Neurons that regulate mouse torpor.

The advent of endothermy, which is achieved through the continuous homeostatic regulation of body temperature and metabolism1,2, is a defining feature of mammalian and avian evolution. However, when challenged by food deprivation or harsh environmental conditions, many mammalian species initiate adaptive energy-conserving survival strategies-including torpor and hibernation-during which their body temperature decreases far below its homeostatic set-point3-5. How homeothermic mammals initiate and regulate these hypothermic states remains largely unknown. Here we show that entry into mouse torpor, a fasting-induced state with a greatly decreased metabolic rate and a body temperature as low as 20 °C6, is regulated by neurons in the medial and lateral preoptic area of the hypothalamus. We show that restimulation of neurons that were activated during a previous bout of torpor is sufficient to initiate the key features of torpor, even in mice that are not calorically restricted. Among these neurons we identify a population of glutamatergic Adcyap1-positive cells, the activity of which accurately determines when mice naturally initiate and exit torpor, and the inhibition of which disrupts the natural process of torpor entry, maintenance and arousal. Taken together, our results reveal a specific neuronal population in the mouse hypothalamus that serves as a core regulator of torpor. This work forms a basis for the future exploration of mechanisms and circuitry that regulate extreme hypothermic and hypometabolic states, and enables genetic access to monitor, initiate, manipulate and study these ancient adaptations of homeotherm biology.

A torpor-like state (TLS) in mice slows blood epigenetic aging and prolongs healthspan.

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase health span, remain unknown. We demonstrate that the activity of a spatially defined neuronal population in the avMLPA, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves health span. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the pro-longevity effect of torpor-like states is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the pro-longevity effects of torpor and hibernation and support the growing body of evidence that Tb is an important mediator of aging processes.

Striatum supports fast learning but not memory recall.

Animals learn to carry out motor actions in specific sensory contexts to achieve goals. The striatum has been implicated in producing sensory-motor associations, yet its contribution to memory formation or recall is not clear. To investigate the contribution of striatum to these processes, mice were taught to associate a cue, consisting of optogenetic activation of striatum-projecting neurons in visual cortex, with forelimb reaches to access food pellets. As necessary to direct learning, striatal neural activity encoded both the sensory context and outcome of reaching. With training, the rate of cued reaching increased, but brief optogenetic inhibition of striatal activity arrested learning and prevented trial-to-trial improvements in performance. However, the same manipulation did not affect performance improvements already consolidated into short- (within an hour) or long-term (across days) memories. Hence, striatal activity is necessary for trial-to-trial improvements in task performance, leading to plasticity in other brain areas that mediate memory recall.

Relative enlargement of the medial preoptic nucleus in the Etruscan shrew, the smallest torpid mammal.

Endothermy is a key feature of mammalian biology and enables mammals to maintain stable body temperature and homeostatic functions in the face of a rapidly changing environment. However, when faced with harsh environmental conditions, certain mammalian species enter torpor, a state characterized by reduced metabolism, body temperature, and activity, to minimize energy loss. Etruscan shrews are the smallest mammals, with a surface-to-volume ratio that is very unfavorable for endothermic animals. As a result, Etruscan shrews have an extremely high metabolic rate and are known to enter torpor frequently, presumably as an energy-saving measure. Despite the recent identification of medial preoptic area (MPA) as a key brain region to regulate torpor in mouse, little is known about neural control of torpor in other endothermic animals, including the Etruscan shrew. Here, we confirmed that Etruscan shrews readily enter torpor even in the absence of strong physiological triggers. We then compared the medial preoptic nucleus (MPN) within the MPA of Etruscan shrew and rat, a mammal that does not enter torpor under physiological conditions. While rats have roughly 100 times the body weight and 33 times the brain weight of Etruscan shrews, we find that the male rat MPN exhibits only 6.7 times the volume of that of the male Etruscan shrew. Accordingly, the relative brain volume of the MPN was 6.5-fold larger in shrews, a highly significant difference. Moreover, MPN neuron counts were only roughly twofold lower in shrews than in rats, an astonishing observation considering the interspecies size difference and that neocortical neurons are ~ 20 × more numerous in rats than in shrews. We suggest that the extraordinary enlargement of the Etruscan shrew MPN is a specialization for orchestrating torpor in a mammal with an exceptional metabolism.

Molecular determinants of permeation in a fluoride-specific ion channel.

Fluoride ion channels of the Fluc family combat toxicity arising from accumulation of environmental F-. Although crystal structures are known, the densely packed pore region has precluded delineation of the ion pathway. Here we chart out the Fluc pore and characterize its chemical requirements for transport. A ladder of H-bond donating residues creates a 'polar track' demarking the ion-conduction pathway. Surprisingly, while track polarity is well conserved, polarity is nonetheless functionally dispensable at several positions. A threonine at one end of the pore engages in vital interactions through its ß-branched methyl group. Two critical central phenylalanines that directly coordinate F- through a quadrupolar-ion interaction cannot be functionally substituted by aromatic, non-polar, or polar sidechains. The only functional replacement is methionine, which coordinates F- through its partially positive γ-methylene in mimicry of phenylalanine's quadrupolar interaction. These results demonstrate the unusual chemical requirements for selectively transporting the strongly H-bonding F- anion.