Sunday, August 7, 2022
8/7/2022
The dentate gyrus contributes to hippocampal memory encoding by transforming dense cortical patterns of sensory and spatial information into sparse neural representations of specific contexts. Diverse local inhibitory circuits are essential for this process, maintaining low levels of neural activity wherein only small fractions of principal neurons are active at any given time. The dentate gyrus also continually generates new neurons throughout life, providing a substrate for adult brain plasticity through experience-dependent construction of new circuits. It is well established that GABA receptor-mediated mechanisms tightly regulate proliferation and functional integration of adult-born neurons. Thus, GABAergic interneurons provide both inhibitory control of mature dentate neurons and regulate the production of adult-born neurons. The goal of this project is to determine how a highly abundant subtype of GABAergic interneuron contributes to both inhibitory and neurogenic functions in the dentate gyrus. This family of interneurons called Ivy/Neurogliaform cells (INGs) has been relatively neglected due to the inability to selectively target them using genetic approaches. We will address this roadblock by validating new tools to identify and manipulate INGs, and compare their functions with the highly-studied parvalbumin (PV)- expressing fast-spiking interneurons. These fast and slow-spiking interneuron subtypes have highly divergent anatomical, intrinsic and synaptic properties, suggesting that they play distinct roles in dentate inhibition and neurogenesis. Based on our preliminary data, we hypothesize that slow-spiking INGs use GABAA and GABAB receptor activation to enforce sparse yet high-fidelity spiking of mature GCs as well as regulate early stages of dentate neurogenesis. We will combine cellular and circuit level analysis with optogenetic approaches to assess the role of slow spiking interneurons in both inhibition and neurogenesis. After understanding the cellular properties of slow-spiking interneurons subtypes, we will dissect their role in controlling GC inhibition and spike timing, comparing with results from fast-spiking interneurons. We will use optogenetic silencing to determine the respective interneuron contributions to dentate excitability with a focus on GABAB mediated-inhibition and interactions between slow and fast-spiking subtypes. Finally, we will test the role of slow-spiking interneurons in stem cell proliferation, and the contribution of GABAB receptor-mediating inhibition in differential excitability of young and mature GCs. The results of these studies will provide fundamental insight into the function of slow-spiking interneurons in dentate excitability and neurogenesis.
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