Neuroimmune and Microbiome Effects on Limbic Reward Structures in Models of Substance Use Disorders

Overview: In recent years there has been growing evidence that neuroimmune and gut-brain interactions have marked effects on brain and behavior, including in models of substance use disorders. While these effects are robust, the underlying molecular pathways are not well characterized. By utilizing the cutting-edge resources available through the Core, we will clarify the molecular mechanism underlying these effects on neuronal and behavioral plasticity in translationally relevant models of substance use disorders.

Our current studies on neuroimmune mechanisms in substance use disorders have focused on cytokine signaling in the brain and found that cytokines interact with cocaine treatment to alter the expression of important synaptic proteins in limbic substructures. Going forward, we will continue to utilize the discovery proteomics core to identify how cytokine signaling alters expression of glutamate and dopamine receptors in isolated synaptic subfractions. Also, we are working with Core to perform proteomic profiling of synaptically expressed receptor populations using cell-surface biotinylation combined with quantitative mass spectrometry.

Studies on the gut brain axis have shown that depletion of the host microbiome results in significant dysregulation of the transcriptional response to either opioids or psychostimulants. Working with the core we will perform discovery proteomics analysis to determine how these transcriptional changes are reflected in protein expression in important limbic structures. This will be coupled with cell sorting of genetically defined cell populations to determine how microbiome shifts are affecting protein expression in distinct populations of neurons and glia. Additionally, given the significant dysregulation of transcription, we will also be using co-immunoprecipitation of nuclear protein complexes to quantitatively determine how alterations in the microbiome affect transcriptional machinery in the brain.