A group of animal biologists and chemists at the Institute of Transformative Bio-Molecules (ITbM), Nagoya University, has used a chemical genomics approach to explore the underlying mechanism of winter depression, according to a study reported in the journal Proceedings of the National Academy of Sciences of the U.S.A.(PNAS). The researchers have succeeded in understanding the underlying mechanism of winter depression-like behavior and identified a drug that treats winter depression-like behavior in medaka fish. The experiments were carried out through a joint research collaboration between researchers at ITbM, the National Institute for Basic Biology, the Exploratory Research Center on Life and Living Systems, Fujita Health University, and The University of Manchester.

Seasonal changes in the environment can lead to depression- and anxiety-like behavior in humans as well as animals. At high latitudes, including northern regions of the United States and Nordic countries, about 10% of the population suffers from winter depression (also known as seasonal affective disorder: SAD). Typical symptoms of SAD include low mood, sleep problems, disrupted circadian rhythms, social withdrawal, decreased libido, and changes in appetite and body weight. The increasing incidence of suicide and social withdrawal associated with winter depression has become a serious public health issue, and new therapeutic targets and therapies are urgently required. However, the underlying mechanisms of winter depression remain unclear.

Animal models play an essential role in virtually all fields of medicine in understanding the mechanistic nature of biological and behavioral processes, as well as in the discovery of new drugs. Small teleosts, such as zebrafish and medaka , have emerged as powerful models for the study of complex brain disorders and have become valuable pharmacogenetic tools. The research group demonstrated that medaka is an excellent animal model for winter depression. They observed decreased sociability and increased anxiety-like behavior in medaka exposed to winter conditions by using a three-chamber sociability test and a light-dark tank test.

To characterize the metabolomic landscape of medaka kept under winter and summer conditions, the research group examined whole brain metabolites by capillary electrophoresis-mass spectrometry (CE-MS) and discovered significant changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression (Fig. 2). Furthermore, transcriptome analysis demonstrated gene expression changes in multiple pathways associated with depression, including the NRF2 antioxidant signaling pathway and cytokines.

Since most psychiatric disorders are not caused by single gene mutations and are the result of dysregulation and abnormalities in multiple brain structures and neural pathways, both forward and reverse genetic approaches are quite difficult. Therefore, to understand the underlying mechanisms of winter depression, the research group has employed a chemical genomics approach. An in vivobroad-spectrum chemical screen identified the traditional Chinese medicine, celastrol, as rescuing winter behavior. NRF2 is a celastrol target expressed in the habenula, known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator also phenocopied the effect of celastrol, and genome edited NRF2mutant showed decreased sociability.

Interestingly, NRF2expression was observed in the habenula. The habenula has emerged as a key brain region in the pathophysiology of depression. Although fish do not have a defined prefrontal cortex (PFC), the habenula is evolutionarily highly conserved and connects the limbic forebrain and monoaminergic system.

Depression is considered an adaptation to a harsh environment. Given the striking parallels between patients with SAD and medaka kept under winter-like conditions, the present findings provide important insights into the mechanism of winter depression and offer new potential therapeutic targets for its treatment involving NRF2.

The study was published in Nagoya University