# Cortical mechanisms of stress-induced cognitive impairment

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $509,437

## Abstract

PROJECT SUMMARY / ABSTRACT
Stress profoundly impacts mental health via impaired cognitive function and increased risk of neuropsychiatric
disorders, resulting in loss of lives, tremendous healthcare costs and reduced economic productivity. Central to
the mechanism of stress-induced cognitive impairment is loss of excitatory synapses and consequently,
disrupted connectivity of key brain areas, including those involved in decision-making. Decisions rely on this
connectivity to combine sensory clues with internal factors like attention, memories and outcome predictions. In
the neocortex, sensory information is provided by bottom-up inputs while internal factors are conveyed via top-
down systems. The capacity of the posterior parietal cortex (PPC) to integrate these various information
streams is fundamental to decision-making. There is emerging evidence from human studies that the parietal
circuit is affected by chronic stress. Yet, there is a critical gap in our knowledge regarding the mechanistic
role the PPC circuit may play in mediating the link between stress and impaired decision-making.
Our preliminary findings indicate that repeated exposure to multiple concurrent stressors (combining physical,
visual and auditory stresses, RMS for short) destroys excitatory synapses in the PPC. Specifically, synaptic
inputs corresponding to the sensory modalities (visual and auditory) conveying the stress are lost while top-
down inputs from frontal brain regions are preserved. These findings motivate our central hypothesis that
stress impedes decision-making by disrupting the integration of sensory and top-down information
streams in the PPC circuit. We will test this hypothesis at the behavioral, circuit and synaptic level. First,
utilizing quantitative behavioral analysis, we will determine which aspects of decision-making are affected by
RMS. We will use chemogenetic circuit manipulation (DREADDs) to link our behavioral findings to sensory and
top-down inputs of the PPC. Next, we will use in vivo two-photon calcium imaging and signal detection theory
to directly test the effect of RMS on information transfer between cortical regions. Finally, we will use dual-color
optogenetics and whole-cell patch clamp recordings in acute brain slices to determine the effect of RMS on the
integration of sensory and top-down synaptic inputs in PPC neurons. Successful completion of the proposed
studies will establish an important mechanistic link between the PPC circuit and stress-induced deficits in
decision-making. The generated insights will pave the way towards identifying novel targets for prevention and
intervention strategies to address stress-related neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 10030148
- **Project number:** 1R01MH123686-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Gyorgy Lur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,437
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030148

## Citation

> US National Institutes of Health, RePORTER application 10030148, Cortical mechanisms of stress-induced cognitive impairment (1R01MH123686-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10030148. Licensed CC0.

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