Neural Basis of Light-dependent Depression and Anxiety

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Seasonal affective disorder (SAD) is a major depressive disorder affecting millions of Americans, who suffer recurring symptoms of depression and anxiety in the winter. Empirical evidence suggests that the depressive episodes are caused by insufficient light exposure during the winter months, but how changes in environmental lighting conditions lead to fluctuations in affective state remains largely unknown. This gap in knowledge presents an important problem for successfully identifying risk factors and biological diagnostic markers for SAD, as well as for developing more effective therapeutic strategies. The long-term goal of this research is to understand the brain mechanisms mediating the effects of light on mood and anxiety. The objective of the proposed work is to identify the role of central orexinergic pathways in mediating light- dependent fluctuations in affective state. The proposed work will utilize the diurnal grass rat (Arvichantis niloticus), an animal model of SAD recently developed in the PI's group. There are substantial differences between nocturnal and diurnal species in their circadian rhythms and central responses to light. Therefore, a diurnal model is of crucial importance for elucidating the fundamental mechanisms critically underlying SAD in the diurnal human. The central hypothesis to be tested in this proposal is that light regulates mood and anxiety by acting on brain pathways containing the neuropeptide, orexin. Using the grass rat model of SAD, the proposed work contains three Specific Aims: 1) To determine the effects of light on orexin and its receptors in the diurnal grass rat model of SAD, 2) To test the hypothesis that bright light alleviates depression- and anxiety-like behaviors via enhancing the orexinergic pathways in the diurnal grass rats, and 3) To identify the downstream targets of orexinergic pathways in alleviating depression- and anxiety-like behaviors with a focus on the 5-HTergic dorsal raphe. The project is innovative because it utilizes a novel diurnal animal model and a multi-method approach including cutting-edge molecular biology techniques i.e. AAV-shRNA, to test a novel hypothesis that the orexinergic system mediates the effects of light on mood and anxiety. The proposed work is significant because it is expected to advance and expand understanding of how changes in environmental lighting conditions produce fluctuations in mood and anxiety, which has the potential to translate into better understanding of the neuropathology underlying SAD in humans. Ultimately, such knowledge will contribute to the development of novel preventive and therapeutic strategies for SAD and other mood disorders.