# Excitatory and Metabotopic Regulation of PKA in Stress and Resilience

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $314,095

## Abstract

STRIATAL EXCITATORY AND METABOTROPIC PKA REGULATION IN STRESS AND RESILIENCE
Mental disorders such as anxiety and depression are major health concerns that contribute
unabated to a large portion of all morbidity and mortality. These complex disorders may be viewed as mal-
adaptations that arise in brain circuitry. In order to achieve more effective treatments, better mechanistic
understanding of brain circuitry integration is needed. Normally, motivated behaviors and executive functions
require processing of sensory-triggered excitatory neurotransmission and assignment of emotional context. This
occurs in the striatum where cortical glutamatergic and midbrain dopaminergic inputs converge to mediate brain
functions such as reward and stress responses. Striatal dysfunction is broadly implicated in the etiology of many
mental illnesses. For example, stress-induced alterations in the activity of reward-related brain regions, such as
the nucleus accumbens (NAc), are linked to the pathophysiology of depression. Insight into the mechanisms by
which glutamate and dopamine neurotransmission are integrated within the NAc may shed light on some causes
of mental illness, or implicate new drug targets and treatment strategies. Here, we introduce a new signaling
mechanism which we hypothesize is controlled by striatal glutamatergic and dopaminergic signaling to allow
concerted regulation of PKA activity. Specifically, our preliminary data indicates that glutamate controls
constitutive phosphorylation of the RII-beta (RIIb) regulatory subunit by Cdk5, which then directly affects PKA
activation by D1-type dopamine receptors via a second PKA-dependent auto-phosphorylation mechanism. We
hypothesize that this unique mechanism mediates striatal plasticity and behavioral responses to stress and that
chronic stress can cause mal-adaptations in this mechanism so that glutamate and dopamine signaling are
uncoupled and PKA signaling is dysregulated. We further hypothesize that this mechanism may be targeted to
improve striatal plasticity and behavioral resilience. To pursue this novel premise, we propose to 1) study the
regulation of RIIb/PKA and explore downstream effectors in vitro and in vivo; 2) study the role of RIIb/PKA
phosphorylation in ventral striatal neuronal excitability and synaptic plasticity and 3) study the regulation of this
mechanism by acute and chronic stress, and determine how it contributes to behavioral responses to stress.
These studies will yield important information on the mechanisms that integrate brain circuitry and how they are
affected by stress. Thus, we will better understand some of the basis by which stress may contribute to complex
mental disorders such as anxiety and depression and how they may be more effectively treated.

## Key facts

- **NIH application ID:** 10836258
- **Project number:** 7R01MH116896-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** James A Bibb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $314,095
- **Award type:** 7
- **Project period:** 2019-05-06 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836258

## Citation

> US National Institutes of Health, RePORTER application 10836258, Excitatory and Metabotopic Regulation of PKA in Stress and Resilience (7R01MH116896-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10836258. Licensed CC0.

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