PERIPHERAL INFLAMMATION AND STRESS DRIVE VENTRAL STRIATAL MALADAPTATIONSPROJECT SUMMARY Mental illnesses such as depression and anxiety are a major disease burden linked tosuicide and mortality. It is well known that exposure to stress can precipitate neuropsychiatric complications. Theimmune system also has a large influence on psychological symptoms and chronic conditions like inflammatorybowel disease dramatically increase risk of depression and anxiety. Surprisingly little is known of the braincircuitry-specific mechanisms that drive this comorbidity. Our goal is to address this need by studying howsystemic 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 apervasive form of systemic inflammation modulates stress-response behavior and dysregulates NAc synapticplasticity 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 opioidreceptor (kOR)-Cdk5/p35-b adducin (ADD2) signaling cascade in the NAc which we hypothesize mediates thesemaladaptations. Based on these findings we propose to study the effects of peripheral inflammation stress andtheir interactions on neurobehavioral functions (Aim 1) and NAc synaptic plasticity cell type-specific excitabilityand DA neurotransmission (Aim 2). The novel kOR-Cdk5/p35-ADD2 pathway we have identified provides amechanism by which maladaptive changes in DA neurotransmission can actuate alterations in DA-cAMP-PKAsignaling and alter structural plasticity. We will study the mechanisms by which this pathway functions and itscontribution to the effects of inflammation and stress on structural plasticity (Aim 3). Innovative components ofthis proposal include the study of inflammation/stress interactions NAc cell type-specific interrogation of the roleof kOR-Cdk5/p35-ADD2 signaling in mediating these effects in vivo fiber photometry to study DA dynamics anda novel systemic Cdk5 inhibitor as a targeted therapeutic approach. This research connects a strong field ofstriatal signal transduction to a major clinical problem. The impact will be to provide a detailed picture of themechanistic basis for systemic inflammation-mental illness comorbidity and possible new approaches fortherapeutic intervention.