Functional architecture of dopamine signaling within a zebrafish sensorimotor network

项目总结 神经递质多巴胺(DA)是众所周知的脊椎动物运动行为的调节器，但在此之前 研究在很大程度上忽略了下丘脑中产生DA的神经元的作用。在工作中 斑马鱼幼体，我们发现在下丘脑视前核中有一群DA神经元， 由酪氨酸羟基酶基因Th2的表达决定的，Th2对大多数 自发性和诱发性游泳的形式。功能成像显示这些细胞表现出复杂的 感觉和运动编码，在与运动、听觉提示、 或者两者兼而有之，光基因操作引发了各种运动学上不同的游泳比赛。当Th2+ 神经元被消融，鱼类发起自发游泳的频率大大降低。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(SPN)是一种特别重要的神经递质。 Th2+神经元的行为功能。激活该区域的Th2+传入迅速引起持续的脉冲波 在大多数SPN中的活动，驱动由此产生的行为。 SPN由一组大约250个神经元组成，它们在解剖和功能上是不变的 动物，个体SPN中的活动与特定行为直接相关。作为Th2+的靶标 DA神经元活动，这些细胞提供了一个独特的机会来理解 调制网络--也就是，投射到不同功能靶点的DA神经元在它们的 生理特性，以及该组织可能如何影响特定DA的行为贡献 细胞。 我们认为视前Th2+神经元的功能异质性亚群不同地将DA释放到 不同感觉运动条件下的特定SPN，使运动前集合的选择性招募成为可能 以驱动与环境相适应的行为。为了测试这一想法，我们将首先在Traceable中使用钙成像 确定Th2+是否传入调节不同行为的SPN亚群--即例行性 VS防守游泳-在相关的比赛类型中被选择性地激活。接下来，我们将直接映象 DA分泌，以确定不同部位的调制信号是否独立于一个 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 电生理学以精确确定Th2+神经元如何影响SPN功能。我们工作的结果将是 是将调制网络中的功能异质性与特定网络的性能联系起来的详细模型 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.