Voluntary exercise improves cognitive deficits in female dominant-negative DISC1 transgenic mouse model of neuropsychiatric disorders

<b>Objectives:</b> Physical exercise has gained increasing interest as a treatment modality that improves prognosis in psychiatric patients. The disrupted in schizophrenia 1 (DISC1) gene is a candidate gene for major mental illness. In this study, we aimed to determine whether voluntary wheel running can improve cognitive deficits of dominant-negative DISC1 transgenic mice (DN-DISC1). <b>Methods:</b> DN-DISC1 and control mice (10-week-old male and female) were placed for 14 days in a cage with or without access to a running wheel. Two weeks later, mice underwent behavioural tests evaluating cognition and social approach and recognition. <b>Results:</b> Voluntary exercise improved performance in the novel object recognition test, restored the impairment in spatial memory in the Y maze, and reversed the deficit in social recognition memory in DN-DISC1 females. DN-DISC1 males did not exhibit behavioural deficits at baseline. Tissue analysis revealed that exercise induced a significant increase in hippocampal expression of doublecortin (DCX), brain-derived neurotrophic factor (BDNF) and cannabinoid receptor type 1 (CB1R) only in DN-DISC1 females. <b>Conclusions:</b> Voluntary exercise is beneficial in attenuating cognitive deficits observed in a rodent model relevant for neuropsychiatric disorders. The data add a preclinical aspect to the accumulating clinical data supporting the incorporation of physical exercise to patients’ care.

**研究目标：** 体育锻炼作为改善精神疾病患者预后的治疗手段，日益受到学界关注。精神分裂症断裂基因1（disrupted in schizophrenia 1, DISC1）是重型精神疾病的候选易感基因。本研究旨在探究自愿跑轮运动能否改善显性负性DISC1转基因小鼠（dominant-negative DISC1 transgenic mice, DN-DISC1）的认知缺陷。
**研究方法：** 将10周龄的雌雄DN-DISC1小鼠与对照小鼠置于带有或不带有跑轮的笼中饲养14天。两周后，对小鼠开展行为学实验，以评估其认知能力、社交趋近与社交识别能力。
**研究结果：** 自愿运动可提升小鼠在新物体识别实验中的表现，修复Y型迷宫实验中观察到的空间记忆损伤，并逆转DN-DISC1雌性小鼠的社交识别记忆缺陷。而DN-DISC1雄性小鼠在基线状态下未表现出行为学缺陷。组织学分析显示，仅在DN-DISC1雌性小鼠中，运动可显著提升海马区双皮质素（doublecortin, DCX）、脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）以及1型大麻素受体（cannabinoid receptor type 1, CB1R）的表达水平。
**研究结论：** 自愿运动可有效减轻该神经精神疾病相关啮齿类动物模型的认知缺陷。日益积累的临床数据支持将体育锻炼纳入患者的诊疗护理方案，本研究为该方向补充了临床前研究维度。