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.

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9
Fiscal Year
2015
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Name
U.S. National Institute of Mental Health
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Liu, Yuanyuan; Latremoliere, Alban; Li, Xinjian et al. (2018) Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561:547-550
Dong, Qiping; Liu, Qing; Li, Ronghui et al. (2018) Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes. Elife 7:
Li, Xinjian; Cao, Vania Y; Zhang, Wenyu et al. (2017) Skin suturing and cortical surface viral infusion improves imaging of neuronal ensemble activity with head-mounted miniature microscopes. J Neurosci Methods 291:238-248
Wang, Xuhua; Liu, Yuanyuan; Li, Xinjian et al. (2017) Deconstruction of Corticospinal Circuits for Goal-Directed Motor Skills. Cell 171:440-455.e14
Ye, Yizhou; Mastwal, Surjeet; Cao, Vania Yu et al. (2017) Dopamine is Required for Activity-Dependent Amplification of Arc mRNA in Developing Postnatal Frontal Cortex. Cereb Cortex 27:3600-3608
Managò, Francesca; Mereu, Maddalena; Mastwal, Surjeet et al. (2016) Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia. Cell Rep 16:2116-2128
Mastwal, Surjeet; Cao, Vania; Wang, Kuan Hong (2016) Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input. Front Neural Circuits 10:100
Kunii, Yasuto; Zhang, Wenyu; Xu, Qing et al. (2015) CHRNA7 and CHRFAM7A mRNAs: Co-Localized and Their Expression Levels Altered in the Postmortem Dorsolateral Prefrontal Cortex in Major Psychiatric Disorders. Am J Psychiatry :appiajp201514080978
Cao, Vania Yu; Ye, Yizhou; Mastwal, Surjeet et al. (2015) Motor Learning Consolidates Arc-Expressing Neuronal Ensembles in Secondary Motor Cortex. Neuron 86:1385-92
Mastwal, Surjeet; Ye, Yizhou; Ren, Ming et al. (2014) Phasic dopamine neuron activity elicits unique mesofrontal plasticity in adolescence. J Neurosci 34:9484-96

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