Functional architecture of dopamine signaling within a zebrafish sensorimotor network

项目摘要 神经递质多巴胺（DA）作为脊椎动物运动行为的调节剂是众所周知的，但先前的研究表明， 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。从事 在斑马鱼幼体中，我们发现下丘脑视前核中的DA神经元群体， 由酪氨酸羟化酶基因Th 2的表达所定义，对于产生大多数 自发和诱发游泳的形式。功能成像显示这些细胞表现出复杂的 感觉和运动编码，与运动、听觉线索、 或两者，并且光遗传学操作激发了各种运动学上不同的游泳比赛。当th 2 + 当神经元被消融时，鱼开始自发游泳的频率显著降低。我们已经确定了一组 中脑和后脑中的运动前脊髓投射神经元（SPNs）作为神经元传导的特别重要的介质， Th 2+神经元的行为功能。该区域的th 2+传入的激活迅速激发持续爆发 大多数SPN中的活动，驱动产生的行为。 SPN包括一组大约250个神经元，它们在解剖学和功能上是不变的， 动物，和活动在个别SPN已直接联系到特定的行为。作为th 2+的目标 DA神经元的活动，这些细胞提供了一个独特的机会，了解功能架构的一个 调制网络-也就是说，投射到不同功能靶点的DA神经元在其功能上可能存在差异。 生理特性，以及该组织如何影响特定DA的行为贡献 细胞 我们认为，视前th 2+神经元的功能异质亚组差异释放DA到 在不同的感觉运动条件下，特定的SPNs，使运动前集合的选择性招募 to drive驱动contextually上下文appropriate适当behaviors行为.为了验证这个想法，我们将首先使用钙成像在可追溯的 神经元，以确定是否th 2+传入到介导不同行为的SPN亚组-即常规 vs.防御性游泳-在相关的回合类型中被选择性地激活。接下来，我们将直接成像 DA分泌，以确定是否调节信号在不同的网站不同，独立于一个 另一种是以与特定SPN的选择性调制兼容的方式。最后，我们将在体内使用 电生理学以精确地确定th 2+神经元如何影响SPN功能。我们的工作成果将 是一个详细的模型，将调节网络中的功能异质性与特定功能的表现联系起来。 行为。

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.