Investigating the Role of Neurotensin on Valence Assignment During Associative Learning in the Basolateral Amygdala

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Abstract

Learned associations between environmental stimuli and organism-effecting outcomes guide adaptive behavior. When healthy, this process results in increased rewards and decreased harm. Indicative of its foundational role in shaping behavior, associative learning dysfunction is comorbid in a host of neuropsychological pathologies including depression, addiction, anxiety disorders, and post-traumatic stress disorder. Increased characterization of neural mechanisms is necessary to improve the design of effective pharmacotherapeutic treatment strategies to address dysfunctional associative learning processes. Decades of research show the basolateral amygdala (BLA) plays a central role in the associative learning process. Recent technological innovations have enabled researchers to dissect the functional circuitry of this region to investigate the underlying mechanisms. Neurons arising from the BLA and projecting to the nucleus accumbens and centromedial amygdala have been shown to causally drive reward and fear learning, respectively. These two populations are interspersed anatomically in the BLA and exhibit similar morphological and electrophysiological profiles during both positive and negative valence (approach and avoidance, respectively) associations. How these neurons are selectively targeted and driven in opposing manners for opposing valence associations in the BLA is currently unknown. Our preliminary data suggests the neuropeptide neurotensin (NT) differentially affects learning in the two projecting populations. We hypothesize that afferents to BLA mediate the valence of learned associations through NT release. The proposed specific aims test this hypothesis through systematic identification, manipulation, and characterization of NT-releasing projections to BLA during Pavlovian fear and reward conditioning paradigms. Utilizing a combination of transgenic animal lines, optogenetic tools, and retrograde tracers, we will map this functional circuitry. CRISPR gene editing technology will enable assessment of the necessity of NT for functional associative learning. Photoidentification techniques will facilitate the contrasting of the electrophysiological activity of the NT input population to the general input population. Finally, we will photomanipulate NT neurons? activity directly to test if they are sufficient for valence encoding during associative learning. This innovative integration of cutting-edge approaches allows us to, for the first time, map out the dynamics and function of this neuropeptidergic input to BLA during associative learning. The findings from this work will greatly advance our understanding of a mechanism for valence encoding and increase knowledge of the functional role of a neuropeptide that may have pharmacotherapeutic possibilities.