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 research progress on these topics is highlighted below. When animals perform an action, neuronal ensembles related to the task are recruited in the frontal cortex. During the initial stage of action learning, the participation of individual neurons in these ensembles is quite variable. But with subsequent practice of motor tasks, the neuronal composition of the ensembles becomes consolidated. So far, little is known about the molecules that identify participating neurons and predict which ones will consolidate during learning. Using a mouse rotarod-learning task, we first demonstrated that inactivation of the secondary motor (M2) area of the frontal cortex disrupts the learning of skilled movements. We then used in vivo two-photon imaging of a genetically encoded reporter to track activity-dependent expression of the Arc gene in M2 cortex while mice undertook the rotarod-learning task. Having demonstrated the regulation of Arc gene-promoter activity in individual M2 neurons during rotarod learning, we went on to show that Arc-expressing neurons are recruited and later consolidated into task-specific ensembles that persistently reactivate. Whether or not a neuron will be included in a particular ensemble depends on the intensity of its initial Arc promoter response. During later training, weakly activated neurons are likely to be dropped from the ensemble. In identifying the locus where cellular consolidation takes place in the brain and elucidating how neurons are selected or rejected for task-specific ensembles during a motor task, our findings have demonstrated an Arc-dependent process for cellular consolidation in M2 cortex during motor learning. This study also suggests that the Arc gene may provide a genetic foothold in specific neurons for predicting and manipulating neuronal ensemble functions in action learning and behavioral control. Nicotinic acetylcholine receptors (nAchRs) are involved in cognition through their modulation of neuronal signaling in the brain. Mutations in specific nAchR genes, CHRNA7 and its partially duplicated chimeric gene CHRFAM7A, have been implicated in schizophrenia. In collaboration with Dr. Barbara Lipska's group at NIMH, we used fluorescent in-situ hybridization to examine the expression of both transcripts in the postmortem human prefrontal cortex. Our results show that these transcripts are co-expressed in the same subset of prefrontal cortical neurons. Given that the expression ratio of CHRFAM7A/CHRNA7 is altered in schizophrenia and the interaction of these two proteins can affect function of nAchRs, this study supports the concept of aberrant nAchRs function in mental disorders.
Showing the most recent 10 out of 17 publications
