Alcohol-induced neuroadapation of prefrontal cortical projections

项目总结/摘要 酒精中毒是一种慢性复发性疾病，其特征是酒精成瘾， 和消极的情绪状态酗酒者的前额皮质体积减少， 腹内侧前额叶皮层（vmPFC）相关的任务，如功能失调的情绪处理和损失的 抑制控制啮齿动物内侧前额叶皮层（mPFC）在功能上与vmPFC相似， 区域通过以“自上而下”的方式调节皮层下区域来指导行为的灵活调节。 在mPFC中，前边缘（PrL）和下边缘（IfL）皮质具有相反的成瘾相关功能， PrL驱动着寻求毒品，IfL则与灭绝有关。IfL与焦虑样和 过度饮酒行为，表明酒精依赖诱导的特定IfL- 皮质下投射可能有助于酒精成瘾期间出现的负面情感状态。 因此，当前和未来研究的挑战是确定特定IfL内的神经适应。 这些皮层下回路驱动着这些酒精依赖诱导行为的不同方面。 CeA募集是酒精依赖的标志，并导致情绪失调， 控制戒断引起的焦虑和酗酒IfL直接投射到CeA，我们建议， 这一通路的神经适应可能激活慢性乙醇暴露后的CeA。临床上 去甲肾上腺素能系统与酒精依赖患者的酒精消耗有关， 严格调节IfL功能。因此，在这里，我们将研究如何酒精依赖诱导去甲肾上腺素能 IfL内的神经适应失调其输出到CeA，以及该系统是否介导酒精 戒断引起的饮酒和焦虑样行为。 我们有意设计这个项目，以最大限度地提高其跨学科的性质，确保 可以比较通过不同实验模态获得的信息。我们将采用逆行 标记IfL-CeA投射神经元的示踪剂，允许电生理和免疫组织化学 酒精依赖诱导的去甲肾上腺素能对这一途径的影响的特征 酒精暴露为了将这些细胞和分子结果扩展到网络水平，在我的K99阶段I中， 将在体内微透析中进行训练，以测量暴露于以下物质的清醒、行为正常的小鼠中IfL去甲肾上腺素的变化： 慢性乙醇我还将接受行为药理学技术的培训，以评估自愿饮用 乙醇依赖小鼠在其焦虑样行为测试之前。总的来说，这项工作将提供洞察力， 研究去甲肾上腺素能信号对IfL-CeA通路的影响及其与酒精的神经适应性 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.