The Intersection of Early Life Experiences and Serotonergic Gene Expression on Behavior and Physiology.

Abstract

Adverse early life experiences (aELEs), such as childhood abuse, neglect, or trauma, increase lifetime vulnerability for mental illness. Interactions between aELEs and polymorphisms in serotonergic (5-HT) genes can further increase risk. However, understanding of how aELEs shape the serotonergic system remains limited, despite extensive clinical evidence implicating 5-HT abnormalities in mental illness. This thesis work investigates the long-term consequence of maternal separation (MS), a rat model of aELE, in c57bl/6 mice. Specifically, changes in the expression and DNA methylation of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in neuronal 5-HT synthesis, as well as associated behavioral and molecular correlates, are evaluated. In parallel, a transgenic TPH2 knockdown mouse line is characterized to evaluate the effect of decreased TPH2 expression on behavior. Brief (MS15) and prolonged (MS180) maternal separation affects long-term decreases in midline dorsal raphe TPH2 mRNA without altering DNA methylation. These changes are concurrent with shared decreases in raphe serotonin transporter mRNA, increases in dorsal hippocampal glucocorticoid receptor mRNA, and decreases in anxiety-like behavior. The expression and behavioral patterns are in contrast to reported changes in MS rats, indicating a unique response to MS that affects a convergence between MS15 and MS180 c57bl/6 mice that resembles patterns reported in early-life induced ‘resilient’ rats. Underlying convergence, maternal behavior during the MS paradigm is transiently increased as a function of separation duration. This implicates enhanced maternal care as a moderating influence on early life stress, promoting later-life ‘resiliency’ in c57bl/6 mice. In parallel, transgenic knockdown of TPH2 affects a significant decrease in anxiety- and depression- like behavior, supporting a functional role of decreased TPH2 mRNA in shaping long-term behavioral changes during early development. In summary, this thesis work demonstrates that low TPH2 mRNA during early development alters long-term behavior, affecting a phenotype of decreased anxiety- and depression- like behavior. Moreover, it suggests a unique response to MS in c57bl/6 mice, in which maternal mediation not only mitigates aELEs, but can also promote lifetime ‘resiliency.’PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97907/1/aureias_1.pd