Our brain can be considered as a type of information processing system like a computer, where input signals need to be first detected and properly represented, then integrated for decision-making and output control. A unique feature of the brain as an information processing system lies in its adaptability. Namely, sensory experience-induced neural activities can trigger cascades of molecular and cellular changes in brain circuits, which subsequently alter brain functions and affect behavioral outputs. In healthy individuals, this adaptive process can adjust the brain in response to the demands of the external physical and social environments, and ultimately benefit the survival of individuals. Abnormalities in the adaptation to environmental and social stressors can contribute to the development of a variety of mental disorders, such as schizophrenia and depression. In order to prevent maladaptations and develop pharmacological treatments for mental disorders, it is important to understand the cellular and molecular mechanisms of experience-dependent information processing in brain circuits. We have chosen to use laboratory mice as a model organism to investigate the basic cellular and molecular mechanisms of experience-dependent cortical processing. This organism offers several major advantages for this line of study. First, mice and humans both have about 30,000 genes, and about 99 percent of them are shared. Second, the cellular organization of mouse cerebral cortex is similar to human, and major cortical regions are also homologous. Third, it is possible to perform precise molecular manipulations in specific types of cells in mouse brain, which is required to establish causal relationships between genes, cells, circuits and behaviors. We have previously developed a technology to directly visualize the molecular activity of a given set of neurons over several days in the live animal, by generating a mouse line in which the coding part of the neural activity-regulated immediate early gene Arc is replaced with a gene encoding green fluorescent protein (GFP) and applying in vivo two-photon microscopy to the genetically engineered animal. With this approach, we demonstrated that Arc gene is activated in stimulus-specific neuronal ensembles by visual experience, and revealed a physiological function of Arc in sharpening stimulus-specific responses in visual cortex. Our lab continues to investigate the mechanisms by which experience-induced molecular changes impact on cortical processing of information, with a particular focus on prefrontal cortical circuits. 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. We have developed techniques to optically identify specific neurons with experience-dependent gene expression changes in prefrontal circuits, and determined the functional contributions of those molecular changes to prefrontal circuit activities using electrophysiological and calcium-imaging methods. In addition, we have developed chronic in vivo imaging techniques to track experience-dependent molecular changes in live animals while the animals are trained in new tasks. This approach has begun to reveal the dynamic processes by which neuronal ensembles in the prefrontal cortex adapt to different behavioral situations. Our group continues to investigate the coupling mechanisms between neuronal activity and plasticity-related gene expression in cortical circuits, using both molecular genetic and optical imaging tools. Particularly, we are examining whether the induction of activity-dependent gene expression is modified under the influence of specific neuromodulators that are associated with the motivational or emotional relevance of a given behavioral experience. Finally, we have applied in vivo imaging and optogenetic techniques to determine the structural and functional plasticity of the mesoprefrontal circuit in normal adolescent and adult animals, and revealed the capacity of this circuit for experience-dependent modifications and their underlying cellular mechanisms. In collaboration with other research groups in the Genes, Cognition and Psychosis Program, we are extending our investigations to examine prefrontal dysfunctions in mouse models of psychiatric disorders. Those studies may help to monitor the development of abnormal cortical circuits in real time, and elucidate the interactions of genetic risks with environmental factors.

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U.S. National Institute of Mental Health
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