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

基本信息

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
项目类别：
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

项目摘要

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唯一的神经保护疗法，可改善脑缺血后的预后。这是心脏骤停后复苏的有效n昏迷患者，但未能显示出中风患者的好处。迄今为止，治疗性体温过低未在中风临床试验中表现出益处，这可能部分是由于难以在患者不昏迷时击败热调节防御和达到治疗性体温。研究在TORPOR发作期间冬眠哺乳动物绕过热调节防御的研究是一种创新的方法，可以揭示更有效的诱导治疗性低温手段。我们最近表明，在冬季，腺苷A1受体（A1AR）的激活是必要且足够的，足以诱导北极地松鼠。有趣的是，A1AR激活不会在夏季诱导Torpor，这表明较高的调节控制腺苷诱导Torpor的能力。在这里，我们将在冬季和夏季绘制A1腺苷受体激动剂的神经化学解剖结构，该神经元在冬季和夏季抑制了A1腺苷受体激动剂，以鉴定脑部区域以进行进一步研究。尽管在很大程度上是描述性的，但这项研究是了解对A1AR激动剂诱导的Torpor的高级控制的第一步，并将为未来的研究构成旨在理解与冬眠相关的睡眠，体温调节和能量稳态变化的分子和生理机制的未来研究的基础。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释放物种。