The precise synaptic connectivity of neurons in the mammalian brain is the underlying cellular substrate that governs perception and behavior. The major psychiatric illnesses, such as schizophrenia and depression, may be caused by abnormalities in the connectivity of forebrain neurons. However, the molecular mechanisms that instruct the precise development of forebrain connectivity are largely unknown. This application examines the hypothesis that cellular processes mediated by calcium and cyclic AMP are critical for the refinement and maturation of neural circuits in the thalamus and neocortex, key forebrain structures that mediate conscious perception. Using the visual system as the experimental model, the specific aims of the research are: (1) to examine the mechanisms that drive calcium/cAMP-regulated gene expression during the development of neocortical and thalamic circuitry, (2) to examine the processes that lead to the down-regulation of neocortical calcium/cAMP-regulated gene expression with maturation, (3) to determine the impact of disruption of calcium/cAMP signaling on neocortical plasticity and thalamic connectivity, (4) to construct a transgenic mouse line that has a thalamus specific disruption of the calcium/cAMP-regulated transcription factor CREB. These experiments will help elucidate how calcium/cAMP signals translate sensory experience into patterns of gene expression, and determine the impact of disruption of calcium/cAMP signaling on neural connectivity. The investigator is a psychiatrist whose long-term interest is to understand how neuronal connectivity develops early in life and how it is modified by experience, with the hope that this knowledge will provide insight into the cellular and molecular abnormalities that underlie behavioral and perceptual disorders. He will have an appointment as assistant professor at the University of Washington School of Medicine. His transition towards research independence will be undertaken with mentoring from Dr. Daniel Storm and Dr. Mark Hamlin of the University of Washington. Also, several collaborations are planned, namely with Dr. Alcino Silva (UCLA), Dr. Barbara Gordon-Lickey (University of Oregon), and Dr. John Neumaier (University of Washington), that will result in a significant broadening of research experience.
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