Alcohol and Interneurons in the Prefrontal Cortex

前额叶皮质(PFC)调节对目标定向行为的控制，被认为是PFC功能障碍。 强制吸毒和复吸是物质滥用者的基础。PFC被牵连到 与社交饮酒相关的酒精水平所产生的行为影响。很少有详细的研究。 酒精在PFC中的作用，或特别是对三种主要中间神经元(INT)的敏感性的影响 这可以增强和控制锥体(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+)-表达整型。我们现在建议检查另外两个主要亚型对酒精的敏感性 INT：小白蛋白(PV+)和血管活性肠多肽(VIP+)表达亚型。这个 该提议的首要假设是一个或多个特定的INT亚群是敏感的 对于酒精，酒精对INT活性的调节是通过从 腹侧被盖区(VTA)，并导致PFC内的去抑制。 我们将利用双光子成像技术研究酒精对PV+和VIP+INT活性的影响 探讨酒精在前庭功能障碍中的作用和机制。我们将研究酒精对PYR活性的影响 和INT在活体小鼠边缘前区(PL)的PFC中使用遗传编码的钙指示剂 GCaMP。我们假设乙醇通过激活一种蛋白来增加PYR和某些INT的活性。 去抑制局部环路，而这些对PYR的影响是由于以下亚群中活性降低所致 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元活动的影响，成像GCaMP 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PFC体内PYR和INT活性的影响。我们假设 PFC中DA传入体内的活动释放了PFC中的DA和调制INT，这可能是 通过抑制来自VTA的多巴胺能输入而被阻止。 我们将在体内用特异性的方法研究PFC中PYR和INT亚型的酒精敏感性机制。 多巴胺受体拮抗剂，以建立抑制PYR和INT的机制 通过低剂量的酒精，以及酒精如何在体内和体外调节特定的INT亚类。我们 假设酒精抑制PYR，并且这是通过酒精的间接作用发生的 由VTA递增的多巴胺能输入介导，作用于PFC中的DA受体。

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.