Light reintroduction after dark exposure reactivates plasticity in adults via perisynaptic activation of MMP-9

The sensitivity of ocular dominance to regulation by monocular deprivation is the canonical model of plasticity confined to a critical period. However, we have previously shown that visual deprivation through dark exposure (DE) reactivates critical period plasticity in adults. Previous work assumed that the elimination of visual input was sufficient to enhance plasticity in the adult mouse visual cortex. In contrast, here we show that light reintroduction (LRx) after DE is responsible for the reactivation of plasticity. LRx triggers degradation of the ECM, which is blocked by pharmacological inhibition or genetic ablation of matrix metalloproteinase-9 (MMP-9). LRx induces an increase in MMP-9 activity that is perisynaptic and enriched at thalamo-cortical synapses. The reactivation of plasticity by LRx is absent in Mmp9−/− mice, and is rescued by hyaluronidase, an enzyme that degrades core ECM components. Thus, the LRx-induced increase in MMP-9 removes constraints on structural and functional plasticity in the mature cortex.

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Arc restores juvenile plasticity in adult mouse visual cortex

10.1101/130880 ◽

2017 ◽

Author(s):

Kyle R. Jenks ◽

Taekeun Kim ◽

Elissa D. Pastuzyn ◽

Hiroyuki Okuno ◽

Andrew V. Taibi ◽

...

Keyword(s):

Visual Cortex ◽

Neural Plasticity ◽

Critical Period ◽

Adult Mouse ◽

Monocular Deprivation ◽

Protein Synthesis Inhibitor ◽

Adult Mice ◽

Mouse Visual Cortex ◽

Activity Dependent

AbstractThe molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation (MD) during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression, and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.Significance StatementNeuronal plasticity peaks early in life during critical periods and normally declines with age, but the molecular changes that underlie this decline are not fully understood. Using the mouse visual cortex as a model, we found that activity-dependent expression of the neuronal protein Arc peaks early in life, and that loss of activity-dependent Arc expression parallels loss of synaptic plasticity in the visual cortex. Genetic overexpression of Arc prolongs the critical period of visual cortex plasticity and acute viral expression of Arc in adult mice can restore juvenile-like plasticity. These findings provide a mechanism for the loss of excitatory plasticity with age, and suggest that Arc may be an exciting therapeutic target for modulation of the malleability of neuronal circuits.

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Synaptic Mechanisms of Activity-Dependent Remodeling in Visual Cortex during Monocular Deprivation

Journal of Experimental Neuroscience ◽

10.4137/jen.s2559 ◽

2009 ◽

Vol 2 ◽

pp. JEN.S2559 ◽

Cited By ~ 4

Author(s):

Cynthia D. Rittenhouse ◽

Ania K Majewska

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Ocular Dominance ◽

Monocular Deprivation ◽

Neuronal Structure ◽

Cortical Cells ◽

Dependent Plasticity ◽

Cortical Synapses ◽

Activity Dependent ◽

Synaptic Mechanisms

It has long been appreciated that in the visual cortex, particularly within a postnatal critical period for experience-dependent plasticity, the closure of one eye results in a shift in the responsiveness of cortical cells toward the experienced eye. While the functional aspects of this ocular dominance shift have been studied for many decades, their cortical substrates and synaptic mechanisms remain elusive. Nonetheless, it is becoming increasingly clear that ocular dominance plasticity is a complex phenomenon that appears to have an early and a late component. Early during monocular deprivation, deprived eye cortical synapses depress, while later during the deprivation open eye synapses potentiate. Here we review current literature on the cortical mechanisms of activity-dependent plasticity in the visual system during the critical period. These studies shed light on the role of activity in shaping neuronal structure and function in general and can lead to insights regarding how learning is acquired and maintained at the neuronal level during normal and pathological brain development.

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Enhancement of visual cortex plasticity by dark exposure

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0159 ◽

2017 ◽

Vol 372 (1715) ◽

pp. 20160159 ◽

Cited By ~ 13

Author(s):

Irina Erchova ◽

Asta Vasalauskaite ◽

Valentina Longo ◽

Frank Sengpiel

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Time Course ◽

Ocular Dominance ◽

Monocular Deprivation ◽

Homeostatic Plasticity ◽

Ocular Dominance Plasticity ◽

Intrinsic Signals ◽

Significant Difference ◽

Dark Exposure

Dark rearing is known to delay the time course of the critical period for ocular dominance plasticity in the visual cortex. Recent evidence suggests that a period of dark exposure (DE) may enhance or reinstate plasticity even after closure of the critical period, mediated through modification of the excitatory–inhibitory balance and/or removal of structural brakes on plasticity. Here, we investigated the effects of a week of DE on the recovery from a month of monocular deprivation (MD) in the primary visual cortex (V1) of juvenile mice. Optical imaging of intrinsic signals revealed that ocular dominance in V1 of mice that had received DE recovered slightly more quickly than of mice that had not, but the level of recovery after three weeks was similar in both groups. Two-photon calcium imaging showed no significant difference in the recovery of orientation selectivity of excitatory neurons between the two groups. Parvalbumin-positive (PV+) interneurons exhibited a smaller ocular dominance shift during MD but again no differences in subsequent recovery. The percentage of PV+ cells surrounded by perineuronal nets, a structural brake on plasticity, was lower in mice with than those without DE. Overall, DE causes a modest enhancement of mouse visual cortex plasticity. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

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Temporal patterns of fluoxetine-induced plasticity in the mouse visual cortex

10.1101/487553 ◽

2018 ◽

Author(s):

Anna Steinzeig ◽

Cecilia Cannarozzo ◽

Eero Castren

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Ocular Dominance ◽

Temporal Patterns ◽

Monocular Deprivation ◽

Adult Brain ◽

Postnatal Life ◽

Critical Periods ◽

Mouse Visual Cortex

Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocular dominance in the mouse visual cortex during the first months of life, but this effect is lost later in life. However, various treatments such as the antidepressant fluoxetine can reactivate a critical period-like plasticity in the adult brain. When monocular deprivation is supplemented with chronic fluoxetine administration, a major shift in ocular dominance is produced after the critical period has ended. In the current study, we characterized the temporal patterns of fluoxetine-induced plasticity in the adult mouse visual cortex, using in vivo optical imaging. We found that artificially-induced plasticity in ocular dominance extended beyond the duration of the naturally occurring critical period, and continued as long as fluoxetine was administered. However, this fluoxetine-induced plasticity period ended as soon as the drug was not given. Taken together, our data highlights how a combination of pharmacological treatment and environmental change could be used to improve strategies in antidepressant therapy in humans.

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Homeostatic regulation of perisynaptic matrix metalloproteinase 9 (MMP9) activity in the amblyopic visual cortex

eLife ◽

10.7554/elife.52503 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Sachiko Murase ◽

Dan Winkowski ◽

Ji Liu ◽

Patrick O Kanold ◽

Elizabeth M Quinlan

Keyword(s):

Visual Cortex ◽

Adult Mouse ◽

Two Photon ◽

Adult Mice ◽

History Of ◽

Proteinase Activation ◽

Ecm Degradation ◽

Dark Exposure ◽

Cortical Synapses ◽

Metalloproteinase 9

Dark exposure (DE) followed by light reintroduction (LRx) reactivates robust synaptic plasticity in adult mouse primary visual cortex (V1), which allows subsequent recovery from amblyopia. Previously we showed that perisynaptic proteolysis by MMP9 mediates the enhancement of plasticity by LRx in binocular adult mice (Murase et al., 2017). However, it was unknown if a visual system compromised by amblyopia could engage this pathway. Here we show that LRx to adult amblyopic mice induces perisynaptic MMP2/9 activity and extracellular matrix (ECM) degradation in deprived and non-deprived V1. Indeed, LRx restricted to the amblyopic eye is sufficient to induce robust MMP2/9 activity at thalamo-cortical synapses and ECM degradation in deprived V1. Two-photon live imaging demonstrates that the history of visual experience regulates MMP2/9 activity in V1, and that DE lowers the threshold for the proteinase activation. The homeostatic reduction of the MMP2/9 activation threshold by DE enables visual input from the amblyopic pathway to trigger robust perisynaptic proteolysis.

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Arc restores juvenile plasticity in adult mouse visual cortex

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700866114 ◽

2017 ◽

Vol 114 (34) ◽

pp. 9182-9187 ◽

Cited By ~ 19

Author(s):

Kyle R. Jenks ◽

Taekeun Kim ◽

Elissa D. Pastuzyn ◽

Hiroyuki Okuno ◽

Andrew V. Taibi ◽

...

Keyword(s):

Visual Cortex ◽

Neural Plasticity ◽

Critical Period ◽

Adult Mouse ◽

Monocular Deprivation ◽

Protein Synthesis Inhibitor ◽

Adult Mice ◽

Mouse Visual Cortex ◽

Activity Dependent

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here, we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild-type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.

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Modification of Peak Plasticity Induced by Brief Dark Exposure

Neural Plasticity ◽

10.1155/2019/3198285 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Alexander J. Lingley ◽

Donald E. Mitchell ◽

Nathan A. Crowder ◽

Kevin R. Duffy

Keyword(s):

Visual System ◽

Neural Plasticity ◽

Critical Period ◽

Ocular Dominance ◽

Monocular Deprivation ◽

Dorsal Lateral Geniculate Nucleus ◽

Soma Size ◽

Slow Progress ◽

Dark Exposure ◽

Central Visual System

The capacity for neural plasticity in the mammalian central visual system adheres to a temporal profile in which plasticity peaks early in postnatal development and then declines to reach enduring negligible levels. Early studies to delineate the critical period in cats employed a fixed duration of monocular deprivation to measure the extent of ocular dominance changes induced at different ages. The largest deprivation effects were observed at about 4 weeks postnatal, with a steady decline in plasticity thereafter so that by about 16 weeks only small changes were measured. The capacity for plasticity is regulated by a changing landscape of molecules in the visual system across the lifespan. Studies in rodents and cats have demonstrated that the critical period can be altered by environmental or pharmacological manipulations that enhance plasticity at ages when it would normally be low. Immersion in complete darkness for long durations (dark rearing) has long been known to alter plasticity capacity by modifying plasticity-related molecules and slowing progress of the critical period. In this study, we investigated the possibility that brief darkness (dark exposure) imposed just prior to the critical period peak can enhance the level of plasticity beyond that observed naturally. We examined the level of plasticity by measuring two sensitive markers of monocular deprivation, namely, soma size of neurons and neurofilament labeling within the dorsal lateral geniculate nucleus. Significantly larger modification of soma size, but not neurofilament labeling, was observed at the critical period peak when dark exposure preceded monocular deprivation. This indicated that the natural plasticity ceiling is modifiable and also that brief darkness does not simply slow progress of the critical period. As an antecedent to traditional amblyopia treatment, darkness may increase treatment efficacy even at ages when plasticity is at its highest.

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Critical period for monocular deprivation in the cat visual cortex

Journal of Neurophysiology ◽

10.1152/jn.1992.67.1.197 ◽

1992 ◽

Vol 67 (1) ◽

pp. 197-202 ◽

Cited By ~ 157

Author(s):

N. W. Daw ◽

K. Fox ◽

H. Sato ◽

D. Czepita

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Single Cells ◽

Ocular Dominance ◽

Monocular Deprivation ◽

Significant Shift ◽

Cat Visual Cortex

1. Cats were monocularly deprived for 3 mo starting at 8-9 mo, 12 mo, 15 mo, and several years of age. Single cells were recorded in both visual cortexes of each cat, and the ocular dominance and layer determined for each cell. Ocular dominance histograms were then constructed for layers II/III, IV, and V/VI for each group of animals. 2. There was a statistically significant shift in the ocular dominance for cells in layers II/III and V/VI for the animals deprived between 8-9 and 11-12 mo of age. There was a small but not statistically significant shift for cells in layer IV from the animals deprived between 8-9 and 11-12 mo of age, and for cells in layers V/VI from the animals deprived between 15 and 18 mo of age. There was no noticeable shift in ocular dominance for any other layers in any other group of animals. 3. We conclude that the critical period for monocular deprivation is finally over at approximately 1 yr of age for extragranular layers (layers II, III, V, and VI) in visual cortex of the cat.

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Critical periods in amblyopia

Visual Neuroscience ◽

10.1017/s0952523817000219 ◽

2018 ◽

Vol 35 ◽

Cited By ~ 47

Author(s):

TAKAO K. HENSCH ◽

ELIZABETH M. QUINLAN

Keyword(s):

Visual Cortex ◽

Critical Period ◽

Molecular Mechanisms ◽

Ocular Dominance ◽

Molecular Genetic ◽

Monocular Deprivation ◽

Critical Periods ◽

Developmental Constraints ◽

Early Postnatal Development ◽

Visual Cortical

AbstractThe shift in ocular dominance (OD) of binocular neurons induced by monocular deprivation is the canonical model of synaptic plasticity confined to a postnatal critical period. Developmental constraints on this plasticity not only lend stability to the mature visual cortical circuitry but also impede the ability to recover from amblyopia beyond an early window. Advances with mouse models utilizing the power of molecular, genetic, and imaging tools are beginning to unravel the circuit, cellular, and molecular mechanisms controlling the onset and closure of the critical periods of plasticity in the primary visual cortex (V1). Emerging evidence suggests that mechanisms enabling plasticity in juveniles are not simply lost with age but rather that plasticity is actively constrained by the developmental up-regulation of molecular ‘brakes’. Lifting these brakes enhances plasticity in the adult visual cortex, and can be harnessed to promote recovery from amblyopia. The reactivation of plasticity by experimental manipulations has revised the idea that robust OD plasticity is limited to early postnatal development. Here, we discuss recent insights into the neurobiology of the initiation and termination of critical periods and how our increasingly mechanistic understanding of these processes can be leveraged toward improved clinical treatment of adult amblyopia.

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Optical imaging of the intrinsic signal as a measure of cortical plasticity in the mouse

Visual Neuroscience ◽

10.1017/s0952523805225178 ◽

2005 ◽

Vol 22 (5) ◽

pp. 685-691 ◽

Cited By ~ 83

Author(s):

JIANHUA CANG ◽

VALERY A. KALATSKY ◽

SIEGRID LÖWEL ◽

MICHAEL P. STRYKER

Keyword(s):

Visual Cortex ◽

Optical Imaging ◽

Critical Period ◽

Cortical Plasticity ◽

Ocular Dominance ◽

Screening Method ◽

Intrinsic Signals ◽

Intrinsic Signal ◽

The Mean ◽

Mouse Visual Cortex

The responses of cells in the visual cortex to stimulation of the two eyes changes dramatically following a period of monocular visual deprivation (MD) during a critical period in early life. This phenomenon, referred to as ocular dominance (OD) plasticity, is a widespread model for understanding cortical plasticity. In this study, we designed stimulus patterns and quantification methods to analyze OD in the mouse visual cortex using optical imaging of intrinsic signals. Using periodically drifting bars restricted to the binocular portion of the visual field, we obtained cortical maps for both contralateral (C) and ipsilateral (I) eyes and computed OD maps as (C − I)/(C + I). We defined the OD index (ODI) for individual animals as the mean of the OD map. The ODI obtained from an imaging session of less than 30 min gives reliable measures of OD for both normal and monocularly deprived mice under Nembutal anesthesia. Surprisingly, urethane anesthesia, which yields excellent topographic maps, did not produce consistent OD findings. Normal Nembutal-anesthetized mice have positive ODI (0.22 ± 0.01), confirming a contralateral bias in the binocular zone. For mice monocularly deprived during the critical period, the ODI of the cortex contralateral to the deprived eye shifted negatively towards the nondeprived, ipsilateral eye (ODI after 2-day MD: 0.12 ± 0.02, 4-day: 0.03 ± 0.03, and 6- to 7-day MD: −0.01 ± 0.04). The ODI shift induced by 4-day MD appeared to be near maximal, consistent with previous findings using single-unit recordings. We have thus established optical imaging of intrinsic signals as a fast and reliable screening method to study OD plasticity in the mouse.

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