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，执行和加强目标指导的行为和 多巴胺信号的缺陷在抑郁症，强迫症等神经精神疾病中很常见 疾病，成瘾和帕金森氏病。我们对多巴胺功能的理解的中心是概念 纹状体调节纹状体输出中的细胞外多巴胺水平的增加和降低 修改短时间和长时间的行为。例如，纹状体多巴胺的阶段升高是由 提出了明显的刺激和预测提示，以促进唤醒，促进行动倡议，并 增加在几秒钟到几分钟的时间尺度上工作的动力，同时也改变了未来的行动和行为 关于较长时间尺度的决定延伸到几天。这提出了一个基本问题：多巴胺如何 调节纹状体神经元的活性以对行为产生影响？体外实验 揭示了多巴胺对调节敏感的无数分子靶标。但是，这些的净影响 体内纹状体输出的变化仍然未知。原因之一是很少有方法能够解剖 多巴胺的细胞类型特异性神经调节作用对突触强度，躯体令人兴奋和网络 清醒中的动态，表现大脑。该建议旨在使用体内全细胞中的知识填补这一空白 电生理学和两光子显微镜，最初集中在发生的神经调节作用上 时间尺度到几分钟。通过我们已发布和初步数据的知识，我们 将检验以下假设，即阶段性多巴胺瞬变反映了积极和阴性奖励 预测误差促进表达D1和D2型的纹状体投影神经元的激活 多巴胺受体（D1-SPN和D2-SPNS）分别通过固有和突触的结合 短期可塑性机制。为此，我们将利用我们记录亚阈值膜的能力 体内潜在动力学，以揭示行为和光遗传性诱发的多巴胺瞬变如何改变 D1和D2-SPN的固有刺激性（AIM 1）以及影响它们的兴奋性突触的效力（AIM 2）。在AIM 3中，我们将采用钙成像来揭示阶段多巴胺瞬变的短期影响 关于纹状体输出。总之，我们的实验将为调节作用提供关键的机理见解 多巴胺在体内，阐明了多巴胺释放和行为修改之间的关键联系 为旨在治疗神经精神疾病的新型热干预措施铺平道路。