Optogenetic Inhibition of the Direct and Indirect Pathways of the Nucleus Accumbens Induces a Sensitivity Effect in a Memory-Based Virtual Navigation Task

Abstract

Study of the nucleus accumbens (NAc) has focused primarily on its role in reward processing and neuropsychiatric disorders like addiction and depression. However, the projections to the nucleus accumbens, such as those from the medial prefrontal cortex and ventral hippocampus, suggest that it may also play a role in cognitive computations like evidence accumulation or memory retention. The present study investigates the role of the direct and indirect pathways in decision making through optogenetic inhibition of D1R and D2R/A2aR receptor-expressing medium spiny neurons (MSNs), respectively, in the nucleus accumbens. Our decision-making task, which mimics the complex contexts of real-world decisions, requires the animals to navigate in virtual reality, to accumulate evidence, and to retain this memory during a delay period to receive reward. Optogenetic inhibition of the direct and indirect pathways of the nucleus accumbens induced a sensitivity effect, impairing performance on moderately difficult trials and transforming a sigmoidal psychometric curve into a linear psychometric curve. Fluorescent in situ hybridization analysis revealed low D1R/D2R overlap in the nucleus accumbens core and shell, ruling out coactivation as an explanation for similar psychometric curve results in the direct and indirect pathways. In addition, optogenetic inhibition altered the weights of cues on the mouse’s decision, as determined by logistic regression analysis. The reduction of the weights of early cues during direct pathway inhibition and early and middle cues during indirect pathway inhibition indicates that the process of evidence accumulation may be altered by optogenetic inhibition. Behavioral differences between laser and control trials were not explained by differences in speed, excess travel, or trial duration, indicating that a cognitive process may be responsible. However, future work is required to determine if optogenetic effects on the psychometric curves result from motivational or memory-related deficits.