CHAPTER 1: INTRODUCTION Heterogeneity of major depressive disorder Depression, or major depressive disorder, is a mental disorder that dramatically affects a person's health and life. It is characterized by persistent low mood, inability to feel pleasure in previously enjoyable activities, feeling of low-esteem, fatigue, sleep disturbances, appetite changes, pain without a clear cause, and thoughts of suicide. It has become the leading cause of disability worldwide with over 300 million people affected. The prevalence of major depressive disorder increased by 18% from 2005 to 2015 (World Health Organization, 2017). Depression is also a chronic disease, as half of a people who experienced a single episode are likely to have recurrent episodes with higher frequency and severity (Akil et al., 2018). Even though major depressive disorder is diagnosed as a single entity, it is a really heterogeneous disorder characterized by patients having widely varied symptoms, with little to even no overlap of symptomatologies in some cases (Akil et al., 2018). This heterogeneity of depression hinders both research and treatment of this highly prevalent disorder (Fried, 2017). Antidepressants available on the market today were developed based on a theory called monoamine hypothesis of depression, which was established on several key observations made in 1950s. The hypothesis states that the underlying biological reason for depression is depletion of dopamine, serotonin, and/or norepinephrine levels in the central nervous system. It has been demonstrated that increasing the levels of the aforementioned monoamine neurotransmitters in the brain, either by blockage of their reuptake or inhibition of their degradation, alleviates the depression symptoms in patients (Delgado, 2000; Hirschfeld, 2000). Despite the relative effectiveness of currently available antidepressant medications, they are still lacking and possess a variety of drawbacks. Less than half of the patients achieve full remission after the first treatment with antidepressants (Rush, 2007). That leads to trial-and-error approach, where multiple trials of different treatment are needed until the patient is matched with optimal medication. Even then, for patients that do respond to treatment, it takes weeks or months until the depressive symptoms are alleviated (Berton and Nestler, 2006). Some patients also exhibit resistance to antidepressants, which can develop spontaneously in patients previously responsive to treatment or as a result of worsening illness over the course of time (Thase and Schwartz, 2015). Moreover, treatment with antidepressants has numerous side effects, such as fatigue, sleep disturbances, weight and appetite, and sexual dysfunction (Fergusson, 2001). Therefore, there is still an unmet need for more effective, faster, and safer treatment for major depressive disorder. A different approach to depression treatment would be to conceptualize this disease as a circuit dysfunction instead of a neurotransmitter dysfunction. It is possible that the heterogene...

The secretion of many hormones, including oxytocin, vasopressin and growth hormone, is not constant but shows a day-night rhythm. The suprachiasmatic nucleus (SCN) is thought to generate most mammalian biological rhythms and previous studies have reported suprachiasmatic efferents to the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). We used in vivo extracellular electrophysiological techniques to show that the SCN also sends direct and indirect neural projections to the arcuate nucleus (ARC). This projection consisted of both excitatory and inhibitory components and may contribute to the entrainment of the rhythm in growth hormone secretion to the day-night cycle. Some SCN neurones appear to project to both the SON and the ARC. The SCN in turn receives excitatory and inhibitory inputs from the ARC and the peri-nuclear zone of the SON (peri-SON), which may provide feedback information, as well as allowing nonphotic entrainment of the SCN, for example, in response to feeding. Our data thus suggest extensive two-way connections between the SCN and its target nuclei which may contribute to the generation of day-night neuroendocrine rhythms. They also suggest the existence of indirect retinal projections to the ARC and PVN. We further investigated the retinal projection to the SCN. We were unable to demonstrate a significant difference in retinal input to those suprachiasmatic cells which had efferent projections to particular hypothalamic targets (SON and/or ARC), and those which did not.