The Modulation Of Retinoic Acid Signal On The Corticotrophin-releasing Factor In The Hypothalamic Paraventricular Nucleus And Its Possible Involvement In The Pathogenesis Of Depression

Depression is one of the common as well as complicated clinical mental diseases with the morbility becoming higher these years, which causes great social burden and economic loss. It is hard but much meaningful work to clarify the pathogenesis of depression and its pathological progress. Until now the etiology and neurobiology of depression are unclear. The hypothalamic-pituitary-adrenal axis (HPA axis) is thought as the final common pathway of depression and plays an important role in the pathogenesis of depression. The corticotrophin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus are the key central driving force of HPA axis and regulate the activity of the HPA axis. The hypothalamic CRF neurons in depressed patients are much more than those in normal persons and the HPA axis is obviously over-activated. The control of hypothalamic CRF neurons is complex at multi levels with many ligands and receptors involved in. Our recent work has indicated that the imbalance of multi paired receptors, including CRF receptors (CRFR), sex hormone receptors, glucocorticoid receptor (GR) and mineralcorticoid receptor (MR), may be the cause of the hyperactivity of CRF neurons in depressed patients. The homeostatic state of the multi paired receptors system and its disruption might be closely related to the pathogenesis of depression.Retinoids are usually applied in clinic for the treatment of dermatogic diseases and tumors. However, it has been reported that many depression-like neuropsychiatric side effects appeared with the use of this kind of medicine, suggesting that retinoids may be involved in the pathogenesis of mood disorders. The potential influence of retinoic acid signaling on the hypothalamic CRF neurons has not been investigated before. The aim of the present study is to demonstrate the possible regulation of CRF neurons as well as HPA axis by retinoic acid in vivo and the inner molecular mechanisms. We found that chronic treatment (6 weeks) with the bioactive retinoid, all-trans retinoic acid (ATRA), caused anxiety-like behavior and decreased spontaneous exploratory activities in young rats. Furthermore, chronic ATRA treatment increased basal serum corticosterone concentration as well as the thickness of adrenal cortex in young rat. The expression of CRF and retinoic acid receptorα(RARα) in the hypothalamus was both markedly increased in ATRA-treated rats compared with vehicle. We also observed that the balance of multi paired receptors was disrupted in the hypothalamus, hippocampus and the prefrontal cortex in chronic ATRA-treated rats. On the other hand, we found that RARαexists in the CRF neurons in some mood-related brain areas in normal adult rats. The above results suggest that retinoic acid signaling pathway may play an important part in the development of mood disorders by influencing the activity of hypothalamic CRF neurons as well as HPA axis and the multi paired receptors in the brain may be the inner mediating system. Retinoic acid signaling and its regulation of CRF neurons might be closely involved in the pathogenesis of depression. We also find that RARαis mainly in the cytoplasm of the hippocampus neurons in normal adult rats. Moreover, chronic RARα-selective antagonist administration with low dose significantly reduced the immobile time in the forced swimming test in adult rats. These data indicate that retinoic acid signaling may modulate CRF neurons indirectly through influencing the activity of hippocampus neurons or monoamine neurotransmitter systems. Our work offers a new thinking for the pathogenesis of depression and helps us further understand the nature of stress response. It may also provide neurobiological basis for looking for new antidepressant drugs as well as therapeutic targets.