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Estrogen receptor a (ERa) signaling in the ventromedial hypothalamus (VMH) contributes to energy homeostasis by modulating physical activity and thermogenesis. However, the precise neuronal populations involved remain undefined. Here, we describe six neuronal populations in the mouse VMH by using single-cell RNA transcriptomics and in situ hybridization. ERa is enriched in populations showing sex biased expression of reprimo (Rprm), tachykinin 1 (Tac1), and prodynorphin (Pdyn). Female biased expression of Tac1 and Rprm is patterned by ERa-dependent repression during male development, whereas male biased expression of Pdyn is maintained by circulating testicular hormone in adulthood. Chemogenetic activation of ERa positive VMH neurons stimulates heat generation and movement in both sexes. However, silencing Rprm gene function increases core temperature selectively in females and ectopic Rprm expression in males is associated with reduced core temperature. Together these findings reveal a role for Rprm in temperature regulation and ERa in the masculinization of neuron populations that underlie energy expenditure.

Estrogen receptor a (ERa) signaling in the ventromedial hypothalamus (VMH) contributes to energy homeostasis by modulating physical activity and thermogenesis. However, the precise neuronal populations involved remain undefined. Here, we describe six neuronal populations in the mouse VMH by using single-cell RNA transcriptomics and in situ hybridization. ERa is enriched in populations showing sex biased expression of reprimo (Rprm), tachykinin 1 (Tac1), and prodynorphin (Pdyn). Female biased expression of Tac1 and Rprm is patterned by ERa-dependent repression during male development, whereas male biased expression of Pdyn is maintained by circulating testicular hormone in adulthood. Chemogenetic activation of ERa positive VMH neurons stimulates heat generation and movement in both sexes. However, silencing Rprm gene function increases core temperature selectively in females and ectopic Rprm expression in males is associated with reduced core temperature. Together these findings reveal a role for Rprm in temperature regulation and ERa in the masculinization of neuron populations that underlie energy expenditure.

Sex differences among neurones in the ventrolateral region of the ventromedial hypothalamic nucleus (VMHvl) allow for the display of a diversity of sex-typical behaviours and physiological responses, ranging from mating behaviour to metabolism. Here, we review recent studies that interrogate the relationship between sex-typical responses and changes in cellular phenotypes. We discuss technologies that increase the resolution of molecular profiling or targeting of cell populations, including single-cell transcriptional profiling and conditional viral genetic approaches to manipulate neurone survival or activity. Overall, emerging studies indicate that sex-typical functions of the VMH may be mediated by phenotypically distinct and sexually differentiated neurone populations within the VMHvl. Future studies in this and other brain regions could exploit cell-type-specific tools to reveal the cell populations and molecular mediators that modulate sex-typical responses. Furthermore, cell-type-specific analyses of the effects of sexually differentiating factors, including sex hormones, can test the hypothesis that distinct cell types within a single brain region vary with respect to sexual differentiation.

Cognitive impairment (CI), a debilitating and pervasive feature of multiple sclerosis (MS), is correlated with hippocampal atrophy. Findings from postmortem MS hippocampi indicate that expression of genes involved in both excitatory and inhibitory neurotransmission are altered in MS, and although deficits in excitatory neurotransmission have been reported in the MS model experimental autoimmune encephalomyelitis (EAE), the functional consequence of altered inhibitory neurotransmission remains poorly understood. In this study, we used electrophysiological and biochemical techniques to examine inhibitory neurotransmission in the CA1 region of the hippocampus in EAE. We find that tonic, GABAergic inhibition is enhanced in CA1 pyramidal cells from EAE mice. Although plasma membrane expression of the GABA transporter GAT-3 was decreased in the EAE hippocampus, an increased surface expression of α5 subunit-containing GABAA receptors appears to be primarily responsible for the increase in tonic inhibition during EAE. Enhanced tonic inhibition during EAE was associated with decreased CA1 pyramidal cell excitability and inhibition of α5 subunit-containing GABAA receptors with the negative allosteric modulator L-655,708 enhanced pyramidal cell excitability in EAE mice. Together, our results suggest that altered GABAergic neurotransmission may underlie deficits in hippocampus-dependent cognitive function in EAE and MS.

Menopause affects over a million individuals annually and is characterized by variable and declining ovarian hormones. Decreasing estrogen levels impact energy homeostasis and increases the risk of metabolic disorders. Energy expenditure is largely directed towards thermoregulation, which is modulated in part by estrogen receptor (ER) α expressing neurons in the hypothalamus. Whether specific sub-populations of ERα+ neurons control the effects of estrogens on thermogenesis remains poorly understood. This study investigates the function of ERα in neurons that express Rprm (Reprimo), a gene we previously linked to thermoregulation in females. Here, we use a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage neurons (Reprimo-specific estrogen receptor α KO; RERKO) and report changes in core temperature in female mice, with no changes in body weight, body composition, or food intake. RERKO females have elevated brown adipose tissue (BAT) temperature and lower tail temperature relative to controls, suggesting increased heat production and impaired heat dissipation, respectively. Developmental expression of Rprm was detected in the brain, but not in BAT or white adipose tissue suggesting temperature changes may be mediated by the nervous system. Thus, we next ablated Rprm expressing neurons in the ventrolateral area of the ventromedial nucleus of the hypothalamus (VMHvl) and observed a reduction in core temperature and increased fat mass in ablated female mice relative to controls. Taken together, these results show that estrogen signaling in Rprm expressing cells and VMHvl Rprm neurons are critical for thermoregulation, mainly through the modulation of brown adipose tissue thermogenesis in female, but not male mice.