamine administration. The relationship with the antidepressant effects of fluvoxamine needs further investigations.

Neural activation following sexual behavior was studied in the male and female rat brain, using Fos-immunoreactivity (Fos-IR) as a measure. In accordance with the available literature, we observed increased expression of c-fos in the medial preoptic nucleus (MPN), in the posteromedial subdivision of the bed nucleus of the stria terminalis, in the posterodorsal part of the medial amygdala, and in the caudal thalamus, in the parvicellular part of the subparafascicular nucleus. After performance of different behavioral elements (anogenital investigation, mounting, intromission or ejaculation) not only the numbers of Fos-IR neurons varied considerably, but also their distribution. Especially after ejaculation, but in females already after intromissions, dense groups of Fos-IR neurons appeared in specific subdivisions of the areas mentioned above. That these groups of dense Fos-IR appeared as a result of the ejaculation per se, was assessed by administrating the 5-HT1A agonist 8-OH-DPAT to the males, whereupon they ejaculated within a few seconds, without the usual amount of preceding behavioral elements. Since the pattern of Fos-IR was similar to the normal ejaculation pattern, we have described the dense activation areas as ‘ejaculation-related clusters’. Our review discusses the stimuli and pathways probably involved in the observed pattern of Fos-IR and we conclude that the ‘deep viscero-genital’ activation, occurring at the moment of ejaculation, running along the pelvic nerve and ascending from the spinal cord, is most probably responsible. We show that the location of the Fos-IR neurons in the medial subparafascicular nucleus perfectly coincides with the location of Galanin-IR fibers, ascending from the spinal cord. The application of anterograde and retrograde neuroanatomical tracers into the MPN, in combination with Fos-IR showed that the medial preoptic nucleus has very specific relationships with the Fos-IR sub-areas, involved in ejaculation. We conclude that within the larger brain structures involved in sexual and other social activities, a specific ejaculation-related subcircuit exists, which may, under normal conditions in the rat, serve a ‘sexual-satiety function’.

In the present study a detailed quantitative analysis was made using Fos as a marker for neural activation to define which subregions in the neural circuitry underlying male sexual behavior are involved in display of anogenital investigation versus copulation. Neural activity was differentially distributed following anogenital investigation versus mating and was restricted to specific subdivisions that form a heavily interconnected network. Chemosensory investigation increased neural activity in the posteromedial subdivision of the bed nucleus of the stria terminalis and the posterodorsal subdivision of the medial amygdala, brain regions that receive chemosensory signals processed through the olfactory bulbs, presumably reflecting the acquisition of chemosensory signals or the display of anogenital investigation. However, other sensory signals or sexual experience may also have contributed to the induction of neural activation in these brain areas. Moreover, consummatory behavior increased neural activity in the subparafascicular nucleus, a brain region that receives genital sensory inputs. In turn, this brain region projects to the medial preoptic nucleus and posterior nucleus of the amygdala, where neural activity was also abundant only following copulation. In addition, clusters of neurons were activated in the posteromedial subdivision of the bed nucleus of the stria terminalis and posterodorsal subdivision of the medial amygdala following consummatory behavior. The present study provides an anatomically detailed picture about the distribution of neural activation following sexual behavior in the rat, specifically in relation to differences following anogenital investigation versus mating.

The "core" region of the suprachiasmatic nucleus (SCN), a central clock responsible for coordinating circadian rhythms, shows a daily rhythm in phosphorylation of extracellular regulated kinase (pERK). This cellular rhythm persists under constant darkness and, despite the absence of light, is dependent upon inputs from the eye. The neural signals driving this rhythmicity remain unknown and here the roles of glutamate and PACAP are examined. First, rhythmic phosphorylation of the NR1 NMDA receptor subunit (pNR1, a marker for receptor activation) was shown to coincide with SCN core pERK, with a peak at circadian time (CT) 16. Enucleation and intraocular TTX administration attenuated the peak in the pERK and pNR1 rhythms, demonstrating that activation of the NMDA receptor and ERK in the SCN core at CT16 are dependent on retinal inputs. In contrast, ERK and NR1 phosphorylation in the SCN shell region were unaffected by these treatments. Intraventricular administration of the NMDA receptor antagonist MK-801 also attenuated the peak in SCN core pERK, indicating that ERK phosphorylation in this region requires NMDA receptor activation. As PACAP is implicated in photic entrainment and is known to modulate glutamate signaling, the effects of a PAC1 receptor antagonist (PACAP 6-38) on SCN core pERK and pNR1 also were examined. PACAP 6-38 administration attenuated SCN core pERK and pNR1, suggesting that PACAP induces pERK directly, and indirectly via a modulation of NMDA receptor signaling. Together, these data indicate that, in the absence of light, retinal-mediated NMDA and PAC1 receptor activation interact to induce cellular rhythms in the SCN core. These results highlight a novel function for glutamate and PACAP release in the hamster SCN apart from their well-known roles in the induction of photic circadian clock resetting.

In the present study a comparison was made between the distribution of Fos immunoreactivity in the brain of female and male rats following successive elements of sexual behavior. The distribution of Fos immunoreactivity following either mounting, eight intromissions or one or two ejaculations was compared with that in control animals. In both females, Fos immunoreactivity was induced in the medial preoptic nucleus, posteromedial part of the bed nucleus of the stria terminalis, posterodorsal part of the medial amygdala, and the parvicellular part of the subparafascicular thalamic nucleus. In addition, Fos immunoreactivity in females was induced in the ventrolateral part and the most caudoventral part of the ventromedial nucleus of the hypothalamus and in the premammillary nucleus. Differences between females and males were detected in the phases of sexual activity that resulted in Fos immunoreactivity in these brain areas, allowing more insight in the nature of the sensory and hormonal stimuli leading to the induction of Fos immunoreactivity. The posteromedial bed nucleus of the stria terminalis appears to be involved in chemosensory investigation, while specific distinct subregions are only activated following ejaculation. In addition, the parvicellular subparafascicular nucleus and the lateral part of the posterodorsal medial amygdala appear to be involved in the integration of viscero-sensory input. The neural circuitries underlying sexual behavior in males and females appear to be similar in terms of integration of sensory information. In males the medial preoptic nucleus may be regarded as the brain area where the integration of sensory and hormonal stimulation leads to the onset of male sexual behavior, while in females the ventrolateral part of the ventromedial hypothalamic nucleus appears to have this function. In addition, Fos immunoreactivity was distributed in distinct clusters in subregions with various brain areas in males and females. This was observed especially in the posteromedial bed nucleus of the stria terminalis and posterodorsal medial amygdala, but also in the parvicellular subparafascicular nucleus, ventromedial hypothalamic nucleus and ventral premammillary nucleus. It appears that relatively small subunits within these nuclei seem to be concerned with the integration of sensory and hormonal information and may play a critical role in sexual behavior.