Architectonic analysis of complex cortical circuits in healthy and diseased brain

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.

Grant Number: 1RF1NS131762-01A1
NIH Institute/Center: NIH
Principal Investigator: Mark Beenhakker