Effects of Early Life Stress on Anhedonia and Striatal Dopamine Concentration Depends on Variation in catechol-O-methyltransferase (COMT) Genotype

6 Chapter 1: Literature Review.7 Anhedonia and Depression.8 Etiology of Depression.9 Chronic Stress and Depression.10 Early Life Trauma and Depression.13 Dopamine Dysregulation and Depression.16 Evidence for a Gene-Environment Interaction in the Etiology of Depression.18 Animal Models of Depression.20 Summary of Rationale and Hypotheses to be Tested.22 Chapter 2: Method.24 Subjects.24 Postnatal Treatment.24 Maternal Separation Stress Paradigm.25 Fecal Corticosterone Analysis.26 Sucrose Consumption Test.27 Tissue Collection and Dopamine Analysis via HPLC.27 Data Analysis.29 Preliminary Analyses.29 Main Analyses.30 EFFECTS OF STRESS AND COMT GENOTYPE ON DEPRESSION 5 Chapter 3: Proposed Results.31 Preliminary Analyses: Fecal Corticosterone Metabolite Levels.31 Anhedonia.32 Striatal Dopamine Concentration.34 Correlation.36 Chapter 4: Discussion.37 Conclusion.44 References.46 Appendix A: IACUC Proposal.58 EFFECTS OF STRESS AND COMT GENOTYPE ON DEPRESSION 6 Abstract Depression is a serious, costly, and heterogeneous disorder for which no one genetic determinant has been identified. Research has shown that stress, and subsequent hypothalamic-pituitaryadrenal (HPA) axis dysregulation, is a significant predictor of depression, and one particular stressor that has been linked to vulnerability to depression and HPA axis dysregulation is early life trauma. Due to the heterogeneity and complexity of depression, it is likely that specific gene-Depression is a serious, costly, and heterogeneous disorder for which no one genetic determinant has been identified. Research has shown that stress, and subsequent hypothalamic-pituitaryadrenal (HPA) axis dysregulation, is a significant predictor of depression, and one particular stressor that has been linked to vulnerability to depression and HPA axis dysregulation is early life trauma. Due to the heterogeneity and complexity of depression, it is likely that specific geneenvironment interactions play a role in the development of depression. Interaction between catechol-O-methyltransferase (COMT) ValMet variants with specific environmental factors can potentially increase vulnerability to depression. The present proposed experiment examines the interaction between COMT genotype and the effects of early life stress in a maternal separation paradigm on behavioral and neurological factors in a rodent model of depression. Outcome measures include anhedonia-like behavior, as indexed by performance on a sucrose consumption test, and striatal dopamine concentration, a neurological measure of depression. I hypothesize that across genotype, stress leads to decreased sucrose consumption and decreased striatal dopamine concentrations. However, the functional COMT ValMet polymorphism will interact with stress such that these results are most pronounced among stressed Met/Met rats, as compared to Val/Met rats and Val/Val rats. These results may have implications for treatment of depression in COMT polymorphic individuals, who appear to be more sensitive to stress and more vulnerable to developing depression. EFFECTS OF STRESS AND COMT GENOTYPE ON DEPRESSION 7 Chapter 1: Literature Review According to the World Health Organization (WHO), depression is currently the leading cause of disability worldwide as measured by years lived with disabilities (YLDs), affecting 350 million people of all ages (WHO, 2015). Depression is characterized by serious impairments in physical and emotional domains (Rost, 2009) such as depressed mood, feelings of worthlessness, anhedonia, and changes in appetite and sleep (APA, 2013). At any given time point, about 6% of the US population meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for depression (Penninx et al., 2013). Depression is costly, accounting for 4.3% of the global burden of disease (WHO, 2013). It is expected that by 2020, depression will be the second leading cause of disease globally, as measured by disability adjusted life years (Chapman and Perry, 2008). Furthermore, a recent meta-analysis has demonstrated that depression increases the risk of overall mortality and is associated with increased medical morbidity (Penninx et al., 2013). Symptom presentation in depression is relatively heterogeneous, due to the categorical nature of DSM diagnosis. For example, some diagnostic features of depression, which were previously referred to as subtypes in the DSM-IV (APA, 2000), include depression with melancholic features, depression with catatonic features, and depression with atypical features (APA, 2013). Depression with melancholic features is marked by anhedonia and loss of pleasure, as well as despair, weight loss, excessive guilt, psychomotor agitation or retardation, earlymorning awakening, and/or depression that is worse in the morning (APA, 2013). Depression with catatonic features is marked by catatonic behavior, such as stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, odd mannerisms, stereotypy, agitation, grimacing, echolalia, and/or echopraxia (APA, 2013). In contrast, depression with atypical features is EFFECTS OF STRESS AND COMT GENOTYPE ON DEPRESSION 8 marked by mood reactivity and weight gain, hypersomnia, leaden feelings of the arms and legs, and/or interpersonal rejection sensitivity (APA, 2013). Because cases of depression vary in terms of symptomatology, it may be beneficial to approach investigation into the mechanisms and etiology of depression by examining specific aspects of depression in a dimensional, rather than a categorical approach to the disorder. Anhedonia and Depression As mentioned above, anhedonia is a core symptom of depression, associated with decreased subjective experience of pleasure and reduced interest in previously enjoyed activities (APA, 2013; Naranjo et al., 2001). A recent review suggests that anhedonia is an aspect of depression distinct from mood disturbance, and that is comprised of motivational (such as diminished drive to achieve a goal) and consummatory components, such as diminished participation in activities that were once considered pleasurable, or decreased consumption of palatable substances in rodent models of depression (Argyropoulos and Nutt, 2013). These two components of anhedonia map onto Berridge and Robinson’s (1998) incentive salience hypothesis, in which reward is comprised of two components: “wanting,” of a stimulus and “liking” or the hedonic value associated with a stimulus. The presence of anhedonia, or the decreased experience of pleasure and decreased motivation to partake in pleasurable activites, in depression may predict worse outcomes with treatment. One study evaluating 811 adults with moderate to severe depression demonstrated that the presence of anhedonia symptoms (such as loss of interest, diminished activity, lack of enjoyment) predicts poorer outcomes in response to selective serotonin reuptake inhibitor (SSRI) or noradrenergic antidepressant treatment (Uher et al., 2012). Similarly, anhedonia has been shown to predict poorer recovery among adolescents with SSRI treatment-resistant depression EFFECTS OF STRESS AND COMT GENOTYPE ON DEPRESSION 9 (McMakin et al., 2012). These findings denote the difficulties in treating depression, as clinical symptoms manifest differently across individuals and signaling via various neurotransmitters with varying neural pathways may subserve different aspects of the disorder. Furthermore, these findings indicate that further research on the mechanisms of anhedonia and outcomes associated with it, as well as on markers of vulnerability to depression with anhedonia, are necessary in order to inform treatment approaches and improve depression