The role of subcortical inputs to the hippocampal CA3 region in fear memory

项目摘要 海马体对于记忆形成和空间导航至关重要。在经典的海马 三突触回路（内嗅皮层→齿状回→ CA 3 → CA 1）、齿状回和CA 1起主要作用 输入和输出区域，分别连接海马体与大脑区域以外的 海马体。相比之下，CA 3通常被视为一种自联想网络，对于上下文学习至关重要， 它的海马内连接。而CA 3的海马内输入和输出，包括苔藓纤维， 从齿状回，CA 3的复发性侧支，和CA 1的Schaffer侧支， 尽管已经进行了大量的研究，但CA 3和其他皮层下区域之间的联系仍然在很大程度上未被探索。这项建议 旨在通过调查的功能连接和行为的作用，填补这一关键的知识空白， 皮层下到CA 3的输入。我们的初步实验表明，大脑皮层外的两个皮层下区域， 海马-杏仁核基底外侧和下丘脑乳头体上核-兴奋和抑制 CA 3锥体神经元活动。因此，我们将测试一个中心假设，即基底外侧 杏仁核和乳头体上核通过增强和抑制情境性恐惧学习， 抑制海马CA 3区锥体神经元的活动。在目标1和2中，我们将确定 基底外侧杏仁核和乳头体上核中的选择性神经元群兴奋和抑制CA 3 锥体神经元活动在体外和体内。在目标3中，我们将确定基底外侧的作用， 杏仁核-CA 3和乳头体上核-CA 3输入在情境性恐惧记忆中的作用。拟议的研究 代表了从传统的CA 3海马内连接研究到其 海马体外连接此外，由于CA 3、基底外侧杏仁核和 乳头体上核与许多神经精神疾病密切相关，包括 创伤后应激障碍（PTSD），抑郁症，慢性压力和癫痫，这项建议将提供一个 为未来研究探索这三个相互关联的区域在疾病中的作用提供了宝贵的知识基础。

PROJECT ABSTRACT The hippocampus is essential for memory formation and spatial navigation. In the classic hippocampal trisynaptic circuit (entorhinal cortex→dentate gyrus→CA3→CA1), dentate gyrus and CA1 act as the primary input and output areas, respectively, that connect the hippocampus with the brain areas outside of the hippocampus. By contrast, CA3 is often viewed as an auto-associative network vital for contextual learning via its intra-hippocampal connections. While CA3’s intra-hippocampal inputs and outputs, including mossy fibers from dentate gyrus, recurrent collaterals from CA3, and Schaffer collaterals to CA1 have been extensively studied, the connections between CA3 and other subcortical areas remain largely unexplored. This proposal aims to fill this critical gap of knowledge by investigating the functional connectivity and behavioral roles of subcortical-to-CA3 inputs. Our preliminary experiments revealed that two subcortical areas outside of the hippocampus – basolateral amygdala and supramammillary nucleus in the hypothalamus – excite and inhibit CA3 pyramidal neuron activity, respectively. We will, therefore, test a central hypothesis that basolateral amygdala and supramammillary nucleus promote and suppress contextual fear learning by enhancing and suppressing the activity of CA3 pyramidal neurons, respectively. In Aims 1 and 2, we will determine whether a selective population of neurons in basolateral amygdala and supramammillary nucleus excite and inhibit CA3 pyramidal neuron activity in vitro and in vivo, respectively. In Aim 3, we will determine the role of basolateral amygdala-CA3 and supramammillary nucleus-CA3 inputs in contextual fear memory. The proposed studies represent a significant shift of focus from traditional research on CA3’s intra-hippocampal connectivity to its extra-hippocampal connectivity. Furthermore, as impairments of CA3, basolateral amygdala, and supramammillary nucleus are strongly associated with many neuropsychiatric disorders, including posttraumatic stress disorders (PTSD), depression, chronic stress and epilepsy, this proposal will provide a valuable knowledge base for future studies to explore the role of these three interconnected regions in disease.