# Mechanisms of noncanonical caspase 1 signaling in the brain.

> **NIH NIH R21** · UPSTATE MEDICAL UNIVERSITY · 2022 · $243,000

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal represents a highly innovative research line focused on investigating the interface between
neuroinflammation and serotonin signaling in chronic stress. Chronic stress is a significant risk factor for
many neurological and neuropsychiatric disorders; it induces changes in neural circuitry and behaviors
that may promote maladaptive integration and functioning of brain regions associated with motivated and
emotional behaviors. There has been an increased interest in the association between stress-induced
neuroinflammatory processes and their impact on brain functions. We and others have reported that
Caspase-1 (CASP1) deficiency leads to attenuated stress-induced behaviors of anhedonia and decreased
motivation, with concurrently reduced neuroinflammation, given that CASP1 is the effector molecule of the
inflammasome. We present novel evidence that chronic stress-induced CASP1 activation decreases
glutamatergic neurotransmission in response to serotonin signaling in the nucleus accumbens (NAc),
specifically mediated by the serotonin 1B receptor (5-HT1B), a highly expressed receptor in the NAc.
Chronic stress-induced CASP1 activation leads to serotonin signaling dysfunction. We will test our
hypotheses that the 5-HT1B is a novel substrate for noncanonical CASP1 signaling and that CASP1-
mediated processes play a role in modulating serotonin signaling. We will elucidate molecular and cellular
mechanisms through which CASP1 in the NAc modulates serotonin signaling. This may provide a robust
scientific foundation for understanding the mechanisms underlying maladaptive responses to chronic
stress. We expect our results to provide evidence-based proof-of-principle for the future development of
translational therapeutics targeting canonical and noncanonical neuroinflammatory NAc-based pathways
in stress-induced disorders.

## Key facts

- **NIH application ID:** 10353135
- **Project number:** 1R21MH128726-01
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Julio Licinio
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353135

## Citation

> US National Institutes of Health, RePORTER application 10353135, Mechanisms of noncanonical caspase 1 signaling in the brain. (1R21MH128726-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10353135. Licensed CC0.

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