2008 — 2010 |
Edgar, Nicole M. |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
The Neurobiology of Susceptibility to Depression @ University of Pittsburgh At Pittsburgh
[unreadable] DESCRIPTION (provided by applicant):Major depressive disorder (MDD) is a debilitating disorder of altered mood regulation that is precipitated by chronic stress, modulated by serotonin and of unknown molecular pathophysiology. Four prominent risk factors have been consistently reported to influence rates of vulnerability to develop depression: sex, genetic make-up, prior MDD episodes, and early life stress; however no single animal model has comprehensively combined these vulnerability factors. Using the unpredictable chronic mild stress (UCMS) protocol and behavioral assessments of anxiety/depression-like behaviors in serotonin transporter (SERT) mutant and control mice, I have modeled the interactions of sex, SERT genetic make-up, and stress in eliciting depressive-like behaviors, including the increased vulnerability to clinical depression observed in human female subjects and the risk that is conferred by low SERT levels. Furthermore, gene microarray studies performed by our laboratory on the amygdala of postmortem human MDD subjects and UCMS-treated mice have identified ~40 genes whose changes are specific to human MDD and rodent UCMS, and reversed by antidepressant treatment in rodents, thus representing a critical pool of genes differentially expressed according to altered mood. Therefore, in addition to modeling aspects of human susceptibility to develop depression (sex and SERT genetic make-up), the rodent UCMS paradigm induces molecular changes that are predictive of ?depressive states? across species. Using a comprehensive UCMS-based experimental design in the mouse, I will first confirm the role of sex and SERT as risk factors to UCMS-induced altered mood regulation and then extend my investigation to two additional factors: disease recurrence and early life stress (Aim 1). Using samples generated in Aim 1, I will then begin characterizing neurobiological phenotypes that underlie the UCMS-evoked depressive-like state (Aim 2), including neuroendocrine changes and quantitative assessment of the amygdala gene expression signature. I hypothesize that while risk factors may differentially increase the susceptibility for developing MDD, the ultimate state of altered mood regulation affects a common set of biological and/or molecular disturbances. Results from these studies will begin characterizing changes in these putative common molecular and neuroendocrine disturbances, will reveal the relative contribution of these susceptibility factors to this common phenotype, and will form the basis of future causative studies aimed at investigating the cellular and molecular basis of MDD.
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2012 — 2013 |
Edgar, Nicole M. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Dissecting Pathways of Circadian Disruption in Major Depressive Disorder @ University of Pittsburgh At Pittsburgh
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.
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