Functional architecture of dopamine signaling within a zebrafish sensorimotor network

斑马鱼感觉运动网络内多巴胺信号传导的功能结构

基本信息

批准号：
10522090
负责人：
ADAM D DOUGLASS
金额：
$ 38.38万
依托单位：
UNIVERSITY OF UTAH
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522090
关键词：
Acute Affect Anatomy Animals Architecture Auditory Automobile Driving Behavior Behavioral Brain Calcium Cells Complex Cues Dopamine Electrophysiology (science)Environment Event Exhibits Fishes Foundations Functional Imaging Genes Glutamates Heterogeneity Hypothalamic structure Image Individual Light Link Location Locomotion Measures Mediating Mediator of activation protein Modeling Motor Movement Nature Neurons Neurotransmitters Outcome Pattern Performance Physiological Play Population Property Protein Isoforms Research Role Sensory Shapes Signal Transduction Site Spinal Subgroup Swimming System Testing Tyrosine 3-Monooxygenase Whole-Cell Recordings Work Zebrafish anatomic imaging behavior influence dopaminergic neuron experience experimental study hindbrain in vivo kinematics mind control neuroregulation optogenetics preoptic nucleus recruit relating to nervous system sensory input spatiotemporal transmission process

项目摘要

PROJECT SUMMARY The neurotransmitter dopamine (DA) is well known as a regulator of vertebrate locomotor behaviors, but prior research has largely ignored the contributions of DA-producing neurons in the hypothalamus. Working in the larval zebrafish, we have discovered that a population of DA neurons in the hypothalamic preoptic nucleus, defined by their expression of the tyrosine hydroxylase gene, th2, are critically important for generating most forms of spontaneous and evoked swimming. Functional imaging reveals that these cells exhibit complex sensory and motor encodings, firing intense bursts of activity in acute correlation with movement, auditory cues, or both, and optogenetic manipulation elicits a variety of kinematically distinct swim bouts. When the th2+ neurons are ablated, fish initiate spontaneous swimming dramatically less often. We have identified a group of premotor spinal projection neurons (SPNs) in the mid- and hindbrain as particularly important mediators of the th2+ neurons’ behavioral functions. Activation of the th2+ afferents to this region rapidly elicits sustained bursts of activity in a majority of SPNs, driving the resulting behavior. The SPNs comprise a group of roughly 250 neurons, which are anatomically and functionally invariant between animals, and activity in individual SPNs has been directly linked to particular behaviors. As the targets of th2+ DA neuron activity, these cells present a unique opportunity for understanding the functional architecture of a modulatory network – that is, how DA neurons that project onto distinct functional targets might differ in their physiological properties, and how that organization might influence the behavioral contributions of specific DA cells. We propose that functionally heterogeneous subgroups of preoptic th2+ neurons differentially release DA onto specific SPNs under different sensorimotor conditions, enabling the selective recruitment of premotor ensembles to drive contextually appropriate behaviors. To test this idea, we will first use calcium imaging in traceable neurons to determine whether th2+ afferents to the SPN subgroups that mediate different behaviors – i.e. routine vs. defensive swimming – are selectively activated during the associated bout type. Next, we will directly image DA secretion to determine whether the modulatory signals at different sites vary independently from one another, in a way compatible with selective modulation of particular SPNs. Last, we will use in vivo electrophysiology to precisely determine how the th2+ neurons affect SPN function. The result of our work will be a detailed model linking functional heterogeneity in a modulatory network to the performance of specific behaviors.

项目概要众所周知，神经递质多巴胺 (DA) 是脊椎动物运动行为的调节剂，但之前研究很大程度上忽略了下丘脑中产生 DA 的神经元的贡献。在斑马鱼幼体中，我们发现下丘脑视前核中有一群 DA 神经元，由酪氨酸羟化酶基因 th2 的表达定义，对于产生大多数自发游泳和诱发游泳的形式表明这些细胞表现出复杂性。感觉和运动编码，与运动、听觉线索密切相关的强烈活动爆发，或两者兼而有之，并且当 th2+ 时，光遗传学操作会引发各种运动学上不同的游泳回合。神经元被消融，鱼类自发游泳的频率显着降低。中脑和后脑的运动前脊髓投射神经元 (SPN) 作为特别重要的介质 th2+ 神经元的行为功能激活该区域的 th2+ 传入神经会迅速引发持续的爆发。大多数 SPN 中的活动，驱动由此产生的行为。 SPN 包含一组大约 250 个神经元，这些神经元在解剖学和功能上保持不变动物中，个体 SPN 的活动与作为 th2+ 目标的特定行为直接相关。 DA 神经元活动，这些细胞为理解 DA 神经元的功能结构提供了独特的机会调节网络——也就是说，投射到不同功能目标的 DA 神经元在其功能上可能有何不同生理特性，以及该组织如何影响特定 DA 的行为贡献细胞。我们提出视前 th2+ 神经元的功能异质亚群差异性地将 DA 释放到不同感觉运动条件下的特定 SPN，从而能够选择性地招募运动前神经元为了推动适当的行为，为了测试这个想法，我们将首先在可追踪中使用钙成像。神经元来确定 th2+ 是否传入介导不同行为（即常规行为）的 SPN 亚组与防御性游泳——在相关的比赛类型中选择性地激活接下来，我们将直接想象。 DA 分泌以确定不同位点的调节信号是否独立变化另一种是与特定 SPN 的选择性调节兼容的方式最后，我们将在体内使用。我们的工作结果将通过电生理学精确确定 th2+ 神经元如何影响 SPN 功能。是一个详细的模型，将调节网络中的功能异质性与特定的性能联系起来行为。