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

• 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
• 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

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.

项目摘要 神经递质多巴胺（DA）众所周知是脊椎动物运动行为的调节剂，但先验 研究在很大程度上忽略了下丘脑中产生DA的神经元的贡献。在工作中工作 幼虫斑马鱼，我们发现下丘脑前核中的DA神经元群， 由酪氨酸羟化酶基因Th2的表达定义，对于产生大多数至关重要 赞助和唤起游泳的形式。功能成像表明这些细胞暴露了复合物 感官和电机编码，与运动，听觉提示，急性相关的激烈活动爆发， 或两者兼有光学遗传操作会引起各种运动学上不同的游泳比赛。当Th2+ 神经元是消融的，鱼类启动的频率较小。我们已经确定了一组 中后脑中的前脊柱投射神经元（SPNS）是特别重要的介体 TH2+神经元的行为功能。 Th2+传入到该区域的激活迅速引起爆发 在大多数SPN中的活动，推动了由此产生的行为。 SPN组成一组大约250个神经元，在解剖学和功能上不变 动物和单个SPN中的活动已与特定行为直接相关。作为Th2+的目标 DA神经元活性，这些细胞为理解A的功能结构提供了独特的机会 调节网络 - 也就 生理特性，以及该组织如何影响特定DA的行为贡献 细胞。 我们提出了上型TH2+神经元的功能异质亚组，将DA差异释放到 在不同的感觉运动条件下的特定SPN​​，可以选择性募集前的合奏 推动上下文适当的行为。为了测试这个想法，我们将首先在可追溯中使用钙成像 神经元确定介导不同行为的SPN亚组的Th2+传入 - 即常规 与防御性游泳 - 在相关的回合类型期间有选择地激活。接下来，我们将直接映像 DA分泌物以确定不同位点的调节信号是否独立于一个 另一个与选择性调制特定SPN​​的方式相兼容。最后，我们将使用体内 精确确定TH2+神经元如何影响SPN功能的电生理学。我们工作的结果将会 成为一个详细的模型，将调制网络中功能异质性连接到特定的性能 行为。