Frontiers in sleep · 2026
Sex-associated circadian signaling signatures in the lateral hypothalamus.
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Pintwala Sara K, Fuller Patrick M
Аннотация
INTRODUCTION: The lateral hypothalamus (LH) is a central integrative hub coordinating arousal, feeding, metabolism, stress responsiveness, and sleep-wake state transitions. These functions are not static across the 24-hour cycle, but instead are dynamically gated according to circadian phase and internal physiological state. Although sex differences have been documented across many homeostatic and behavioral domains linked to LH function, the molecular substrates underlying these differences within defined LH neuronal populations remain poorly understood.
METHODS: Here, using single-nucleus RNA sequencing, we examined the expression patterns of core clock genes and circadian signaling-associated pathways across transcriptionally resolved populations of female- and male-derived LH neurons.
RESULTS: While the overall cellular architecture of the LH was highly conserved between sexes, we identified distributed and cell-type-specific differences in the expression of genes associated with intrinsic circadian regulation and sensitivity to canonical circadian neuromodulatory pathways, including vasoactive intestinal peptide, arginine vasopressin, neuromedin signaling, and melatonin receptors. These differences were observed across glutamatergic, GABAergic, orexinergic, and melanin-concentrating hormone-associated neuronal populations, suggesting that female and male LH circuits may differentially integrate temporal and physiological information despite preserving shared cellular organization.
DISCUSSION: Rather than indicating sex-specific neuron classes, our findings support a model in which subtle but coordinated shifts in molecular signaling architectures are linked to female- and male-derived LH neurons. These data provide a framework for understanding how temporal regulation of competing homeostatic drives may differ between sexes and underscore the importance of incorporating sex as a biological variable in transcriptomic analyses of hypothalamic circuits.
METHODS: Here, using single-nucleus RNA sequencing, we examined the expression patterns of core clock genes and circadian signaling-associated pathways across transcriptionally resolved populations of female- and male-derived LH neurons.
RESULTS: While the overall cellular architecture of the LH was highly conserved between sexes, we identified distributed and cell-type-specific differences in the expression of genes associated with intrinsic circadian regulation and sensitivity to canonical circadian neuromodulatory pathways, including vasoactive intestinal peptide, arginine vasopressin, neuromedin signaling, and melatonin receptors. These differences were observed across glutamatergic, GABAergic, orexinergic, and melanin-concentrating hormone-associated neuronal populations, suggesting that female and male LH circuits may differentially integrate temporal and physiological information despite preserving shared cellular organization.
DISCUSSION: Rather than indicating sex-specific neuron classes, our findings support a model in which subtle but coordinated shifts in molecular signaling architectures are linked to female- and male-derived LH neurons. These data provide a framework for understanding how temporal regulation of competing homeostatic drives may differ between sexes and underscore the importance of incorporating sex as a biological variable in transcriptomic analyses of hypothalamic circuits.