Brain regions involved in seasonally dependent A1AR agonist-induced torpor

参与季节性依赖性 A1AR 激动剂诱导的麻木状态的大脑区域

• 批准号: 8582902
• 负责人: KELLY L DREW
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF ALASKA FAIRBANKS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582902
• 关键词: Ablation; Acute; Address; Adenosine; Adenosine A1 Receptor; Agonist; Alteplase; Anatomy; Animal Model; Animals; Attenuated; Body Temperature; Brain; Brain Injuries; Brain region; Bypass; Cells; Cerebral Ischemia; Cessation of life; Characteristics; Clinical; Clinical Trials; Coma; Combined Modality Therapy; Conscious; Data; Development; Disinhibition; Event; FOS gene; Failure; Future; Goals; Heart Arrest; Hibernation; Homeostasis; Hypothalamic structure; Individual; Inflammation; Injection of therapeutic agent; Internet; Intervention; Ischemic Stroke; Knowledge; Lead; Location; Mammals; Maps; Measurement; Mediating; Methods; Molecular; Neuraxis; Neurons; Outcome; Output; Patients; Pharmacotherapy; Phenotype; Physiologic Thermoregulation; Physiological; Play; Process; Receptor Signaling; Regulation; Reperfusion Therapy; Rodent; Role; Seasons; Shivering; Site; Sleep; Staining method; Stains; Stroke; Techniques; Testing; Therapeutic; Tissues; Translating; adenosine receptor activation; arctic ground squirrel; base; disability; excitotoxicity; extracellular; immunocytochemistry; improved; induced hypothermia; injured; innovation; lateral ventricle; natural hypothermia; neural circuit; neurobiological mechanism; neurochemistry; neurotoxic; novel; optogenetics; outcome forecast; public health relevance; receptor expression; receptor sensitivity; relating to nervous system; response; standard of care

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.

描述（由申请人提供）：治疗性低温是临床试验中发现的唯一一种改善脑缺血预后的神经保护治疗方法。它对心脏骤停后的昏迷患者复苏有效，但对中风患者无效。迄今为止，治疗性低温在中风临床试验中未能显示出益处，部分原因可能是当患者未昏迷时，难以击败体温调节防御并达到治疗性体温。研究冬眠的哺乳动物如何绕过体温调节防御系统，是一种创新的方法，可以揭示更有效的诱导治疗性低温的方法。我们最近表明，腺苷A1受体（A1ARs）的激活是必要的，足以诱导冬眠在北极地松鼠在冬季。有趣的是，A1AR激活在夏天不会诱导休眠，这表明更高阶的调节控制腺苷诱导休眠的能力。在这里，我们将绘制在冬季和夏季的北极地松鼠A1腺苷受体激动剂解除抑制的神经元的神经化学解剖，以确定进一步研究的目标大脑区域。虽然在很大程度上是描述性的，但这项研究是了解A1AR激动剂诱导的麻木的更高控制顺序的第一步，并将为未来旨在了解睡眠，体温调节和能量稳态中冬眠相关变化的分子和生理机制的研究奠定基础。初步数据表明，冬眠哺乳动物降低体温的机制将转化为非冬眠物种。