Hypothalamic Preoptic Neurons Control Fasting-Induced Torpor

Hrvatin S, Sun S, Wilcox OF, Yao H, Lavin-Peter AJ, Cicconet M, Assad EG, Palmer ME, Aronson S, Banks AS, Griffith EC, Greenberg ME. Neurons that regulate mouse torpor. Nature 2020;583(7814):115-121. doi: 10.1038/s41586-020-2387-5.

Background: Mammalian torpor and hibernation are adaptive states that allow survival during food scarcity and cold by greatly reducing body temperature and metabolism. Although thermoregulatory mechanisms in the hypothalamus are well characterized, the neural basis of how homeothermic animals actively suppress these mechanisms to enter hypothermic states such as torpor remains unclear.

Hypothesis: This study tested the hypothesis that specific neurons in the hypothalamic preoptic area control the initiation and maintenance of fasting-induced torpor in mice.

Methods: The authors used a fasting-induced mouse model of torpor combined with whole-brain activity mapping, genetic labeling (FosTRAP) of neurons active during torpor, and chemogenetic reactivation using Gq-DREADDs. They identified active brain regions through FOS expression and systematically tested the sufficiency and necessity of these neurons in inducing torpor. Single-nucleus RNA sequencing characterized molecular identities, and calcium imaging using fiber photometry (FP3002) monitored neuronal activity during natural torpor.

Results: Chemogenetic stimulation of neurons activated during natural torpor, specifically in the anteroventral medial and lateral preoptic area (avMLPA), was sufficient to induce torpor-like hypothermia and inactivity in fed mice. Single-cell profiling revealed glutamatergic Adcyap1-expressing neurons as key regulators. Silencing these neurons impaired natural torpor, while calcium recordings showed their activity tightly correlated with torpor onset and maintenance.

Conclusions: This study identified glutamatergic Adcyap1-positive neurons in the avMLPA as core regulators of torpor in mice. Their activation alone reproduced torpor’s physiological features, and their inhibition disrupted it. These findings define a specific hypothalamic circuit governing entry into hypometabolic states, providing a foundation for exploring mechanisms that could enable controlled hypothermia in non-hibernating species.