Optogenetic studies of hypocretin in binge drinking and negative hedonic valence

描述（由申请人提供）：酒精中毒是一种慢性疾病，对社会造成严重后果，压力在酒精依赖者酒精（EtOH）消费复发中起着关键作用。即使在非依赖人群中，证据也支持神经应激网络在乙醇摄入量中的关键作用。因此，需要进一步的研究来推进复杂的神经生物学的科学知识，这些神经生物学是压力相关行为和过量乙醇饮用的基础。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。C57 BL/6 J（B6）小鼠是询问过量EtOH摄入的神经生物学的理想模型，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量的EtOH，以产生超过NIAAA的酗酒标准（80 mg/dL，或0.08%）的血液EtOH浓度（BEC）。该提案将整合体内光遗传学刺激/抑制实验与长期间歇性酗酒和厌恶性场所条件反射模型，以建立（或反驳）下丘脑泌素系统，应激样过度觉醒状态和病理性EtOH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来解剖学地定义连接促肾上腺皮质激素释放因子（CRF）和下丘脑泌素系统的途径，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作图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今后减少药物滥用和复吸的战略提供信息。

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.