Unraveling VTA modulation of hippocampal encoding

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。大脑是一个储存、比较和解释有关身体状态的信息以及生物体如何与环境相互作用的器官。生物体可以获得关于物体、时间、空间和事件的大量信息。然而，大脑的存储能力，以及可以立即处理的信息量是有限的。出于这个原因，大脑需要为环境刺激分配优先级，并选择在给定时间点最适用的刺激。这种机制以及控制它的大脑区域之间的联系仍然知之甚少。这项研究将探讨大脑中与新奇感检测有关的两个关键区域如何协同工作，在不断变化的环境中不断地对信息进行分类和优先排序。这项研究将通过增加我们对正常状态认知的认识和理解，对社会产生广泛的影响。通过阐明特定细胞类型在学习中的作用，以及它们的失调如何导致神经系统疾病，这项研究将进一步产生更广泛的影响。最后，本研究旨在通过促进学生在可广泛应用于生物医学科学研究和行业的尖端技术方面的培训，提高STEM的参与度。VTA和海马体（CA1）之间的相互连接形成了一个控制新颖性检测的循环。虽然VTA包含多巴胺、谷氨酸和GABA神经元，但该回路的功能主要归因于VTA多巴胺的投射。本研究的目的是分析VTA谷氨酸在海马区的功能意义及其在新颖性学习和情境辨别中的作用。为了实现这一目标，将神经记录与自由行为小鼠CA1中VTA末端的光遗传调制相结合。这种方法将为解决两个主要目标创造前提；(1)确定VTA-CA1通道在工作记忆与情境的CA1整合中的功能。(2)确定VTA突触前输入在CA1锥体细胞-神经元间同步中的作用。这项研究将填补对控制新颖性学习和环境歧视行为的神经回路的认识和理解的空白。尖端的遗传和电子工具将被用于在行为任务中靶向和调节小鼠CA1中的VTA终端。进行这些实验将显著增加对vta -海马体回路内细胞特异性投射的理解。它还将阐明细胞特异性神经回路的功能，这些功能被传统的关注VTA多巴胺投射所忽视。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).The brain is an organ that stores, compares, and interprets information about the state of the body, and how organisms interact with their environment. There is a wealth of information about objects, time, space, and events available to the organism. However, the storage capacity of the brain, and the volume of information that can be processed – at once – is limited. For this reason, there is a need for the brain to assign priority levels to environmental stimuli and select what is most applicable at a given time point. This mechanism and connections between the brain regions of the brain that controls it are still poorly understood. This research will investigate how two key brain regions concerned with novelty detection work together to continuously classify and prioritize the information to be stored in a continuously changing environment. This research will have a broad impact on society by increasing our knowledge and understanding of cognition in normal states. This research will further have broader impacts by elucidating the role of specific cell types in learning, and how their dysregulation can lead to neurological disorders. Lastly, this research is designed to increase participation in STEM by facilitating the training of students in cutting-edge techniques that can be applied broadly in biomedical science research and industries.Reciprocal connection between the VTA and hippocampus (CA1) forms a loop that governs novelty detection. While the VTA contains dopamine, glutamate, and GABA neurons, the function of the loop has been primarily attributed to the VTA dopamine projections. The goal of this research is to dissect the functional significance of VTA glutamate projections to the hippocampus, and their role in novelty learning and context discrimination. To achieve this goal, neural recording will be combined with optogenetic modulation of VTA terminals in the CA1 of freely behaving mice. This method will create the premise to address two main objectives; (1) Determine the function of the VTA-CA1 tract in CA1 integration of working memory and context. (2) Ascertain the role of VTA presynaptic inputs in CA1 pyramidal cell-interneuron synchrony. This research will fill gaps in the knowledge and understanding of neural circuits that govern novelty learning and context discrimination behavior. Cutting-edge genetic and electronic tools will be deployed to target and modulate VTA terminals in the CA1 of mice during behavioral tasks. Performing these experiments will significantly increase the understanding of cell-specific projections within the VTA-hippocampus loop. It will also elucidate the function of cell-specific neural circuits that have been overlooked by a traditional focus on VTA dopamine projections.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.