Striatal Regulation of Cortical Acetylcholine Release

纹状体对皮质乙酰胆碱释放的调节

基本信息

批准号：
10549320
负责人：
Christoph Kellendonk
金额：
$ 22.77万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-12 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549320
关键词：
Acetylcholine Address Affect Anatomy Area Attention Back Basal Ganglia Behavior Behavioral Brain Brain Diseases Cell Nucleus Choline O-Acetyltransferase Cognitive Corpus striatum structure Data Disease Disinhibition Dissection Dorsal Drug Addiction Fiber Globus Pallidus Human Image Impairment Knowledge Link Measures Mental disorders Modeling Modernization Motor Cortex Mus Neurons Obsessive-Compulsive Disorder Opsin Outcome Output Pathway interactions Photometry Physiology Preparation Regulation Reversal Learning Rewards Rodent Role Schizophrenia Short-Term Memory Slice Stimulus Substantia nigra structure System Testing Thalamic structure basal forebrain behavior measurement cholinergic cholinergic neuron cognitive process experimental study flexibility frontal lobe insight nonhuman primate optogenetics response segregation sensor tool

项目摘要

The basal ganglia regulate cortical function via cortico-striatal-thalamo-cortical loops. Two functionally opposing pathways the direct and indirect pathway either activate or inhibit thalamo-cortical circuits via the basal ganglia output nuclei, the globus pallidus and the substantia nigra. Recent slice physiology experiments, however, suggest an additional more direct link by which the striatum regulates cortical activity. In slices both direct and indirect pathway neurons of the dorsal striatum inhibit cholinergic neurons that project to frontal cortical areas. One area that receives inputs from striatal-inhibited cholinergic neurons is the orbitofrontal cortex (OFC). The OFC supports reversal learning a measure of behavioral flexibility that is affected in several mental disorders including obsessive-compulsive disorder, schizophrenia and drug addiction. Strikingly, not much is known about the regulation of the OFC by cholinergic neurons, whether cholinergic projections to the OFC modulate reversal learning and whether cholinergic projections to the OFC are regulated by the striatum during behavior. This explorative R21 application is a first step to address these gaps in knowledge. We will use the mouse and the modern circuit dissection tools available to the mouse to test the overarching hypothesis that direct and indirect pathways regulate reversal learning via inhibition of OFC-projecting cholinergic neurons. To address this hypothesis we propose the following two aims: Aim 1: To determine whether cholinergic neurons projecting to the OFC support reversal learning In aim 1.1 we will use Ca2+ imaging to measure the activity of OFC-projecting cholinergic neurons. In aim 1.2 we will inhibit OFC-projecting cholinergic neurons and determine how this affects cortical acetylcholine release and reversal learning. Aim 2: To determine whether the striatum regulates reversal learning via the cholinergic system In aim 1.2 and aim 1.2 we will inhibit indirect or direct pathway neurons during reversal learning to determine how this affects cortical acetylcholine release and reversal learning. Understanding the role of the basal ganglia in regulating OFC function and reversal learning will have important implications for brain disorders with abnormalities in cortico-striatal circuitry and impaired reversal learning including schizophrenia, obsessive-compulsive disorder and drug addiction.

基底神经节通过皮质-纹状体-丘脑-皮质环调节皮质功能。功能上有两个相反的途径，直接和间接途径通过激活或抑制丘脑皮质回路基底神经节输出核、苍白球和黑质。最近的切片生理学实验，然而，提出了纹状体调节皮质活动的另一个更直接的联系。在切片中背侧纹状体的直接和间接通路神经元抑制投射到额叶的胆碱能神经元皮质区域。接收来自纹状体抑制的胆碱能神经元的输入的一个区域是眶额叶皮质（OFC）。 OFC 支持逆向学习，这是一种行为灵活性的衡量标准，受到多种因素的影响精神障碍包括强迫症、精神分裂症和毒瘾。引人注目的是，不是人们对胆碱能神经元对 OFC 的调节了解很多，无论胆碱能投射到 OFC 调节逆转学习以及向 OFC 的胆碱能投射是否受纹状体调节行为过程中。这个探索性的 R21 应用程序是解决这些知识差距的第一步。我们将使用鼠标和鼠标可用的现代电路剖析工具来测试总体假设直接和间接途径通过抑制 OFC 投射来调节逆转学习胆碱能神经元。为了解决这个假设，我们提出以下两个目标：目标 1：确定投射到 OFC 的胆碱能神经元是否支持逆转学习在目标 1.1 中，我们将使用 Ca2+ 成像来测量 OFC 投射胆碱能神经元的活动。目标 1.2 我们将抑制 OFC 投射的胆碱能神经元，并确定这如何影响皮质乙酰胆碱的释放以及逆向学习。目标 2：确定纹状体是否通过胆碱能系统调节逆转学习在目标 1.2 和目标 1.2 中，我们将在逆转学习期间抑制间接或直接通路神经元，以确定这如何影响皮质乙酰胆碱的释放和逆转学习。了解基底神经节在调节 OFC 功能和逆转学习中的作用将有助于对皮质纹状体回路异常和逆转受损的脑部疾病具有重要意义学习包括精神分裂症、强迫症和毒瘾。