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.

人们认为，前额叶皮层（PFC）介导了对目标指导行为和PFC功能障碍的控制 为了使滥用药物的毒品和复发构成强迫性吸毒和复发。 PFC与 与社交饮酒相关的酒精水平上发生的行为影响。详细研究很少 关于酒精在PFC中的作用，特别是对三个主要亚型中间神经元（INT）的敏感性 增强和控制锥体（Pyr）神经元的活性。 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+） - 表示INT。现在，我们建议检查对两个其他主要亚型的酒精的敏感性 INT：白蛋白（PV+） - 和表达亚型的血管活性肠多肽（VIP+）。这 该提案的总体假设是一个或多个特定的INT亚种群是敏感的 酗酒，酒精对INT活性的调节是通过从 腹侧对盖区（VTA），并导致PFC内的抑制作用。 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 探测PFC中酒精的作用和机制。我们将研究酒精对PYR活性的影响 使用遗传编码的钙指标 GCAMP。我们假设乙醇通过A的激活增加了PYR和某些INT的活性 抑制局部电路，并且这些对PYR的影响是由于在 SST+ INT，也许是通过激活VIP+ INTS的激活。 我们还将研究酒精对PFC中多巴胺能传入的活性的影响，对GCAMP进行成像 在酪氨酸羟化酶启动子的控制下，测量激活GI Dreadds的影响 腹侧VTA阻断了酒精对体内PFC中PYR和INT活性的影响。我们假设这一点 PFC中DA传入中的活动释放DA并调节PFC中的INT，这可能是 通过使VTA中的多巴胺能输入沉默。 我们将使用特异 多巴胺受体拮抗剂，以建立抑制pyr和int的机制 通过低剂量酒精以及特定的INT子类是如何通过体内和体外调节酒精调节的。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 通过来自VTA的升高多巴胺能输入，作用于PFC中的DA受体。