ENVIRONMENTAL INFLUENCES AND EPIGENETIC MECHANISMS IN RISK FOR DEPRESSION

Genetic and environmental factors interact to influence vulnerability for internalizing psychopathology, including Major Depressive Disorder (MDD). The mechanisms that account for how environmental stress can alter biological systems are not yet well understood yet are critical to develop more accurate models of vulnerability and targeted interventions. Epigenetic influences, and more specifically, DNA methylation, may provide a mechanism by which stress could program gene expression, thereby altering key systems implicated in depression, such as frontal-limbic circuitry and its critical role in emotion regulation. This thesis investigated the role of environmental factors from infancy and throughout the lifespan affecting the serotonergic (5-HT) system in the vulnerability to and treatment of depression and anxiety and potential underlying DNA methylation processes. First, we investigated the contributions of additive genetic vs. environmental factors on an early trait phenotype for depression (negative emotionality) in infants and their stability over time in the first 2 years of life. We provided evidence of the substantial contributions of both genetic and shared environmental factors to this trait, as well as genetically- and environmentally- mediated stability and innovation. Second, we studied how childhood environmental stress is associated with peripheral DNA methylation of the serotonin transporter gene, SLC6A4, as well as long-term trajectories of internalizing behaviours. There was a relationship between childhood psychosocial adversity and SLC6A4 methylation in males, as well as between SLC6A4 methylation and internalizing trajectory in both sexes. Third, we investigated changes in emotion processing and epigenetic modification of the SLC6A4 gene in depressed adolescents before and after Mindfulness-Based Cognitive Therapy (MBCT). The alterations from pre- to post-treatment in connectivity between the ACC and other network regions and SLC6A4 methylation suggested that MBCT may work to optimize the connectivity of brain networks involved in cognitive control of emotion as well as also normalize the relationship between SLC6A4 methylation and activation patterns in frontal-limbic circuitry. Our results from these three studies strengthen the theory that environmental influences are critical in establishing early vulnerability factors for MDD, driving epigenetic processes, and altering brain processes as an individual undergoes treatment, or experiences relapse.

The Function of Intestinal Afferent Neurons in Regulating Satiety During Health and Obesity

Background and aim: Within the gastrointestinal tract, vagal afferents regulate satiety and food intake via chemical and mechanical mechanisms. Cysteinyl Leukotrienes (CysLTs) are lipid mediators that are believed to regulate food intake and body weight. However, the involvement of vagal afferents in this effect remains to be established. Conversely, Glucagon like peptide-1 (GLP-1) is a satiety and incretin peptide hormone. The effect of obesity on GLP-1 mediated gut-brain signaling has yet to be investigated. Since intestinal vagal afferents’ activity is reduced during obesity, it is intriguing to investigate their responses to GLP-1 in such conditions. Methods: Extracellular recordings were performed on intestinal afferents from normal C57Bl6, low fat fed (LFF), and high fat fed (HFF) mice. To examine the effect on neuronal calcium signaling, calcium-imaging experiments were performed on isolated nodose ganglion neurons. Food intake experiments were conducted using LFF and HFF mice. Oral glucose tolerance tests (OGTT) were carried out. Whole cell patch clamp recordings were performed on nodose ganglion neurons from A) normal C57Bl mice to test the effect of CysLTs on membrane excitability, B) LFF and HFF mice to examine GLP-1 effect on membrane excitability during obesity. c-Fos immunohistochemical techniques were performed to measure the level of neuronal activation in the brainstem of both LFF and HFF mice in response to Ex-4. Results: CysLTs increased intestinal afferent firing rate and mechanosensitivity. In single nodose neuron experiments, CysLTs increased excitability. The GLP-1 agonist Ex-4 significantly decreased food intake in LFF but not HFF mice. However, Ex-4 markedly attenuated the rise in blood glucose in both LFF and HFF mice. The observed increase in nerve firing and mechanosensitivity following the application of GLP-1 and Ex-4 was abolished in HFF mice. Cell membrane excitability was significantly increased by Ex-4 in nodose from LFF but not HFF mice. Ex-4 significantly increased the number of activated neurons in the NTS area of LFF mice but not in their HFF counterparts. Conclusion: The previous observations indicate that the role CysLTs play in regulating satiety is likely to be vagally mediated. Also that satiety, but not incretin, effects of GLP-1 are impaired during obesity.