# Tuning cortical E/I balance for translational modeling of psychiatric disorders

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2020 · —

## Abstract

OBJECTIVE: Cognitive deficits are a major determinant of the long-term disability associated with severe
neuropsychiatric disorders, including schizophrenia (Sz). This warrants increased interest in the VA
research community, given the higher instance of psychiatric illness among the veteran population,
treatment of which accounts for some 40% of VA mental healthcare costs nationally. Current therapeutic
strategies (first and second-generation antipsychotics) do not satisfactorily address Sz-related cognitive issues.
Abnormalities in the patterns of cortical EEG, most notably elevated spontaneous gamma band activity (GBA)
and reduced task-evoked GBA, have been observed in a number of clinical studies of severe neuropsychiatric
conditions, and have been indicated to underlie both the psychosis linked impairment of sensory, cognitive,
and social domains of function. Thus, it may prove advantageous to address these symptom domains with a
greater consideration to the patterns of electrophysiological activity and testing whether modulation of these
patterns can improve function. One crucial variable regulating such activity is the balance between excitatory
and inhibitory (E/I Balance) cortical neural activity. Recent work from our lab suggests that long range
GABAergic projections from basal forebrain parvalbumin neurons (BF-PV) are capable of bi-directionally
modulating E/I balance. These studies serve to provide a better understanding of the role of impaired E/I
balance in the emergence of cognitive and social deficits associated with Sz, and other psychiatric disorders,
as well as provide a rationale for targeting restoration of E/I balance as a novel therapeutic approach.
RESEARCH DESIGN: In this study, our Overall Hypothesis postulates that modulation of BF-PV output
allows tuning of cortical E/I balance, via direct projections to the cortical circuitry and through projections to the
thalamic reticular nucleus (TRN). Aim 1 will characterize a powerful systems-level model to better define how
abnormal patterns of cortical activity impact cognitive and social domains of function relevant to psychiatric
disease. Aim 2 seeks to provide a more complete understanding of the mechanism behind BF-PV modulation
of E/I balance. Finally, Aim 3 will test manipulations of this mechanism as a novel therapeutic means to restore
cortical E/I balance, and improve cognition in two translationally relevant models of Sz.
METHODOLOGY: Here we will utilize an innovative combination of electrophysiological, optogenetic, and
behavioral paradigms. First, to directly examine the relationship between impaired E/I balance and cognition,
we will assess performance of mice on translationally relevant sensory and cognitive paradigms both with and
without BF-PV mediated alteration of cortical E/I. Using, both an immunohistochemical and optogenetic
approach, we will attempt to better characterize the circuit pathway involved in BF-PV modulation of E/I
balance. Finally, we will u...

## Key facts

- **NIH application ID:** 9868808
- **Project number:** 5I01BX004500-02
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** JAMES M MCNALLY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868808

## Citation

> US National Institutes of Health, RePORTER application 9868808, Tuning cortical E/I balance for translational modeling of psychiatric disorders (5I01BX004500-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868808. Licensed CC0.

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