A sex-specific thermogenic neurocircuit induced by predator smell recruiting cholecystokinin neurons in the dorsomedial hypothalamus

Abstract

Olfactory cues are vital for prey animals like rodents to perceive and evade predators. Stress-induced hyperthermia, via brown adipose tissue (BAT) thermogenesis, boosts physical performance and facilitates escape. However, many aspects of this response, including thermogenic control and sex-specific effects, remain enigmatic. Our study unveils that the predator odor trimethylthiazoline (TMT) elicits BAT thermogenesis, suppresses feeding, and drives glucocorticoid release in female mice. Chemogenetic stimulation of olfactory bulb (OB) mitral cells recapitulates the thermogenic output of this response and associated stress hormone corticosterone release in female mice. Neuronal projections from OB to medial amygdala (MeA) and dorsomedial hypothalamus (DMH) exhibit female-specific cFos activity toward odors. Cell sorting and single-cell RNA-sequencing of DMH identify cholecystokinin (CCK)-expressing neurons as recipients of predator odor cues. Chemogenetic manipulation and neuronal silencing of DMHCCK neurons further implicate these neurons in the propagation of predator odor-associated thermogenesis and food intake suppression, highlighting their role in female stress-induced hyperthermia.

Wiring the Brain for Wellness: Sensory Integration in Feeding and Thermogenesis: A Report on Research Supported by Pathway to Stop Diabetes

“…The neural basis for predator-induced hypophagia was recently shown to recruit CCK neurons found in the dorsal premammilary nucleus, which has activity that suppresses AgRP neurons ( 90 ). Remarkably, we also observed that DMH-CCK neurons contribute to stress-induced hypophagia, with their activation inhibiting feeding and their inhibition restoring normal food intake despite the presence of a predator odor ( 83 ). Interestingly, physical restraint selectively induced anorexigenic POMC neuron activity in ARC to suppress feeding, whereas other stressors, such as TMT, had no effect on POMC neuronal activation ( 91 ).…”

“…This rise in temperature likely serves to enhance both physical and neural performance by raising the temperature of muscles and the central nervous system by a few degrees Celsius. PSH represents an automatic stress reaction that activates the sympathetic nervous system, triggering a series of physiological responses and resulting in increased energy expenditure ( 83 ). Blockade of β3-adrenoreceptors efficiently reduces PSH, whereas cyclooxygenase inhibitors, which are used to decrease inflammation-induced fever, are ineffective ( 84 – 86 ).…”

“…Similarly, PSH resulting from psychological stress induced by social defeat stress in rats was suppressed by inactivation of DMH neurons using muscimol microinjections ( 88 ). We recently demonstrated that CCK neurons in the DMH are activated by predator smell, with stronger responses observed in female mice ( 83 ). The stimulation of DMH-CCK neurons promotes energy expenditure through increased BAT thermogenesis, whereas their neuronal silencing reduces predator-induced energy expenditure in the presence of predator odor.…”

Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control

“…A recent study showed that after exposing mice to predator odors, there is a stress-induced hyperthermia and Fos expression in the MeA, DMH, LH, and ARC regions. Chemogenetic activation of the DMH neurons is sufficient to induce thermogenesis in females (Jovanovic, Pool et al 2023). This study did not evaluate if those Fos-activated neurons were Kp expresing neurons, however, according to our data, those neurons are likely to be Kp neurons due to its close anatomical locations in the precise regions where we report here the presence of kisspeptinergic neurons.…”

Unveiling Hypothalamic Molecular Signatures via Retrograde Viral Tracing and Single-Cell Transcriptomics

“…Understanding the complexity of hypothalamic neurocircuits and identifying their molecular signatures is crucial for comprehending the coordinated physiological responses 1 – 3 . In past years, the high-throughput single-cell RNA sequencing (scRNA-seq) analytical and experimental approaches have facilitated the understanding of the transcriptional cataloging of cell types in the hypothalamus and many other adjacent tissues of the brain 4 – 6 .…”