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 maladaptation 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 genetic manipulations in specific types of cells in mouse brain, which is required to establish causal relationships between genes, cells, circuits and behaviors. Our lab investigates 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 behavioral experiences and specific genetic factors may influence the functional cellular architecture and the developmental trajectory of frontal cortical circuits remain largely unknown. Our recent studies have used activity-dependent gene Arc as a cellular marker to identify functional neuronal ensembles and a molecular probe to modulate circuit functions. These studies have demonstrated that the transcription of Arc is activated in selective groups of frontal cortical neurons in response to specific behavioral tasks. Arc expression regulates the persistent firing of individual neurons and predicts the consolidation of neuronal ensembles during repeated learning. Therefore, the Arc pathway represents a prototypical example of activity-dependent genetic feedback regulation of neuronal ensembles. The activation of this pathway in the frontal cortex starts during early postnatal development and requires dopaminergic (DA) input. Conversely, genetic disruption of Arc leads to a hypoactive mesofrontal dopamine circuit and its related cognitive deficit. This mutual interaction suggests an auto-regulatory mechanism to amplify the impact of neuromodulators and activity-regulated genes during postnatal development. Such a mechanism may contribute to the association of mutations in dopamine and Arc pathways with neurodevelopmental psychiatric disorders. As the mesofrontal dopamine circuit shows extensive activity-dependent developmental plasticity, activity-guided modulation of DA projections or Arc ensembles during development may help to repair circuit deficits related to neuropsychiatric disorders. It is generally thought that mental functions depend on coordinated activities of specific neuronal ensembles and aberrant neuronal ensemble dynamics forms the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles during freely behaving state and determine what circuit mechanisms constrain their emergence and consolidation during development and learning. In vivo optical imaging of neural activity provides important insights into brain functions at the single-cell level. Recently, head-mounted one-photon microscopes have been developed for imaging in freely behaving animals. However, achieving high-resolution imaging of individual neurons in the cerebral cortex while avoiding tissue damage is challenging. To address this challenge, we have developed new approaches to specifically label subsets of neurons in the superficial or deep layers of the cortex, and improved experimental procedures to maintain the clarity of optical windows. Our new methods allow for high-yield calcium imaging of cortical neurons with head-mounted microscopes in freely behaving animals and mapping of the spatial locations of recorded neuronal ensembles across the cortex. In addition to improving the imaging capability of miniature microscopes in freely moving mice, this technique may be beneficial for many other optical applications such as two-photon microscopy, multi-site imaging, and optogenetic modulation.
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