Removal of Perineuronal Nets Unlocks Juvenile Plasticity Through Network Mechanisms of Decreased Inhibition and Increased Gamma Activity

May combine two claims.

After chABC treatment, WFA intensity gradually increased, reaching 30% after 14 d and almost 90% after 60 d.

“a gradual increase in WFA intensity was observed, reaching 30% after 14 d and almost 90% after 60 d (Fig. 1D).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Most PNNs in V1 overlap with PV-expressing neurons.

“As described previously (Ha ¨rtig et al., 1992), most of the PNNs in V1 overlap with PV-expressing neurons (Fig. 1A).”

• cites Ha ¨rtig et al., 1992Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Approximately 20% of both control and chABC-treated populations were characterized as narrow-spiking putative inhibitory units.

“Approximately 20% of both the control and chABC-treated populations were characterized as narrow-spiking, putative inhibitory (pIN) units (Fig. 2A, green), matching the distribution found in the neocortex in general (Markram et al., 2004).”

• cites Markram et al., 2004Not checked yet

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May combine two claims.

These high-frequency oscillations were abundant in all chABC-treated rats that underwent monocular deprivation, but disappeared gradually about 1 h after eye closure.

“These high-frequency oscillations were abundant in all chABC-treated rats that underwent MD, but disappeared gradually ϳ1 h after the eye closure (52-65 Hz, repeatedmeasures ANOVA, F ϭ 8.69, p ϭ 0.01 and 35-48 Hz, F ϭ 10.13, p ϭ 0.01).”

May combine two claims.

In chABC-treated animals, ipsilateral unit activity showed no change at 12 h after MD start, but showed a significant increase in activity after 24 h.

“The ipsilateral unit activity showed no change at 12 h after MD start, but showed a significant increase in activity after 24 h (Fig. 6B, far right, p ϭ 0.03, Mann-Whitney U test).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Both groups of animals had sparse gamma oscillations compared with previous recordings from head-fixed mice.

“We found that both groups of animals had sparse gamma oscillations compared with previous recordings from head-fixed mice (Niell and Stryker, 2010).”

• cites Niell and Stryker, 2010Not checked yet

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The quote only partly states this claim.

Without PNNs, spiking variability was increased.

“whereas spiking variability was increased as predicted in a simulation with a Brunel neural network.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The responsiveness to visual stimulation was low overall compared with previous findings in rodents.

“Compared with previous findings in rodents, the responsiveness to visual stimulation was low overall (Girman et al., 1999;Niell andStryker, 2008, 2010).”

• cites Girman et al., 1999Not checked yet

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• cites Niell andStryker, 2008Not checked yet

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• cites Niell andStryker, 2010Not checked yet

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May combine two claims.

A pronounced and immediate increase in gamma activity was followed by changes in unit responses in the first 12-24 h.

“A pronounced and immediate increase in gamma activity was followed by changes in unit responses in the first 12-24 h”

May combine two claims.

In control animals after monocular deprivation, there was a nonsignificant potentiation of activity after 12 h, which returned to baseline activity after 48 h.

“In control animals after MD, there was a nonsignificant potentiation of activity after 12 h ( p ϭ 0.06), which went back to baseline activity after 48 h.”

May combine two claims.

The LFP effects were observed both in the ipsilateral and contralateral hemispheres to the closed eye, although they were strongest in the contralateral side.

“The LFP effects were observed both in the ipsilateral and contralateral hemispheres to the closed eye, although they were strongest in the contralateral side.”

May combine two claims.

Time periods with gamma oscillations (gamma events) were not different in chABC-treated animals, neither events per unit time nor gamma event power.

“Time periods with gamma oscillations (gamma events) were not different in chABC-treated animals, neither events per unit time nor gamma event power.”

May combine two claims.

Our data from chronically recorded single units are similar to previous work on CP aged animals looking at population activity alone, but the changes in activity occur earlier in our data.

“Together, our data from chronically recorded single units are similar to previous work on CP aged animals looking at population activity alone, but the changes in activity occur earlier in our data (Frenkel and Bear, 2004;Gandhi et al., 2008; but see Kuhlman et al., 2013).”

• cites Frenkel and Bear, 2004Not checked yet

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• cites Gandhi et al., 2008Not checked yet

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• cites Kuhlman et al., 2013Not checked yet

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Classified as probably not a substantial claim.

The assembly of PNNs coincides with the end of the period of heightened visual cortex plasticity in juveniles.

“The assembly of PNNs coincides with the end of the period of heightened visual cortex plasticity in juveniles”

May combine two claims.

The time window for heightened activity-dependent plasticity, or critical period, is limited and depends on maturation of inhibitory neurons after eye opening, in particular maturation of GABAergic fast-spiking parvalbumin-positive inhibitory neurons and their network integration.

“The time window for heightened activity-dependent plasticity, or critical period (CP), is limited and depends on the maturation of inhibitory neurons after eye opening, in particular the maturation of the GABAergic fast-spiking parvalbumin (PVϩ) inhibitory neurons and their network integration (Fagiolini and Hensch, 2000;Fagiolini et al., 2004;Hensch, 2005;Southwell et al., 2010).”

• cites Fagiolini and Hensch, 2000Not checked yet

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• cites Fagiolini et al., 2004Not checked yet

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• cites Hensch, 2005Not checked yet

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May combine two claims.

PNN removal in adults resets the neuronal network to an immature, juvenile state with reduced inhibitory activity and high spiking variability similar to that of the critical period.

“we show for the first time that PNN removal in adults resets the neuronal network to an immature state with reduced inhibitory activity and high spiking variability similar to that of the CP.”

• Also stated in: § Abstract · plain

  “we show that PNN removal resets the neural network to an immature, juvenile state.”

Classified as probably not a substantial claim.

Parvalbumin-positive inhibitory neuron maturation suppresses spontaneous activity of excitatory neurons, thereby promoting visually evoked activity after eye opening.

“Recent work suggests that the PVϩ inhibitory neuron maturation suppresses spontaneous activity of excitatory neurons, thereby promoting visually evoked activity after eye opening (Toyoizumi et al., 2013).”

• cites Toyoizumi et al., 2013Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

Beyond 48 h after MD, it became difficult to confirm the identity of the neurons, so those data were excluded from analysis.

“Beyond this point, it became difficult to confirm the identity of the neurons; these data were therefore excluded from analysis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

Spike sorting separation quality was assessed using autocorrelation and cross-correlation, Mahalanobis distance, and visual inspection, and approximately 30% of recorded units were left out of the analysis.

“Separation quality was assessed further using the Mahalanobis distance and by visual inspection.On this basis, ϳ30% of recorded units were left out of the analysis.”

Classified as probably not a substantial claim.

Brain state was quantified based on the method used by Wang et al. (2013).

“Brain state was quantified based on the method used by Wang et al. (2013).”

• cites Wang et al. (2013)Not checked yet

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Classified as probably not a substantial claim.

Putative excitatory neurons were distinguished from putative inhibitory neurons based on characteristics of their mean waveform.

“Putative excitatory neurons were distinguished from putative inhibitory neurons based on characteristics of their mean waveform, as recorded by the electrode in which the amplitude was largest (Bruno and Simons, 2002;Bartho ´et al., 2004;Niell and Stryker, 2008).”

• cites Bruno and Simons, 2002Not checked yet

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• cites Bartho ´et al., 2004Not checked yet

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• cites Niell and Stryker, 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All data were tested for normality before analysis by Shapiro-Wilk test and statistical testing was performed accordingly.

“All data were tested for normality before analysis (by Shapiro-Wilk test) and statistical testing was performed accordingly.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The Brunel model has become established as a canonical model for the description of spontaneous cortical activity because it captures many essential features observed in experiments, such as asynchronous irregular spiking activity.

“This model has become established as a canonical model for the description of spontaneous cortical activity because it captures many essential features observed in experiments; for example, asynchronous irregular spiking activity.”

• cites Brunel, 2000Not checked yet

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May combine two claims.

The LFP recordings were consistent with the single unit responses in that chABC treatment changed the baseline state of the neuronal network, but not the processing of visual stimuli.

“Therefore, the LFP recordings were consistent with the single unit responses in that the chABC treatment changed the baseline state of the neuronal network, but not the processing of visual stimuli.”

Classified as probably not a substantial claim.

Electrophysiological recordings were conducted in V1 as verified by postmortem histochemistry to confirm electrode position.

“All electrophysiological recordings were conducted in the V1 as verified by postmortem histochemistry to confirm electrode position (Fig. 1B).”

May combine two claims.

The state shift of the network toward a more irregular state is consistent with in vivo findings and supports that chABC treatment may cause a shift in the excitatory-inhibitory balance, correlating with changes in spiking variability and spiking activity.

“This state shift of the network toward a more irregular state is consistent with our in vivo findings and supports that chABC treatment may cause a shift in the excitatory-inhibitory balance, correlating with changes in spiking variability and spiking activity.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All experimentation was approved by the Norwegian Animal Research Committee before initiation.

“All experimentation was approved by the Norwegian Animal Research Committee before initiation.”

Classified as probably not a substantial claim.

Gamma events were detected using the method described in Colgin et al. (2009).

“Gamma events were detected using the method described in Colgin et al. (2009).”

• cites Colgin et al. (2009)Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The ocular dominance index findings are consistent with previous work.

“These findings are consistent with previous work (Pizzorusso et al., 2002).”

• cites Pizzorusso et al., 2002Not checked yet

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Classified as probably not a substantial claim.

High-frequency gamma oscillations (30-80 Hz) are likely due to highly synchronized activity in parvalbumin-positive cells.

“The high-frequent gamma oscillations (30 -80 Hz) are likely due to highly synchronized activity in the PVϩ cells (Cardin et al., 2009)”

• cites Cardin et al., 2009Not checked yet

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May combine two claims.

PNNs may stabilize the network and limit plasticity.

“Adjusting inhibitory synaptic efficacy alone was sufficient to cause increased spiking variability (Fig. 5), supporting the hypothesis that the level of inhibition is indicative of network maturation state and that the PNNs may stabilize the network and limit plasticity.”

Classified as probably not a substantial claim.

Oscillations in the gamma-frequency range result from synchronized activity of PV+ neurons.

“Oscillations in the gamma-frequency range result from synchronized activity of PVϩ neurons (Cardin et al., 2009).”

• cites Cardin et al., 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Gamma oscillations have been correlated with sensory stimulation in anesthetized animals, locomotion, attention, and memory load.

“Gamma oscillations have been correlated with sensory stimulation in anesthetized animals, locomotion, attention, and memory load (Niell andStryker, 2008, 2010;Igarashi et al., 2014;Pritchett et al., 2015).”

• cites Niell and Stryker, 2008, 2010Not checked yet

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• cites Igarashi et al., 2014Not checked yet

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• cites Pritchett et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Anesthesia is known to affect correlated activity and the activity of both inhibitory and excitatory units.

“Anesthesia is known to affect correlated activity and the activity of both inhibitory and excitatory units (Vizuete et al., 2012;Goltstein et al., 2015).”

• cites Vizuete et al., 2012Not checked yet

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• cites Goltstein et al., 2015Not checked yet

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May combine two claims.

Removal of PNNs leads to reduced inhibitory activity, with only minor effects on basic information processing by the network.

“Our data suggest that removal of PNNs leads to reduced inhibitory activity, with only minor effects on basic information processing by the network.”

• AssumptionRests on an assumption: Evidence to support the facilitation of PV+ neuron activity by PNNs has largely been absent.

Probably not a substantial claim: may not pass S3 (load-bearing).

Reduced inhibitory activity after PNN removal may be of relevance for several neurological diseases in which dysfunction of inhibitory PV+ neurons have been implicated, most notably schizophrenia.

“Furthermore, reduced inhibitory activity after PNN removal may be of relevance for several neurological diseases in which dysfunction of inhibitory PVϩ neurons have been implicated, most notably schizophrenia (Lewis et al., 2012).”

• cites Lewis et al., 2012Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

We cannot infer directly that the changes in unit activity observed during monocular deprivation in awake recordings correspond directly to recordings performed under anesthesia after monocular deprivation.

“We cannot infer directly that the changes in unit activity observed during MD in awake recordings correspond directly to recordings performed under anesthesia after MD.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Stronger gamma oscillations may be expected if the animal is alert, such as during an associative learning task.

“Stronger gamma oscillations may be expected if the animal is alert, such as during an associative learning task (Igarashi et al., 2014).”

• cites Igarashi et al., 2014Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Postmortem studies of schizophrenia patients indicate that PNNs are depleted.

“Interestingly, postmortem studies of schizophrenia patients indicate that PNNs are depleted (Berretta, 2012;Pantazopoulos et al., 2015).”

• cites Berretta, 2012Not checked yet

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• cites Pantazopoulos et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Visual responses of neurons in visual cortex in awake and freely moving rodents have rarely been examined.

“To date, visual responses of neurons in visual cortex in awake and freely moving rodents have rarely been examined (Ji and Wilson, 2007;Toyoizumi et al., 2013;Haggerty and Ji, 2015).”

• cites Ji and Wilson, 2007Not checked yet

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• cites Toyoizumi et al., 2013Not checked yet

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• cites Haggerty and Ji, 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The effect of anesthesia on spiking activity is stronger during spontaneous activity compared with stimulus-evoked firing, for which behavioral state has a stronger impact.

“However, the effect of anesthesia on spiking activity is stronger during spontaneous activity compared with stimulus-evoked firing, for which behavioral state has a stronger impact (Niell and Stryker, 2010).”

• cites Niell and Stryker, 2010Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The difference in gamma oscillations could be due to differences in the experimental setup or differences between species.

“The difference could be due to differences in the experimental setup or differences between species (Buzsa ´ki et al., 2003;Niell and Stryker, 2010).”

• cites Buzsáki et al., 2003Not checked yet

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• cites Niell and Stryker, 2010Not checked yet

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May combine two claims.

The high activity of mature PV+ neurons may be facilitated by PNNs by providing a favorable extracellular environment, protection against oxidative stress after high metabolic demands, and capture of Otx2.

“The high activity of mature PVϩ neurons may be facilitated by the PNNs by providing a favorable extracellular environment (Bru ¨ckner et al., 1993;Ha ¨rtig et al., 1999;Morawski et al., 2015), protection against oxidative stress after the high metabolic demands (Cabungcal et al., 2013), and capture of Otx2 (Beurdeley et al., 2012).”

• cites Brückner et al., 1993Not checked yet

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• cites Härtig et al., 1999Not checked yet

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• cites Morawski et al., 2015Not checked yet

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May combine two claims.

Compared with in vivo data from adult rats and in silico data from the Brunel model, this points to similar network states between CP aged animals and the chABC-treated group, in which reduced inhibitory activity may cause increased spiking variability.

“Compared with our in vivo data from adult rats and the in silico data from the Brunel model (Fig. 5), this points to similar network states between the CP aged animals and the chABC-treated group, in which reduced inhibitory activity may cause increased spiking variability.”

May combine two claims.

A similar trend was observed in juvenile rats, in which inhibition is lower than in adults, suggesting a common feature of an immature network state.

“A similar trend was observed in juvenile rats, in which inhibition is lower than in adults, suggesting a common feature of an immature network state (Hensch et al., 1998).”

• cites Hensch et al., 1998Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

This is one of very few investigations to monitor the activity of the same units in the binocular region of V1 during ocular dominance plasticity.

“This is one of very few investigations to monitor the activity of the same units in the binocular region of V1 during OD plasticity (Mioche and Singer, 1989;Rose et al., 2016).”

• cites Mioche and Singer, 1989Not checked yet

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• cites Rose et al., 2016Not checked yet

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• AssumptionRests on an assumption: The most prominent plasticity changes during ocular dominance plasticity occur in the binocular part of V1.

May combine two claims.

A similar effect was seen with monocular deprivation in CP aged animals, suggesting that this may be a common feature of circuits of high plasticity when load is placed on the network, such as during the initial phase of sensory deprivation.

“A similar effect was seen with MD in CP aged animals (Fig. 8), suggesting that this may be a common feature of circuits of high plasticity when load is placed on the network, such as during the initial phase of sensory deprivation.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

The neuronal circuitry of the juvenile brain is likely different from resetting the circuitry of adult brain, likely also affecting the mechanisms of ocular dominance plasticity.

“However, the neuronal circuitry of the juvenile brain is likely different from resetting the circuitry of adult brain, likely also affecting the mechanisms of OD plasticity.”

Classified as probably not a substantial claim. May combine two claims.

The use of chronically implanted tetrodes enabled recordings in awake rats without movement restraint and monitoring the activity of the very same neurons across several sessions.

“The use of chronically implanted tetrodes enabled recordings in awake rats without movement restraint and monitoring the activity of the very same neurons across several sessions, bringing novel insight into the mechanisms of OD plasticity.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The small peak at 50 Hz reflects local line noise and is not biological activity, and was filtered out for power analysis.

“The small peak at 50 Hz reflects local line noise and is not biological activity (filtered out for power analysis).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The underlying mechanisms and time course of events of ocular dominance plasticity remain unresolved.

“Although OD plasticity has been the canonical model to study activity-dependent plasticity for decades, the underlying mechanisms and time course of events remain unresolved (Kuhlman et al., 2013;Cooke and Bear, 2014).”

• cites Kuhlman et al., 2013Not checked yet

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• cites Cooke and Bear, 2014Not checked yet

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