Harris Tatiyana, Bugescu Raluca, Kelly Jaylyn, Makela Anna, Sotzen Morgan, Sisk Cheryl, Atkin Graham, Pratt Rebecca, Crockett Elahé, Leinninger Gina
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Neuroscience Program, Department of Psychology, Michigan State University, East Lansing, MI 48824, USA.
Brain Sci. 2020 Dec 12;10(12):975. doi: 10.3390/brainsci10120975.
Lateral hypothalamic area (LHA) neurons expressing the neuropeptide orexin (OX) are implicated in obesity and anxio-depression. However, these neurons release OX as well as a host of other proteins that might contribute to normal physiology and disease states. We hypothesized that delta-like homolog 1 (DLK1), a protein reported to be co-expressed by all OX neurons, contributes to the regulation of energy balance and/or anxio-depression. Consistent with previous reports, we found that all rat OX neurons co-express DLK1. Yet, in mice and humans only a subset of OX neurons co-expressed DLK1. Since human OX-DLK1 distribution is more similar to mice than rats, mice are a comparable model to assess the human physiologic role of DLK1. We therefore used a viral lesion strategy to selectively delete DLK1 within the LHA of adult mice (DLK1) to reveal its role in body weight and behavior. Adult-onset DLK1 deletion had no impact on body weight or ingestive behavior. However, DLK1 mice engaged in more locomotor activity than control mice and had decreased anxiety and depression measured via the elevated plus maze and forced swim tests. These data suggest that DLK1 expression via DLK1-expressing OX neurons primarily contributes to anxio-depression behaviors without impacting body weight.
表达神经肽食欲素（OX）的下丘脑外侧区（LHA）神经元与肥胖和焦虑抑郁有关。然而，这些神经元会释放OX以及许多其他可能对正常生理和疾病状态有影响的蛋白质。我们推测，δ样同源物1（DLK1），一种据报道在所有OX神经元中共同表达的蛋白质，有助于调节能量平衡和/或焦虑抑郁。与之前的报道一致，我们发现所有大鼠OX神经元都共同表达DLK1。然而，在小鼠和人类中，只有一部分OX神经元共同表达DLK1。由于人类OX-DLK1的分布与小鼠比与大鼠更相似，小鼠是评估DLK1在人类生理作用的可比模型。因此，我们使用病毒损伤策略选择性地删除成年小鼠LHA内的DLK1（DLK1基因敲除小鼠），以揭示其在体重和行为中的作用。成年期开始删除DLK1对体重或摄食行为没有影响。然而，DLK1基因敲除小鼠比对照小鼠有更多的自发活动，并且通过高架十字迷宫和强迫游泳试验测量，其焦虑和抑郁程度有所降低。这些数据表明，通过表达DLK1的OX神经元表达的DLK1主要影响焦虑抑郁行为，而不影响体重。
