Alcohol and Interneurons in the Prefrontal Cortex

前额叶皮层（PFC）介导对目标导向行为的控制，PFC功能障碍被认为是 导致药物滥用者强迫性吸毒和复发。一等兵涉嫌 行为影响，发生在酒精水平与社会饮酒。很少有详细的研究 对酒精在PFC中的作用，或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的刺激作用和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。的 该提案的首要假设是，一个或多个特定的INT亚群对 酒精对INT活性的调节是由来自多巴胺能神经元的 腹侧被盖区（VTA），并导致PFC内的抑制解除。 我们将使用双光子成像技术研究酒精对PV+和VIP+ INT活性的影响， 探讨乙醇在PFC中的作用及机制，研究乙醇对PYR活性的影响 和INT在PFC在体内在小鼠前边缘区（PL）使用遗传编码的钙指示剂 GCaMP。我们假设乙醇通过激活一种新的蛋白质来增加PYR和某些INT的活性。 这些对PYR的影响是由于一个亚组中的活性降低， 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，并测量激活细胞内Gi DREADD的作用。 腹侧VTA阻断酒精对PFC中PYR和INT活性的影响。我们假设 PFC中DA传入内的活动释放DA并调节PFC中的INT，这可能是 通过抑制腹侧被盖区的多巴胺能输入来防止。 我们将在体内使用特异性免疫荧光技术研究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被解除抑制的机制 通过低剂量酒精和特定的INT亚类是如何调节酒精在体内和体外。我们 假设酒精抑制PYR，这是通过酒精的间接作用发生的， 由腹侧被盖区的多巴胺能上行输入介导，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.