Dissecting the Synaptic and Cellular Actions of Dopamine in Vivo

剖析体内多巴胺的突触和细胞作用

• 批准号: 10504155
• 负责人: Tanya Sippy
• 金额: $ 69.34万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504155
• 关键词: Address; Affect; Arousal; Aversive Stimulus; Behavior; Behavior Therapy; Behavioral; Brain; Calcium; Cells; Characteristics; Chronic; Closure by clamp; Corpus striatum structure; Cues; Data; Detection; Dopamine; Dopamine Receptor; Electrophysiology (science); Excitatory Postsynaptic Potentials; Excitatory Synapse; Functional disorder; Future; Goals; Image; Impairment; In Vitro; Knowledge; Light; Link; Mammals; Measures; Membrane; Membrane Potentials; Mental Depression; Mental disorders; Methods; Midbrain structure; Molecular Target; Monitor; Mood Disorders; Motivation; Movement; Mus; Neurologic; Neuromodulator; Neurons; Obsessive-Compulsive Disorder; Output; Parkinson Disease; Pathway interactions; Pharmacology; Phase; Physiological; Population; Population Dynamics; Property; Psychotic Disorders; Publishing; Reporting; Rewards; Role; Sensory; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Techniques; Testing; Time; Translating; Work; addiction; awake; cell type; dopaminergic neuron; experimental study; extracellular; in vivo; in vivo calcium imaging; insight; motivated behavior; nervous system disorder; neuropsychiatric disorder; neuroregulation; novel; novel therapeutic intervention; optogenetics; phase change; relating to nervous system; response; two photon microscopy

Project Summary The neuromodulator dopamine is critical for motivating, performing, and reinforcing goal-directed behaviors, and deficits in dopamine signaling are common in neuropsychiatric disorders like depression, obsessive-compulsive disorder, addiction and Parkinson’s disease. Central to our understanding of dopamine function is the notion that phasic increases and decreases in extracellular dopamine levels in the striatum modulate striatal output to modify behavior on short and long timescales. For instance, phasic elevations in striatal dopamine elicited by salient stimuli and reward-predicting cues have been proposed to promote arousal, facilitate action initiation and increase motivation to work on timescales of seconds to minutes, but also to modify future actions and behavioral decisions on longer timescales extending to days. This raises a fundamental question: How does dopamine modulate the activity of striatal neurons to exert its influence on behavior? Experiments in vitro have revealed a myriad of molecular targets sensitive to modulation by dopamine. However, the net effects of these changes on striatal output in vivo remain unknown. One reason is that few methods are capable of dissecting dopamine’s cell type-specific neuromodulatory effects on synaptic strength, somatic excitability and network dynamics in the awake, behaving brain. This proposal aims to fill this gap in knowledge using in vivo whole-cell electrophysiology and two-photon microscopy, focusing initially on the neuromodulatory effects occurring on timescales of seconds to minutes. Informed by our published and preliminary data with these techniques, we will test the hypothesis that phasic dopamine transients reflecting positive and negative reward prediction errors promote the activation of striatal projection neurons expressing D1- and D2-type dopamine receptors (D1-SPNs and D2-SPNs), respectively, via a combination of intrinsic and synaptic short-term plasticity mechanisms. To do so, we will harness our ability to record sub-threshold membrane potential dynamics in vivo to reveal how behaviorally- and optogenetically-evoked dopamine transients alter the intrinsic excitability of D1- and D2-SPNs (Aim 1) and the potency of excitatory synapses impinging on them (Aim 2). In Aim 3, we will employ calcium imaging to uncover the short-term influence of phasic dopamine transients on striatal output. Together, our experiments will provide crucial mechanistic insights into the modulatory actions of dopamine in vivo, shedding light on a key link between dopamine release and behavioral modifications, and paving the way for novel therapeutic interventions aimed at treating neuropsychiatric disorders.

项目摘要 神经调节剂多巴胺对于激励、执行和强化目标导向行为至关重要， 多巴胺信号的缺陷在神经精神疾病中很常见，如抑郁症、强迫症、 障碍、成瘾和帕金森病。我们理解多巴胺功能的核心是 纹状体细胞外多巴胺水平的阶段性增加和减少调节纹状体输出， 在短期和长期的时间尺度上改变行为。例如， 已经提出了显著刺激和奖励预测线索来促进唤醒、促进动作启动和 增加在秒到分钟的时间尺度上工作的动力，同时也改变未来的行动和行为 决定更长的时间尺度扩展到天。这就提出了一个基本问题：多巴胺是如何 调节纹状体神经元的活动从而影响行为？体外实验有 揭示了无数对多巴胺调节敏感的分子靶点。然而，这些措施的净效果 纹状体输出在体内的变化仍然未知。原因之一是很少有方法能够解剖 多巴胺对突触强度、躯体兴奋性和网络的细胞类型特异性神经调节作用 在清醒的、行为的大脑中的动力学。该提案旨在填补这一知识空白，使用体内全细胞 电生理学和双光子显微镜，最初集中在神经调节作用发生在 秒到分钟的时间尺度。通过这些技术的公开和初步数据，我们 将测试的假设，相位多巴胺瞬变反应积极和消极的奖励 预测错误促进表达D1和D2型的纹状体投射神经元的激活 多巴胺受体（D1-SPN和D2-SPN），分别通过内源性和突触性的结合， 短期塑性机制。为了做到这一点，我们将利用我们的能力，记录阈下膜 潜在的动力学在体内揭示行为和光遗传学诱发的多巴胺瞬变如何改变 D1-和D2-SPN的内在兴奋性（目的1）和撞击它们的兴奋性突触的效力（目的 2）。在目标3中，我们将使用钙成像来揭示阶段性多巴胺瞬变的短期影响。 纹状体的输出总之，我们的实验将为调节作用提供重要的机制见解 多巴胺在体内的作用，揭示了多巴胺释放和行为改变之间的关键联系， 为旨在治疗神经精神疾病的新型治疗干预铺平了道路。