Dopaminergic modulation in auditory decision-making

项目摘要 我建议研究多巴胺信号在新纹状体中的作用， 制作。基于感官知觉的决策是日常生活不可或缺的一部分，也是 以适当的行动应对环境的能力。这一关键过程功能失调， 神经精神疾病，如帕金森病和精神分裂症。研究证明 新纹状体是基于感知决策的神经相关物，且纹状体神经递质 不平衡会破坏这些行为。我们的实验室研究了背侧纹状体的尾部， “听觉纹状体”，我们已经表明，这个纹状体区域是重要的听觉线索为基础的决策- 制作和强化学习。虽然已经表明听觉皮质纹状体投射驱动 听觉决策的啮齿动物，目前还不清楚如何建立纹状体神经调质，包括多巴胺 影响这些功能。最近的证据表明，神经调节控制和行为状态发挥作用， 在各种各样的听觉行为中起着关键作用。我的初步药理学和神经追踪数据显示 多巴胺，一种关键的纹状体神经调质，确实在听觉纹状体中发挥作用， 决策的这些数据和以前的文献有助于我的中心假设，这是， 听觉纹状体中的多巴胺能信号通过调节纹状体内的多巴胺能神经元， 健全的代表。为了解决这一假设，并磨练多巴胺的作用，我提出了两个目标。第一、 在目标1中，我将监测已确定的投射多巴胺的听纹黑质部的活动 通过在体内Ca 2+成像和映射这些动态相对于特定时期的神经元， 听觉决策任务了解这些多巴胺神经元的活动如何随着 对决策行为的影响将使我能够推断多巴胺能机制如何调节选择的准确性。 例如，如果DA活动与声音提示呈现相对应，则可能表明DA活动调节 听觉纹状体中的声音表征。在目标2中，我将评估多巴胺能调节的重要性， 在听觉任务中，通过在相同的限定时期组中光遗传学地抑制多巴胺能投射， 目标1中评估的听觉决策任务。这将证明多巴胺是否是必要的 用于调解听觉决策的特定方面，包括声音提示表示。总的来说，我将使用 电路特异性标记，显微内窥镜监测和小鼠中的光遗传学，以研究 多巴胺在听觉决策中的作用这项研究的结果将促进对纹状体如何 多巴胺有助于听觉知觉决策，这反过来又可以带来新的病因学见解 治疗听觉处理障碍和神经精神疾病

PROJECT SUMMARY I propose to study the role of dopamine signaling within the neostriatum in the context of auditory-based decision- making. Decision-making based on sensory perception is an integral part of everyday life and a cornerstone of ones ability to respond to the environment with appropriate actions. This pivotal process is dysfunctional in neuropsychiatric disorders such as Parkinson’s disease and schizophrenia. Studies demonstrate that the neostriatum is a neural correlate for perception-based decision-making and that striatal neurotransmitter imbalances can disrupt such behaviors. Our lab studies a caudal portion of the dorsal striatum—referred to as the “auditory striatum,” and we have shown that this striatal region is important for auditory cue-based decision- making and reinforcement learning. While it has been shown that auditory corticostriatal projections drive auditory decision-making in rodents, it is unclear how established striatal neuromodulators including dopamine influence these functions. Recent evidence indicates that neuromodulatory control and behavioral states play a critical role in a wide variety of auditory behaviors. My preliminary pharmacological and tract-tracing data indicate that dopamine, a key striatal neuromodulator, indeed plays a role in within the auditory striatum for auditory decision-making. These data and previous literature contribute to my central hypothesis, which is that dopaminergic signaling in the auditory striatum contributes to auditory decision-making by modulating striatal sound representation. To address this hypothesis and to hone in on dopamine’s role, I propose two aims. First, in Aim 1, I will monitor the activity of identified auditory striatum-projecting dopaminergic substantia nigra pars compacta neurons through in vivo Ca2+ imaging and map these dynamics with respect to specific epochs of the auditory decision-making task. Knowledge of how the activity of these dopamine neurons changes with respect to decision-making behavior will allow me to infer how dopaminergic mechanisms modulate choice accuracy. For instance, if DA activity corresponds to sound cue presentation, it may suggest that DA activity modulates sound representation in the auditory striatum. In Aim 2, I will evaluate the importance of dopaminergic modulation in the auditory task by optogenetically inhibiting dopaminergic projections during the same sets of defined epochs of the auditory decision-making task evaluated in Aim 1. This will demonstrate whether dopamine is necessary for mediating specific aspects of auditory decision-making, including sound cue representation. Overall, I will use circuit-specific labeling, microendoscopic monitoring, and optogenetics in mice to investigate the role of dopamine in auditory decision-making. Results from this study will advance understanding of how striatal dopamine contributes to auditory perceptual decision-making, which in turn could bring new etiological insights for auditory processing disorders and neuropsychiatric disease.