The role of dorsomedial striatum and parvalbumin interneurons in schizophrenia-related cognitive deficits: insights from disrupted strategic decision-making in Akt1 heterozygous mice.

Schizophrenia, a debilitating disorder with genetic and neurobiological underpinnings, often manifests cognitive deficits, including impaired decision-making. Utilizing Akt1 heterozygous mutant (HET) mice as a model, which mimic schizophrenia due to AKT1's implication as a susceptibility gene, we investigated the involvement of Akt1 and its neural mechanisms influencing strategic decision-making to identify potential therapeutic targets for schizophrenia-associated cognitive impairments. In six experiments, we first revealed that lesions targeting the dorsomedial striatum (DMS) significantly impacted performance in a mouse version of the two-choice probabilistic decision-making task, surpassing effects observed in other striatal subregions. Behavioral assessments in HET mice unveiled notable disturbances, including reduced accumulated trials to reach criteria, diminished ratio of lose-stay behavior, elevated learning rates, and decreased choice consistency in reinforcement learning models. Moreover, we found a strong correlation between DMS local field potential power and choice outcome, particularly evident in no-reward condition. The behavioral abnormalities observed in HET mice were restored when the DMS was chemogenetically inhibited, while their locomotor activity remained unaffected. Furthermore, RNA-seq analysis and immunohistochemistry uncovered a decrease in the number of striatal parvalbumin (PV) interneurons in HET mice. Targeted lesioning of PV interneurons in the DMS of wild-type mice resulted in behavioral alterations mirroring those in HET mice. In summary, our findings suggest that Akt1 deficiency-induced downregulation of PV expression alters neural oscillations in the DMS, influencing choice strategies, especially in no-reward condition during probabilistic decision-making. These results underscore the crucial involvement of AKT1 and PV interneurons in modulating strategic decision-making, with particular relevance to the understanding of schizophrenia.