Role of specific cortico-basal ganglia pathways in animal models of addiction

项目摘要 皮质基底神经节系统是一个复杂的网络，参与动机和奖励。中型多棘 纹状体内的投射神经元（MSN）充当该回路的主要中继站，并引导 行为输出通过两个不同的途径。含有神经肽强啡肽的纹状体MSN (DYN)和P物质是直接通路的一部分，而含有神经肽的纹状体神经元 脑啡肽（ENK）是间接途径的一部分。反复接触滥用药物会产生 皮质-基底神经节回路的失调，部分是通过皮质下结构的异常可塑性， 例如纹状体，以及通过失去来自多巴胺能传入系统的自上而下的控制。直接 间接纹状体MSNs最近被证明在行为中发挥重要但独特的作用 由精神兴奋剂药物产生。然而，关于这些不同细胞的作用知之甚少， 在产生强迫性吸毒模式的模型中， 和寻求药物的成瘾特征，如长期获得药物自我管理。在 此外，这些纹状体细胞群中的信号活动如何在强迫性药物使用后发生变化， as调节成瘾样行为的机制尚不清楚。拟议实验的总体目标是 使用表达工程化DREADD（设计者特异性激活的设计者受体）的新型病毒载体 药物）受体，以确定直接和间接途径MSN的作用，以及多巴胺能传入， 强迫性吸毒和寻求毒品的行为。此外，强迫性吸毒模式如何改变 将检测纹状体细胞群中的细胞内信号传导活性。这个问题的核心假设是 建议重复使用药物产生谷氨酸依赖性修饰G蛋白依赖性 在一部分个体中，纹状体中的信号级联，导致强迫性、成瘾性行为 （定义为吸毒的强烈动机，以及在无法获得毒品期间和 惩罚）。具体地说，我们认为ERK/MAPK信号级联在直接途径中增强， MSNs和抑制间接途径MSNs，这将这些途径的平衡转向'去' 从而增加吸毒和寻求毒品。这项工作有可能确定新的目标， 处理（即，特定的细胞群或传入投射）以及可能 逆转成瘾行为，如DREADD受体对细胞内信号级联的调节。

Project Summary The cortico-basal ganglia system is a complex network involved in motivation and reward. Medium spiny projection neurons (MSNs) within the striatum serve as the primary relay station of this circuit, and guide behavioral output through two divergent pathways. Striatal MSNs that contain the neuropeptides dynorphin (DYN) and substance P are part of the direct pathway whereas striatal neurons that contain the neuropeptide enkephalin (ENK) are part of the indirect pathway. Repeated exposure to drugs of abuse can produce dysregulation in the cortico-basal ganglia circuit, in part through aberrant plasticity at sub-cortical structures, such as the striatum, as well as through a loss of top-down control from glutamatergic afferent systems. Direct and indirect striatal MSNs have recently been shown to play important, but distinct, roles in behaviors produced by psychostimulant drugs. However, little is known regarding the roles of these distinct cell populations, as well as their afferent connections, in models that produce patterns of compulsive drug-taking and drug-seeking that are characteristic of addiction, such as prolonged access drug self-administration. In addition, how signaling activity in these striatal cell populations changes following compulsive drug use, as well as regulates addiction-like behavior is not well understood. The overall aim of the proposed experiments is to use novel viral vectors expressing engineered DREADD (Designer Receptor Exclusively Activated by Designer Drug) receptors to define the role of direct and indirect pathway MSNs, as well as glutamatergic afferents, in compulsive drug-taking and drug-seeking behaviors. In addition, how compulsive patterns of drug use alter intracellular signaling activity in striatal cell populations will be examined. The central hypothesis of this proposal is that repeated drug use produces glutamate-dependent modifications to G-protein dependent signaling cascades in the striatum in a subset of individuals, leading to compulsive, addiction-like behavior (defined by high motivation to take drugs, and drug-seeking during periods of drug unavailability and during punishment). Specifically, we propose that ERK/MAPK signaling cascades are enhanced in direct pathway MSNs and suppressed in indirect pathway MSNs, which shifts the balance of these pathways towards the 'go' drive, thereby increase drug-taking and drug-seeking. This work has the potential to identify new targets for treatment (i.e., specific cell populations or afferent projections) as well as new types of treatments that may reverse addictive behaviors, such as DREADD receptor modulation of intracellular signaling cascades.