PARCPolysubstance Addiction Research Center

Research

Research Projects

Three coordinated projects study the same behaviorally phenotyped heterogeneous stock rats at different biological scales. Together they build the One-Individual Multiscale Atlas, linking gene expression, brain networks, and gut–vagus–brain signaling to individual differences in addiction vulnerability across alcohol, opioids, and cocaine.

The projects

Gaps and Barriers facing addiction research

Addiction research has traditionally studied one drug, in one rodent strain, at one biological level. PARC was designed to remove those barriers systematically:

Two-column comparison of gaps and barriers in addiction research versus PARC solutions: single drug studies versus polysubstance studies; single rodent strain versus heterogeneous stock rats; passive exposure versus self-administration with deep phenotyping; limited access (1 hour for a few days) versus extended access (6 to 14 hours for weeks); single biological level versus PanOmic profiling; separate animals for separate omics versus the One-Individual Multiscale Atlas.
Gaps and barriers in traditional addiction research, and the center's solutions, from single-drug, single-strain, passive-exposure designs to polysubstance studies in heterogeneous stock rats with extended-access self-administration and one-individual multi-omic integration. (Figure from the PARC research proposal.)

Experimental design

The center compares substances (cocaine, oxycodone, alcohol, and cocaine + oxycodone polydrug use), disease severity (from healthy controls to severe addiction-like behavior), and species (rat models against human datasets) within one integrated design:

Diagram of the center's three comparison axes: a drug comparison across cocaine, alcohol, oxycodone, and cocaine plus oxycodone cohorts; a disease comparison from healthy controls to mild, moderate, and severe addiction-like behaviors; and cross-species comparisons between human populations and heterogeneous stock rats.
Three comparison axes in one design: drug (cocaine, oxycodone, alcohol, polydrug), disease severity (healthy control to severe addiction-like behavior), and species (human and rat). (Figure from the PARC research proposal.)

Converging mechanisms, common targets

The projects converge on shared multiscale mechanisms, from gut–vagus signaling and metabolic stress to brain-network hypomodularity, and on common molecular targets studied across all three substances:

Schematic of multiscale mechanisms linking cocaine, oxycodone, and alcohol to addiction-like behaviors: gut microbiome and intestinal signaling through the vagus nerve to the brain, cellular stress and reactive oxygen species, single-cell transcriptomics, whole-brain connectomics with central network hubs, and a panel of common molecular targets including CRFBP, GLO1, CHRM4, and gp130.
Working model: cocaine, oxycodone, and alcohol engage convergent gut–vagus–brain, cellular-stress, and brain-network mechanisms, with common candidate targets (CRFBP, GLO1, CHRM4, gp130). (Figure from the PARC research proposal.)
Concentric-ring diagram of the center's theoretical framework: cocaine, oxycodone, alcohol, and polydrug use act through gut–vagus dysfunction (impaired intestinal barrier, decreased mAChR4/gp130 signaling), metabolic and cellular stress (increased metabolic and excitotoxic stress, impaired OxPhos and Glo1 function), and brain hypomodularity (cortico-subcortical disinhibition), converging on addiction-like behaviors.
Theoretical framework: substance use drives gut–vagus dysfunction, metabolic and cellular stress, and brain hypomodularity, which converge to produce addiction-like behaviors. (Figure from the PARC research proposal.)

The projects are supported by the center's five cores and feed shared samples into the Addiction Biobank.