# Brain regional extracellular matrix molecules, corticostriatal circuitry function and alcohol drinking in monkeys and mice

> **NIH NIH P60** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $390,459

## Abstract

PROJECT SUMMARY
 This is a renewal application to the P60-Portland Alcohol Research Center (PARC). In the past funding
period we added key knowledge to our understanding of the predictive nature of corticostriatal circuitry and
cognitive flexibility in mediating risk for chronic heavy alcohol drinking in rhesus monkeys. The monkey model
has also provided evidence that chronic heavy drinking results in synaptic remodeling and an imbalance in
striatal output towards glutamatergic excitatory tone[1,2]. Finally, genomic data from the PFC and the nucleus
accumbens of heavy drinking monkeys (preliminary data) point to the extracellular matrix (ECM) component of
the “tetrapartite synapse”[3] in mediating excessive alcohol drinking and impaired cognitive flexible behavior. A
main constituent of the ECM related to synaptic function is the glycosaminoglycan Hyaluronic Acid (HA)[4,5].
Data supporting the importance of HA to the function of ECM in synaptic plasticity is expanding rapidly[6]. To
our knowledge, there are no studies that directly link ethanol-associated changes in HA synthesis and
metabolism to altered synaptic plasticity. Nevertheless, our preliminary data show that ethanol leads to altered
expression of hyaluronidases, HA synthases and HA-binding proteins in support of the hypothesis that heavy
alcohol drinking alters HA metabolism in synaptic ECM and perineuronal nets (PNNs) to alter striatal neuronal
activity. Thus, this proposal seeks to provide pivotal information on HA as a target for ethanol-induced
adaptations to Medium Spiny Neurons (MSNs), the projection neurons of the striatum. To determine the effect
of chronic drinking on HA composition and subsequent alterations in striatal MSN synaptic plasticity, we
propose a combination of molecular, histological and electrophysiological techniques. These findings will then
be placed into a larger framework of functional measures of corticostriatal circuitry involved in chronic heavy
alcohol drinking as mapped by fMRI (monkeys) and cognitive flexibility (mice and monkeys). We posit that this
circuitry, particularly corticostriatal loops conveying sensory-motor information, are involved in both the risk for
heavy alcohol drinking as well as the propagation of heavy drinking once it is established. We will use the
proposed research PARC cores and integrate these findings with the PARC projects to gain a deeper
understanding of other ECM constituents in chronic alcohol drinking. Overall, if successful, this project will
provide critical information establishing a link between HA-ECM content and ethanol-associated synaptic
adaptations within the sensorimotor corticostriatal circuitry that promote habitual (inflexible) behavior.

## Key facts

- **NIH application ID:** 10056069
- **Project number:** 2P60AA010760-26
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** KATHLEEN A GRANT
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,459
- **Award type:** 2
- **Project period:** 1996-12-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056069

## Citation

> US National Institutes of Health, RePORTER application 10056069, Brain regional extracellular matrix molecules, corticostriatal circuitry function and alcohol drinking in monkeys and mice (2P60AA010760-26). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10056069. Licensed CC0.

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