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 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.

Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc

“…In contrast to c-fos or egr1 , this gene is known to code for a synaptic protein. Arc is one of the effectors of the BDNF, glutamatergic, dopaminergic and serotonin signaling (Chowdhury et al, 2006 ; Granado et al, 2008 ; Karabeg et al, 2013 ; Leal et al, 2014 ; Panja and Bramham, 2014 ; Pastuzyn and Keefe, 2014 ; Managò et al, 2016 ; Mastwal et al, 2016 ). arc expression is under regulation of Egr1 (Li et al, 2005 ).…”

Developmental Exposure to Psychostimulant Primes Activity‐dependent Gene Induction in Frontal Cortex

“…Arc mRNA expression in the human frontal cortex also increases significantly after birth (Colantuoni et al ., ). As the Arc signaling complex has been implicated in neurodevelopmental psychiatric disorders such as schizophrenia and intellectual disability disorders (Kirov et al ., ; Fromer et al ., ; Purcell et al ., ), perinatal amphetamine exposure may disrupt the normal maturation of Arc signaling and synaptic functions (Mastwal et al ., ), thereby increasing the risk for psychiatric disorders later in life.…”

“…These genes include both transcription factors such as cFos and synaptic adaptor molecules such as Arc. The function of Arc has been particularly well studied as a master regulator of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), homeostatic scaling and persistent firing activity (Bramham et al, 2008; Marballi and Gallitano, 2018; Mastwal et al, 2016; Ren et al, 2014; Shepherd and Bear, 2011). Both loss of function and overexpression of Arc can disrupt synaptic plasticity and lead to cognitive dysfunctions and psychiatric phenotypes (Jenks et al, 2017; Manago et al, 2016; Plath et al, 2006; Wall et al, 2018).…”

Molecular physiology of Arc/Arg3.1: The oligomeric state hypothesis of synaptic plasticity

“…During motor learning, Arc expression in neuronal ensembles of the secondary motor cortex is necessary for the consolidation of task-specific motor responses. 42,[52][53][54] During post-natal maturation of the visual cortex in rodents, Arc expression supports ocular dominance column formation and orientation tuning of visual inputs, as well as receptive field plasticity. 33,[55][56][57][58] Collectively, research indicates a role for Arc in post-natal maturation of the visual cortex as well as consolidation of hippocampal-dependent memory (spatial learning and contextual fear) and hippocampalindependent motor learning.…”

“…Arc also has important functions in neocortical circuits. During motor learning, Arc expression in neuronal ensembles of the secondary motor cortex is necessary for the consolidation of task‐specific motor responses 42,52–54 . During post‐natal maturation of the visual cortex in rodents, Arc expression supports ocular dominance column formation and orientation tuning of visual inputs, as well as receptive field plasticity 33,55–58 .…”