Characterizing superior colliculus inputs to midbrain dopamine centers in cue learning

项目总结 动物生活在复杂的、感官丰富的环境中。某些环境刺激(即线索)可以预测 对生存至关重要的有益结果(即奖励)。为了恰当地应对这些 预测性刺激，我们必须能够将这些线索与其他感官输入区分开来，并了解 他们在线索奖赏学习过程中预测的奖赏。了解它们背后的神经回路 过程是至关重要的，因为感觉处理障碍是几种精神疾病的标志，例如 ADHD和物质使用障碍。腹侧被盖区(VTA)和中脑实质中的多巴胺神经元 黑质部分致密区(SNC)在线索-奖赏学习中起关键作用，但这些区域如何整合尚不清楚。 关于线索的感官信息，以驱动条件性行为的独特方面。上丘(SC)， 它接受视网膜的输入，已被证明能驱动DA神经元对视觉刺激的反应， 而扰乱SC可以阻止DA活动和对视觉线索的条件性反应。解剖学和 SC对VTA/SNC的投射在线索-奖赏学习中的作用尚不清楚。 为了解决这个知识上的差距，我将描述大脑的解剖和功能连接 SC至VTA/SNC回路(目标1)，并确定在视觉提示期间SC投影的贡献 学习(目标2)。为了研究这个电路的拓扑图，我将追踪从SC到 VTA或SNc，并确定接受SC输入的神经元的投射靶点。要确定 SC输入到VTA和SNC的功能连接，我将通过光遗传学激发SC投射，而 通过在体纤维分光光度法记录VTA和SNc内DA能神经元的活动。这些研究将检验 SC通过VTA和SNc的内侧至外侧联系驱动DA放电的假说。我也会 测量和操作SC投射活动(分别使用纤维光度学和光遗传学) 视觉辨别学习任务，以检验SC向DA中脑投射增加的假设 对预测性线索的条件性行为。这些研究将揭示SC如何与VTA沟通，以及 SNC，以获得对线索-奖赏学习回路机制的基本见解。

PROJECT SUMMARY Animals exist in complex, sensory rich environments. Certain environmental stimuli (i.e. cues) predict beneficial outcomes (i.e., rewards) that are crucial for survival. In order to appropriately respond to these predictive stimuli, we must be able to discriminate these cues from other sensory input and learn the value of the rewards they predict, during cue-reward learning. Understanding the neural circuits underlying these processes is critical, as disordered sensory processing is a hallmark of several psychiatric diseases such as ADHD and substance use disorders. Dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are critical in cue-reward learning, but it is not understood how these regions integrate sensory information about cues to drive unique aspects of conditioned behavior. The superior colliculus (SC), which receives input from the retina, has been shown to drive DA neuron activity in response to visual stimuli, and disrupting the SC can prevent DA activity and conditioned responding to visual cues. The anatomy and function of SC projections to the VTA/SNc in cue-reward learning is not known. To address this gap in knowledge, I will characterize the anatomical and functional connectivity of the SC to VTA/SNc circuit (Aim 1) and determine the contributions of SC projections during visual cue learning (Aim 2). To study the topography of this circuit, I will trace distinct pathways from the SC to either the VTA or SNc and determine the projection targets of the neurons that receive SC input. To determine the functional connectivity of SC inputs onto the VTA and SNc, I will excite SC projections via optogenetics while recording the activity of DA neurons in the VTA and SNc through in vivo fiber photometry. These studies will test the hypothesis that the SC drives DA firing via medial to lateral connections on the VTA and SNc. I will also measure and manipulate SC projection activity (using fiber photometry and optogenetics, respectively) during a visual discrimination learning task, to test the hypothesis that SC projections to the DA midbrain augment conditioned behaviors to predictive cues. These studies will reveal how the SC communicates with the VTA and SNc, for fundamental insights into the circuit mechanisms of cue-reward learning.