Abstract
Orexin-A (OX-A) and orexin-B (OX-B) are neuropeptides produced in the hypothalamus. Preclinical and clinical studies suggest that depression and anxiety are associated with the orexin system. In the current study, we used the learned helplessness (LH) animal model of depression to identify rats displaying LH behaviors (LH rats) and those that did not (No-LH rats). We compared the number of orexin-containing neurons in the hypothalamus of LH, No-LH, and control rats. Orexin peptides, orexin receptor 1 (OXR1) and 2 (OXR2) in brain areas involved in major depression and serum OX-A and corticosterone (CORT) concentrations were quantified and compared between rat groups. We found that LH and No-LH rats displayed higher serum OX-A concentrations compared with control rats. Comparison between LH and No-LH rats revealed that No-LH rats had significantly higher OX-A levels in the brain, more OX-A neurons, and more OX-A neuron activation. LH rats had more OX-B neurons and more OX-B neuron activation. Orexin peptides and receptors in the brain areas involved in major depression exhibited different patterns in LH and NoLH rats. Our findings revealed that activation of OX-A neurons could promote resilient behaviors under stressful situations and OX-A and OX-B neuropeptides exhibit dissimilar functions in LH behaviors.
Highlights
IntroductionOrexins ( known as hypocretins) include orexin A (OX-A) and orexin B (OX-B) neuropeptides produced by a population of neurons located in the hypothalamus that encompasses the lateral hypothalamus, dorsomedial hypothalamus, and perifornical hypothalamus
The first hint of a potential link between the orexin system and major depression was derived from the clinical observation that the oscillating amplitude of the orexin A (OX-A) concentration in the cerebrospinal fluid (CSF) during the diurnal cycle was significantly reduced in patients with major depression compared with that in healthy controls, but the mean OX-A level tended to be higher in patients with depression than in controls [11]
These results indicated that rats that did not display helplessness behaviors had more OX-A–positive neuron activation in the hypothalamus, whereas rats that displayed helplessness behaviors had greater orexin B (OX-B)–positive neuron activation
Summary
Orexins ( known as hypocretins) include orexin A (OX-A) and orexin B (OX-B) neuropeptides produced by a population of neurons located in the hypothalamus that encompasses the lateral hypothalamus, dorsomedial hypothalamus, and perifornical hypothalamus. Orexin peptides act on two differentially distributed G-protein–coupled receptors, OXR1 and OXR2, throughout the brain [2,3]. Since their discovery in 1998, these neuropeptides have been linked with several physiological functions, including appetite and sleep [4,5,6,7]. An orexin genotype study of patients with depression revealed that a polymorphism (Ile408Val) in the OXR1 gene HCRTR1 significantly differed between cases and controls [14]. Despite clinical studies indicating considerable variation, sufficient evidence exists to suggest that dysregulation of the orexin system could play a role in depressive disorder
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