title: Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression.
abstract: BACKGROUND
  Neurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects.
  
  
  METHODS
  We quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat.
  
  
  RESULTS
  i) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats.
  
  
  CONCLUSIONS
  The clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Mental Disorder's Management, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China; Zhejiang Province Key Laboratory of Mental Disorder's Management, Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Rawien
authors.initials: R
authors.lastname: Balesar
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rolf
authors.initials: R
authors.lastname: Fronczek
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Mental Disorder's Management, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Qiong-Bin
authors.initials: QB
authors.lastname: Zhu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Mental Disorder's Management, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Wu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Mental Disorder's Management, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China; Zhejiang Province Key Laboratory of Mental Disorder's Management, Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Hu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Mental Disorder's Management, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China. Electronic address: baoaimin@zju.edu.cn.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Bao
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Mental Disorder's Management, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China; Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Dick F
authors.initials: DF
authors.lastname: Swaab
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001714:Bipolar Disorder / Q000378:metabolism / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D003865:Major Depressive Disorder / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism; D000068797:Orexins / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics
chemical_list: D064446:Orexin Receptors; D000068797:Orexins; D011498:Protein Precursors; D012333:RNA, Messenger; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: Depression; Hypocretin; Hypocretin receptors; Hypothalamus; Sex difference