Therapeutic hypothermia is the only neuroprotective treatment found in clinical trials to improve outcome following cerebral ischemia. It is effective n comatose patients resuscitated after cardiac arrest but has failed to show benefit for stroke patients. The failure of therapeutic hypothermia to show benefits in stroke clinical trials to dateis likely due in part to the difficulty of defeating thermoregulatory defenses and achieving therapeutic body temperatures when patients are not comatose. Study of how hibernating mammals bypass thermoregulatory defenses during onset of torpor is an innovative approach to unveil more effective means of inducing therapeutic hypothermia. We have shown recently that activation of adenosine A1 receptors (A1ARs) is necessary and sufficient to induce torpor in arctic ground squirrels in winter. Interestingly, A1AR activation does not induce torpor in the summer, indicating that a higher order of regulation controls the ability of adenosine to induce torpor. Here we will map the neurochemical anatomy of neurons disinhibited by A1 adenosine receptor agonist in arctic ground squirrels in winter and summer to identify brain regions to target for further study. Although largely descriptive, this study is a first step towards understanding higher order of control over A1AR agonist-induced torpor and will form the basis for future studies aimed at understanding the molecular and physiological mechanisms of hibernation-associated changes in sleep, thermoregulation, and energy homeostasis. Preliminary data suggest that mechanisms used by hibernating mammals to decrease body temperature will translate to non-hibernating species.
Therapeutic hypothermia is becoming the standard of care for comatose patients after cardiac arrest, but has proven difficult to implement in conscious stroke patients. This study will help identify brain regions to target for future study of molecular and physiological mechanisms of hibernation-associated changes in thermoregulation. Understanding how hibernating animals bypass thermoregulatory defenses to facilitate cooling during onset of torpor is likely to lead to improved pharmacotherapies to induce therapeutic hypothermia in conscious stroke patients.