The role of retino-raphe projection in light therapy for non-seasonal depression

Abstract

Objective: Depression, a serious mental disorder, often leads to insomnia, depressed mood, chronic disability and even suicide. Recently, clinical trials demonstrated that bright light therapy was not only effective for seasonal affective disorder (SAD) but also working for non-seasonal depression. However, little is known about the mechanism. Our previous study indicated that light signals transmitted into dorsal raphe nucleus (DRN) through retino-raphe projection which can modulate serotonin (5-HT) production and affective behavior. Thus we hypothesize that the retino-raphe projection plays a vital role in the light therapy for non-seasonal depression.

Methods: Sprague Dawley rats with daily injection of 40 mg/kg corticosterone (CORT, stress hormone) for 2 weeks were established as a model of non-seasonal depression. Their behavior can be evaluated by forced swim test, sucrose preference test and antidepressant sensitivity of fluoxetine. Light-emitting diodes (LEDs) light including blue light (470 nm) and full white light were chosen as light therapy for those stressed rats with 30 minutes each morning for 7 days.

Results: Using anterograde and retrograde injection of cholera toxin subunit B (CTB), the DRN-projecting retinal ganglion cells (RGCs) were demonstrated a bit diverse, including ON / OFF alpha cells (~72%) and M1 / M2 melanopsin cells (~9%). The light therapy was effective in reversing the depressive-like responses of those stressed rats. In particular, the blue light therapy with 400 lux for 7 days exerted the efficacy similar to the fluoxetine treatment for 14 days. It was implicated that light therapy had a relatively rapid antidepressant effect. It was further found that the c-Fos positive cells in ganglion cell layer were remarkably increased with light therapy particularly using the blue light. While in the DRN the expression levels of c-Fos and phosphorylated cyclic AMP response element binding protein (p-CREB) were lower dramatically in the blue light-treated group. The decline of p-CREB in DRN supported the result of a decrease of c-Fos expression since p-CREB is upstream of c-Fos. Interestingly, the c-Fos positive serotonergic neurons in the DRN remained no change, just approximately 4% of total serotonergic neurons, during the corticosterone administration and light therapy. However, the c-Fos expression of the GABAergic interneurons in the lateral regions of DRN was significantly increased with corticosterone administration, which could lead to the inhibition of 5-HT synthesis. While the activation of GABAergic interneurons was almost reversed to a basal line using the blue light therapy for a week. The elimination of the retino-raphe projection via a saporin treatment significantly attenuated the antidepressant effect achieved by light therapy on those stressed rats.

Conclusion: Depressive behavior of rat model, caused by high dosage of stress hormone, can be reversed by light therapy especially the blue light therapy. The retino-raphe projection plays a critical role in the light therapy for those rats with non-seasonal depression. The activation of GABAergic interneurons with c-Fos expression in the DRN involved in inducing the inhibition of 5-HT neuronal activity and subsequent depressive behavior. Whereas light therapy through retino-raphe projection deactivated the GABAergic interneurons, which eventually contributed to the antidepressant effect.