Role of functional and anatomical heterogeneity in ventral pallidum circuits underlying behavioral reinforcement

功能和解剖异质性在腹侧苍白球回路中行为强化的作用

基本信息

批准号：
9789943
负责人：
Thomas Hnasko
金额：
$ 19.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-21 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789943
关键词：
Address Anatomy Anhedonia Animal Model Appetitive Behavior Attention Aversive Stimulus Back Behavior Behavior Disorders Behavioral Brain Compulsive Behavior Conceptions Conditioned Stimulus Cues Data Desire for food Development Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Electrophysiology (science)Etiology Event Exploratory/Developmental Grant Fiber Fire - disasters Genetic Globus Pallidus Glutamates Habenula Heterogeneity Impairment Interneurons Knowledge Lateral Measures Mental Depression Modeling Motivation Mus Negative Reinforcements Negative Valence Neurobiology Neurons Neurotransmitters Nucleus Accumbens Output Pattern Perception Pharmacotherapy Photometry Physiology Population Positive Reinforcements Positive Valence Process Psychological reinforcement Punishment Reporter Research Rewards Role Schizophrenia Signal Transduction Stimulus Symptoms Testing Ventral Tegmental Area Work addiction approach avoidance behavior avoidance behavior behavior influence calcium indicator cell type common symptom dopaminergic neuron experimental study gamma-Aminobutyric Acid hedonic in vivo calcium imaging in vivo imaging motivated behavior neurochemistry neuropsychiatric disorder neuropsychiatric symptom neuropsychiatry optogenetics preference programs reinforcer response reward processing

项目摘要

Dysfunctional reward processing is a symptom common of major neuropsychiatric disorders including addiction, schizophrenia and depression. Perturbations in neuronal dopamine signaling have been implicated in the etiology of this symptom and is a target of current pharmacotherapies. Less is known about how neuropsychiatric symptoms manifest downstream of altered dopamine signaling, or the mechanisms by which dopamine signaling becomes perturbed in the first place. The ventral pallidum (VP) is a prime suspect that is receiving increasing attention. The VP is the major output of nucleus accumbens (NAc) and a key input back to the ventral tegmental area (VTA). Activity in VP is sensitive to hedonic stimuli and can potently drive motivated behaviors. Yet the VP is heterogeneous containing neurons with diverse neurotransmitters and projection targets. For example, VP glutamate and GABA neurons share similar projection patterns but drive opposite patterns of behavior on reinforcement tasks. Optogenetic activation of NAc D1-type and D2-type medium spiny neurons can similarly bi-directionally influence reinforcement, but how defined NAc and defined VP cell types are connected is unknown. In Aim 1 we employ optogenetic-assisted electrophysiology and reporter mice to establish the cell-type-specific connectivity between NAc and VP. Aim 2 will use in vivo calcium imaging to assess the intrinsic activity of defined VP populations in response to positive and negative valence stimuli and associated contexts. These studies will build on our recent work, address key knowledge gaps, and facilitate a programmatic assessment of the role of VP circuit heterogeneity in reward processing and neuropsychiatric illness.

功能失调的奖励处理是主要神经精神疾病的常见症状成瘾，精神分裂症和抑郁症。神经元多巴胺信号的扰动已涉及在这种症状的病因中，是当前药物疗法的目标。少知道如何神经精神症状表现出多巴胺信号传导的下游，或者表现出的机制多巴胺信号首先受到干扰。腹侧颗粒（VP）是一个主要嫌疑人受到越来越多的关注。副总裁是伏隔核（NAC）的主要输出，键输入回到腹侧盖区域（VTA）。 VP中的活动对享乐刺激敏感，可以有效地动机行为。然而，VP是含有不同神经递质和投影的神经元的异质性目标。例如，VP谷氨酸和GABA神经元具有相似的投影模式，但驱动相反强化任务的行为模式。 NAC D1型和D2型培养基的光遗传激活神经元类似地在两方向上影响强化，但定义NAC和定义的VP细胞类型如何连接是未知的。在AIM 1中，我们采用光遗传辅助电生理学和记者小鼠建立NAC和VP之间的细胞类型特异性连通性。 AIM 2将使用体内钙成像为评估针对正价刺激和负价刺激的响应定义VP种群的内在活性相关上下文。这些研究将以我们最近的工作为基础，解决关键知识差距，并促进副总VP电路异质性在奖励处理和神经精神病学中的作用的程序化评估疾病。