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 shed light on the reciprocal regulation between the dopaminergic neuromodulatory circuit and the activity-dependent Arc gene expression in the frontal cortex, and provided initial biological support implicating the importance of such mechanisms in neuropsychiatric disorders. Our specific findings on these topics are described below. The activity-regulated gene Arc/Arg3.1 encodes a postsynaptic protein crucially involved in synaptic plasticity. Genetic mutations in Arc pathway and altered Arc expression in human frontal cortex have been associated with schizophrenia. Although Arc expression has been reported to vary with age, what mechanisms regulate Arc mRNA levels in frontal cortex during postnatal development remains unclear. Using quantitative mRNA analysis of mouse frontal cortical tissues, we mapped the developmental profiles of Arc expression and found that its mRNA levels are sharply amplified near the end of the second postnatal week, when mouse pups open their eyes for the first time after birth. Surprisingly, electrical stimulation of the frontal cortex before eye-opening is not sufficient to drive the amplification of Arc mRNA. Instead, this amplification needs both electrical stimulation and dopamine D1-type receptor (D1R) activation. Furthermore, visual stimuli-driven amplification of Arc mRNA is also dependent on D1R activation and dopamine neurons located in the ventral midbrain. These results indicate that dopamine is required to drive activity-dependent amplification of Arc mRNA in the developing postnatal frontal cortex and suggest that joint electrical and dopaminergic activation is essential to establish the normal expression pattern of a schizophrenia-associated gene during frontal cortical development. Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton- associated protein (Arc) complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia.
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