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 gene Arc/Arg3.1 as 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.
Highlights
Mental functions involve coordinated activities among specific groups of neurons, or neuronal ensembles, that are embedded in complex brain circuits (Hebb, 1949; Harris and Shepherd, 2015)
Arc expression is induced in a behavioral task-specific manner, regulates persistent firing of frontal cortical neurons, and predicts the consolidation of neuronal ensembles during learning
The Arc pathway presents a prototypical example of an activity-dependent genetic feedback mechanism in the regulation of neuronal ensembles
Summary
Mental functions involve coordinated activities among specific groups of neurons, or neuronal ensembles, that are embedded in complex brain circuits (Hebb, 1949; Harris and Shepherd, 2015). We provide our perspective through a series of recent studies on frontal cortical circuits which used Arc as a cellular marker to track active neuronal ensembles, and as a molecular probe to modulate neuronal function and behavior. Using a rotarod motor learning task in mice, we examined the effects of prior training on Arc expression and neuronal firing properties (Ren et al, 2014; Figures 1A,B).
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