PROJECT 4 - Monoamine regulation of basal ganglia output

一组大脑核团统称为基底神经节参与学习执行复杂的 行为任务学习这些任务的一个主要指导信号是大脑中的化学物质多巴胺， 被认为是与奖励或积极结果相关的重要环境线索的信号，从而允许 大脑更有效地学习如何执行导致奖励的任务。不幸的是，成瘾药物劫持 该系统通过直接引起多巴胺的释放，从而发出错误的“奖励”信号， 导致与药物管理本身相关的行为的强化。通过了解如何 多巴胺引起大脑的可塑性变化，导致成瘾行为，我们希望能够 为这种毁灭性的神经系统疾病开发治疗方法。这个项目采取了独特而新颖的 解决这个问题的方法。在目标1中，我们应用新的工具和方法， 刺激确定的细胞群。我们将对脑切片进行电生理记录， 来自基底神经节最不为人所知的部分：黑质网状部（SNr）。的 SNr是基底神经节的两个主要输出区域之一，因此处于有利地位， 控制离开基底神经节的信号，调节皮质和皮质下运动控制系统。 虽然早期的研究表明它对多巴胺信号的敏感性及其在动物实验中的重要性， 虽然在成瘾的各种范式中，由于在解开成瘾者的神经网络方面存在技术困难， 这个区域的复杂脑回路的功能。在目标2中，我们将开发和利用 成瘾的新范例，涉及直接通路电路的光遗传学自我刺激。这 行为是高度强化的，并且在许多天内频率增加，并且可能共享关键机制。 精神兴奋剂成瘾的特征我们将剖析这种行为强化的机制， SNr，然后在目标3中，我们将进行体内记录，以确定直接通路强度如何 在获得涉及直接通路激活的高度强化行为期间进行修改。

A group of brain nuclei collectively known as the basal ganglia are involved in learning to perform complex behavioral tasks. A major instructive signal for learning these tasks is the brain chemical dopamine, which is thought to signal important environmental cues related to rewards or positive outcomes, thereby allowing the brain to more effectively learn how to perform tasks that lead to reward. Unfortunately, addictive drugs hijack this system by directly causing the release of dopamine, thereby signaling a false "reward" signal, and leading to reinforcement ofthe behaviors associated with drug administration itself. By understanding how dopamine causes plastic changes in the brain that lead to addictive behaviors, we hope to be able to develop treatments for this devastating neurological condition. This project takes a unique and novel approach to this problem. In Aim 1, we apply new tools and methods that allow for highly selective stimulation of defined cell populations. We will perform electrophysiological recordings in brain slices taken from one ofthe least understood parts ofthe basal ganglia: the substantia nigra pars reticulata (SNr). The SNr is one ofthe two major output regions ofthe basal ganglia, and is therefore in a privileged position to control the signals that leave the basal ganglia and regulate cortical and subcortical motor control systems. Although early studies demonstrated its sensitivity to dopamine signaling and its importance in animal paradigms of addiction, little progress has been made, due to technical difficulties in disentangling the function ofthe complex brain circuits that are integrated in this region. In Aim 2, we will develop and exploit a new paradigm for addiction that involves optogenetic self-stimulation ofthe direct pathway circuit. This behavior is highly reinforcing and increases in frequency over many days, and may share key mechanistic features with psychostimulant addiction. We will dissect the mechanisms ofthis behavioral reinforcement in the SNr, and then in Aim 3, we will perform in vivo recordings to determine how direct pathway strength is modified during the acquisition of a highly-reinforced behavior involving direct pathway activation.