# Impact of social isolation on cognitive function and neural circuitry abnormalities

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

Veterans with schizophrenia are among the most ill of those treated at VA facilities, which presents a great
burden on care and VA resources. The inadequacy of treatment response and myriad side effects of current
medications makes long-term care and medication adherence difficult. Hence, better treatment of Veterans
with psychotic disorders will greatly improve their overall quality of life and long-term care. Recent evidence
suggests that social isolation or withdrawal may contribute to the emergence of psychiatric illness, or be a
precipitating factor. For example, social withdrawal in schizophrenia occurs prior to symptoms of psychosis and
continued social decline predicts conversion to psychosis. Individuals with schizophrenia show disruptions in
frontal cortex and hippocampal circuitry, which contribute to negative symptoms and cognitive deficits.
Cognitive deficits are particularly debilitating and remain undertreated with current antipsychotic medications.
Based on the course of illness it is likely that the severity of social withdrawal/isolation contributes to the
neuropathology in schizophrenia; however, the mechanism through which this progression occurs is not
known. Because of ongoing deterioration in symptoms and better prognosis with early therapeutic
interventions, there is a need to identifying potential risk factors, prodromal symptoms, and biomarkers to help
screen military personnel at risk for serious mental illness and provide opportunities for early intervention. The
goals of the proposed studies are (1) to determine the impact of social isolation (SI) in rodents on frontal cortex
and hippocampal circuitry and behaviors relevant to schizophrenia (e.g. deficits in cognitive flexibility and
sensorimotor gating) and (2) identifying biomarkers predictive of susceptibility, and (3) develop more
efficacious early interventions for neuropsychiatric disorders, particularly schizophrenia. Aim 1 studies assess
the contribution of glutamate and GABA function in cortex and hippocampus to the development of cognitive
deficits in socially isolated rats. Studies examine the progression of both cognitive deficits and alterations in
markers of excitatory and inhibitory neurons via immunohistochemistry and glutamatergic neuronal activity via
in vivo fiber photometry. Aim 2 studies use optogenetics to determine whether neuromodulation of orbitofrontal
cortex (OFC) to dorsomedial striatum (DMS) glutamate projections can remediate cognitive deficits in socially
isolated rats. Aim 3 studies examine whether early interventions with a metabotropic glutamate receptor
agonist, LY379268, to decrease glutamate signaling can prevent the development of cognitive dysfunction
associated with social isolation. These preclinical studies will provide a better understanding of the impact of
social isolation on neural circuitry and cognitive behavior and identify potential therapeutic targets for future
studies in Veterans.

## Key facts

- **NIH application ID:** 10514594
- **Project number:** 5I01BX005209-03
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Susan B Powell
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514594

## Citation

> US National Institutes of Health, RePORTER application 10514594, Impact of social isolation on cognitive function and neural circuitry abnormalities (5I01BX005209-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10514594. Licensed CC0.

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