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...

Circuit formation in the central nervous system has been historically studied during development, after which cell-autonomous and nonautonomous wiring factors inactivate. In principle, balanced reactivation of such factors could enable further wiring in adults, but their relative contributions may be circuit dependent and are largely unknown. Here, we investigated hippocampal mossy fiber sprouting to gain insight into wiring mechanisms in mature circuits. We found that sole ectopic expression of Id2 in granule cells is capable of driving mossy fiber sprouting in healthy adult mouse and rat. Mice with the new mossy fiber circuit solved spatial problems equally well as controls but appeared to rely on local rather than global spatial cues. Our results demonstrate reprogrammed connectivity in mature neurons by one defined factor and an assembly of a new synaptic circuit in adult brain.

Highlights d Single-cell RNA-seq uncovers differential exon-usage events in neurexins d Developmentally related cell types display invariance in neurexin splicing d Mature and embryonic neurons reveal ontogenetic stability of neurexin isoforms

The diversity reflected by >100 different neural cell types fundamentally contributes to brain function and a central idea is that neuronal identity can be inferred from genetic information. Recent large-scale transcriptomic assays seem to confirm this hypothesis, but a lack of morphological information has limited the identification of several known cell types. In this study, we used single-cell RNA-seq in morphologically identified parvalbumin interneurons (PV-INs), and studied their transcriptomic states in the morphological, physiological, and developmental domains. Overall, we find high transcriptomic similarity among PV-INs, with few genes showing divergent expression between morphologically different types. Furthermore, PV-INs show a uniform synaptic cell adhesion molecule (CAM) profile, suggesting that CAM expression in mature PV cells does not reflect wiring specificity after development. Together, our results suggest that while PV-INs differ in anatomy and in vivo activity, their continuous transcriptomic and homogenous biophysical landscapes are not predictive of these distinct identities.

Highlights d Specific VIP+ neurons of the SCN fire at night when most others are silent d Activating or silencing these VIP+ neurons controls nighttime but not daytime sleep d Circadian clockwork within these specific neurons times the daily ''siesta'' d The activity of these neurons, in turn, programs subsequent end-of-day alertness