Determining how neurotensin mediates valence processing and compulsive cocaine seeking

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PROJECT SUMMARY/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. This evidence strongly suggests that BLA-NAc and BLA-CeM neurons could encode valence processing during compulsive cocaine seeking and collectively mediate decision-making during ongoing behavior. This proposed project aims to identify basic neural substrates that guide the valence assignment among BLA-NAc and BLA-CeM neurons (K99 Phase), and examine whether the same mechanism contributes to the encoding of compulsive cocaine-seeking (R00 Phase). Preliminary data suggest that neurotensin (NT), a 13 amino acid peptide, plays a critical role in mediating valence processing in the BLA. Specifically, activation of terminals of the paraventricular nucleus of thalamus (PVT) NT neurons in the BLA enhanced reward learning and impaired punishment learning, while disruption of the PVT-BLA NTergic signaling produced the opposite behavioral effects. During the K99 phase of the award, the applicant will receive training on using CRISPR-Cas9 mediated gene manipulation to interrogate NTergic contributions without affecting glutamate and applying machine learning-based computer vision tools and classification algorithms to extract distinct behavioral motifs and decode neural correlates. This training will allow the applicant to investigate the specific roles of NT in valence assignment and coding properties of BLA neurons during valence processing. To test this, the applicant will examine the impact of the CRISPR-mediated knockdown of the Nt gene in BLA-projecting PVT neurons on reward and punishment learning (Aim 1) and the effects of the knockdown on valence encoding properties of BLA-NAc and BLA-CeM neurons during a reward and punishment discrimination task (Aim 2). After securing an independent research position, the applicant will begin the R00 phase of the award by combining these approaches gleaned from the K99 phase with applicant’s expertise in studying cocaine addiction with self- administration and punished reward-seeking paradigms, to investigate how PVT NTergic inputs modulate the encoding of compulsive cocaine-seeking (Aim 3). Together, the training and scientific advances that will be achieved through the completion of this project will allow the applicant to secure a tenure track faculty position in a top research university and provide critical pilot data necessary to prepare the first R01 application to study more distributed neural pathways that govern motivated behavior and compulsive drug-seeking.