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：
8648432
负责人：
William J Giardino
金额：
$ 4.71万
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/8648432
关键词：
Alcohol consumption Alcoholism Anxiety 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 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 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 public health relevance 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）：酒精中毒是一种慢性疾病，对社会造成了严重后果，并且在促成依赖性酒精中毒的乙醇（ETOH）消费量的复发中起着关键作用。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中的关键作用。因此，需要进一步的研究来促进科学知识，了解与压力有关的行为和过度饮酒的基本神经生物学。实际上，多种应激神经肽系统以复杂的方式有助于与埃托相关的行为。 C57BL/6J（B6）小鼠是询问过度EtOH摄入神经生物学的理想选择，因为它们在昼夜节律黑暗周期的离散时期内自愿消耗足够数量的ETOH，以产生血液ETOH浓度（BEC），这些eTOH浓度（BEC）超过了NIAAA对饮酒的标准（80 mg/dl，或.08％）。该提案将与长期间歇性暴饮暴食和厌恶位置调节模型相结合，以建立（或抗拒）下丘脑下腔蛋白系统，高主体和病理ETOH消耗量之间的应激状态（或抗拒）因果关系。此外，这些实验将使用病毒追踪和双荧光免疫组织化学来解剖学上定义连接皮质激素释放因子（CRF）和降压素系统的途径，并确定这些相互作用如何控制应激应力反应和eTOH饮酒行为。应力激素测量值，亚型特异性药理学和转录因子映射将提供互补的措施，以确认发现并进一步定义这些行为背后的精确神经底物。从拟议的实验中获得的知识将为减轻药物滥用和复发的未来策略提供信息。