Alcohol and Interneurons in the Prefrontal Cortex

酒精和前额皮质的中间神经元

• 批准号: 10567414
• 负责人: NEIL L. HARRISON
• 金额: $ 46.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567414
• 关键词: Alcohols; Area; Behavior; Behavioral; Brain; Complex; Cues; Data; Decision Making; Disinhibition; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dose; Ethanol; Functional disorder; Genetic; Goals; Image; Imaging Techniques; Impulsive Behavior; In Vitro; Interneurons; Light; Measures; Mediating; Methods; Microscope; Mus; Neurons; Parvalbumins; Pharmaceutical Preparations; Prefrontal Cortex; Publishing; Pyramidal Cells; Relapse; Reporting; Role; Somatostatin; Subgroup; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide; Ventral Tegmental Area; Work; alcohol abuser; alcohol effect; alcohol exposure; alcohol measurement; alcohol sensitivity; alcohol use disorder; antagonist; brain cell; calcium indicator; cellular imaging; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drinking; drug abuser; experimental study; hippocampal pyramidal neuron; in vivo; in vivo imaging; mind control; neuronal circuitry; pharmacologic; prevent; promoter; receptor; response; social; substance abuser; two-photon

The prefrontal cortex (PFC) mediates control over goal-directed behaviors and dysfunction of the PFC is thought to underlie compulsive drug-taking and relapse in substance abusers. The PFC has been implicated in behavioral effects that occur at levels of alcohol associated with social drinking. There are few detailed studies on the actions of alcohol in PFC, or specifically on the sensitivity of three major subtypes of interneurons (INTs) that augment and control the activity of pyramidal (PYR) neurons. We recently reported the stimulatory effects of alcohol on PYR and its inhibitory effect on somatostatin (SST+)-expressing INTs. We now propose to examine the sensitivity to alcohol of two additional major subtypes of INTs: parvalbumin (PV+)-, and vasoactive intestinal polypeptide (VIP+) expressing subtypes. The overarching hypothesis of the proposal is that one or more specific sub-populations of INTs are sensitive to alcohol, that modulation of INT activity by alcohol is mediated by ascending dopaminergic inputs from the ventral tegmental area (VTA) and leads to disinhibition within the PFC. We will study the effects of alcohol on the activity of PV+ and VIP+ INT using 2-photon imaging techniques to probe the actions and mechanisms of alcohol in the PFC. We will study the effects of alcohol on activity in PYR and INT in the PFC in vivo in the mouse pre-limbic area (PL) using the genetically-encoded calcium indicator GCaMP. We hypothesize that ethanol increases activity in PYR and certain INTs via the activation of a disinhibitory local circuit, and that these effects on PYR result from decreases in activity in a subgroup of SST+ INTs, perhaps via activation of VIP+ INTs. We will also study the effect of alcohol on activity in dopaminergic afferents within the PFC, imaging GCaMP under the control of the tyrosine hydroxylase promoter and measure the effects of activating Gi DREADDs within the ventral VTA to block the effects of alcohol on PYR and INT activity in the PFC in vivo. We hypothesize that activity within DA afferents in the PFC releases DA and modulate INTs in PFC, and that this may be prevented by silencing dopaminergic inputs from the VTA. We will examine the mechanisms of alcohol sensitivity of PYR and INT subtypes in PFC in vivo using specific dopamine receptor antagonists, in order to establish the mechanisms by which PYR and INTs are disinhibited by low dose alcohol and how specific INT sub-classes are modulated by alcohol in vivo and in vitro. We hypothesize that alcohol disinhibits PYR and that this occurs via indirect effects of alcohol that are mediated by ascending dopaminergic inputs from the VTA, acting on DA receptors in the PFC.

前额皮质 (PFC) 介导对目标导向行为的控制，并且认为 PFC 功能障碍 是药物滥用者强迫性吸毒和复发的基础。 PFC 已被牵连 与社交饮酒相关的酒精水平下发生的行为影响。详细的研究还很少 酒精对 PFC 的作用，或者特别是对中间神经元 (INT) 的三种主要亚型的敏感性 增强和控制锥体（PYR）神经元的活动。 我们最近报道了酒精对 PYR 的刺激作用及其对生长抑素的抑制作用 (SST+)-表达 INT。我们现在建议检查另外两种主要亚型对酒精的敏感性 INT：小清蛋白 (PV+)- 和血管活性肠多肽 (VIP+) 表达亚型。这 该提案的总体假设是，一个或多个特定的 INT 子群体是敏感的 酒精对 INT 活性的调节是通过上升的多巴胺能输入介导的 腹侧被盖区 (VTA) 并导致 PFC 内的去抑制。 我们将使用 2 光子成像技术研究酒精对 PV+ 和 VIP+ INT 活性的影响 探究酒精在 PFC 中的作用和机制。我们将研究酒精对 PYR 活性的影响 使用基因编码的钙指示剂测量小鼠前边缘区 (PL) 体内 PFC 中的 INT 和 INT GCaMP。我们假设乙醇通过激活一个酶来增加 PYR 和某些 INT 的活性 去抑制局部电路，并且这些对 PYR 的影响是由于一个亚组的活性降低造成的 SST+ INT，可能通过激活 VIP+ INT。 我们还将研究酒精对 PFC 内多巴胺能传入神经活动的影响，对 GCaMP 进行成像 在酪氨酸羟化酶启动子的控制下并测量激活 Gi DREADDs 的效果 腹侧 VTA 阻断酒精对体内 PFC 中 PYR 和 INT 活性的影响。我们假设 PFC 中 DA 传入神经内的活动释放 DA 并调节 PFC 中的 INT，这可能是 通过抑制 VTA 的多巴胺能输入来预防。 我们将使用特定的方法在体内研究 PFC 中 PYR 和 INT 亚型的酒精敏感性机制 多巴胺受体拮抗剂，以建立 PYR 和 INT 的去抑制机制 低剂量酒精的作用以及酒精在体内和体外如何调节特定的 INT 亚类。我们 假设酒精会抑制 PYR，并且这是通过酒精的间接作用发生的 由来自 VTA 的上行多巴胺能输入介导，作用于 PFC 中的 DA 受体。