This is a revised application for two years support to study the neurobiological mechanisms underlying seasonal affective disorder (SAD). SAD is a major depressive disorder that affects millions of Americans, who suffer recurring depressive symptoms in the winter when there is less sunlight. The leading theory for explaining SAD is the phase-shifting hypothesis, which suggests that the depressive episodes are caused by misalignments between the circadian rhythms and the habitual sleep time. However, there is a fundamental gap in understanding how changes in environmental lighting conditions lead to the fluctuations in affective state in individuals with SAD. The neural circuitries and the neurobiological events underlying mood changes induced by light are largely unknown. This gap represents an important problem for identifying risk factors and biological diagnostic markers as well as for developing more effective therapeutic strategies. The long-term goal of my research is to understand the brain mechanisms mediating the effects of light on mood. The objective of the proposed work is to develop the diurnal grass rats (Arvichantis niloticus) as an animal model for SAD and to identify the neural substrates associated with the light-dependent depression-like behaviors in the grass rats. There are substantial differences in the circadian rhythms and in the direct responses to light between nocturnal and diurnal species such as humans. Therefore, given the role that light and circadian rhythms play in SAD, developing a diurnal animal model of this disorder is of crucial importance for elucidating the fundamental mechanisms that critically underlie SAD in humans. The central hypothesis to be tested in this proposal is that light regulates mood through acting on the wakefulness promoting Orexinergic system. The activation of arousal pathways by light is unique for diurnal species, therefore this can only be studied in a diurnal model. The proposed work contains two specific aims: 1) Establish the validity of using the diurnal grass rats as a model for SAD;and 2) Test the hypothesis that an altered Orexinergic system is associated with light-dependent changes in mood. The approach is innovative because it utilizes a diurnal animal model and tests a novel hypothesis that the wakefulness promoting Orexinergic system mediates photic effects on mood. The proposed work is significant because it will serve as the basis of future studies (R01 application) to furthr investigate the neurobiological mechanisms of how changes in environmental lighting conditions produce fluctuations in mood. Ultimately, such knowledge will contribute to the development of preventive and therapeutic strategies for SAD and result in breakthroughs for the treatment of mental illness.
The proposed research is relevant to public health because elucidating the neurobiological mechanisms through which light affects mood will substantially increase our understanding of the pathophysiology of seasonal affective disorder, as well as the suitability of light therapy in the treatment of other depressive disorders. Therefore, the proposed research is relevant to the part of the NIMH's mission that aims to transform the understanding and treatment of mental illnesses through basic research.
