The role of serotonin in human brain development: validation studies on the use of peripheral measures of serotonin in children and adults

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Animal studies have shown that the serotonin (5-HT) system plays a major role in brain development, participating in structural and functional shaping of the neuronal circuit. However, surprisingly little is known about the roles of 5-HT in normal human brain development. This gap in knowledge is largely due to the fact that it is difficult to study brain 5-HT in humans. Positron Emission Tomography (PET) is the most direct way to study human brain 5-HT, but it is invasive and can't be used in research with minors.******The long-term goal of this research program is to develop non-invasive methods to measure living brain 5-HT levels that can be used in studies on the roles of 5-HT in the function of the human brain throughout the lifespan. We will study 2 potential indicators of brain 5-HT: DNA methylation of 5-HT system genes in peripheral cells and the electroencephalogram (EEG) N1/P2 component of auditory evoked potential (IDAEP).******The first indicator candidate was chosen based on data from us and others, showing correlations between DNA methylation of 5-HT system genes in peripheral cells and in vivo PET measures of 5-HT. The rationale to study the IDAEP EEG signal is evidence in animals demonstrating its relevance for measuring 5-HT transmission. The research program will focus on important questions related to measurement validity and reliability of these potential two indicators: how stable are these measures over time? What is their relevance for youth brain development? Are both indicators interrelated and tapping into similar brain and cognitive processes?******We will perform 3 studies in healthy individuals, using DNA methylation, EEG, PET and fMRI techniques. The program involves correlational studies as well as experimental 5-HT depletion studies, allowing investigation of causal relationships. Regarding methylation, based on our pilot data, our primary interest are the data obtained from buccal cells that we will compare with results obtained from blood. We will use pyrosequencing assays that we have found to reliably quantify methylation in specific gene promoters. We will also study other regulatory elements throughout the research program, such as enhancers, that often act in a developmental stage-specific way.******The proposed program can lead to the development of non-invasive indicator(s) for brain 5-HT which will be incredibly useful in research on multiple aspects of human brain development.******The program will also provide students opportunities to work in a highly multidisciplinary training environment and gain experience in cutting-edge research methods in behavioural neuroscience. There is increasing demand for students who have been trained in such settings. Thus, the proposed research program has important implications at both scientific and socio-economic levels.