Major depressive disorder (MDD), a devastating chronic disorder often precipitated by stress, is defined by the core symptoms of low mood and anhedonia (the inability to experience pleasure or reward). Despite the substantial financial and emotional burden of MDD, understanding the neurobiological mechanisms of this disorder remains a considerable challenge in neuropsychiatric research. Increasing evidence points toward circadian abnormalities as a component of the pathophysiology of major depressive disorder (MDD) and treatments modulating circadian rhythms, such as the melatonin receptor agonist agomelatine, have been shown to be successful treatments for MDD. Thus, a thorough understanding of the role of circadian mechanisms in mood regulation is critical to developing successful treatments for MDD. Reports have indicated a role for specific circadian genes in modulating mesolimbic dopaminergic circuitry, a pathway known to play a role in reward, stress, and depression-related behaviors. For instance, mice with a downregulation of the circadian locomotor output cycles kaput (Clock) gene in the ventral tegmental area (VTA) display increased depressive-like behaviors under baseline conditions (Mukherjee et al. 2010). These mice also display increased dopaminergic transmission in mesolimbic circuits [i.e. the VTA to the nucleus accumbens (NAc)]. As the primary nucleus for dopaminergic projections, the VTA has several downstream targets, including other brain regions implicated in MDD [e.g. NAc, amygdala (AMY), and prefrontal cortex (PFC)]. Critically, increasing evidence is implicating brain region-specific circadian oscillations as instrumental regulators of emotional and motivational stimuli (Amir et al. 2009), suggesting circadian oscillations in these downstream regions may underlie depression-related behaviors. To examine the role of circadian genes in MDD, we plan to combine VTA-specific genetic and optogenetic manipulations with the chronic social defeat stress paradigm, a rodent model of MDD that recapitulates many common features of depression (e.g. anhedonia, anxiety, and social disruptions). This project will determine whether 1) downregulation of Clock in the VTA alters vulnerability to a depressive-like state, 2) downregulation of Clock in the VTA alters circadian oscillations in downstream brain regions associated with MDD, and 3) chronic optogenetic stimulation of a mesolimbic dopaminergic pathway can recapitulate behaviors induced by VTA-specific Clock downregulation.
Abnormalities in molecular components of circadian rhythms (the 24 hour biological cycle) are thought to be a pathological component of major depressive disorder. The proposed research will investigate the role of circadian genes in precipitating major depression by focusing on specific brain regions involved in mood regulation. Application of this knowledge may be critical to developing successful treatments for MDD.