# Orbitofrontal cortical coordination of action-consequence decision making

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $441,939

## Abstract

Elevated glucocorticoids, particularly during specific developmental periods, cause long-term biases towards
habit-based behaviors that are linked with depression, obesity, and other maladaptive outcomes in adulthood.
Neurobiological mechanisms remain largely unclear. Integrin receptors are cell adhesion factors linked with the
stress response system and genetic risk for neurodevelopmental disease. Composed of an α subunit responsible
for ligand binding and a β subunit that activates intracellular signaling, integrins respond to extracellular matrix
proteins, influencing cell structure through downstream cytoskeletal signaling factors. Integrin-mediated
signaling stabilizes cell structure in the transition from adolescence to adulthood, such that genetic ablation of
the β1 subunit, highly expressed in the cortex and hippocampus, causes dendritic spine loss starting in
adolescence. In humans, ITGB1, encoding β1-integrin, is identified in genome-wide association studies of
depression and schizophrenia, diseases characterized by deficits in PFC-dependent planning and action.
Despite connections with neurodevelopmental disease, β1-integrin involvement in PFC-dependent action
selection remains opaque. We will test the hypothesis that a β1-integrin-Abl2/Arg-cortactin-ROCK2 signaling
axis coordinates goal-directed action selection and thus, is a sensible target for blocking habits due to
glucocorticoid and stressor exposure. Aligned with RDoC-defined positive valence domains, specific aims are:
Aim 1. To identify how the β1-integrin-Arg-cortactin-ROCK2 signaling axis influences oPFC-
dependent action selection. We will use a combination of viral-mediated gene silencing and pharmacological
manipulations to test the hypothesis that β1-integrin-Arg-cortactin-ROCK2 interactions in the oPFC coordinate
goal-directed response choice, countering inflexible habits. Next, we will test the hypothesis that β1-integrin-
dependent oPFC interactions with the basolateral amygdala support goal-directed response choice. Last, we will
test the hypothesis that site-selective Itgb1 silencing structurally phenocopies glucocorticoid exposure,
eliminating dendritic spines on excitatory neurons within the oPFC.
Aim 2. To mitigate stressor-related habits and dendritic spine abnormalities in the oPFC. Next, we will
test the hypothesis that stimulation of Arg and cortactin will block habits and changes in dendritic spine densities
and morphologies following developmental corticosterone or exposure to social isolation. This aim will reveal
strategies by which to correct cyto-structural change and habit biases following adversity.
Aim 3. To reveal functional interactions with tyrosine receptor kinase B (trkB). Activation of β1-integrin-
mediated signaling events that inhibit ROCK2 stimulates BDNF, which binds to its high-affinity receptor trkB.
ROCK2 inhibition also modifies the ratio of full-length/truncated trkB in the PFC, favoring the active full-length
isoform, and it enhances ...

## Key facts

- **NIH application ID:** 10401335
- **Project number:** 5R01MH117103-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shannon Leigh Gourley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,939
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-11-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401335

## Citation

> US National Institutes of Health, RePORTER application 10401335, Orbitofrontal cortical coordination of action-consequence decision making (5R01MH117103-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401335. Licensed CC0.

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