Neurons in the Dorsomedial Hypothalamus Promote, Prolong, and Deepen Torpor in the Mouse

Abstract

Torpor is a naturally occurring, hypometabolic, hypothermic state engaged by a wide range of animals in response to imbalance between the supply and demand for nutrients. Recent work has identified some of the key neuronal populations involved in daily torpor induction in mice, in particular, projections from the preoptic area of the hypothalamus to the dorsomedial hypothalamus (DMH). The DMH plays a role in thermoregulation, control of energy expenditure, and circadian rhythms, making it well positioned to contribute to the expression of torpor. We used activity-dependent genetic TRAPing techniques to target DMH neurons that were active during natural torpor bouts in female mice. Chemogenetic reactivation of torpor-TRAPed DMH neurons in calorie-restricted mice promoted torpor, resulting in longer and deeper torpor bouts. Chemogenetic inhibition of torpor-TRAPed DMH neurons did not block torpor entry, suggesting a modulatory role for the DMH in the control of torpor. This work adds to the evidence that the preoptic area of the hypothalamus and the DMH form part of a circuit within the mouse hypothalamus that controls entry into daily torpor. SIGNIFICANCE STATEMENT Daily heterotherms, such as mice, use torpor to cope with environments in which the supply of metabolic fuel is not sufficient for the maintenance of normothermia. Daily torpor involves reductions in body temperature, as well as active suppression of heart rate and metabolism. How the CNS controls this profound deviation from normal homeostasis is not known, but a projection from the preoptic area to the dorsomedial hypothalamus has recently been implicated. We demonstrate that the dorsomedial hypothalamus contains neurons that are active during torpor. Activity in these neurons promotes torpor entry and maintenance, but their activation alone does not appear to be sufficient for torpor entry.

Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound

“…2c ). These effect sizes were similar to the previously reported fasting-induced torpor in mice 11 , 24 . Ultrasound suppressed oxygen consumption before the fall in body temperature (Extended Data Fig.…”

“…Ultrasound stimulation systemically suppressed metabolism and thermogenesis, switched energy substrate utilization to fat and decreased heart rate, which collectively are key features of natural torpor 11 , 23 . Single ultrasound stimulation was found to induce a hypothermic and hypometabolic state lasting up to approximately 1 h, which is consistent with natural torpor 24 , 25 . This prolonged duration was also consistent with a previous report that found optogenetic activation of QRFP neurons in the POA resulted in a state of hypothermia lasting for longer than 30 min following a 1-s light illumination 12 .…”

“…The duration of T core reduction below body temperature was 51.98 ± 5.52 min by UIH (Extended Data Fig. 2d ), which was comparable to natural torpor 24 , 25 . Ultrasound also decreased the RQ to 0.72 ± 0.01 (Fig.…”

Optogenetic induction of hibernation-like state with modified human Opsin4 in mice

“…We confirmed that female mice also showed a similar sufficient and persistent hypothermia using the same method ( Figure 1 E) because sex differences exist in fasting-induced daily torpor and that the duration of torpor is longer in female mice. 33 , 34 The optogenetic induction of QIH may help identify the physiological changes in the recovery/arousal phase of hibernation and the mechanisms underlying sex differences.…”

Synthetic torpor protects rats from exposure to accelerated heavy ions

“…Only recently the neural pathways that control torpor are being unraveled 15 – 17 . Moreover, it could also provide a much-needed method to improve the radiation resistance of space crews 18 .…”