Architectonic analysis of complex cortical circuits in healthy and diseased brain

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PROJECT SUMMARY/ABSTRACT The central tenet of connectomics is to reconstruct enough neuronal constituents with their synaptic connections that encompass a neural circuit to reveal its architectural organization. Yet, despite the rapid technical progress, it remains a prohibitively challenging task to elucidate complex cortical neuronal circuit architectures, which dictate principles of cortical operation essential for delineating cortical physiology and pathology. Recently, we developed a prototype of simultaneous and sequential octuple-sexdecuple (8−16) whole-cell patch-clamp recording system that enabled reconstruction of complex cortical circuits consisting of ≥10 types of identified neurons. Our preliminary study showed that 8−16 patch-clamp recordings could reconstruct sufficient components of layer 1 (L1) single bouquet cell (SBC)-led disinhibitory circuit in the mouse somatosensory cortex, and the preliminary data began to reveal its overall architectural design. Therefore, we hypothesize that 8−16 patch-clamp recordings enable architectonic analysis of complex cortical L1 SBC-led disinhibitory circuits in healthy and diseased brains. In this project, we will test whether 8−16 patch-clamp recordings enable reconstruction of a complex L1 SBC-led disinhibitory circuit in the mouse somatosensory cortex (Aim 1). Moreover, we plan to examine whether 8−16 patch-clamp recordings enable architectonic analysis of modular L1 SBC-led disinhibitory circuits across various cortical areas, including the mouse motor, prefrontal, and medial entorhinal cortices (Aim 2). Finally, we will explore whether 8−16 patch-clamp recordings detect architectonic deficits in modular L1 SBC-led disinhibitory circuits in aged and Alzheimer’s brains (Aim 3). We expect the proposed experiments to endorse the broad applicability of 8−16 patch-clamp recordings in decoding complex circuit architectures, elucidate the modular organization of L1 SBC-led disinhibitory circuits, explicate a few fundamental principles of cortical operation, and unveil the first few architectonic deficits of modular L1 SBC-led disinhibitory circuits in aged and Alzheimer’s brains. The proposed project goals are in line with NINDS First Strategy Goal that is to understand fundamentals of neuroscience, including brain circuits that control complex behaviors and treatments for neurological disorders, and NIA Strategy Goal D that is to identify neural changes and mechanisms related to normal brain aging and Alzheimer’s and other age-related neurological conditions.