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

ABSTRACT: Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise, and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (> 24 hours) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state. To investigate the mechanism of ultrasound-induced neuronal activation, we applied ultrasound stimulation in hypothalamic preoptic area region and performed single-nuclei RNA sequencing in the ultrasound stimulated neurons (US+) and neurons without ultrasound stimulation (US-). In our sn-RNAseq analysis, we examined the association between the expression of neuronal activation markers (or IEGs) and ion channels, as well as neuron types.

ORGANISM(S): Mus musculus

PROVIDER: GSE228180 | GEO | 2023/03/29

REPOSITORIES: GEO

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Project description:During the winter, hibernating mammals undergo extreme changes in physiology which allow them to survive without access to food. These animals enter a state of torpor, which is characterized by a decreased metabolism, near-freezing body temperatures, and a dramatically reduced heart rate. The neurochemical basis of this regulation is largely unknown. Based on prior evidence suggesting that the peptide-rich hypothalamus plays critical roles in hibernation, we hypothesized that changes in specific cell-cell signaling peptides (neuropeptides and peptide hormones) underlie physiological changes during torpor/arousal cycles. To test this hypothesis, we used a mass spectrometry-based peptidomics approach to examine seasonal changes of endogenous peptides that occur in the hypothalamus and pituitary of a model hibernating mammal, the thirteen-lined ground squirrel (Ictidomys tridecemlineatus). In the pituitary, we observed changes in a number of distinct peptide hormones as animals prepare for torpor in October, exit torpor in March, and progress from Spring (March) to Fall (August). In the hypothalamus, we observed an overall increase in neuropeptides in October (pre-torpor), a decrease as the animal enters torpor, and an increase in a subset of neuropeptides during normothermic interbout arousals. Notable changes were observed for feeding regulatory peptides from NPY and proSAAS prohormones, opioid peptides from PENK, PDYN, and POMC prohormones, and a number of peptides without well-established functions. In contrast to transcriptome and antibody-based measurements, our mass spectrometry-based approach allowed the identification and measurement of the final processed forms of these peptides after extensive post-translational modifications. Overall, our study provides critical insight into changes in endogenous peptides in the hypothalamus and pituitary during mammalian hibernation that were not available from transcriptome measurements. Understanding the molecular basis underlying the hibernation phenotype may pave the way for future efforts to employ hibernation-like strategies for organ preservation, combating obesity, and treatments for stroke.

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

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