Loss of Inhibitory Control in Alcohol Seeking and Dependence: Role of Thalamostriatal Circuitry

酒精寻求和依赖中抑制控制的丧失：丘脑纹状体回路的作用

• 批准号: 10802977
• 负责人: James M Otis
• 金额: $ 33.78万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10802977
• 关键词: Acute; Alcohol consumption; Alcohol dependence; Alcohols; Behavior; Behavioral; Behavioral Assay; Behavioral inhibition; Brain; Calcium; Characteristics; Chronic; Collaborations; Complex; Consummatory Behavior; Consumption; Dangerousness; Data; Dependence; Development; Dopamine Receptor; Economics; Electrophysiology (science); Ethanol; Etiology; Fright; Genetic; Glutamates; Head; Health; Heavy Drinking; Image; Individual; Interneurons; Knowledge; Laboratories; Learning; Literature; Measures; Modeling; Mus; Neurons; Neurophysiology - biologic function; Nucleus Accumbens; Odors; Parvalbumins; Physiology; Quinine; Reporter; Rewards; Role; Safety; Self Administration; Shapes; Slice; Stimulus; Structure of paraventricular nucleus of thalamus; Sucrose; Synapses; Testing; Thalamic structure; Time; Work; alcohol effect; alcohol exposure; alcohol relapse; alcohol research; alcohol seeking behavior; alcohol use disorder; behavior test; experimental study; insight; maladaptive behavior; motivated behavior; neural; neural circuit; neuronal circuitry; novel; optogenetics; patch clamp; prevent; reward circuitry; social; stressor; targeted treatment; two-photon; vapor

PROJECT SUMMARY Maladaptive alcohol seeking, a hallmark of alcohol use disorder (AUD), is thought to be driven not only by increased function of neural circuitry that drives natural reward seeking, but also by loss of control of circuitry that serves to suppress behaviors incompatible with safety and survival. The posterior paraventricular thalamus, (pPVT), and its projections to the nucleus accumbens (NAc), provide feedforward inhibition onto dopamine receptor-expressing medium spiny neurons (MSNs) which are largely responsible for promoting reward- motivated behaviors. Stimuli and situations that naturally serve to limit maladaptive behaviors, such as behavioral threats, have been shown to activate these pPVT®NAc projection neurons and suppress behavior through the activation of downstream parvalbumin inhibitory interneurons (PV-INs). Our labs have shown that an acute stressor (TMT predator odor), quinine-adulteration of alcohol and optogenetic activation of pPVT®NAc circuitry reduces reward- and, of particular importance to this proposal, alcohol-seeking in non-dependent mice. Furthermore, we show that the ability of this circuit to provoke behavioral inhibition is lost after the induction of alcohol dependence. These behavioral adaptations parallel reduced synaptic efficacy at pPVT®NAc glutamatergic synapses onto downstream PV-INs in alcohol-dependent mice. Our data therefore suggest, for the first time, that pPVT®NAc projection neurons are responsible for the suppression of alcohol-seeking behavior but are dysregulated by chronic alcohol exposure. We formally test independent components of this hypothesis in three independent Aims. In Aim 1, using two-photon calcium imaging we will measure and longitudinally track neuronal ensemble dynamics in both pPVT®NAc projections and NAc PV-INs during alcohol self-administration, consumption, and tests of behavioral inhibition in non-dependent and dependent mice. Aim 2 will explore the effects of chronic alcohol exposure on intrinsic and synaptic adaptations in pPVT synaptic inputs to both PV-INs and MSNs in the NAc using slice electrophysiology. Lastly, in Aim 3 we will determine whether activation of pPVT®NAc inputs and/or activation of PV-INs in the NAc are sufficient to restore feedforward inhibition and control alcohol-seeking in non-dependent vs. dependent mice. This project will identify how activity in a principal – but understudied – reward circuit changes from the onset of alcohol use to dependence and will further determine how this activity influences the expression and suppression of alcohol seeking.

项目概要 适应不良的饮酒行为是酒精使用障碍 (AUD) 的一个标志，被认为不仅是由以下因素驱动的： 神经回路的功能增强，驱动自然的奖励寻求，但也由于回路控制的丧失 用于抑制与安全和生存不相容的行为。 (pPVT) 及其对伏隔核 (NAc) 的投射，提供对多巴胺的前馈抑制 表达受体的中型多棘神经元（MSN）主要负责促进奖赏- 自然有助于限制适应不良行为的动机行为，例如行为。 威胁，已被证明可以激活这些 pPVT®NAc 投射神经元并通过 我们的实验室表明，下游小清蛋白抑制性中间神经元 (PV-IN) 的激活是一种急性的。 应激源（TMT 捕食者气味）、酒精奎宁掺假和 pPVT®NAc 电路的光遗传学激活 奖励-减少非依赖小鼠的酒精寻求，并且对于本建议特别重要。 此外，我们表明，在诱导 这些行为适应与 pPVT®NAc 的突触功效降低同时发生。 因此，我们的数据表明，对于酒精依赖小鼠，谷氨酸能突触作用于下游 PV-IN。 首次证明 pPVT®NAc 投射神经元负责抑制对酒精的渴求 行为，但因长期接触酒精而失调，我们正式测试了其中的独立组成部分。 在目标 1 中，我们将使用双光子钙成像来测量和假设。 酒精期间 pPVT®NAc 投影和 NAc PV-IN 中的纵向追踪神经集合动力学 非依赖性和依赖性小鼠的自我给药、消耗和行为抑制测试。 2 将探讨慢性酒精暴露对 pPVT 突触内在和突触适应的影响 使用切片电生理学对 NAc 中的 PV-IN 和 MSN 进行输入 最后，在目标 3 中，我们将确定。 激活 pPVT®NAc 输入和/或激活 NAc 中的 PV-IN 是否足以恢复 该项目将确定非依赖性小鼠与依赖性小鼠的前馈抑制和酒精控制寻求。 主要的（但尚未得到充分研究的）奖励回路的活动从饮酒开始到 依赖性，并将进一步确定该活动如何影响酒精的表达和抑制 寻求。