Ventral Tegmental Area and Hippocampal Interactions in Reinforced Spatial Learnin

描述（由申请人提供）：本研究旨在探索强化空间学习过程中腹侧被盖区（VTA）神经元活动的结构及其与海马体（HC）神经元活动的关系。VTA多巴胺（DA）系统是强化学习的关键基础，似乎是动物用来选择目标的内部价值图的基础。前前额叶在强化空间学习中也起作用，因为它是导航和情景记忆所必需的。在自由运动的动物中，在空间域中，VTA活动可能还有助于向目标导航。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细胞的奖励预测误差（reward prediction error， RPE）计算并调节DA细胞的输出。GABA神经元也可以通过它们的投射动态地选择DA信号的目标结构，并可能向它们提供与DA无关的奖励相关信息。本研究将利用VTA和HC神经元群的多电极记录来阐明它们通过3个特定目的的相互作用。首先，它将评估VTA、DA和GABA神经元表示预测未来奖励轨迹的能力。然后，我们将探讨GABA神经元活动在RPE表征中的作用。最后，它将检查VTA-HC在正常条件下和DA功能药理学扰动后加强空间学习的相互作用。候选人的直接目标是获得由Matthew Wilson博士资助的清醒行为大鼠的VTA和HC的多电极记录训练，以及由John Growdon博士资助的运动和记忆障碍的补充临床训练。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麻省总医院的加强。长期目标是了解VTA如何通过其内在回路和与其他大脑区域的相互作用来促进正常和异常的认知控制。考虑到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，深入了解VTA功能及其与大脑区域（如HC）通信的机制将具有很高的临床意义。

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.