Ventral Tegmental Area and Hippocampal Interactions in Reinforced Spatial Learnin

描述（由申请人提供）：本提案旨在探索强化空间学习期间腹侧被盖区（VTA）神经元活动的结构及其与海马（HC）神经元活动的关系。腹侧被盖区多巴胺（DA）系统是强化学习的关键底物，似乎是动物用来选择目标的内部价值地图的基础。HC还在强化空间学习中发挥作用，因为它是导航和情景记忆所必需的。在自由移动的动物中，在空间域中，腹侧被盖区活动可能还有助于朝向目标的导航。VTA GABA神经元可能在指导和调节价值编码中起关键作用。它们投射到与DA细胞相同的结构，包括HC，并抑制DA神经元。在局部，VTA GABA神经元可能参与DA细胞的奖赏预测误差（RPE）计算，并可能调节DA细胞的输出。通过它们的投射，GABA神经元也可以动态地选择DA信号传导的靶结构，并可以为它们提供与DA无关的奖励相关信息。本研究将采用多电极记录的VTA和HC中的神经元集合，通过3个特定的目的来阐明它们的相互作用。首先，它将评估VTA DA和GABA神经元代表预测未来奖励的轨迹的能力。然后，将探讨GABA神经元活动在RPE再现中的作用。最后，它将研究在正常条件下和DA功能的药理学扰动后，在强化空间学习中VTA-HC的相互作用。候选人的直接目标是获得由Matthew Wilson博士赞助的清醒行为大鼠VTA和HC中多电极记录的培训，以及由John Growdon博士赞助的运动和记忆障碍的补充临床培训。因此，实验室和麻省理工学院神经科学界的许多资源将得到哈佛大学和马萨诸塞州总医院的加强。长期目标是了解腹侧被盖区如何通过其内在电路和与其他大脑区域的相互作用，对正常和异常的认知控制做出贡献。鉴于DA系统在强化学习、认知控制、帕金森病、药物成瘾和精神分裂症中的关键作用，以及HC在情景记忆、空间导航和精神分裂症中的重要性，对VTA功能及其与大脑区域（如HC）通信的机制的了解将具有高度的临床意义。

DESCRIPTION (provided by applicant): This proposal seeks to explore the structure of neuronal activity in the ventral tegmental area (VTA) and its relationship with neuronal activity in the hippocampus (HC) during reinforced spatial learning. The VTA dopamine (DA) system is a key substrate of reinforcement learning that appears to underlie the internal map of value that animals use to select goals. The HC also functions in reinforced spatial learning, as it is necessary for navigation and episodic memory. In freely moving animals, in the spatial domain, VTA activity may additionally contribute to navigation towards goals. VTA GABA neurons may play a critical role in directing and regulating the encoding of value. They project to the same structures as DA cells, including the HC, and inhibit DA neurons. Locally, VTA GABA neurons may participate in the DA cell computation of reward prediction error (RPE) and may regulate DA cell output. Through their projections, GABA neurons may also dynamically select target structures for DA signaling and may provide them with DA-independent reward-related information. This study will employ multielectrode recordings of neuronal ensembles in the VTA and HC to elucidate their interactions through 3 specific aims. First, it will assess the capacity for VTA DA and GABA neurons to represent trajectories predictive of future reward. Then, it will explore the role of GABA neuronal activity in the RPE representation. Lastly, it will examine VTA-HC interactions in reinforced spatial learning in normal conditions and after pharmacological perturbations of DA function. The immediate goal of the candidate is to obtain training in multielectrode recording in the VTA and HC of awake behaving rats, sponsored by Dr. Matthew Wilson, with complementary clinical training in movement and memory disorders, sponsored by Dr. John Growdon. The many resources of the lab and MIT neuroscience community will thus be enhanced by those of Harvard University and Massachusetts General Hospital. The long- term goal is to learn how the VTA contributes to normal and aberrant cognitive control, through its intrinsic circuitry and interactions with other brain regions. Given the pivotal role of the DA system in reinforcement learning, cognitive control, Parkinson's disease, drug addiction, and schizophrenia, and the importance of the HC in episodic memory, spatial navigation, and schizophrenia, insights into VTA function and the mechanisms by which it communicates with brain areas such as the HC will have high clinical relevance.