Dopaminergic modulation in auditory decision-making

听觉决策中的多巴胺能调节

• 批准号: 10599273
• 负责人: Allen Chen
• 金额: $ 5.27万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2024-04-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599273
• 关键词: Address; Affect; Animals; Auditory; Auditory Perception; Auditory Perceptual Disorders; Auditory area; Behavior; Behavioral; Brain Diseases; Brain imaging; Calcium; Cells; Central Auditory Processing Disorder; Cognition; Corpus striatum structure; Cues; Data; Decision Making; Discrimination; Disease; Dopamine; Dopamine Antagonists; Dopamine Receptor; Dorsal; Elements; Environment; Etiology; Frequencies; Functional disorder; Goals; Image; Impairment; Knowledge; Label; Learning; Life; Literature; Maps; Mediating; Monitor; Mus; Neostriatum; Neuromodulator; Neurons; Neurotransmitters; Parkinson Disease; Pattern; Perception; Performance; Phase; Play; Population; Process; Psychological reinforcement; Psychometrics; Reaction Time; Rodent; Role; Schizophrenia; Sensory; Signal Transduction; Substantia nigra structure; Task Performances; Technical Expertise; Testing; Time; Viral; auditory processing; auditory stimulus; autism spectrum disorder; dopaminergic neuron; in vivo; innovation; insight; neural correlate; neuromechanism; neuropsychiatric disorder; neuroregulation; optogenetics; pars compacta; pharmacologic; sound; timeline

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.

项目概要 我建议在基于听觉的决策背景下研究新纹状体中多巴胺信号传导的作用 基于感官知觉的决策是日常生活的一个组成部分，也是人类生活的基石。 一个人以适当的行动应对环境的能力在以下方面出现了失调。 研究表明，帕金森病和精神分裂症等神经精神疾病。 新纹状体是基于感知的决策的神经相关物，并且纹状体神经递质 不平衡会破坏这种行为。我们的实验室研究了背侧纹状体的尾部部分——称为“背侧纹状体”。 “听觉纹状体”，我们已经证明这个纹状体区域对于基于听觉线索的决策很重要 虽然已经证明听觉皮质纹状体投射会驱动学习。 啮齿类动物的听觉决策中，尚不清楚包括多巴胺在内的纹状体神经调节剂是如何建立的 最近的证据表明神经调节控制和行为状态发挥着影响作用。 我的初步药理学和纤维追踪数据表明，它在多种听觉行为中发挥着关键作用。 多巴胺是一种关键的纹状体神经调节剂，确实在听觉纹状体中发挥着作用 这些数据和以前的文献有助于我的中心假设，即 听觉纹状体中的多巴胺能信号通过调节纹状体有助于听觉决策 为了解决这个假设并深入研究多巴胺的作用，我提出两个目标。 在目标 1 中，我将监测已识别的听觉纹状体投射多巴胺能黑质部的活动 通过体内 Ca2+ 成像对致密神经元进行成像，并将这些动态映射到特定时期的 了解这些多巴胺神经元的活动如何变化。 决策行为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 活动对应于声音提示呈现，则可能表明 DA 活动调节 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，通过在同一组定义的时期内通过光遗传学抑制多巴胺能投射 目标 1 中评估的听觉决策任务的结果。这将证明多巴胺是否是必要的 为了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光遗传学，以研究 这项研究的结果将促进对纹状体如何发挥作用的理解。 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 用于听觉处理障碍和神经精神疾病。