Understanding the role of paraventricular neurotensin neurons in valence processing

ABSTRACT A hallmark of substance use disorders is continued drug use despite profound adverse consequences. While studies in rodents have suggested that leveraging both positive and negative valence processing can affect this compulsive pattern of reward-seeking behavior in conflict with punishment, the underlying mechanisms that regulate valence processing and guide ultimate behavioral selections remain unknown. Studies have shown that the basolateral amygdala (BLA) projections to the nucleus accumbens (BLA-NAc) preferentially encode positive valence, including sucrose and cocaine predictive cues and drive approach behaviors, while projections to the central nucleus of the amygdala (BLA-CeM) encode negative valence and drive avoidance. Findings from my K99 phase further demonstrated that neurotensin (NT), a 13 amino acid peptide, released from the paraventricular nucleus of thalamus (PVT) NT neurons in the BLA can bidirectionally modulate reward and punishment learning in a concentration-dependent manner (Li et al., Nature, 2023). These findings suggest that PVT: NT-BLA projection is critical for valence evaluation and can potentially modulate compulsive reward-seeking in face of punishment. Together, this proposal will investigate how PVT NTergic inputs mediate the encoding of compulsive reward-seeking and are dysregulated by chronic cocaine self-administration.