Cell Type and Circuit Mechanisms of Non-Invasive Brain Stimulation by Sensory Entrainment

Cell Type and Circuit Mechanisms of Non-Invasive Brain Stimulation by Sensory Entrainment
Patterned sensory stimulation (PSS) is a non-invasive technique for manipulating brain activity and states,
typically employing periodic light flicker or auditory tones presented at regular intervals. We and others have
recently shown that PSS at certain frequencies (centered at 40 Hz) causes widespread neural entrainment and
state changes in non-neuronal cell populations (including, e.g., effects on the activity of microglia and on
vasomotion), improvements in memory and cognitive function, and clearance of markers of neurodegeneration
in animal models of brain disease. These observations suggest a strong potential of PSS for non-invasive brain
stimulation applications in basic science and as a therapeutic tool.
To enable such applications, however, it is important to know the mechanisms mediating the complex effects
of PSS on neurons and non-neuronal cells. These mechanisms are poorly understood. In this project, we
systematically investigate mechanisms of PSS by dissecting how cell types and circuit properties in the brain
mediate the entrainment of neural activity and modifications of the states of neuronal and non-neuronal cell
populations, with the focus on the mouse cortex as a model system.
The central component of this project is a systematic modeling effort, relying on our recent progress in
integrating diverse structural and functional data into highly detailed, bio-realistic models of the mouse cortical
circuits. These models will be applied and refined to simulate the effects of PSS at the level of a single cortical
area (primary visual cortex) and the whole mouse cortex. We will also develop models of coupling from the
activity of different neuron types to non-neuronal cells, providing insights into the effects of neuronal
entrainment to PSS on, e.g., microglia and vasculature.
These modeling efforts will go hand-in-hand with electrophysiology recordings in awake mice, accompanied by
chronic and acute perturbations (using chemogenetics and optogenetics). In multiple iterative stages, modeling
predictions regarding the roles of excitatory and inhibitory (e.g., PV, SST, VIP) cell types in different cortical
layers on the entrainment to PSS will be tested experimentally, and models will be refined to match data. The
project will also characterize transcriptomic and epigenetic responses to PSS in different cell types, which will
be correlated with circuit effects revealed by simulations and perturbative experiments in vivo.
The results of these studies will provide a rich description of molecular, cell type, and circuit mechanisms
mediating the PSS effects, which will be crucial for future rational development of applications of this brain
stimulation technique. Besides the knowledge, this project will also provide highly biologically realistic, ready-
to-use computational models applicable for studies of PSS and other phenomena, which we will freely share
with the community.

Grant Number: 4R01NS122742-02
NIH Institute/Center: NIH
Principal Investigator: ANTON ARKHIPOV