Low Jac Kee, Ambikairajah Ananthan, Shang Kani, Brown David A, Tsai Vicky W W, Breit Samuel N, Karl Tim
Neuroscience Research Australia (NeuRA), Randwick, New South Wales, Australia.
School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia.
PLoS One. 2017 Jan 12;12(1):e0168416. doi: 10.1371/journal.pone.0168416. eCollection 2017.
Macrophage inhibitory cytokine-1 (MIC-1), also known as growth differentiation factor 15 (GDF15), is a stress response cytokine. MIC-1/GDF15 is secreted into the cerebrospinal fluid and increased levels of MIC-1/GDF15 are associated with a variety of diseases including cognitive decline. Furthermore, Mic-1/Gdf15 knockout mice (Mic-1 KO) weigh more, have increased adiposity, associated with increased spontaneous food intake, and exhibit reduced basal energy expenditure and physical activity. The current study was designed to comprehensively determine the role of MIC-1/GDF15 on behavioural domains of male and female knockout mice including locomotion, exploration, anxiety, cognition, social behaviours, and sensorimotor gating. Mic-1 KO mice exhibited a task-dependent increase in locomotion and exploration and reduced anxiety-related behaviours across tests. Spatial working memory and social behaviours were not affected by Mic-1/Gdf15 deficiency. Interestingly, knockout mice formed an increased association with the conditioned stimulus in fear conditioning testing and also displayed significantly improved prepulse inhibition. Overall sex effects were evident for social behaviours, fear conditioning, and sensorimotor gating. This is the first study defining the role of Mic-1/Gdf15 in a number of behavioural domains. Whether the observed impact is based on direct actions of Mic-1/Gdf15 deficiency on the CNS or whether the behavioural effects are mediated by indirect actions on e.g. other neurotransmitter systems must be clarified in future studies.
巨噬细胞抑制细胞因子-1（MIC-1），也称为生长分化因子15（GDF15），是一种应激反应细胞因子。MIC-1/GDF15分泌到脑脊液中，其水平升高与包括认知衰退在内的多种疾病相关。此外，Mic-1/Gdf15基因敲除小鼠（Mic-1 KO）体重更重，肥胖增加，伴有自发性食物摄入量增加，且基础能量消耗和体力活动减少。本研究旨在全面确定MIC-1/GDF15对雄性和雌性基因敲除小鼠行为领域的作用，包括运动、探索、焦虑、认知、社交行为和感觉运动门控。Mic-1 KO小鼠在运动和探索方面表现出任务依赖性增加，并且在各项测试中与焦虑相关的行为减少。空间工作记忆和社交行为不受Mic-1/Gdf15缺乏的影响。有趣的是，基因敲除小鼠在恐惧条件反射测试中与条件刺激形成的关联增加，并且其前脉冲抑制也显著改善。社交行为、恐惧条件反射和感觉运动门控方面存在明显的总体性别效应。这是第一项确定Mic-1/Gdf15在多个行为领域作用的研究。观察到的影响是基于Mic-1/Gdf15缺乏对中枢神经系统的直接作用，还是行为效应由对其他神经递质系统等的间接作用介导，必须在未来的研究中加以阐明。
