Brain regions involved in seasonally dependent A1AR agonist-induced torpor

描述(申请人提供)：治疗性低温是在临床试验中发现的唯一能改善脑缺血后预后的神经保护治疗方法。它对心脏骤停后复苏的昏迷患者有效，但对中风患者并未显示出好处。到目前为止，治疗性低温在中风临床试验中未能显示出好处，部分原因可能是在患者不昏迷的情况下，难以击败体温调节防御系统，实现治疗性体温。研究冬眠哺乳动物在昏迷期间如何绕过体温调节防御是一种创新的方法，可以揭示更有效的诱导治疗性低体温的方法。我们最近已经证明，腺苷A1受体(A1ARs)的激活是必要的，也是在冬季诱导北极黄鼠麻木的充分条件。有趣的是，A1AR的激活在夏季并不会导致麻木，这表明更高级别的调控控制着腺苷诱导麻木的能力。在这里，我们将绘制A1腺苷受体激动剂在冬季和夏季在北极地鼠体内解除抑制的神经元的神经化学解剖图，以确定进一步研究的目标脑区。尽管这项研究在很大程度上是描述性的，但它是了解对A1AR激动剂诱导的麻木的更高级别控制的第一步，并将为未来旨在了解冬眠相关的睡眠、体温调节和能量平衡变化的分子和生理机制的研究奠定基础。初步数据表明，冬眠哺乳动物用来降低体温的机制将转化为非冬眠物种。

DESCRIPTION (provided by applicant): 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.