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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结