Activation of the parasubthalamic nucleus in alcohol dependence

摘要 酒精使用障碍的部分特征是对饮酒失去控制，并出现 戒酒期间的消极情绪。而大脑区域和神经递质系统 对慢性酒精暴露的影响有很好的特征，我们对特定神经回路的理解 驾驶饮酒升级和戒酒期间的负面影响仍然有限。我们已经生成了数据 提示神经元位于丘脑旁核(PSTN)，这是后外侧的一个小区域 下丘脑在成瘾中的作用目前尚不清楚，它可能是这一回路的关键组成部分。 具体地说，我们发现，对表达神经肽促肾上腺皮质激素的PSTN神经元的化学发生刺激- 释放因子(CRF)复制了戒断的行为症状，PSTN神经元成为 在经历戒断的酒精依赖小鼠中被激活。这项提议的第一个目标是探索 PSTN CRF神经元化学生成激活导致表型的潜在机制。我们 将评估投射到杏仁中央核的PSTN神经元的贡献(与 PSTN的其他靶点)和CRF信号的作用(与由 PSTN CRF神经元)。另一个目标是检验PSTN是神经元的关键节点的假设 网络驱动了酒精戒断的行为症状。我们将确定是否激活 PSTN神经元对依赖小鼠戒断症状的表达是必要的，无论它是驱动 杏仁核下游中央神经元的激活，以及与哪种神经递质有关。最后，我们 目的了解酒精戒断时PSTN神经元是如何激活的。我们将使用逆行 示踪结合c-Fos标测和电生理记录探讨其机制 在酒精戒断的背景下控制PSTN神经元的活动。在整个项目中，我们将 利用最先进的遗传工具对特定神经通路进行功能性操作，局部沉默 基因表达和神经元映射，以及全脑成像。此外，我们将使用一口井- 我们用新的情感测量方法改进了经过验证的酒精依赖小鼠模型 微扰。总之，建议的实验旨在加强我们对神经的理解。 导致酒精使用障碍的动机和情绪障碍的回路，并可能提供 开发更有效的治疗方法的新途径。

SUMMARY Alcohol use disorders are in part characterized by the loss of control over alcohol drinking and the emergence of negative emotionality during abstinence from alcohol. While the brain regions and neurotransmitter systems affected by chronic alcohol exposure are well characterized, our understanding of the specific neural circuits driving drinking escalation and negative affect during withdrawal remains limited. We have generated data indicating that neurons located in the parasubthalamic nucleus (PSTN), a small region of the posterior lateral hypothalamus whose function in addiction is currently unknown, may be a critical component of this circuitry. Specifically, we show that chemogenetic stimulation of PSTN neurons expressing the neuropeptide corticotropin- releasing factor (CRF) replicates the behavioral symptomatology of withdrawal and that PSTN neurons become activated in ethanol-dependent mice experiencing withdrawal. A first aim of this proposal is to explore the mechanisms underlying the phenotypes resulting from the chemogenetic activation of PSTN CRF neurons. We will evaluate the contribution of PSTN neurons projecting to the central nucleus of the amygdala (as opposed to other targets of the PSTN) and the role of CRF signaling (as opposed to other neurotransmitters co-released by PSTN CRF neurons). Another goal is to test the hypothesis that the PSTN is a critical node of the neuronal network driving the behavioral symptomatology of ethanol withdrawal. We will determine whether the activation of PSTN neurons is necessary to the expression of withdrawal symptoms in dependent mice, whether it drives the activation of downstream central amygdala neurons, and which neurotransmitter is implicated. Finally, we aim to understand how PSTN neurons become activated during ethanol withdrawal. We will use retrograde tracing combined with c-Fos mapping as well as electrophysiological recordings to investigate the mechanisms controlling the activity of PSTN neurons in the context of ethanol withdrawal. Throughout the project, we will leverage state-of-the-art genetic tools for the functional manipulation of specific neural pathways, local silencing of gene expression and neuronal mapping, along with whole-brain imaging. In addition, we will use a well- validated mouse model of ethanol dependence that we have refined with novel measures of affective perturbation. Altogether, the proposed experiments are designed to enhance our understanding of the neural circuitry that contributes to motivational and emotional dysfunction in alcohol use disorders and may provide novel avenues for the development of more efficacious treatments.