Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression

• Published in: EBioMedicine Vol. 18; no. C; pp. 311 - 319
• Main Authors: Lu, Jing, Zhao, Juan, Balesar, Rawien, Fronczek, Rolf, Zhu, Qiong-Bin, Wu, Xue-Yan, Hu, Shao-Hua, Bao, Ai-Min, Swaab, Dick F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2017; Elsevier
• Subjects: Advanced Basic Science; Aged; Aged, 80 and over; Animals; Bipolar Disorder - metabolism; Bipolar Disorder - pathology; Corticosterone - blood; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Depression; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - pathology; Disease Models, Animal; Female; Gyrus Cinguli - metabolism; Humans; Hypocretin; Hypocretin receptors; Hypothalamus; Hypothalamus - metabolism; Immunohistochemistry; Internal Medicine; Male; Middle Aged; Orexin Receptors - genetics; Orexin Receptors - metabolism; Orexins - genetics; Orexins - metabolism; Prefrontal Cortex - metabolism; Protein Precursors - metabolism; Rats; Rats, Sprague-Dawley; Research Paper; RNA, Messenger - metabolism; Sex Characteristics; Sex difference; Depression; Hypothalamus; Hypocretin receptors; Sex difference; Hypocretin
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.03.043

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. 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. 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. 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. •Hypocretin (orexin) changes were studied in human postmortem brain in depression.•A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression.•A rat depression model did not reflect the changes in the hypocretin system in the human brain in depression. The stress systems of depressed patients are put into a higher gear by genetic and developmental factors. Over-reaction of these systems to stressful environmental situations makes people vulnerable to depression and suicide. This is the first postmortem study on changes in a relatively novel stress system in depression, consisting of the hypothalamic hypocretin neurons and hypocretin receptors in the prefrontal cortex. A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. Evaluation of the hypocretin system in a frequently used depression animal model, i.e. chronic unpredictable mild stress rats, did not replicate changes found in the hypocretin systems in the human brain in depression.