Neuronal encoding of habit-like alcohol self-administration in dorsal striatum

描述（由申请人提供）：酒精中毒的特征是持续饮酒，可能包括从目标导向到习惯性饮酒的转变，因为这种行为变得根深蒂固，对治疗产生抗药性。最近的证据表明，这些行为具有不同的解剖学基础，背内侧纹状体（DMS）与目标导向行为有关，而背外侧纹状体（DLS）则需要习惯形成。然而，在酒精强化过程中，这些区域是否被不同地激活，以及DLS中特定的神经递质系统在习惯性饮酒中可能发挥什么作用，目前尚不清楚。本文提出的研究将通过长期植入电极的细胞外记录，研究DMS和DLS神经元如何在操作性自我给予酒精和非酒精奖励时编码线索、动作和奖励传递。这些神经元放电模式将在酒精自我给药模型中进行比较，该模型通常用于产生习惯性的酒精寻求：可变间隔时间表。下一步，电生理学将结合局部药理学研究多巴胺在DLS中对背纹状体神经元的行为和放电模式的作用。我们的中心假设是，习惯行为的表达依赖于竞争中的平行回路，在习惯性酒精自我给药过程中，DLS的感觉运动加工表现出更大的激活和行为控制。这些创新和机制的研究将极大地促进我们对习惯性酒精寻求和饮酒行为的神经基础的理解，并阐明这种行为的不灵活性是否依赖于多巴胺。了解酒精中毒这一关键方面背后的神经生物学，对于预防和治疗这种慢性疾病的未来是必要的。此外，这里提出的培训将提供强大的技术和教育基础，并促进成瘾神经生物学的生产性职业生涯。

DESCRIPTION (provided by applicant): Alcoholism is characterized by persistent drinking that may involve a shift from goal-directed to habitual drinking as the behavior becomes engrained and resistant to treatment. Recent evidence suggests these behaviors have distinct anatomical substrates, with the dorsomedial striatum (DMS) implicated in goal-directed behavior, while the dorsolateral striatum (DLS) is required for habit formation. It remains unknown, however, whether these regions are differentially activated during alcohol reinforcement and what role specific neurotransmitter systems in the DLS might play in habitual alcohol drinking. The studies proposed here will investigate how DMS and DLS neurons encode cues, actions, and reward deliveries during operant self- administration of alcoholic versus non-alcoholic rewards via extracellular recordings from chronically implanted electrodes. These neuronal firing patterns will be compared in a model of alcohol self-administration commonly used to generate habitual alcohol seeking: a variable interval schedule. Next, electrophysiology will be combined with local pharmacology to investigate the role of dopamine in the DLS on behavior as well as firing patterns of dorsal striatal neurons. Our central hypothesis is that the expression of habitual behavior depends on parallel circuits acting in competition, with sensorimotor processing in the DLS exhibiting greater activation and behavioral control during habit-like alcohol self-administration. These innovative and mechanistic studies will significantly advance our understanding of the neural substrates of habitual alcohol seeking and drinking behavior, and elucidate whether this behavioral inflexibility is dependent on dopamine. Understanding the neurobiology underlying this critical aspect of alcoholism will be necessary for the future of prevention and treatment of this chronic disease. In addition, the training proposed here will provide a strong technical and educational foundation and promote a productive career in addiction neurobiology.