Neural circuit mechanisms for temporal association learning

项目摘要 情景记忆形成的一个关键特征是将时间上分离的事件关联为一个事件的能力。 这就是所谓的时间联想学习。时间关联学习的故障代表了- 描述了患有精神分裂症和阿尔茨海默病的人类患者的发现。有几 我们对当前理论模型和神经生物学证据的认识存在重大差距， 时间联想学习我的长期目标是阐明驱动和 通过理解神经回路及其神经过程来调节时间关联学习， 内嗅皮层-海马（EC-HPC）网络，使用巴甫洛夫跟踪恐惧条件反射（TFC）作为 行为范式 我们以前证明了内侧内嗅皮层第三层的pOxr 1+兴奋细胞（pOxr 1+细胞） 投射到海马CA 1锥体细胞，是TFC所必需的。另一方面，一些CalB+ MECII中的兴奋性细胞（CalB+细胞）投射到海马CA 1中的GABA能神经元，抑制 MECIII通过前馈抑制作用输入到CA 1锥体细胞，抑制TFC。这些发现 导致我们提出了一个去抑制模型来调节TFC，通过pOxr 1+细胞驱动TFC，并通过 CalB+细胞。该模型的核心假设是，成功的TFC取决于学习依赖性 海马CA 1区锥体细胞通过减少前馈抑制介导的去抑制 CalB+细胞。对于这一假设，我们已经确定pOxr 1+细胞表现出音调诱导的持续神经细胞凋亡。 在TFC期间的所有试验中，CalB+细胞的活性均显示出试验依赖性的色调诱导的持续活性降低。 神经活动我们还发现CalB+细胞特异性表达多巴胺D1受体， (D1R)MEC中D1 R的激活对c-Fos的学习依赖性降低是必不可少的 在CalB+细胞中的表达和成功的TFC。在强有力的初步数据的指导下，我们建议 研究驱动和调节TFC的神经回路机制有三个具体目的：（1）确定TFC的作用 pOxr 1+细胞和CalB+细胞的TFC。(2)目的：探讨D1 R在CalB+细胞中的活化对TFC的作用。（三） 阐明多巴胺能神经元传入MEC对TFC的作用。 总的来说，我们提出的研究将广泛影响学习和记忆领域的特点， EC-HPC中驱动和调节时间联想记忆的新神经回路及其神经过程 网络.我们提出的研究将揭示时间联想记忆的神经基质， 依赖于学习的看门人电路，用于调节时间联想学习，并且可能还包括 电路机制可以成为预防记忆形成不足的药物新靶点。

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.