# Gating of Information Flow Within the Nucleus Accumbens

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $662,395

## Abstract

Abstract:
Schizophrenia is among the most devastating of the psychiatric disorders, robbing more than 1% of the
population worldwide of quality of life. While schizophrenia tends to run in families, the disorder is not completely
genetically determined, and depends on an interaction with the environment. Among the most robust findings
in schizophrenia is the nearly 30% decrease in parvalbumin (PV)-labeled GABAergic interneurons, particularly
in the limbic hippocampus. This loss is paralleled by hyperactivity in the limbic hippocampus, which we have
found in animal models drives increased dopamine system responsivity. It has been known that early life stress
and anxiety often precedes the psychotic break, and moreover adolescent stress in rats is known to lead to PV
neuron loss. Interestingly, stress can damage PV interneurons only when it occurs during adolescence;
afterwards, the PV neurons develop perineuronal nets that protect them from damage. We have previously
employed a developmental disruption model of schizophrenia based on gestational administration of a mitotoxin.
Interestingly, these rats show increased anxiety and heightened stress response during adolescence, before the
emergence of a dysregulated dopamine system. If we mimic this adolescent condition by combined stressors,
we can induce a MAM-like phenotype in normal rats. Therefore, we posit that susceptibility to stressors that
occur prior to the formation of perineuronal nets lead to damage of vHipp PV interneurons, vHipp
hyperactivity, and the emergence of the hyperdopaminergic state in the adult. We further suggest that the
increased stress responsivity in susceptible adolescents may be due to a failure of the prelimbic prefrontal cortex
to limit the impact of stress. Finally, given that females have a later onset of schizophrenia and less pathology,
we posit that adolescent stress will not impact female rats to the degree seen in males. We will assess this
model via the following Specific Aims: 1) Determine the development of stress-induced pathology in normal adult
male and female rats, and how this correlates with PNN and PV interneuron staining; 2) Determine the role of
prepubertal plPFC lesions and BLA activity on stress reactivity, anxiety, and footshock-induced PV loss/DA
hyperresponsivity in peripubertal and adult rats, and the role of plPFC inhibition of the BLA in the pathology; and
3) Examine whether re-opening the critical period or PNN disruption in the adult can cause the rat to regain
stressor-induced PV neuron loss and DA system hyperresponsivity, and if this is driven by the BLA. In this way,
we hope to be able to provide a link between genetic/gestational susceptibility and environmental factors that
occur early in life, initiating a cascade of events that lead to the emergence of schizophrenia later in life. This
will provide insights not only into the pathophysiology of schizophrenia, but also into establishing predictive
criteria for psychosis susceptibili...

## Key facts

- **NIH application ID:** 9828600
- **Project number:** 5R01MH057440-23
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ANTHONY A GRACE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $662,395
- **Award type:** 5
- **Project period:** 1997-08-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828600

## Citation

> US National Institutes of Health, RePORTER application 9828600, Gating of Information Flow Within the Nucleus Accumbens (5R01MH057440-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828600. Licensed CC0.

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