Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

Abstract

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...

Red wine polyphenols reverse depressive-like behaviors in mice induced by repeated corticosterone treatment

“…Anhedonia a core symptom of major depression among humans is modeled by inducing a decrease in responsiveness to rewards, as reflected by the reduced consumption of and/or preference for sweetened solutions (Rzepa and McCabe, 2019). In the present study, the data are in line with previous findings showing that a significant decrease in the percentage of sucrose consumption of mice (Cerniauskas et al, 2019). Red wine extract significantly reversed this behavioral change, which suggested the antidepressant-like function.…”

Stress induces divergent gene expression among lateral habenula efferent pathways

“…Perhaps, stress-sensitive inputs preferentially synapse onto neurons projecting to specific targets, and differential activation leads to changes in their subsequent gene expression. Indeed, a recent paper found that CaMKII-expressing neurons projecting from the entopeduncular nucleus tended to synapse onto LHb neurons projecting to the VTA; whereas, those from the lateral hypothalamus and VTA tended to synapse onto neurons projecting to the DRN 33 .…”

“…Cerniauskas, et al 33 characterized the effect of chronic mild stress on LHb neurons projecting to either the VTA/RMTg or the DRN. They observed greater excitability in neurons projecting to the VTA/RMTg in mice with the greatest composite depressionlike behaviors.…”

Heterogeneous habenular neuronal ensembles during selection of defensive behaviors

“…Exploiting this genetic knowledge may provide an entry point to specifically probe the functional and behavioral relevance of individual LHb neuronal clusters identified in this study. Alternative to a genetic basis, clusters may emerge according to topographical organization, input-specific connectivity or discrete projection targets (Cerniauskas et al, 2019; Lecca et al, 2017; Meye et al, 2016; Shabel et al, 2012; Valentinova et al, 2019). Our analysis indicates that some LHb neuronal clusters are topographically distinct.…”