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 established 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). Using this line, we have studied the experience-dependent expression pattern of Arc in the visual cortex, and revealed a physiological function of Arc in sharpening stimulus-specific visual responses. Our lab continues to investigate the mechanisms by which experience-induced molecular changes impact on cortical processing of information, with a particular focus on frontal cortical circuits. Normal executive function in goal-directed behavior depends on the frontal cortex, and functional brain imaging studies have revealed altered frontal lobe activity in response to cognitive challenges in psychiatric patients. However, the mechanisms by which specific genetic risk factors and behavioral experiences may influence the functional cellular architecture and the developmental trajectory of frontal cortical circuits remain largely unknown. To begin to investigate the impact of behavioral experience on plasticity-related gene expression dynamics in the frontal cortex, we have developed and published a method that combines in vivo two-photon microscopy with a genetically encoded fluorescent reporter to track experience-dependent gene expression changes in individual frontal cortical neurons over the course of day-to-day experience (Cao et al, J Vis Exp 2013). We have applied this imaging method to animals that are trained under various motor tasks, and revealed the dynamic processes by which neuronal ensembles in the frontal cortex adapt to different behavioral situations. Furthermore, we have optically identified individual neurons with experience-dependent gene expression changes in frontal cortical circuits, and determined the functional contributions of those molecular changes to circuit activities and behavioral responses. Our group is also interested in investigating the coupling mechanisms between neuronal activity and plasticity-related gene expression in frontal 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. Among the several neuromodulator systems in the brain, dopaminergic signaling has a particularly powerful impact on behavior. In collaboration with our colleagues at NICHD, we have reviewed the critical roles of dopaminergic signaling in cognitive functions and circuit activities (Furth et al., Front Cell Neurosci 2013). Since dysfunctions in the mesofrontal dopaminergic circuit have been implicated in many psychiatric disorders in human, a better understanding of the plasticity mechanisms in the mesofrontal dopaminergic circuit may inform therapeutic approaches aimed at restoring normal functioning to this circuit in psychiatric patients. Recent development of optogenetic techniques offers a great opportunity to dissect circuit plasticity mechanisms. In collaboration with our colleagues at NEI, we have experimentally evaluated the critical factors affecting the efficacy of optogenetic perturbations in animals (Cavanaugh et al., Neuron 2012). We are now applying in vivo imaging and optogenetic techniques to evaluate the structural and functional plasticity of the mesofrontal dopaminergic circuit and determine the underlying cellular and molecular mechanisms. Finally, in collaboration with other research groups in the Clinical Brain Disorders Branch, we are extending our investigations to examine frontal 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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