A concept central to the projects in this Center is that serotonin (SHT) functions both as a neurotransmitter and as a growth factor during the maturation of the central nervous system. Based on this concept the overarching hypothesis for the center is that genetic and/or pharmacologic factors that increase 5Ht signaling during development affect brain structure and function and consequently influence vulnerability to behavioral disorders later jn life. The link between increased SHT signaling and to disease susceptibility is largely based on recent data demonstrating that increased SHT signaling during development alters brain maturation to affect adult emotional behavior in mice. Mechanistic insight into this phenomenon-is provided by findings demonstrating that these behavioral effects correlate with profound effects on brain structure (white matter tract abnormalities by DTI, volumetric differences in brain structures by MR assessment, dendritic morphology changes in key brain structures as assessed by Golgi staining). In Project 4 we use both mouse and primate models to pursue these findings and answer key questions posed by the Center. Specifically, Project 4 investigates three Aims which have been chosen to create synergies with Projects 1-3 to provide novel insight into SHT-mediated genetic and pharmacologic influences on the development of brain structure and behavior.
In Aim 1 we investigate the developmental origins and ontogeny of structural and white matter tract abnormalities seen in adult 5htt-/- mice. We will test the hypotheses that (a) MRI and DTI based phenotypes in 5htt-/- mice originate during developmental and progress with age and that (b) early life 5HTT blockade will mimic at least some of the structural brain alterations elicited by genetic SHTT ablation and captured through MRI and DTI imaging.
In Aim 2 we investigate the molecular and cellular basis for structural and white matter tract abnormalities seen in adult mice after SHTT blockade during early development. We vyill test the hypothesis that MR and DTI related changes are due to changes in neuronal properties (cell number/density, dendritic material, axonal properties, and synaptic material).
In Aim 3 we investigate the influence of 5httlpr polymorphisms on rhesus macaque SHTT expression and brain structure. We will test the hypotheses that (a) 5htt promoter variants affect 5htt expression during development and that (b) 5htt promoter variants affect brain structure.
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