Dopaminergic modulation of brain circuits that control movement

描述（由申请人提供）：在人类中，自主运动的控制严重依赖于中脑含多巴胺神经元和纹状体目标神经元之间的神经元通讯。事实上，帕金森氏症中脑多巴胺神经元的退化会导致震颤、行动迟缓和僵硬。相反，过度的多巴胺能刺激会导致过度活跃、冲动和强迫性药物使用。尽管这些神经元很重要，但它们塑造纹状体目标神经元活动的机制却知之甚少。我的近期目标是阐明中脑多巴胺神经元对运动相关纹状体回路的强大影响。从长远来看，我希望利用这些知识来了解多巴胺神经元信号的功能障碍如何导致神经系统疾病。在博士的指导下。贝尔纳多·萨巴蒂尼和克里斯托弗·哈维以及马克·安德曼博士的支持下，我将获得必要的科学和专业培训来解决这些长期存在的问题，并成为一名成功的独立研究者。哈佛医学院神经生物系的资源和设施非常适合我实现我的研究和职业目标。我的研究计划分为三个主要目的：1)解剖多巴胺神经元对纹状体投射神经元的突触和细胞效应；2)定义行为小鼠纹状体神经元的时空活动模式；3)确定多巴胺神经元如何调节体内纹状体活动。我将首先使用电生理学、双光子钙成像和双光子谷氨酸释放来确定多巴胺神经元的光遗传刺激如何影响纹状体投射神经元的兴奋性以及影响它们的兴奋性突触的强度（目的1）。同时，我将开发纹状体窗口准备，以监测在球形跑步机上运行的小鼠纹状体中的神经活动，使用双光子钙成像。然后，我将使用这种技术来揭示识别纹状体神经元在感觉和运动行为中的空间和时间活动模式（目的2）。这些实验不仅将揭示体内纹状体电路动力学的典型特征，而且它们也将作为一个模板

DESCRIPTION (provided by applicant): In humans, the control of voluntary movements is critically dependent on neuronal communication between dopamine-containing neurons in the midbrain and target neurons in the striatum. Indeed, the degeneration of midbrain dopamine neurons in Parkinson's disease results in tremor, slowness of movement and rigidity. Conversely, excessive dopaminergic stimulation induces hyperactivity, impulsiveness and compulsive drug use. Despite the importance of these neurons, the mechanisms by which they shape the activity of target neurons in the striatum are poorly understood. My immediate goal is to shed light on the powerful influence that midbrain dopamine neurons exert on movement-related striatal circuits. In the long run, I wish to use this knowledge to understand how dysfunction of dopamine neuron signaling engenders neurological illnesses. Under the mentorship of Drs. Bernardo Sabatini and Christopher Harvey and with the support of Dr. Mark Andermann, I will acquire the scientific and professional training necessary to address these long-standing questions and to succeed as an independent researcher. The resources and facilities within the Harvard Medical School Department of Neurobiology are ideal to ensure I realize my research and career objectives. My research plan is divided into three main aims: 1) To dissect the synaptic and cellular effects of dopamine neurons on striatal projection neurons, 2) To define the spatial and temporal activity patterns of striatal neurons in behaving mice, and 3) To determine how dopamine neurons modulate striatal activity in vivo. I will first use electrophysiology, two-photon calcium imaging and two-photon glutamate uncaging to determine how optogenetic stimulation of dopamine neurons impacts the excitability of striatal projection neurons and the strength of excitatory synapses that impinge on them (Aim 1). In parallel, I will develop a striatal window preparation to monitor neural activity en masse in the striatum of mice running on a spherical treadmill using two-photon calcium imaging. I will then use this technique to reveal the spatial and temporal patterns of activity of identified striatal neurons during sensory and motor behaviors (Aim 2). These experiments will not only uncover canonical features of striatal circuit dynamics in vivo, but they will also serve as a template for the detection of circuit elements that are modified by dopamine neurons. In Aim 3, I will identify these modifications by optically monitoring the activity of striatal neurons in behaving mice before and after optogenetic or pharmacogenetic manipulation of dopamine neuron discharge. By revealing how brief and prolonged changes in dopamine neuron activity impact striatal neurons at the synaptic, cellular and circuit levels, the proposed work will shed light on the mechanisms employed by dopamine neurons to influence voluntary movements and the disturbances that lead to motor impairments in Parkinson's disease. Importantly, this knowledge will guide the development of therapeutic interventions for this and other neurological diseases.