Orexin’s role in mouse behavioral endophenotypes for schizophrenia

食欲素系统主要以其在调节进食和促进清醒方面的重要作用而闻名。然而，食欲素系统也投射到与上述功能无关的大脑区域，这意味着它的作用比之前假设的要复杂得多。这一观点得到了动物研究的支持——部分来自我们的团队——研究表明，食欲素系统参与了其他一些行为和生理过程，如情绪、奖励、社交和认知。对嗜睡症（即食欲素神经元缺失）或精神分裂症患者的人体研究进一步表明，食欲素系统与几种精神症状之间存在联系。例如，嗜睡症和精神分裂症有一些共同的症状，如幻觉，血浆促食欲素水平的改变与精神分裂症的特定症状有关，用抗精神病药治疗会影响大脑促食欲素水平。基于这些发现，我们提出了食欲素系统在精神分裂症的行为内表型中起作用的假设。在目前的提议中，我们将通过对不同行为范式小鼠的食欲素系统的遗传、药理学和化学遗传学操作来解决这一假设。在这些范例中，将测试与精神分裂症的阳性、阴性、情感和认知症状相关的行为内表型。首先，实验将在缺乏食欲素的小鼠中进行，这将有助于了解嗜睡症的精神病症状。然后，我们将局部抑制食欲素在野生型小鼠特定大脑区域的传递，以便更好地了解潜在的神经机制。最后，我们将激活食欲素系统，并研究这种激活是否能逆转精神分裂症样内表型。总之，拟议的研究将扩大我们对食欲素脑系统及其在精神分裂症行为内表型中的作用的理解。我们希望我们的数据将有助于改进精神分裂症和嗜睡症的药物治疗的发展。

The orexin system is mainly known for its important role in mediating feeding and promoting wakefulness. However, the orexin system also projects to brain areas that are not involved in the aforementioned functions implying a more complex role as previously assumed. This idea is supported by animal studies – partly from our group – revealing that the orexin system participates in several other behavioral and physiological processes such as emotions, reward, sociability, and cognition. Human studies in patients with narcolepsy (i.e. with a loss of orexin neurons) or with schizophrenia further indicate connections between the orexin system and several psychiatric symptoms. For example, narcolepsy and schizophrenia share some symptoms such as hallucinations, altered plasma orexin levels are associated with particular symptoms of schizophrenia, and treatment with neuroleptics influences brain orexin levels.Based on all these findings, we propose the hypothesis that the orexin system plays a role in behavioral endophenotypes for schizophrenia. In the present proposal, we will address this hypothesis using genetic, pharmacological and chemogenetic manipulations of the orexin system in mice submitted to different behavioral paradigms. In these paradigms, behavioral endophenotypes will be tested which are associated with the positive, negative, affective and cognitive symptoms of schizophrenia. First, experiments will be performed in orexin-deficient mice which will help to understand psychotic symptoms in narcolepsy. Then, we will locally inhibit orexin transmission in particular brain areas in wildtype mice in order to better understand the underlying neural mechanisms. Last, we will activate the orexin system and investigate whether this activation reverse schizophrenia-like endophenotypes.Taken together the proposed study will expand our understanding of the orexin brain system and its role in behavioral endophenotypes of schizophrenia. We hope that our data will contribute to the development of improved pharmacological therapies of schizophrenia and narcolepsy.