Friday, April 4, 2025
4/4/2025
The Role of the Extracellular Matrix in Alcohol Use Disorder - Project Summary Exposure to drugs of abuse, such as alcohol, induces plasticity in the brain and creates persistent drug-related memories. These brain changes and persistent activation of drug memories are believed to be central in contributing to drug addiction. A preponderance of literature has studied the tripartite synapse (pre- and postsynaptic cells, and astrocytes) in addiction; however, mounting evidence has implicated the tetrapartite synapse to indicate the additional involvement of extracellular matrix (ECM) molecules in this process. The ECM is comprised of a complex network of glycoproteins, chondroitin sulfate proteoglycans (CSPG), and enzymes, which interact to control underlying cell plasticity and excitability. Glycoproteins and CSPGs aggregate around inhibitory fast-spiking parvalbumin (PVB) interneurons throughout the brain to form perineuronal nets (PNN) which maintain and strengthen synapses. In rodents, PNNs are temporarily degraded after acute exposure to drugs, a process that relies on the activity of glial cells which secrete endogenous proteases that cleave PNN components. After persistent activation of reward memories (i.e., dependence), PNNs numbers are increased, indicating that neuronal ensembles associated with drugs of abuse are enveloped by PNNs. While the findings studying PNNs in preclinical addiction models are compelling, there are currently no data regarding PNNs in humans with alcohol use disorder (AUD) or other substance use disorders. This proposal focuses on alcohol- induced changes in PNNs and the molecules that regulate PNNs in humans, and how modifying neuron- microglia signaling cascades in rodents alters the regulation of contextual alcohol reward memory and the composition of PNNs. In Aim 1, we will evaluate PNN densities in human postmortem hippocampus tissue using quantitative brightfield microscopy together with measures of protein and mRNA expression for several of the endogenous ECM proteases, GABAergic neurons (e.g., PVB), and synaptic markers in tissue samples from the same subject cohort. We predict that individuals with AUD will have increased numerical densities of PNNs and increased PVB expression that coincide with decreased expression of ECM proteases. These findings will delineate how PNNs are impacted in humans with AUD and provide a basis for evaluating whether PNN changes in rodent models of substance use disorders are translatable to humans. In Aim 2, we will use mice to evaluate how knockout of the interleukin-33 receptor, ST2, impacts reward memory using conditioned place preference. Interleukin-33 is secreted by neurons in an experience-dependent manner, where it signals to its obligate ST2 receptor on microglia to mediate the release of several endogenous ECM proteases. We predict that knockout of the interleukin-33 receptor will impede the proteolytic cascades that mediate memory formation and consolidation, thereby curbing alcohol-induced place preference acquisition and consolidation. We believe the proposed studies will inform the use of pharmacologic agents which target the ECM to treat AUD and other substance use disorders, and will confirm and expand on findings from preclinical studies of the ECM in addiction.
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