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 ? subunit responsible for ligand binding and a ? 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 ?1 subunit, highly expressed in the cortex and hippocampus, causes dendritic spine loss starting in adolescence. In humans, ITGB1, encoding ?1-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, ?1-integrin involvement in PFC-dependent action selection remains opaque. We will test the hypothesis that a ?1-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 ?1-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 ?1-integrin-Arg-cortactin-ROCK2 interactions in the oPFC coordinate goal-directed response choice, countering inflexible habits. Next, we will test the hypothesis that ?1-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 ?1-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 action-outcome memory in multiple contexts.
Our final aim will test the hypothesis that the enrichment of action-outcome decision making (blocking habits) via ROCK2 inhibition is trkB-dependent.

Public Health Relevance

Stressor exposure during adolescence has long-term negative consequences for decision making and mood. These outcomes may relate to the effects of stress on brain maturation. We will attempt to better understand how the proteins that coordinate brain maturation during adolescence organize complex decision making, and to develop interventions for individuals with mental health struggles resulting from adversities experienced in adolescence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH117103-03
Application #
9923734
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
2018-08-01
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322