Orexin’s role in mouse behavioral endophenotypes for schizophrenia

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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.