# Basal forebrain regulation of default mode and task-on functional network activity: translational modeling of psychiatric disorders

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2024 · —

## Abstract

OBJECTIVE: Cognitive deficits are a major determinant of the long-term disability associated with severe
neuropsychiatric disorders, including schizophrenia (Sz). The antipsychotic medications currently available do
not satisfactorily address Sz-related cognitive symptoms. Normal brain and cognitive function require networks
of distributed brain regions to maintain stable, yet flexible communication. The focus of this study is the default
mode network (DMN), which is a brain-wide functional network that is generally associated with introspective
processes and is conserved across mammalian species. Suppression of DMN activity is important to allow
Task-On associated network when subjects are performing tasks that require interaction with the environment.
Impaired DMN suppression has been observed in Sz patients and is associated with psychopathology,
particularly cognitive impairments. Recent evidence suggests the basal forebrain (BF) represents an important
DMN node and may play a central role in the regulation of DMN activity. Deficits in functional network
dynamics have been suggested to be related to perturbations in the balance of cortical excitatory and inhibitory
neurotransmission (E/I Balance). Our published findings show that optogenetic stimulation of BF parvalbumin
neurons (BF-PV) alters cortical E/I balance, eliciting an elevation in spontaneous cortical gamma band activity
(>30 Hz, GBA), and behavioral phenotypes that resemble psychosis. Through our proposed work, we will
illuminate the mechanisms behind subcortical modulation of DMN versus the Task-On network activity and
inform novel therapeutics to restore impaired network connectivity in psychiatric disorders affecting Veterans.
RESEARCH DESIGN: The Overall Hypothesis postulates that long range inhibitory GABAergic BF-PV
output from the BF fine tunes cortical E/I balance and that this process is critical for efficient suppression of
DMN activity that is needed for the transition to a predominance of Task-On network activity required for
cognitive performance. Aim 1 will confirm that local BF GBA is associated with GBA throughout the DMN and
will characterize the cortical regions associated with DMN-like neural oscillations in mice. Aim 2 will build upon
these findings by examining how transitions between DMN and Task-On network function is regulated by BF,
specifically BF-PV neurons, during operant tasks targeting both attentional and executive function domains of
cognition. Finally, Aim 3 will utilize cutting-edge fiber photometric techniques to directly assess the ability of
BF-PV neurons to influence cortical E/I balance across a range of behavioral contexts. Further, these aims will
examine DMN activity, and its regulation via BF, in two translationally relevant mouse models of Sz that mimic
the neurochemical changes of the human Sz brain (i.e., 2 models of glutamatergic NMDA receptor
hypofunction). Finally, optogenetic modulation of BF-PV neurons will be used to probe both E/...

## Key facts

- **NIH application ID:** 10798581
- **Project number:** 2I01BX004500-05A1
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** JAMES M MCNALLY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798581

## Citation

> US National Institutes of Health, RePORTER application 10798581, Basal forebrain regulation of default mode and task-on functional network activity: translational modeling of psychiatric disorders (2I01BX004500-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10798581. Licensed CC0.

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