Friday, May 9, 2025
5/9/2025
Mechanisms of noncanonical caspase 1 signaling in the brain. - 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.
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