Hisayoshi Kubota

Schizophrenia is a psychiatric disorder characterized by positive, negative, and cognitive symptoms. MK-801, an N-methyl-D-aspartate receptor antagonist, has been used to induce schizophrenia-like behaviors in animal models. Here, we employed IntelliCage, an automated system used for tracking behavior, to assess schizophrenia-like behaviors in MK-801-treated mice under semi-naturalistic conditions. Mice that had been treated with MK-801 for 2 weeks were analyzed for locomotion, emotional, and cognitive functions. Repeated MK-801-treated mice exhibited transient hyperactivity in a novel environment, without significant changes in overall circadian activity. Sucrose preference remained intact, suggesting preserved reward sensitivity. However, less time spent in the corner during the early phase of the competition test indicated reduced competitive behavior for limited water rewards. In the behavioral flexibility test, repeated MK-801-treated mice showed impaired reversal learning, suggesting reduced cognitive flexibility, although the acquisition of initial place discrimination was comparable to that observed in control mice. These behavioral impairments parallel core symptoms of schizophrenia, particularly in the social and cognitive domains. Our findings demonstrate the utility of IntelliCage in detecting behavioral phenotypes over prolonged periods in group-housed settings. This study provides an ecologically valid platform for assessing schizophrenia-like behaviors and may facilitate the development of translationally relevant therapeutic interventions.

Background and Purpose Alterations in tryptophan‐kynurenine (TRP‐KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3‐monooxygenase (KMO) induces depression‐like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP‐KYN pathway in stress‐induced behavioural changes and the regulation of the HPA axis. Experimental Approach Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP‐KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS‐induced behavioural changes and an increase in serum corticosterone (CORT) concentration. Key Results CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo^+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short‐term CUMS. Nicotine attenuated CUMS‐induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin‐releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine. Conclusions and Implications CUMS‐induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.