Alcohol-induced neuroadapation of prefrontal cortical projections

项目摘要/摘要 酒精中毒是一种慢性复发性障碍，其特征是沉迷于酒精，对摄入量失去控制 以及消极的情绪状态。酗酒者前额叶皮质体积减少，大脑 与腹内侧前额叶皮质(VmPFC)相关的任务，如情绪处理障碍和 抑制性控制。啮齿动物的内侧前额叶皮质(MPFC)在功能上与vmPFC相似，因为两者 区域通过以“自上而下”的方式调节皮质下区域来指导灵活的行为调节。 在mPFC内，前交叉(PRL)和下缘(IfL)皮质具有相反的成瘾相关功能， 革命制度党驱使着人们寻找毒品，而民族解放力量则卷入了灭绝之中。IfL卷入了焦虑症和 过度饮酒行为，提示酒精依赖导致特异性IfL-1调节失调。 皮层下投射可能导致酒精成瘾期间出现的负面情绪状态。 因此，当前和未来研究的挑战是确定特定IfL内的神经适应。 皮层下回路驱动这些酒精依赖诱导行为的不同方面。 招募CEA是酒精依赖的一个标志，并导致情绪失调， 控制戒断引起的焦虑和饮酒。IfL直接投射到CEA，我们建议 这一通路的神经适应性可能激活慢性乙醇暴露后的CEA。在临床上， 去甲肾上腺素能系统与酒精依赖患者的酒精消费有关，并且 严格调控IfL功能。因此，这里我们将研究酒精依赖是如何诱导去甲肾上腺素能的。 Ifl内的神经适应性，以失调其向CEA的输出，以及该系统是否调节酒精 戒断导致的饮酒和焦虑样行为。 我们特意设计了这个项目，通过确保 通过不同的实验模式获得的信息可以进行比较。我们将采用逆行 示踪剂标记IfL-CEA投射神经元，允许电生理和免疫组织化学 慢性酒精依赖后去甲肾上腺素对此通路影响的特征 酒精暴露。在我的K99阶段I期间，将这些细胞和分子结果扩展到网络级别 将在体内进行微透析训练，以测量清醒状态下暴露于 慢性酒精中毒。我还将培训行为药理学技术，以评估自愿饮酒 酒精依赖小鼠在焦虑样行为测试之前。总的来说，这项工作将提供洞察力 去甲肾上腺素能信号对IfL-CEA通路的影响及其对酒精的神经适应 依赖。

Project Summary / Abstract Alcoholism is a chronic relapsing disorder characterized by alcohol preoccupation, loss of control over intake and a negative emotional state. Alcoholics have reduced prefrontal cortex volumes and significant deficits in ventromedial prefrontal cortex (vmPFC)-related tasks, such as dysfunctional emotional processing and loss of inhibitory control. The rodent medial prefrontal cortex (mPFC) is functionally analogous to the vmPFC as both regions direct the flexible regulation of behavior by regulating subcortical regions in a “top-down” manner. Within the mPFC, the prelimbic (PrL) and infralimbic (IfL) cortices have opposing addiction-related functions, with the PrL driving drug-seeking and the IfL involved with extinction. The IfL is implicated in anxiety-like and excessive drinking behaviors, suggesting that alcohol dependence-induced dysregulation of specific IfL- subcortical projections may contribute to the negative affective state that emerges during alcohol addiction. Thus, the challenge of current and future studies is to identify the neuroadaptations within specific IfL- subcortical circuits that drive different aspects of these alcohol dependence-induced behaviors. CeA recruitment is a hallmark of alcohol dependence and leads to the emotional dysregulation that governs withdrawal-induced anxiety and drinking. The IfL directly projects to the CeA, and we propose that neuroadaptation of this pathway may activate the CeA after chronic ethanol exposure. Clinically, the noradrenergic system has been implicated in the alcohol consumption of alcohol-dependent patients, and tightly regulates IfL function. Therefore, here we will examine how alcohol dependence induces noradrenergic neuroadaptation within the IfL to dysregulate its output to the CeA, and whether this system mediates alcohol withdrawal-induced drinking and anxiety-like behaviors. We have intentionally designed this project to maximize its interdisciplinary nature by ensuring that the information obtained via the different experimental modalities can be compared. We will employ retrograde tracers to label IfL-CeA projection neurons, allowing for the electrophysiological and immunohistochemical characterization of alcohol dependence-induced noradrenergic influence over this pathway after chronic ethanol exposure. To extend these cellular and molecular results to the network level, during my K99 phase I will train in in vivo microdialysis to measure changes in IfL norepinephrine in awake, behaving mice exposed to chronic ethanol. I will also train in behavioral pharmacology techniques to assess the voluntary drinking of ethanol-dependent mice prior to their anxiety-like behavioral testing. Collectively, this work will provide insight into the influence of noradrenergic signaling on the IfL-CeA pathway, and its neuroadaptation with alcohol dependence.