The hypothalamic control of fertility is a quintessential homeostatic function. Given that reproduction is metabolically demanding, coordination between energy status and reproductive function is essential. Since GnRH neurons lack receptors for key metabolic hormones, nutrient sensing must occur via presynaptic neurons. Among the candidates are anorexigenic POMC and orexigenic NPY/AgRP neurons, both of which are in close apposition to the median eminence, a circumventricular organ permissive to circulating signals. These neurons are inversely regulated by glucose and metabolic hormones, with POMC neurons generally excited by insulin and leptin, and NPY/AgRP neurons inhibited by them. However, their synaptic input to GnRH neurons is sparse, and GnRH neurons may lack the necessary postsynaptic receptors. The discovery of kisspeptin neurons in the early part of this century revolutionized our understanding of reproductive regulation. These neurons project to and control GnRH neuronal excitability. More recently, arcuate kisspeptin neurons (KNDy) have been identified as the command neurons driving pulsatile release of GnRH and are essential for the GnRH/LH surge. Notably, these neurons express both steroid hormone receptors and metabolic hormone receptors and, like POMC neurons, are excited by insulin and leptin. Therefore, arcuate kisspeptin neurons likely serve as a central hub in linking metabolic signals with reproduction. This review will examine how these vital neurons control pulsatile GnRH release, their reciprocal synaptic connections with POMC and NPY/AgRP neurons, and how E2 can regulate their excitability. Through integration of metabolic and hormonal cues, these neurons help align reproductive capacity with the organism's energy status.

During development, there is a significant sex difference in the expression of progestin receptor (PR) in the medial preoptic nucleus (MPN) of rodents. Males express high levels of PR immunoreactivity (PR-ir) in the MPN beginning at embryonic day 19, whereas PR is virtually absent in females until the second postnatal week. This sex difference indicates a developmental window during which the male MPN is more sensitive to progestins than the female MPN. The two PR isoforms, full-length PRB and the truncated PRA, can differentially regulate the expression of specific genes. Yet, it is unknown how these isoforms contribute to the sex difference in PR expression. In the present study, we investigated the relative contributions of PRA and PRB expression in the MPN during development. PR-ir in neonatal male and female PRA knockout (PRAKO) or PRBKO mice were compared with their wildtype (WT) counterparts. In the MPN, levels of PR-ir were higher in WT males than in WT females consistent with previous results from our lab. Moreover, this sex difference was also detected in both PRAKO and PRBKO mice, suggesting that both isoforms contribute to PR expression in males. We also investigated the expression of PRA and PRB in the ventrolateral subdivision of the ventromedial nucleus of the hypothalamus (VMN) and arcuate nucleus (ARC), two additional brain regions implicated in progestin function in reproduction in which males expressed PR at higher levels than females. Interestingly, in the VMN and the ARC, PRA was the predominant isoform. These findings suggest that the differential expressions of PRA and PRB result in sex differences in PR in the brain regions associated with sexually dimorphic behaviors and neuroendocrine functions.

Arginine vasopressin (AVP) modulates stress responsivity and social-affective behaviors, but its role in mood and trauma-related disorders remains poorly defined due to challenges in peripheral measurement. This study used copeptin, a stable, reliable, and well-validated surrogate marker of AVP secretion, to assess vasopressinergic function in a transdiagnostic sample of individuals experiencing a major depressive episode (MDE) with and without post-traumatic stress disorder (PTSD), as well as healthy volunteers (HVs). Baseline levels of copeptin, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and urine cortisol were compared across groups and examined in relation to clinical symptoms and behavioral traits. Acute changes in copeptin and other hypothalamic-pituitary-adrenal axis markers following a single subanesthetic-dose ketamine infusion were also investigated in a subset of patients. Participants with MDE + PTSD exhibited significantly lower baseline copeptin levels and a blunted reduction in copeptin levels post-ketamine compared to MDE-only participants. Copeptin was unrelated to primary mood diagnosis and to symptom severity of depression, anxiety, post-traumatic stress, anhedonia, suicidal ideation, childhood trauma history, or behavioral traits other than aggression. Higher baseline copeptin levels were associated with verbal aggression, and PTSD comorbidity attenuated these associations. Collectively, these findings suggest a possible biological subtype of attenuated AVP secretion in the dual diagnostic subgroup of co-occurring MDE and PTSD that is independent of symptom burden. Plasma copeptin might therefore serve not only as a peripheral biomarker but also as a proxy for central neuromodulatory changes relevant to AVP-driven circuits in the study of neuropsychiatric disorders. Future studies integrating the temporal dynamics of copeptin with neuroimaging, genetic, and stress-challenge paradigms are needed to delineate the potential neural pathways through which AVP contributes to the pathophysiology and treatment responsiveness of mood and trauma-related disorders. Clinical Trial Registration: www.clinicaltrials.gov (NCT02543983).

Successful reproduction requires coordinated regulation of gonadal function and sexual behavior. Nonetheless, the mechanisms underlying this coordination in teleosts remain elusive. Here, we aimed to find out the possible involvement of ovulation in the control of female sexual behavior using medaka. We analyzed the sexual behavior of medaka with targeted knockouts of genes involved in ovulation. We also examined the actual timing of ovulation and sexual behavior. Furthermore, we investigated the possible contribution of a progesterone derivative through pharmacological treatment and analyzed the localization of the progesterone receptor in the brain using in situ hybridization. Genetically anovulatory female medaka did not show female receptivity, although they were normally courted by males. Consistently, intact females exhibited sexual behavior only after ovulation. Additionally, the administration of progesterone, which is released during ovulation, partially reinstated the sexual receptivity of anovulatory knockout females. Taken together with our result that progesterone receptor is expressed in brain regions that are considered strong candidates for regulation of sexual behavior, we propose that female sexual receptivity is facilitated in synchrony with the ovulatory cycle via progesterone receptor signaling in specific brain regions around the time of ovulation.

Glucocorticoids are produced through activation of the hypothalamic-pituitary-adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF1 and CRF2 receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF1 or CRF2 receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF1 and CRF2 wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF1 WT and HET mice but not in CRF1 KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF1 genotype. In CRF1 males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF1 females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF1 deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF1 deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF2 mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF2 deficiency. Moreover, CRF2 deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF1 receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF1 function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.

The neurohypophysis is a major central neuroendocrine interface regulating reproductive functions and water homeostasis. Distinct neurovascular cell types interact via evolutionarily conserved signaling molecules in the developing neurohypophysis, providing a model system for studying principles in neuroendocrine interface morphogenesis. This review provides an overview of neurohypophysis development with a focus on paracrine signaling and the intrinsic mechanisms that regulate the major cell types and neurovascular interface development.

In species where males provide parental care, the transition to fatherhood involves a shift in life history strategy in the direction of increased parenting and decreased mating effort. In non-human mammals, the transition to parenthood involves an increase in the motivation to approach and care for offspring, which is mediated by changes in a neural system that includes the medial preoptic area and the mesolimbic dopamine system. Whether humans experience increased activity in this parental brain system with the transition to parenthood has not been established. Here, we use an effort-based decision-making task to longitudinally track changes in parenting and mating motivation, and functional MRI to track accompanying changes in brain function across the transition to first-time fatherhood in men and compare these changes with those found in a sample of non-father control males. Fathers were generally less willing than non-fathers to exert effort to view female stimuli; however, there were no apparent changes in motivation to engage with either infant or female stimuli across the transition to fatherhood. On the other hand, changes in brain activation were evident. In response to cues predicting infant pictures, new fathers showed a pre- to post-natal increase in activation of brain regions that are part of the mesolimbic dopamine system, and this change was not found in non-father male controls. Fathers, but not non-fathers, also showed increases in activation to infant stimuli in brain regions implicated in empathy, such as the anterior insula. While univariate analyses showed no significant change in the neural response to pictures of adult females among fathers, a multivariate brain signature that was previously found to classify pleasure responses to a wide range of stimuli revealed that fathers showed an increase in pleasure-related activity to infant stimuli, as well as a decrease in pleasure-related activity to female stimuli. Our findings suggest that human fathers experience neurofunctional changes that may adapt them to their new parental role.

Neurons in the arcuate nucleus of the hypothalamus (ARH) that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy neurons) are considered the gonadotropin‐releasing hormone (GnRH) pulse generator necessary for fertility. KNDy neurons are also metabolic sensors controlling the hypothalamic–pituitary‐gonadal (HPG) axis. Insulin‐like growth factor‐1 (IGF‐1) secretion is influenced by nutritional status and may serve as a cue detected by neurons to regulate various physiological processes, including reproduction. However, whether IGF‐1 modulates KNDy neuron activity remains unclear. RNAscope was used to assess the number of kisspeptin neurons expressing the IGF‐1 receptor (IGF1R). Additionally, the effects of IGF‐1 on LH secretion, Kiss1 mRNA levels, intracellular calcium concentration ([Ca2+]i) in KNDy neurons, and resting membrane potential of kisspeptin neurons were investigated. Kisspeptin cells located at the ARH and anteroventral periventricular and rostral periventricular nuclei (here designated as AVPV) expressed the Igf1r in male and female mice. Intracerebroventricular IGF‐1 administration acutely increased LH secretion without altering hypothalamic Kiss1 mRNA in male mice. In brain slices, IGF‐1 administration elevated [Ca2+]i in KNDy cells of male mice and depolarized KNDy neurons in both sexes. IGF‐1‐induced depolarization was abolished by TTX and amino acid receptor antagonists, indicating an indirect mechanism. In contrast, IGF‐1 has no effect on the RMP of AVPV kisspeptin neurons in female mice. IGF‐1 acutely stimulates KNDy neuron activity via indirect effects despite Igf1r expression in these cells. These findings identify IGF‐1 as a metabolic signal that modulates KNDy neuron excitability and, consequently, influences the reproductive axis.

Oxytocin is involved in the regulation of maternal behavior by binding to the oxytocin receptor (OXTR) in various parts of the brain. Our previous studies demonstrated that OXTRs are specifically expressed in the anteroventral periventricular nucleus (AVPV) of female mice, but not in male mice. Furthermore, the activity of the OXTR neurons is essential for proper expression of maternal behavior. The present study aimed to characterize two different populations of OXTR neurons found in the AVPV in the previous study: tyrosine hydroxylase immunoreactive (TH+) and non-TH immunoreactive (TH-) neurons. Whole-cell patch clamp recordings were used to observe the intrinsic electrophysiological properties of the OXTR neurons. TH+ neurons displayed a pacemaker-like intrinsic rhythmic short bursting activity, whereas TH- neurons displayed either no firing at all, irregular firing, or phasic firing. Some TH- OXTR neurons could switch back and forth among these firing patterns. The differences in the firing patterns between these two populations were likely derived from the difference in their expression of afterpotentials. TH+ OXTR neurons showed more depolarizing afterpotential (DAP) than after-hyperpolarization (AHP), while TH- OXTR neurons exhibited more AHP than DAP. Activation of OXTR by a specific agonist caused a steady state depolarization and increase in Ca2+ transient resulting in changes in the firing activity in both TH+ and TH- neurons. Lastly, biocytin was injected into the OXTR neurons during the whole-cell recordings to visualize the recorded neurons for immuno-identification of neuron type and morphological analysis. TH- neurons displayed significantly more dendritic arborization than TH+ neurons. Therefore, TH+ and TH- neurons are electrophysiologically and morphologically distinct. Moreover, because activation of OXTR caused a change in the firing activity of these neurons, oxytocin likely modulates the firing activity of both TH+ and TH- OXTR neurons to influence maternal behavior.