Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

Managò, Francesca; Mereu, Maddalena; Mastwal, Surjeet; Mastrogiacomo, Rosa; Scheggia, Diego; Emanuele, Marco; Luca, Maria Antonietta De; Weinberger, Daniel R.; Wang, Kuan Hong; Papaleo, Francesco

doi:10.1016/j.celrep.2016.07.044

Cited by 95 publications

(142 citation statements)

References 74 publications

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“…Our observations here reveal reliable anxiolytic-like effects in Arc KO mice across three different behavioral tests While previous reports using the same strain of Arc KO mice have noted significant decreases 60 and increases 58 in locomotion, we observe no significant differences in Arc KO mouse activity in a locomotor assay (Fig. 1 d-f).…”

Section: Discussionsupporting

confidence: 60%

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Penrod

Kumar

Smith

et al. 2019

Genes Brain and Behavior

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The activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc) – a brain region implicated in mood and anxiety behaviors. Global Arc knockout mice have altered AMPAR-subunit surface levels in the adult NAc, and the Arc-deficient mice show reductions in anxiety-like behavior, deficits in social novelty preference, and anti-depressive-like behavior. Viral-mediated expression of Arc in the adult NAc of male, global Arc KO mice restores normal levels of anxiety-like behavior in the elevated plus maze. Consistent with this finding, viral-mediated reduction of Arc in the adult NAc reduces anxiety-like behavior in male, but not female, mice in the elevated plus maze. NAc-specific reduction of Arc also produced significant deficits in both object and social novelty preference tasks. Together our findings indicate that Arc is essential for regulating normal mood-and anxiety-related behaviors and novelty discrimination, and that Arc’s function within the adult NAc contributes to these behavioral effects.

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Section: Discussionsupporting

confidence: 60%

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Penrod

Kumar

Smith

et al. 2019

Genes Brain and Behavior

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“…Chronic cranial windows are broadly used to study the morphology of neurons (Fu et al, 2012; Holtmaat et al, 2009; Mastwal et al, 2014; Yang et al, 2010), to examine gene expression patterns in individual neurons (Cao et al, 2015; Wang et al, 2006), for photo-stimulation through optogenetic methods (Carrillo-Reid et al, 2016; Silasi et al, 2013), and to image neural activity through genetically encoded calcium indicators such as GCaMP (Andrew et al, 2014; Chen et al, 2013; Manago et al, 2016). However, due to inflammation and tissue regrowth after surgery, success rates of clear windows vary and tend to be low (Holtmaat et al, 2009; Yang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Skin suturing and cortical surface viral infusion improves imaging of neuronal ensemble activity with head-mounted miniature microscopes

Cao

Zhang

et al. 2017

Journal of Neuroscience Methods

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Background In vivo optical imaging of neural activity provides important insights into brain functions at the single-cell level. Cranial windows and virally delivered calcium indicators are commonly used for imaging cortical activity through two-photon microscopes in head-fixed animals. Recently, head-mounted one-photon microscopes have been developed for freely behaving animals. However, minimizing tissue damage from the virus injection procedure and maintaining window clarity for imaging can be technically challenging. New method We used a wide-diameter glass pipette at the cortical surface for infusing the viral calcium reporter AAV-GCaMP6 into the cortex. After infusion, the scalp skin over the implanted optical window was sutured to facilitate postoperative recovery. The sutured scalp was removed approximately two weeks later and a miniature microscope was attached above the window to image neuronal activity in freely moving mice. Results We found that cortical surface virus infusion efficiently labeled neurons in superficial layers, and scalp skin suturing helped to maintain the long-term clarity of optical windows. As a result, several hundred neurons could be recorded in freely moving animals. Comparison with existing methods Compared to intracortical virus injection and open-scalp postoperative recovery, our methods minimized tissue damage and dura overgrowth underneath the optical window, and significantly increased the experimental success rate and the yield of identified neurons. Conclusion Our improved cranial surgery technique allows for high-yield calcium imaging of cortical neurons with head-mounted microscopes in freely behaving animals. This technique may be beneficial for other optical applications such as two-photon microscopy, multi-site imaging, and optogenetic modulation.

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“…In addition to schizophrenia-related behavioral phenotypes, we found that genetic disruption of Arc in mice reduces frontal dopamine release (Managò et al, 2016). In further support of this finding, two-photon imaging of genetically encoded calcium indicators in the frontal cortex revealed that VTA stimulation-evoked activity is significantly reduced in Arc mutant mice in comparison to wild-type mice (Figure 2B).…”

Section: Genetic Disruption Of Arc Causes Alterations In the Dopaminementioning

confidence: 99%

“…The slower processes in the hierarchy integrate the faster dynamics and reach threshold for activation gradually. But once activated, the effects of slower processes persist longer and modulate the amplitude of the faster dynamics (Figures are modified with permission from Mastwal et al, 2014; Managò et al, 2016; Ye et al, 2016). …”

Section: Dopamine Is Required For the Amplification Of Activity-depenmentioning

confidence: 99%

“…Francesco Papaleo and Daniel Weinberger, we have conducted a broad range of behavioral tests in Arc knockout mice (Managò et al, 2016). While Arc genetic disruption does not affect general health and lower-level reflexive behaviors, it causes a number of higher level behavioral deficits consistent with schizophrenia-related phenotypes, including deficits in sensorimotor gating, social behaviors, cognitive functions, and amphetamine-induced psychomotor responses.…”

Section: Genetic Disruption Of Arc Causes Alterations In the Dopaminementioning

confidence: 99%

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Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input

Mastwal

Cao

Wang

2016

Front. Neural Circuits

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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.

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Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

Cited by 95 publications

References 74 publications

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Skin suturing and cortical surface viral infusion improves imaging of neuronal ensemble activity with head-mounted miniature microscopes

Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input

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