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Neural circuit mechanisms for temporal association learning

时间关联学习的神经回路机制

基本信息

批准号：
10300428
负责人：
Takashi Kitamura
金额：
$ 41万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300428
关键词：
Alzheimer&apos s Disease Association Learning Automobile Driving Behavioral Paradigm Calcium Cells Cognitive Data Disinhibition Dopamine D1 Receptor Episodic memory Event FOS gene Gatekeeping Goals Hippocampus (Brain)Human Image Knockout Mice Knowledge Lead Learning Maps Medial Mediating Memory Modeling Molecular Motor Muscarinic Acetylcholine Receptor Neurobiology Neurons Patients Performance Pharmacologic Substance Process Pyramidal Cells Receptor Activation Regulation Research Role Schizophrenia Sensory System Testing Theoretical model Transgenic Mice Ventral Tegmental Area Viral cholinergic conditioned fear entorhinal cortex field study genetic manipulation in vivo in vivo calcium imaging locus ceruleus structure metabotropic glutamate receptor type 1 neural circuit neuromechanism novel optogenetics prevent relating to nervous system

项目摘要

PROJECT SUMMARY A critical feature of episodic memory formation is the ability to associate temporally segregated events as an episode, called temporal association learning. Malfunctions of temporal association learning represent well- described findings in human patients suffering from schizophrenia and Alzheimer's disease. There are several critical gaps in our knowledge of current theoretical model and neurobiological evidence about mechanisms of temporal association learning. My long-term goal is to elucidate the neural mechanisms that drive and regulate temporal association learning by understanding neural circuits and their neural processes in entorhinal cortical-hippocampal (EC-HPC) networks, using Pavlovian trace fear conditioning (TFC) as the behavioral paradigm. We previously demonstrated that pOxr1+ excitatory cells in the medial entorhinal cortex layer III (pOxr1+ cells) project to the hippocampal CA1 pyramidal cells and are necessary for TFC. On the other hand, some CalB+ excitatory cells in MECII (CalB+ cells) project to GABAergic neurons in hippocampal CA1, suppress the MECIII input into the CA1 pyramidal cells through the feed-forward inhibition, and inhibit TFC. These findings lead us to propose a disinhibition model to regulate TFC, driving TFC by pOxr1+ cells and regulating TFC by CalB+ cells. The central hypothesis of this model is that successful TFC depends on learning-dependent disinhibition of hippocampal CA1 pyramidal cells through the reduction of feed-forward inhibition mediated by CalB+ cells. Towards this hypothesis, we have identified that pOxr1+ cells show tone-induced sustained neural activity in all trials during TFC, while CalB+ cells show trial-dependent reduction of the tone-induced sustained neural activity. We have also discovered that the CalB+ cells specifically express dopamine D1 receptors (D1R) in MEC and the activation D1R in MEC is essential for the learning-dependent reduction of the c-Fos expression in CalB+ cells and for successful TFC. Guided by strong preliminary data, we propose to pursue three Specific Aims to examine neural circuit mechanism that drive and regulate TFC: (1) To define the roles of pOxr1+ cells and CalB+ cells for TFC. (2) To determine the role of D1R activation in CalB+ cells for TFC. (3) To elucidate the role of dopaminergic inputs into the MEC for TFC. Collectively, our proposed research will broadly impact the field of learning and memory by characterizing novel neural circuits and their neural process that drive and regulate temporal association memory in EC-HPC networks. Our proposed studies will uncover neural substrates for temporal association memory and novel learning-dependent gatekeeper circuits for the regulation of temporal association learning, and potentially, the circuit mechanism can be a pharmaceutical new target for preventing inadequate memory formation.

项目总结