title: Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input.
abstract: Mental functions involve coordinated activities of specific neuronal ensembles that are embedded in complex brain circuits. Aberrant neuronal ensemble dynamics is thought to form the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles and determine what molecular mechanisms constrain their emergence and consolidation during development and learning. Here, we provide a perspective based on recent studies that use activity-dependent geneArc/Arg3.1as a cellular marker to identify 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.
authors.affiliation: Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health Bethesda, MD, USA.
authors.forename: Surjeet
authors.initials: S
authors.lastname: Mastwal
authors.affiliation: Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health Bethesda, MD, USA.
authors.forename: Vania
authors.initials: V
authors.lastname: Cao
authors.affiliation: Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health Bethesda, MD, USA.
authors.forename: Kuan Hong
authors.initials: KH
authors.lastname: Wang
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005625:Frontal Lobe / Q000254:growth & development / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D007858:Learning / Q000502:physiology*; D051379:Mice; D009043:Motor Activity / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D004298:Dopamine
keywords: Arc/Arg3.1; activity-dependent genetic feedback; development; dopamine; frontal cortical circuits; learning; neuromodulation; neuronal ensembles