¹National Taiwan University, Department of Psychology, Taipei, Taiwan, ²National Taiwan University, Graduate Institute of Brain and Mind Sciences, Taipei, Taiwan

Background: Schizophrenia is characterized by pervasive cognitive impairments that emerge early in the illness and strongly predict functional outcomes. Among these deficits, disruptions in decision-making are consistently observed, suggesting abnormalities in reward-learning mechanisms. AKT1, a major schizophrenia susceptibility gene involved in dopamine signaling, shows reduced expression in patients and in Akt1-deficient mouse models, which display altered striatal function and abnormal reward updating. The striatum plays a central role in integrating feedback and guiding adaptive choices, yet its specific contribution to complex decision-making and its interaction with AKT1-related dysfunction remain insufficiently understood.

Aims & Objectives: Utilizing Akt1 heterozygous mutant (HET) mice as a model, which mimic schizophrenia due to AKT1’s implication as a susceptibility gene, we aimed to elucidate the role of Akt1 and its associated neural mechanisms in strategic reward-based decision-making and to identify region- and cell-type–specific targets relevant to cognitive impairments in schizophrenia.

Method: A set of six experiments examined decision-making in a mouse model of schizophrenia risk. Experiment 1 assessed the contribution of distinct striatal subregions using targeted lesions and computational model fitting in a two-choice probabilistic task (2C). Experiment 2 tested Akt1 HET mice to evaluate how reduced AKT1—a schizophrenia susceptibility gene—affects choice behavior and model parameters compared with wild-type controls. Experiment 3 recorded dorsomedial striatum (DMS) local field potentials during task performance to link neural dynamics to behavior. Experiment 4 applied chemogenetic inhibition of the DMS in HET and wild-type mice to establish causal effects on decision-making. Experiment 5 used striatal RNA sequencing and immunohistochemistry to identify gene-expression differences associated with altered behavior in HET mice. Experiment 6 selectively lesioned DMS parvalbumin interneurons to determine their role in regulating decision-making in the 2C task.

Results: Our results indicate: (1) Lesions in the DMS notably disrupted performance in the 2C task more than other striatal subregions (Experiment 1). (2) HET mice displayed aberrant behaviors in the 2C task compared to their wild-type littermates (Experiment 2). (3) The power of local field potential in the DMS is highly correlated with no-reward condition (Experiment 3). (4) Observed behavioral abnormalities in HET mice were restored by DMS inhibition (Experiment 4). (5) RNA-seq analysis and immunohistochemistry data highlight unique expression of striatal parvalbumin (PV) interneurons in HET mice (Experiment 5). (6) Selective lesion of PV interneurons in the DMS of DTA-treated PV-Cre mice disrupted choice behaviors as observed in HET mice (Experiment 6).

Discussion & Conclusions: Together, these findings demonstrate that reduced Akt1 signaling disrupts reward-guided decision-making by altering strategic choice patterns, feedback processing, and associated neural computations. The results highlight the dorsomedial striatum—and specifically its PV interneuron population—as a critical substrate through which Akt1 modulates probabilistic choice behavior, particularly under no-reward conditions. This study provides mechanistic insight into how AKT1-related dysfunction contributes to cognitive deficits in schizophrenia and identifies potential region- and cell-type–specific targets for therapeutic intervention.