Substance P-Mediated Enhancement of Salience for Cues Predicting Aversive Outcomes

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Project Summary Maladaptive fear exacerbates responses to aversive stimuli and enhances stress and anxiety. However, brain mechanisms that drive these aversive responses and enhance salience of aversive stimuli are not known. The excitatory peptide substance P produces a spatially restricted, glutamatergic long-term potentiation on a subset of Nucleus Accumbens core neurons that are known to promote aversion. Furthermore, this long-term potentiation occurs in the Nucleus Accumbens core following fear conditioning and can be suppressed by blocking substance P signaling. Glutamatergic inputs, particularly limbic inputs, to this sub-region are among several brain systems that encode salience to cues, suggesting substance P may drive integration of salience-related signals on these cells to promote learning about aversive stimuli that proceeds behavioral action. Using a multi-level approach including slice electrophysiology, optogenetics, and fiber photometry, this project aims to understand how substance P-mediated potentiation of saliencerelated inputs to the nucleus accumbens core promotes salience to cues predicting aversive outcomes and aims to develop brain stimulation paradigms to suppress fear responding.