Opportunities and barriers to translating the hibernation phenotype for neurocritical care

Abstract

Targeted temperature management (TTM) is standard of care for neonatal hypoxic ischemic encephalopathy (HIE). Prevention of fever, not excluding cooling core body temperature to 33°C, is standard of care for brain injury post cardiac arrest. Although TTM is beneficial, HIE and cardiac arrest still carry significant risk of death and severe disability. Mammalian hibernation is a gold standard of neuroprotective metabolic suppression, that if better understood might make TTM more accessible, improve efficacy of TTM and identify adjunctive therapies to protect and regenerate neurons after hypoxic ischemia brain injury. Hibernating species tolerate cerebral ischemia/reperfusion better than humans and better than other models of cerebral ischemia tolerance. Such tolerance limits risk of transitions into and out of hibernation torpor and suggests that a barrier to translate hibernation torpor may be human vulnerability to these transitions. At the same time, understanding how hibernating mammals protect their brains is an opportunity to identify adjunctive therapies for TTM. Here we summarize what is known about the hemodynamics of hibernation and how the hibernating brain resists injury to identify opportunities to translate these mechanisms for neurocritical care.

Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus

“…Following extended torpor, hibernators must rapidly recover from immobility ( 15 , 68 , 69 ), nutrient deprivation, insulin resistance ( 16 , 70 ), accumulated wastes and toxins ( 71 ), and tauopathy ( 14 ). Moreover, synaptic connections are regenerated, and neuroprotective mechanisms defend against brain damage from reperfusion with suddenly increased blood flow that has similarities to stroke ( 11 ). Our study illuminates CREs and cellular mechanisms involved.…”

“…On the other hand, facultative hibernators respond to acute food deprivation or cold stresses with short periods of torpor with suppressed metabolism and body temperature (7,10), while homeothermic mammals are incapable of such dramatic metabolic changes and maintain more stable metabolic rates and body temperatures through different seasons and environmental conditions (7,8). Studies of different hibernator adaptations suggest that changing components of mammalian metabolism offers benefits such as metabolic rate and feeding control, neuroprotection (11), reversal of neurodegenerative processes (12)(13)(14), obesity and insulin resistance control (9,15,16), tumor dormancy (17,18), and enhanced longevity (19). Uncovering the genetic mechanisms involved is expected to provide important advances in our understanding of mammalian metabolism and health.…”

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice

“…Studies of hibernator adaptations suggest that changing components of mammalian metabolism offers benefits such as energy balance control, neuroprotection (11), reversal of neurodegenerative processes (12)(13)(14), reversal of obesity and insulin resistance (8,15,16), and enhanced longevity (17). Uncovering the genetic mechanisms involved is expected to provide important advances in our understanding of mammalian metabolism and health.…”