Orexins (also known as hypocretins) are two excitatory neuropeptides, including orexin-A (OX-A) and orexin B (OXB), produced by a small population of neurons located in the lateral hypothalamus, the dorsomedial hypothalamus, and the perifornical hypothalamus. The orexin neurons have projection fields widely distributed throughout the central nervous system, including several brain regions implicated in mood disorders. Recent studies reveal that in addition to feeding and sleep regulation orexin system is also involved in the modulation of autonomic and neuroendocrine function, energy regulation, reward and stress responses, and attention. There is an especially dense projection of orexin-containing terminals in locus coeruleus and raphe nucleus, both areas are important for sleep regulation. Orexins also play a role in positively regulating cognitive processes of attention and memory. In addition, orexin system modulates HPA axis stress response by directly stimulating corticotropin-releasing hormone (CRH)-synthesizing neurons in the paraventricular nucleus of the hypothalamus. The broad physiological functions and its extensive interaction with dopamine, serotonin, and norepinephrine systems made orexin a potential player in neuropsychiatric disorders. Both preclinical and clinical studies suggest orexin system is been associated addiction and mood disorders, including depression and anxiety. In the present study we investigated the correlation of orexin system and depression-like behaviors using learned helplessness animal model of depression. We compared the number of orexin neurons among rats that displayed learned helplessness behaviors following inescapable electrical shocks (LH rats), rat that did not display LH behaviors (NoLH rats), and non-shocked control rats. We also examined orexin peptides and receptors in brain areas involved in major depression and serum OX-A and corticosterone concentrations. We found that in comparison to control rats the shocked rats all showed higher OX-A concentrations in the serum. However, the NoLH rats had significantly higher serum OX-A levels comparing to that of the LH rats. The NoLH rats also had significantly more OX-A neurons than LH rats while the LH rats had more OX-B neurons. Among the brain areas examined the orexin peptides and receptors also displayed different changes in the LH and NoLH rats. The detailed study of orexin-A and orexin-B peptide concentrations and receptor distributions in various brain areas involved in depression could facilitate our understanding of the role of orexin system in major depression and contribute to our basic knowledge of orexin neuropeptides, particularly on their antagonizing function proposed in past literatures.
Audience take away:
- Serum orexin A level does not always show positive correlation with the orexin A change in brain areas involved in major depression
- Orexin A neuron might play a role in depression resilience
- The rats that displayed LH behaviors has higher activation of hypothalamic OX-B neurons. The orexin B peptide seems correlate with depression-like behavior
- More and more evidences indicate orexin system is involved in major depression pathophysiology