Understanding the behavioral function of striatal tyrosine-hydroxylase interneurons.

项目摘要/摘要 新纹状体直接参与了几种临床上有意义的神经病的病理生理学。 以及神经精神疾病。一个至关重要的问题是理解多巴胺是如何 调节这一大脑区域的功能。最近，我们进行了初步的实验，以检验 新发现的GABA能中间神经元在多巴胺能调控中的可能作用 新纹状体。令人惊讶的是，我们发现细胞类型特异性神经毒性损伤的酪氨酸羟化酶 表达GABA能中间神经元显著改变小鼠的行为反应 精神刺激剂安非他明的使用。这些结果表明，尽管他们非常 种群规模小，稀释物在调节多巴胺能控制 新纹状体和纹状体依赖行为。该提案评估了一项新的 薄层细胞的功能及其在多巴胺能调控中的作用 行为。该提案涉及以下目标。第一，开发和优化技术 这将使转基因小鼠中Thin的可逆和有效失活。第二，我们将 测试使用这些工具的稀释物的瞬时失活是否概括了神经毒性的结果 损伤实验。初步结果表明，部分、短暂的药物遗传抑制可以 定性地再现了用不可逆方法观察到的现象。接下来，我们将测试 假设稀释物的可逆灭活增强了苯丙胺的作用，从而导致长时间的... 纹状体回路的持久变化，特别是到投射神经元的兴奋性皮质输入。 对Thins功能的研究可能会在阐明Thins的功能方面取得重大突破 精神刺激剂的作用机制以及更广泛的多巴胺能问题 信号传递包括运动、学习和强化的控制，以及 导致从帕金森氏症到药物的各种病理情况的发展 虐待。

Project Summary/Abstract The neostriatum is directly involved in the pathophysiology of several clinically significant neurological and neuropsychiatric conditions. A crucially important question is to understand how dopamine regulates the function of this brain area. Recently, we conducted preliminary experiments to examine the possible roles of newly discovered GABAergic interneurons in the dopaminergic control of the neostriatum. Surprisingly, we found that cell-type specific neurotoxic lesion of tyrosine hydroxylase expressing GABAergic interneurons (THINs) dramatically alters the behavioral response of mice to the administration of the psychostimulant amphetamine. These results suggest that despite their very small population size, THINs have a crucial role in regulating the dopaminergic control of the neostriatum and that of striatal-dependent behavior. The proposal evaluates the feasibility of a new avenue of investigation into the functioning of THINs and their role in the dopaminergic control of behavior. The proposal addresses the following aims. First, we will develop and optimize techniques that will enable the reversible and effective inactivation of THINs in transgenic mice. Second, we will test if transient inactivation of THINs using these tools recapitulates the results of the neurotoxic lesion experiments. Preliminary results indicate that partial, transient pharmacogenetic inhibition can qualitatively reproduce the phenomena observed with irreversible methods. Next, we will test the hypothesis that reversible inactivation of THINs enhances the effect of amphetamine resulting in long- lasting changes in the striatal circuitry, in particular the excitatory cortical inputs to projection neurons. Investigation of the function of THINs may lead to significant breakthroughs in elucidating the mechanism of action of psychostimulants and more generally numerous problems of dopaminergic signaling including the control of movement, learning and reinforcement as well as the processes that contribute to the development of pathological conditions ranging from Parkinson's disease to drug abuse.