Inhibition of Slc17a7 expressing neurons in the basolateral amygdala which project to the nucleus accumbens shapes the fidelity of motivated behavior

Abstract

Adaptive behavior depends on the ability to form predictive associations between environmental cues and biologically relevant outcomes. Classical models posit that projections from the basolateral amygdala (BLA) to the nucleus accumbens (NAc) promote reward seeking, whereas projections to the central amygdala facilitate defensive responding. However, accumulating evidence indicates that molecular identity and inhibitory dynamics introduce additional layers of functional heterogeneity within these pathways. Genetically defined subsets of BLA[->]NAc neurons can drive either reward-related or aversive behaviors, and single-cell imaging studies show that cue-responsive BLA ensembles undergo an inhibitory shift as conditioning progresses. How these molecular and inhibitory mechanisms interact within defined projections to shape motivated behavior remains unclear. To address this, we examined Vglut1-expressing BLA[->]NAc neurons (Vglut1BLA[->]NAc), the predominant excitatory population within this pathway. Whole-cell electrophysiology revealed that reward conditioning increases inhibitory synaptic input onto Vglut1BLA[->]NAc neurons and reduces intrinsic excitability. Using a dual-recombinase chemogenetic strategy, we found that selective inhibition of this projection enhances acquisition of a cued reward task, increases instrumental reward seeking, and elevates reward valuation in a two-choice preference assay. Similar enhancement was observed in a fear-discrimination task, where inhibition of Vglut1BLA[->]NAc neurons improved differentiation between threat- and safety-associated cues. These findings identify inhibitory regulation of Vglut1BLA[->]NAc neurons as a key mechanism that strengthens stimulus-outcome associations. By demonstrating that conditioning-associated inhibitory plasticity modulates this major BLA output pathway, the work refines prevailing models of BLA[->]NAc function and highlights inhibition as an important contributor to the fidelity of motivated behavior.