Reductionist's madness ─ a Bayesian approach to investigate the possible role of AKT1 in the dopamine hypothesis of schizophrenia
Date Issued
2010
Date
2010
Author(s)
Chen, Yao-Chu
Abstract
The current research aims to investigate how the schizophrenia candidate gene Akt1 (protein kinase Bα) participates in functions of the dopamine system, and further to identify its role in the dopamine hypothesis of schizophrenia. According to recent findings, AKT is found to be a downstream regulator under dopamine D2 receptor, and participates in antipsychotics remedy by acting as an intermediate in the antipsychotics-induced signaling cascade. The dopamine hypothesis of schizophrenia emphasized that psychosis is resulted from excessive dopamine concentration in the striatum, furthermore, antipsychotics mitigates psychosis by acting on dopamine D2 receptors. Recent theory, based on the view that brain is a Bayesian inference machine, regards psychosis is related to disruptions in the reward prediction error (RPE) signal produced by the midbrain dopamine system. Based on these findings, we hypothesized that if AKT1 is involved in the pathogenesis of psychosis, the RPE signal should be different in magnitude between Akt1 deficient and normal mice. In experiment 1, we estimated parameters in the reinforcement learning model by utilizing the behavioral data collected from a dynamic foraging T maze task perform by male Akt1 heterozygous (HET) and wildtype (WT) mice in order to infer the reward prediction error magnitude. The results showed that, compared with WT littermates, Akt1 HET exhibits higher reward prediction error magnitude among all three testing sections. In experiment2, consistent with the prediction of higher RPE magnitude, Akt1 HET mice learned more rapidly than WT mice in reward-related tasks. Revealed by the Western blots analysis, a reduction of methamphetamine-induced phosphorylated AKT1 was found in the ventral and dorsal striatum of Akt1 HET mice but not in WT controls, indicating the activity of AKT1 is indeed related to dopamine. Matching law analysis further revealed that Akt1 HET mice have higher reward sensitivity compared with WT controls. Finally, in experiment 3, revealed by latent inhibition paradigm, we showed that higher RPE signal cannot predict performance in an aversive-based behavioral paradigm. Our study suggests that, AKT1 might participate in the pathogenesis of psychosis by regulating the RPE magnitude in the dopamine system.
Subjects
schizophrenia
dopamine
reward prediction error
Bayesian inference
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