Determining the efficacy of therapeutic interventions after stroke from cell specific functional connectomes

PROJECT SUMMARY/ABSTRACT
Understanding circuit-level maneuvers that affect brain plasticity will inform the design of targeted interventions
after stroke. Experiments outlined in this proposal will determine the contributions of excitatory/inhibitory circuits
on brain repair processes after focal ischemia, and how changes in behavioral performance relate to cell-specific
changes in connectivity. Stroke causes direct structural damage to local brain circuitry and indirect disruption of
global networks resulting in behavioral deficits spanning multiple domains. Stroke recovery is associated with
functional brain reorganization, a process involving the formation of new or alternative circuits. Along with
behavioral recovery, damaged regions remap to adjacent tissue while patterns of resting-state functional
connectivity (RS-FC) within and across resting-state networks gradually renormalize. While local and global
changes in functional brain organization are consistently observed during recovery, how these processes relate
to the underlying neuronal circuitry supporting recovery of function is unknown. This knowledge gap exists
partially because stimulus-evoked and resting-state patterns reflect ensemble activity from many cell types, and
patterns of RS-FC can be orchestrated through indirect pathways. Understanding how disconnected inhibitory
and excitatory circuits reintegrate into global networks to support recovery requires examination of neural
network connectivity structure as it evolves with neuroanatomical markers of circuit repair. While an integrated
mechanism relating cellular plasticity with network plasticity has yet to be established, inhibitory circuits have
been shown to play a key role. Stroke disrupts the brain’s balance of excitation and inhibition. Restoring this
balance through non-invasive brain stimulation techniques can improve recovery. However, treatment efficacy
using these methods is extremely varied, partially due to the imprecision and indiscriminate activation or
inhibition of all cells near the stimulated site. Parvalbumin interneurons (PV-INs) are the most prevalent of all
GABAergic interneurons, play key roles in shaping excitability over long distances, and regulate functional brain
rhythms reflected in coherent patterns of RS-FC. Though their role in post-stroke plasticity is unknown, PV-INs
are known to mediate several other forms of activity-dependent plasticity, making them compelling candidates
for affecting repair processes after stroke. Using optogenetic targeting and wide field optical imaging of cortical
calcium dynamics in awake mice, we will establish functional connectomes of excitatory (CamK2a-based) and
inhibitory (PV-based) circuits and how they evolve following focal ischemia (Aim 1). We will utilize the well-
characterized motor-barrel network in the mouse to directly test the influence of activity in cortical
excitatory/inhibitory nodes exhibiting strong (Aim 2) or weak (Aim 3) inter- or intra-hemispheric connectivity with
perilesional tissue, and how these manipulations affect neuroanatomical markers of circuit repair. At the
conclusion of this grant, we will determine the contributions of CamK2a/PV circuits on post-stroke recovery, and
further understand the components of connectivity restoration required for more complete behavioral recovery.

Grant Number: 5R01NS126326-03
NIH Institute/Center: NIH
Principal Investigator: ADAM BAUER