The long-term goal of Dr. Wang’s laboratory is to understand how genetic and environmental factors cause psychiatric disorders in order to develop improved treatment and management for these diseases. Among the core deficits associated with serious psychiatric disability, the impairment of executive cognitive function, affecting the planning, initiation and regulation of goal-directed behaviors, has been increasingly highlighted as of central importance. Normal executive function in goal-directed behavior depends on the prefrontal cortex, and functional brain imaging studies have revealed altered prefrontal activity in response to cognitive challenges in schizophrenia patients. However, the mechanisms by which specific genetic risk factors and behavioral experiences may influence the functional cellular architecture and the developmental trajectory of prefrontal cortical circuits remain largely unknown. The current objective is to obtain an integrated understanding of the mechanisms by which experience-dependent gene regulation affects prefrontal cognitive functions at the molecular, cellular, systems, and behavioral levels. A variety of cutting-edge technologies in molecular and cellular biology, mouse genetics, in vivo multi-photon imaging, and electrophysiology as well as sophisticated behavioral analyses will be combined to investigate the ability of the brain to change in response to behavioral experiences during normal adaptive cognition and in the context of maladaptive psychiatric disorders such as schizophrenia, depression and drug addiction. Dr. Wang has genetically engineered a mouse line that enables direct visualization and tracking of experience-dependent and stimulus-specific molecular changes in the brain of live animals with single-cell resolution. With the aid of this line of mice, as well as new lines being developed that will provide more exquisite spatial and temporal controls of optical labeling and allow for functional manipulations of selected neurons, Dr. Wang’s laboratory will identify and characterize the molecular and cellular changes in the prefrontal cortex that are regulated by the internal drives, environmental exposures and social interactions of an animal. Furthermore, Dr. Wang’s group will examine the neurophysiological correlates of these molecular and cellular changes and investigate the mechanisms by which these changes are integrated in the cortical circuits to control behavioral decisions and motor plans. Dr. Wang’s group will also combine the optical-genetic systems that they are developing with mouse models of mental disorders to monitor the development of brain dysfunctions in real time, and test the effects of genetic risk factors as well as pharmacological and behavioral treatments.

• Lu, B., Wang K.H., Nose, A. Molecular mechanisms underlying neural circuit formation. Current Opinion in Neurobiology 19:162-7. 2009.
• Leamey, C.A., Glendining, K.A., Kreiman, G., Kang, N.D., Wang, K.H., Fassler, R., Sawatari, A., Tonegawa, S., Sur, M.  Differential Gene Expression between Sensory Neocortical Areas: Potential Roles for Ten_m3 and Bcl6 in Patterning Visual and Somatosensory Pathways. Cereb Cortex 18, 53-66. 2008.
• Wang, K.H., Majewska, A., Schummers, J., Farley, B., Hu, C., Sur, M. and Tonegawa, S. In vivo two-photon imaging reveals a role of Arc in enhancing orientation specificity in visual cortex.  Cell 126, 389-402. 2006.
• Kawai, J, et al., Wang, K.H., et al., Hayashizaki, Y. The RIKEN Genome Exploration Research Group Phase II Team and the FANTOM Consortium (2001)  Functional annotation of a full-length mouse cDNA collection.  Nature 409, 685-690. 2001.
• Nguyen-Ba-Charvet, K.T., Brose, K., Ma, L., Wang, K.H., Marillat, V., Sotelo, C., Tessier-Lavigne, M. and Chédotal, A.  Diversity and specificity of actions of Slit2 proteolytic fragments in axon guidance.  Journal of Neuroscience 21, 4281-4289. 2001.
• Wang, K.H., Brose, K., Arnott, D., Kidd, T., Goodman, C.S., Henzel, W. and Tessier-Lavigne, M. Biochemical purification of a mammalian Slit protein as a positive regulator of sensory axon elongation and branching.  Cell 96, 771-784. 1999.
• Brose, K., Bland, K.S., Wang, K.H., Arnott, D., Henzel, W., Goodman, C.S., Tessier-Lavigne, M. and Kidd, T. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance.  Cell 96, 785-794. 1999.