# Peripheral Inflammation and Stress Drive Ventral Striatal Maladaptations

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $494,922

## Abstract

PERIPHERAL INFLAMMATION AND STRESS DRIVE VENTRAL STRIATAL MALADAPTATIONS
PROJECT SUMMARY Mental illnesses such as depression and anxiety are a major disease burden linked to
suicide and mortality. It is well known that exposure to stress can precipitate neuropsychiatric complications. The
immune system also has a large influence on psychological symptoms and chronic conditions like inflammatory
bowel disease dramatically increase risk of depression and anxiety. Surprisingly, little is known of the brain
circuitry-specific mechanisms that drive this comorbidity. Our goal is to address this need by studying how
systemic inflammation and stress cause maladaptations in reward/aversion circuitry of the ventral striatum
(nucleus accumbens, NAc). In preliminary studies, we found that gastrointestinal (GI) inflammation, as a
pervasive form of systemic inflammation, modulates stress-response behavior, and dysregulates NAc synaptic
plasticity and excitability of D1 dopamine (DA) receptor (D1R) expressing medium spiny neurons (MSNs). Multi-
omic exploration of the mechanistic basis for these effects implicated a novel dynorphin (DYN)-kappa opioid
receptor (kOR)-Cdk5/p35-b adducin (ADD2) signaling cascade in the NAc which we hypothesize mediates these
maladaptations. Based on these findings we propose to study the effects of peripheral inflammation, stress, and
their interactions on neurobehavioral functions (Aim 1), and NAc synaptic plasticity, cell type-specific excitability,
and DA neurotransmission (Aim 2). The novel kOR-Cdk5/p35-ADD2 pathway we have identified provides a
mechanism by which maladaptive changes in DA neurotransmission can actuate alterations in DA-cAMP-PKA
signaling and alter structural plasticity. We will study the mechanisms by which this pathway functions and its
contribution to the effects of inflammation and stress on structural plasticity (Aim 3). Innovative components of
this proposal include the study of inflammation/stress interactions, NAc cell type-specific interrogation of the role
of kOR-Cdk5/p35-ADD2 signaling in mediating these effects, in vivo fiber photometry to study DA dynamics, and
a novel systemic Cdk5 inhibitor as a targeted therapeutic approach. This research connects a strong field of
striatal signal transduction to a major clinical problem. The impact will be to provide a detailed picture of the
mechanistic basis for systemic inflammation-mental illness comorbidity and possible new approaches for
therapeutic intervention.

## Key facts

- **NIH application ID:** 10848469
- **Project number:** 5R01MH126948-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** James A Bibb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $494,922
- **Award type:** 5
- **Project period:** 2023-05-11 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848469

## Citation

> US National Institutes of Health, RePORTER application 10848469, Peripheral Inflammation and Stress Drive Ventral Striatal Maladaptations (5R01MH126948-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10848469. Licensed CC0.

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