Optogenetic and pharmacological interventions link hypocretin neurons to impulsivity in mice.

Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice. We show that Hypocretin neuronal activity correlates with anticipation of reward. We then assessed the causal role of Hypocretin neuronal activity using optogenetics in a Go/NoGo task. We show that stimulation of Hypocretin neurons during the cue period dramatically increases the number of premature responses. These effects are mimicked by amphetamine, reduced by atomoxetine, a norepinephrine uptake inhibitor, and blocked by a Hypocretin receptor 1 selective antagonist. We conclude that Hypocretin neurons have a key role in the integration of salient stimuli during wakefulness to produce appropriate and timely responses to rewarding and aversive cues.

Neural and Hormonal Control of Sexual Behavior.

Gonadal hormones contribute to the sexual differentiation of brain and behavior throughout the lifespan, from initial neural patterning to "activation" of adult circuits. Sexual behavior is an ideal system in which to investigate the mechanisms underlying hormonal activation of neural circuits. Sexual behavior is a hormonally regulated, innate social behavior found across species. Although both sexes seek out and engage in sexual behavior, the specific actions involved in mating are sexually dimorphic. Thus, the neural circuits mediating sexual motivation and behavior in males and females are overlapping yet distinct. Furthermore, sexual behavior is strongly dependent on circulating gonadal hormones in both sexes. There has been significant recent progress on elucidating how gonadal hormones modulate physiological properties within sexual behavior circuits with consequences for behavior. Therefore, in this mini-review we review the neural circuits of male and female sexual motivation and behavior, from initial sensory detection of pheromones to the extended amygdala and on to medial hypothalamic nuclei and reward systems. We also discuss how gonadal hormones impact the physiology and functioning of each node within these circuits. By better understanding the myriad of ways in which gonadal hormones impact sexual behavior circuits, we can gain a richer and more complete appreciation for the neural substrates of complex behavior.

Neurobiological and Hormonal Mechanisms Regulating Women's Sleep.

Sleep is crucial for optimal well-being, and sex differences in sleep quality have significant implications for women's health. We review the current literature on sex differences in sleep, such as differences in objective and subjective sleep measures and their relationship with aging. We then discuss the convincing evidence for the role of ovarian hormones in regulating female sleep, and survey how these hormones act on a multitude of brain regions and neurochemicals to impact sleep. Lastly, we identify several important areas in need of future research to narrow the knowledge gap and improve the health of women and other understudied populations.

The Preoptic Area and the RFamide-Related Peptide Neuronal System Gate Seasonal Changes in Chemosensory Processing.

Males of many species rely on chemosensory information for social communication. In male Syrian hamsters (Mesocricetus auratus), as in many species, female chemosignals potently stimulate sexual behavior and a concurrent, rapid increase in circulating luteinizing hormone (LH) and testosterone (T). However, under winter-like, short-day (SD) photoperiods, when Syrian hamsters are reproductively quiescent, these same female chemosignals fail to elicit behavioral or hormonal responses, even after T replacement. It is currently unknown where in the brain chemosensory processing is gated in a seasonally dependent manner such that reproductive responses are only displayed during the appropriate breeding season. The goal of the present study was to determine where this gating occurred by identifying neural loci that respond differentially to female chemosignals across photoperiods, independent of circulating T concentrations. Adult male Syrian hamsters were housed under either long-day (LD) (reproductively active) or SD (reproductively inactive) photoperiods with half of the SD animals receiving T replacement. Animals were exposed to either female hamster vaginal secretions (FHVSs) diluted in mineral oil or to vehicle, and the activational state of chemosensory processing centers and elements of the neuroendocrine reproductive axis were examined. Components of the chemosensory pathway upstream of hypothalamic centers increased expression of FOS, an indirect marker of neuronal activation, similarly across photoperiods. In contrast, the preoptic area (POA) of the hypothalamus responded to FHVS only in LD animals, consistent with its role in promoting expression of male sexual behavior. Within the neuroendocrine axis, the RF-amide related peptide (RFRP), but not the kisspeptin neuronal system responded to FHVS only in LD animals. Neither response within the POA or the RFRP neuronal system was rescued by T replacement in SD animals, mirroring photoperiodic regulation of reproductive responses. Considering the POA and the RFRP neuronal system promote reproductive behavior and function in male Syrian hamsters, differential activation of these systems represents a potential means by which photoperiod limits expression of reproduction to the appropriate environmental context.

Aggressive interactions are associated with reductions in RFamide-related peptide, but not kisspeptin, neuronal activation in mice.

Aggressive interactions lead to changes in both future behavior and circulating testosterone (T) concentrations in animals across taxa. The specific neural circuitry and neurochemical systems by which these encounters alter neuroendocrine functioning are not well understood. Neurons expressing the inhibitory and stimulatory neuropeptides, RFamide-related peptide (RFRP) and kisspeptin, respectively, project to neural loci regulating aggression in addition to neuroendocrine cells controlling sex steroid production. Given these connections to both the reproductive axis and aggression circuitry, RFRP and kisspeptin are in unique positions to mediate post-encounter changes in both T and behavior. The present study examined the activational state of RFRP and kisspeptin neurons of male C57BL/6 mice following an aggressive encounter. Both winners and losers exhibited reduced RFRP/FOS co-localization relative to handling stress controls. Social exposure controls did not display reduced RFRP neuronal activation, indicating that this effect is due to aggressive interaction specifically rather than social interaction generally. RFRP neuronal activation positively correlated with latencies to display several offensive behaviors within winners. These effects were not observed in the anteroventral periventricular (AVPV) nucleus kisspeptin cell population. Together, these findings point to potential neuromodulatory role for RFRP in aggressive behavior and in disinhibiting the reproductive axis to facilitate an increase in T in response to social challenge.

Circadian Control of the Female Reproductive Axis Through Gated Responsiveness of the RFRP-3 System to VIP Signaling.

Throughout most of the ovulatory cycle, estrogen negative feedback restrains the GnRH neuronal system. Just before ovulation, however, estrogen negative feedback is removed to permit stimulation of the preovulatory GnRH/LH surge (positive feedback) by the circadian clock in the suprachiasmatic nucleus (SCN). The mammalian ortholog of avian gonadotropin-inhibitory hormone, RFamide-related peptide 3 (RFRP-3), participates in the circadian-timed removal of estrogen negative feedback to permit the LH surge. The present study examined the specific neurochemical means by which the SCN controls RFRP-3 activity and explored whether the RFRP-3 system exhibits time-dependent responsiveness to SCN signaling to precisely time the LH surge. We found that RFRP-3 cells in female Syrian hamsters (Mesocricetus auratus) receive close appositions from SCN-derived vasopressin-ergic and vasoactive intestinal peptide (VIP)-ergic terminal fibers. Central VIP administration markedly suppressed RFRP-3 cellular activity in the evening, but not the morning, relative to saline controls, whereas vasopressin was without effect at either time point. Double-label in situ hybridization for Rfrp-3 and the VIP receptors VPAC1 and VPAC2 revealed that the majority of RFRP-3 cells do not coexpress either receptor in Syrian hamsters or mice, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly. The timing of this VIP-mediated disinhibition is further coordinated via temporally gated responsiveness of RFRP-3 cells to circadian signaling. Together, these findings reveal a novel circadian hierarchy of control coordinating the preovulatory LH surge and ovulation.

Chronic social stress in puberty alters appetitive male sexual behavior and neural metabolic activity.

Repeated social subjugation in early puberty lowers testosterone levels. We used hamsters to investigate the effects of social subjugation on male sexual behavior and metabolic activity within neural systems controlling social and motivational behaviors. Subjugated animals were exposed daily to aggressive adult males in early puberty for postnatal days 28 to 42, while control animals were placed in empty clean cages. On postnatal day 45, they were tested for male sexual behavior in the presence of receptive female. Alternatively, they were tested for mate choice after placement at the base of a Y-maze containing a sexually receptive female in one tip of the maze and an ovariectomized one on the other. Social subjugation did not affect the capacity to mate with receptive females. Although control animals were fast to approach females and preferred ovariectomized individuals, subjugated animals stayed away from them and showed no preference. Cytochrome oxidase activity was reduced within the preoptic area and ventral tegmental area in subjugated hamsters. In addition, the correlation of metabolic activity of these areas with the bed nucleus of the stria terminalis and anterior parietal cortex changed significantly from positive in controls to negative in subjugated animals. These data show that at mid-puberty, while male hamsters are capable of mating, their appetitive sexual behavior is not fully mature and this aspect of male sexual behavior is responsive to social subjugation. Furthermore, metabolic activity and coordination of activity in brain areas related to sexual behavior and motivation were altered by social subjugation.

A time to remember: the role of circadian clocks in learning and memory.

The circadian system has pronounced influence on learning and memory, manifesting as marked changes in memory acquisition and recall across the day. From a mechanistic perspective, the majority of studies have investigated mammalian hippocampal-dependent learning and memory, as this system is highly tractable. The hippocampus plays a major role in learning and memory, and has the potential to integrate circadian information in many ways, including information from local, independent oscillators, and through circadian modulation of neurogenesis, synaptic remodeling, intracellular cascades, and epigenetic regulation of gene expression. These local processes are combined with input from other oscillatory systems to synergistically augment hippocampal rhythmic function. This overview presents an account of the current state of knowledge on circadian interactions with learning and memory circuitry and provides a framework for those interested in further exploring these interactions.

Gonadotropin-inhibitory hormone reduces sexual motivation but not lordosis behavior in female Syrian hamsters (Mesocricetus auratus).

Reproductive success is maximized when female sexual motivation and behavior coincide with the time of optimal fertility. Both processes depend upon coordinated hormonal events, beginning with signaling by the gonadotropin-releasing hormone (GnRH) neuronal system. Two neuropeptidergic systems that lie upstream of GnRH, gonadotropin-inhibitory hormone (GnIH; also known as RFamide related peptide-3) and kisspeptin, are potent inhibitory and excitatory modulators of GnRH, respectively, that participate in the timing of the preovulatory luteinizing hormone (LH) surge and ovulation. Whether these neuropeptides serve as neuromodulators to coordinate female sexual behavior with the limited window of fertility has not been thoroughly explored. In the present study, either intact or ovariectomized, hormone-treated female hamsters were implanted for fifteen days with chronic release osmotic pumps filled with GnIH or saline. The effect of GnIH on sexual motivation, vaginal scent marking, and lordosis was examined. Following mating, FOS activation was quantified in brain regions implicated in the regulation of female sexual behavior. Intracerebroventricular administration of GnIH reduced sexual motivation and vaginal scent marking, but not lordosis behavior. GnIH administration altered FOS expression in key neural loci implicated in female reproductive behavior, including the medial preoptic area, medial amygdala and bed nucleus of the stria terminalis, independent of changes in circulating gonadal steroids and kisspeptin cell activation. Together, these data point to GnIH as an important modulator of female proceptive sexual behavior and motivation, independent of downstream alterations in sex steroid production.