Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
Microbiome and Host Health, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia.
J Affect Disord. 2024 Oct 15;363:520-531. doi: 10.1016/j.jad.2024.07.143. Epub 2024 Jul 21.
Compulsive- and anxiety-like behaviour can be efficiently modelled in SAPAP3 knockout (KO) mice, a preclinical model of relevance to obsessive-compulsive disorder (OCD). Although there is emerging evidence in the clinical literature of gastrointestinal dysfunction in OCD, no previous studies have investigated gut function in preclinical models of relevance to OCD. Similarly, the effects of voluntary exercise (EX) or environmental enrichment (EE) have not yet been explored in this context.
We comprehensively phenotyped the SAPAP3 KO mouse model, including the assessment of grooming microstructure, anxiety- and depressive-like behaviour, and gastrointestinal function. Mice were exposed to either standard housing (SH), exercise (EX, provided by giving mice access to running wheels), or environmental enrichment (EE) for 4 weeks to investigate the effects of enriched housing conditions in this animal model relevant to OCD.
Our study is the first to assess grooming microstructure, perseverative locomotor activity, and gastrointestinal function in SAPAP3 KO mice. We are also the first to report a sexually dimorphic effect of grooming in young-adult SAPAP3 KO mice; along with changes to grooming patterning and indicators of gut dysfunction, which occurred in the absence of gut dysbiosis in this model. Overall, we found no beneficial effects of voluntary exercise or environmental enrichment interventions in this mouse model; and unexpectedly, we revealed a deleterious effect of wheel-running exercise on grooming behaviour. We suspect that the detrimental effects of experimental housing in our study may be indicative of off-target effects of stress-a conclusion that warrants further investigation into the effects of chronic stress in this preclinical model of compulsive behaviour.
强迫和焦虑样行为可以在 SAPAP3 敲除（KO）小鼠中得到有效模拟，这是一种与强迫症（OCD）相关的临床前模型。尽管临床文献中有胃肠道功能障碍与 OCD 相关的新兴证据，但以前没有研究调查过 OCD 相关临床前模型中的肠道功能。同样，自愿运动（EX）或环境丰富（EE）的影响在这种情况下也尚未被探索。
我们全面表型分析了 SAPAP3 KO 小鼠模型，包括梳理微观结构、焦虑和抑郁样行为以及胃肠道功能的评估。将小鼠暴露于标准饲养（SH）、运动（EX，通过给予小鼠跑步轮使用权来提供）或环境丰富（EE）中 4 周，以研究丰富饲养条件对 OCD 相关动物模型的影响。
我们的研究首次评估了 SAPAP3 KO 小鼠的梳理微观结构、持续运动活动和胃肠道功能。我们也是首次报道了年轻成年 SAPAP3 KO 小鼠梳理行为存在性二态性效应；同时，在没有肠道菌群失调的情况下，该模型中还出现了梳理模式的变化和肠道功能障碍的指标。总体而言，我们在这种小鼠模型中没有发现自愿运动或环境丰富干预的有益效果；而且出人意料的是，我们发现轮跑运动对梳理行为有有害影响。我们怀疑我们研究中实验性饲养的有害影响可能表明应激的非靶向效应，这一结论需要进一步研究慢性应激对这种强迫行为的临床前模型的影响。
