Sex differences in activation of extra-hypothalamic forebrain areas during hedonic eating.

Palatable foods can stimulate appetite without hunger, and unconstrained overeating underlies obesity and binge eating disorder. Women are more prone to obesity and binge eating than men but the neural causes of individual differences are unknown. In an animal model of hedonic eating, a prior study found that females were more susceptible than males to eat palatable food when sated and that the neuropeptide orexin/hypocretin (ORX) was crucial in both sexes. The current study examined potential extra-hypothalamic forebrain targets of ORX signaling during hedonic eating. We measured Fos induction in the cortical, thalamic, striatal, and amygdalar areas that receive substantial ORX inputs and contain their receptors in hungry and sated male and female rats during palatable (high-sucrose) food consumption. During the test, hungry rats of both sexes ate substantial amounts, and while sated males ate much less than hungry rats, sated females ate as much as hungry rats. The Fos induction analysis identified sex differences in recruitment of specific areas of the medial prefrontal cortex, paraventricular nucleus of the thalamus (PVT), nucleus accumbens (ACB), and central nucleus of the amygdala (CEA), and similar patterns across sexes in the insular cortex. There was a striking activation of the infralimbic cortex in sated males, who consumed the least amount food and unique correlations between the insular cortex, PVT, and CEA, as well as the prelimbic cortex, ACB, and CEA in sated females but not sated males. The study identified key functional circuits that may drive hedonic eating in a sex-specific manner.

Age-dependent sexual dimorphism in hippocampal cornu ammonis-1 perineuronal net expression in rats.

INTRODUCTION: Perineuronal nets (PNNs) are extracellular matrices that encompass parvalbumin-expressing parvalbumin positive (PVALB+) fast-spiking inhibitory interneurons where they protect and stabilize afferent synapses. Recent observations that gonadal hormones influence PVALB+ neuron development suggest that PNN regulation may be sexually dimorphic. Sex differences in PNN abundance and complexity have been reported in sexually dimorphic nuclei in zebra finch brains; however, corresponding differences in mammalian brains have not been investigated. METHODS: In this study we assessed the number of cortical and hippocampal PNNs in juvenile and young adult male and female rats using fluorescent immunohistochemistry for PVALB and the PNN marker Wisteria Floribunda Lectin. RESULTS: We report here that PNNs are numerous and well developed in hippocampal cornu ammonis-1 of adult males but are lower in juvenile and possibly adult females. No significant differences were observed between sexes in cornu ammonis-3 or adjacent neocortex. There was an observed developmental difference in the neocortex as juveniles had more PVALB+ cells, but fewer PNN+ cells, than adults. CONCLUSIONS: Because PNNs are integral for several hippocampal-mediated learning and memory tasks, these observations have potential sex-dependent translational implications for clinical strategies targeting cognitive dysfunction.

Serotonin receptor regulation as a potential mechanism for sexually dimorphic oxytocin dysregulation in a model of Autism.

Perinatal administration of serotonin (5HT) agonist 5-methoxytryptamine (5MT) induces developmental hyperserotonemia (DHS; elevated blood serotonin) and produces behavioral and neurochemical changes in rats relevant to Autism Spectrum Disorder (ASD), such as oxytocin dysregulation. Disruption of the oxytocin system may underlie many of the social deficits present in ASD individuals, thus we investigated the mechanism(s) underlying DHS-induced oxytocin dysregulation. The most parsimonious mechanism of 5HT action would be alteration of 5HT receptors on oxytocin cells; 5HT is known to influence cell survival as well as influence oxytocin release via 5HT1A and 5HT2A receptors, which co-localize in oxytocin-expressing (OXT+) cells in the paraventricular nucleus (PVN) of the hypothalamus. We report that both male and female DHS rats have a lower percentage of OXT+ cells co-localized with excitatory 5HT2A receptors than control animals, while only DHS females have a higher percentage of OXT+ cells co-localized with inhibitory 5HT1A receptors compared to controls. Importantly, DHS also reduces the number of OXT+ cells in the PVN of adult male, but not female, rats. This pattern suggests that females, but not males, can regulate 5HT receptors in response to DHS in a manner that promotes oxytocin cell survival and functional efficiency. In addition, it has been previously reported that DHS alters normal juvenile play, especially in males, thus we also tested play partner preference among juvenile control and DHS males. Sex differences observed using the DHS model of ASD add to its validity, given the pronounced male sex bias in the prevalence of ASD, and emphasize the need for inclusion of both sexes in ASD research.

Gonadal hormone modulation of intracellular calcium as a mechanism of neuroprotection.

Hormones have wide-ranging effects throughout the nervous system, including the ability interact with and modulate many aspects of intracellular calcium regulation and calcium signaling. Indeed, these interactions specifically may help to explain the often opposing or paradoxical effects of hormones, such as their ability to both promote and prevent neuronal cell death during development, as well as reduce or exacerbate damage following an insult or injury in adulthood. Here, we review the basic mechanisms underlying intracellular calcium regulation-perhaps the most dynamic and flexible of all signaling molecules-and discuss how gonadal hormones might manipulate these mechanisms to coordinate diverse cellular responses and achieve disparate outcomes. Additional future research that specifically addresses questions of sex and hormone effects on calcium signaling at different ages will be critical to understanding hormone-mediated neuroprotection.

Serotonin promotes feminization of the sexually dimorphic nucleus of the preoptic area, but not the calbindin cell group.

Testosterone and its metabolites masculinize the brain during a critical perinatal window, including the relative volume of sexually dimorphic brain areas such as the sexually dimorphic nucleus of the preoptic area (SDN), which is larger in males than females. Serotonin (5HT) may mediate this hormone action, since 5HT given during the second week of life decreases (i.e., feminizes) SDN volume in males and testosterone-treated females. Although previous work indicates that the 5HT2A/2C receptor is sufficient to induce feminization, it is unclear whether other serotonin receptors are required and which subpopulation(s) of SDN cells are specifically organized by 5HT. Therefore, we injected male and female Sprague-Dawley rat pups with saline, a nonselective 5HTR agonist, a 5HT2A/2C agonist, or a 5HT2A/2C antagonist over several timecourses in early life, and measured the Nissl-SDN as well as a calbindin+ subdivision of the SDN, the CALB-SDN. When examined on postnatal day 18 or early adulthood, the size of the Nissl-SDN was feminized in males treated with any of the serotonergic drugs, eliminating the typical sex difference. In contrast, the sex difference in CALB-SDN size was maintained regardless of serotoninergic drug treatment. This pattern suggests that although gonadal hormones shape the whole SDN, individual cellular phenotypes respond to different intermediary signals to become sexually dimorphic. Specifically, 5HT mediates sexual differentiation of non-calbindin population(s) within the SDN. The results also caution against using measurement of the CALB-SDN in isolation, as the absence of an effect on the CALB-SDN does not preclude an effect on the overall nucleus. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1241-1253, 2016.

Effects of developmental hyperserotonemia on juvenile play behavior, oxytocin and serotonin receptor expression in the hypothalamus are age and sex dependent.

There is a striking sex difference in the diagnosis of Autism Spectrum Disorder (ASD), such that males are diagnosed more often than females, usually in early childhood. Given that recent research has implicated elevated blood serotonin (hyperserotonemia) in perinatal development as a potential factor in the pathogenesis of ASD, we sought to evaluate the effects of developmental hyperserotonemia on social behavior and relevant brain morphology in juvenile males and females. Administration of 5-methoxytryptamine (5-MT) both pre- and postnatally was found to disrupt normal social play behavior in juveniles. In addition, alterations in the number of oxytocinergic cells in the lateral and medial paraventricular nucleus (PVN) were evident on postnatal day 18 (PND18) in 5-MT treated females, but not treated males. 5-MT treatment also changed the relative expression of 5-HT(1A) and 5-HT(2A) receptors in the PVN, in males at PND10 and in females at PND18. These data suggest that serotonin plays an organizing role in the development of the PVN in a sexually dimorphic fashion, and that elevated serotonin levels during perinatal development may disrupt normal organization, leading to neurochemical and behavioral changes. Importantly, these data also suggest that the inclusion of both juvenile males and females in studies will be necessary to fully understand the role of serotonin in development, especially in relation to ASD.

Increased dendritic spine density and tau expression are associated with individual differences in steroidal regulation of male sexual behavior.

Male sexual behavior (MSB) is modulated by gonadal steroids, yet this relationship is highly variable across species and between individuals. A significant percentage (~30%) of B6D2F1 hybrid male mice demonstrate MSB after long-term orchidectomy (herein after referred to as "maters"), providing an opportunity to examine the mechanisms that underlie individual differences in steroidal regulation of MSB. Use of gene expression arrays comparing maters and non-maters has provided a first pass look at the genetic underpinnings of steroid-independent MSB. Surprisingly, of the ~500 genes in the medial preoptic area (MPOA) that differed between maters and non-maters, no steroid hormone or receptor genes were differentially expressed between the two groups. Interestingly, best known for their association with Alzheimer's disease, amyloid precursor protein (APP) and the microtubule-associated protein tau (MAPT) were elevated in maters. Increased levels of their protein products (APP and tau) in their non-pathological states have been implicated in cell survival, neuroprotection, and supporting synaptic integrity. Here we tested transgenic mice that overexpress tau and found facilitated mounting and intromission behavior after long-term orchidectomy relative to littermate controls. In addition, levels of synaptophysin and spinophilin, proteins generally enriched in synapses and dendritic spines respectively, were elevated in the MPOA of maters. Dendritic morphology was also assessed in Golgi-impregnated brains of orchidectomized B6D2F1 males, and hybrid maters exhibited greater dendritic spine density in MPOA neurons. In sum, we show for the first time that retention of MSB in the absence of steroids is correlated with morphological differences in neurons.