Wednesday, February 5, 2025
2/5/2025
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.
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