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

• 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
• 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

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.

奖赏处理功能失调是主要神经精神疾病的常见症状，包括 成瘾、精神分裂症和抑郁症。神经元多巴胺信号传导的扰动与此有关 在这种症状的病因学中，它是当前药物治疗的目标。人们对如何做到这一点知之甚少 神经精神症状表现在多巴胺信号传导改变的下游，或改变的机制 多巴胺信号传导首先受到干扰。腹侧苍白球（VP）是一个主要嫌疑人 受到越来越多的关注。 VP 是伏隔核 (NAc) 的主要输出，也是返回神经元的关键输入。 腹侧被盖区（VTA）。 VP 的活动对享乐刺激很敏感，可以有效地激发积极性 行为。然而，VP 是异质的，包含具有不同神经递质和投射的神经元 目标。例如，VP 谷氨酸和 GABA 神经元具有相似的投射模式，但驱动相反 强化任务的行为模式。 NAc D1型和D2型中刺的光遗传学激活 神经元可以类似地双向影响强化，但如何定义 NAc 和定义 VP 细胞类型 是否连接未知。在目标 1 中，我们采用光遗传学辅助电生理学和报告小鼠 建立 NAc 和 VP 之间的细胞类型特定连接。目标 2 将使用体内钙成像 评估定义的 VP 群体响应正价和负价刺激的内在活动， 相关的上下文。这些研究将以我们最近的工作为基础，解决关键的知识差距，并促进 VP 回路异质性在奖励处理和神经精神病学中的作用的程序评估 疾病。