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Optogenetic studies of hypocretin in binge drinking and negative hedonic valence

酗酒和负享乐价中下丘脑分泌素的光遗传学研究

基本信息

批准号：
8974206
负责人：
William J Giardino
金额：
$ 5.61万
依托单位：
STANFORD UNIVERSITY
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：
2013-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8974206
关键词：
Alcohol consumption Alcoholism Arousal Behavior Behavioral Binding Biological Assay Blood Brain Cations Characteristics Chloride Channels Chronic Disease Circadian Rhythms Complex Consummatory Behavior Consumption Corticosterone Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Development Drug abuse Ethanol FOS gene Face Food Future G-Protein-Coupled Receptors Health Hormones Human Hypothalamic structure Immunohistochemistry Individual Injection of therapeutic agent Intake Knowledge Laboratories Lateral Level of Evidence Life Stress Light Link Literature Locomotion Maps Measurement Measures Mediating Memory Messenger RNA Modeling Mus National Institute on Alcohol Abuse and Alcoholism Neurobiology Neurons Neuropeptides Neurosecretory Systems Optics Pathway interactions Pattern Peptides Pharmacology Plasma Play Population Publications Rattus Receptor Signaling Recruitment Activity Relapse Reporting Research Rewards Role Scientific Advances and Accomplishments Self Stimulation Side Societies Source Stress Structure Sucrose Synapses System Testing Ventral Tegmental Area Viral Withdrawal alcohol relapse alcohol research anxiety-like behavior binge drinking biological adaptation to stress conditioning design drinking drinking behavior drug relapse excessive behavior experience hedonic hypocretin improved in vivo mouse model negative emotional state optogenetics prevent problem drinker promoter receptor relating to nervous system research study tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Alcoholism is a chronic disease with severe consequences to society, and stress plays a key role in precipitating relapse of ethanol (EtOH) consumption in dependent alcoholics. Even in non-dependent populations, evidence supports a key role for neural stress networks in binge EtOH intake. Therefore, further research is required to advance scientific knowledge of the intricate neurobiology underlying stress-related behavior and excessive EtOH drinking. Indeed, multiple stress neuropeptide systems contribute to EtOH- related behaviors in complex ways. C57BL/6J (B6) mice serve as an ideal for model interrogating the neurobiology of excessive EtOH intake, as they voluntarily consume sufficient quantities of EtOH within discrete periods of the circadian dark cycle to produce blood EtOH concentrations (BECs) that surpass the NIAAA's criteria for binge drinking (80 mg/dL, or .08 percent). This proposal will integrate in vivo optogenetic stimulation/inhibition experiments with models of long-term intermittent binge drinking and aversive place conditioning in order to establish (or refute) causal relationships between the hypothalamic hypocretin system, stress-like states of hyperarousal, and pathological EtOH consumption. In addition, these experiments will use viral tracing and double fluorescent immunohistochemistry to anatomically define the pathways connecting the corticotropin-releasing factor (CRF) and hypocretin systems, and determine how these interactions control the stress response and EtOH drinking behavior. Stress hormone measurements, subtype-specific pharmacology, and transcription factor mapping will provide complementary measures to confirm the findings and further define the precise neural substrates underlying these behaviors. Knowledge gained from the proposed experiments will inform future strategies for mitigation of drug abuse and relapse.

描述（由申请人提供）：酗酒是一种对社会造成严重后果的慢性疾病，压力在促使酗酒者复发乙醇 (EtOH) 方面发挥着关键作用。即使在非依赖人群中，证据也支持神经压力网络在暴饮暴食乙醇中发挥着关键作用。因此，需要进一步的研究来增进对压力相关行为和过量乙醇饮酒背后复杂的神经生物学的科学认识。事实上，多种应激神经肽系统以复杂的方式促成乙醇相关行为。 C57BL/6J (B6) 小鼠是研究过量 EtOH 摄入神经生物学的理想模型，因为它们在昼夜节律暗周期的离散周期内自愿消耗足够量的 EtOH，产生的血液 EtOH 浓度 (BEC) 超过 NIAAA 的暴饮标准（80 mg/dL，或 0.08%）。该提案将体内光遗传学刺激/抑制实验与长期间歇性暴饮暴食和厌恶性场所调节模型相结合，以便建立（或反驳）下丘脑下丘脑分泌素系统、过度兴奋的应激样状态和病理性乙醇消耗之间的因果关系。此外，这些实验将使用病毒示踪和双荧光免疫组织化学从解剖学上定义连接促肾上腺皮质激素释放因子（CRF）和下丘脑分泌素系统的途径，并确定这些相互作用如何控制应激反应和乙醇饮酒行为。应激激素测量、亚型特异性药理学和转录因子图谱将提供补充措施来证实这些发现并进一步定义这些行为背后的精确神经基质。从拟议的实验中获得的知识将为未来减轻药物滥用和复发的策略提供信息。