Clock Genes Control Cortical Critical Period Timing
Open accessAbstract
Summary Circadian rhythms control a variety of physiological processes, but whether they may also time brain development remains largely unknown. Here, we show that circadian clock genes control the onset of critical period plasticity in the neocortex. Within visual cortex of Clock-deficient mice, the emergence of circadian gene expression was dampened, and the maturation of inhibitory parvalbumin (PV)-cell networks slowed. Loss of visual acuity in response to brief monocular deprivation was concomitantly delayed and rescued by direct enhancement of GABAergic transmission. Conditional deletion of Clock or Bmal1 only within PV-cells recapitulated the results of total Clock-deficient mice. Unique downstream gene sets controlling synaptic events and cellular homeostasis for proper maturation and maintenance were found to be regulated by CLOCK specifically within PV-cells. These data demonstrate a developmental role for circadian clock genes outside the suprachiasmatic nucleus, which may contribute mis-timed brain plasticity in associated mental disorders.
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- Findingown data
In Clock-mutant mice, inhibitory PV-cell networks matured more slowly.
“and the maturation of inhibitory parvalbumin (PV)-cell networks slowed.”
Quote in the paperSubstantial claim - Findingown data
In Clock-mutant mouse visual cortex, circadian gene expression emerged less strongly.
“Within visual cortex of Clock-deficient mice, the emergence of circadian gene expression was dampened”
Quote in the paperSubstantial claim - Findingown data
Enhancing GABAergic transmission directly restored monocular-deprivation acuity loss in Clock-mutant mice.
“and rescued by direct enhancement of GABAergic transmission.”
Quote in the paperSubstantial claim - Findingown data
Brief monocular deprivation caused a delayed loss of visual acuity in Clock-mutant mice.
“Loss of visual acuity in response to brief monocular deprivation was concomitantly delayed”
Quote in the paperSubstantial claim - Findingown data
Deleting Clock or Bmal1 only in PV-cells reproduced the phenotype of whole-body Clock mutants.
“Conditional deletion of Clock or Bmal1 only within PV-cells recapitulated the results of total Clock-deficient mice.”
Quote in the paperSubstantial claim
- Findingown data
CLOCK within PV-cells regulates distinct downstream gene sets tied to synaptic events and cellular homeostasis needed for maturation and maintenance.
“Unique downstream gene sets controlling synaptic events and cellular homeostasis for proper maturation and maintenance were found to be regulated by CLOCK specifically within PV-cells.”
Quote in the paperSubstantial claim - Findingown data
Clock deletion did not change intrinsic electrophysiological properties of PV-cells.
“Moreover, intrinsic electrophysiological properties of PV-cells were unaffected by Clock deletion (Figure S4 and Table S1).”
Quote in the paperNot a substantial claim - Findingown data
Monocular deprivation at P25-P26 did not change visual acuity in Clock-mutant mice.
“However, visual acuity was not changed in Clock−/− mice (Figures 2B and 2C).”
Quote in the paperSubstantial claim - Findingown data
Pvalb expression fell more in conditional Bmal1 knockouts than in conditional Clock knockouts.
“Reduction of Pvalb expression was more prominent in the conditional knock-out of Bmal1 than that of Clock (Figure 7H)”
Quote in the paperNot a substantial claim - Findingown data
GO analysis of transcripts changed by Clock deletion showed enrichment for synaptic function, mitochondrial function, and ATPase activity.
“Gene ontology (GO) analysis of transcripts expressed differentially upon Clock deletion (Figure 6B) revealed an over-representation of GO terms related to synaptic function (Cluster 1), mitochondrial function (Cluster 2) and ATPase activity (Cluster 3) (Figure 6C).”
Quote in the paperSubstantial claim - Findingown data
Brief monocular deprivation reduced visual acuity in PV-Cre; Clockf/f mice only in adulthood.
“visual acuity was significantly reduced in PV-Cre; Clockf/f mice by brief MD only in adulthood (Figure 7I).”
Quote in the paperSubstantial claim - Findingown data
A delayed ocular dominance shift after monocular deprivation confirmed the delayed visual plasticity in Clock-mutant mice.
“This delayed onset of visual plasticity was also confirmed by a delayed ocular dominance shift (contra/ipsi ratio at low spatial frequency) following MD in Clock−/− mice (Figures S2A and S2B).”
Quote in the paperSubstantial claim - Findingown data
The PER1 pattern was similar inside PV-cells.
“This PER1 profile was similar within PV-cells (Figure S6E), indicating a functional CLOCK-mediated circadian machinery within PV-cells.”
Quote in the paperNot a substantial claim - Findingown data
PER1 expression was lower in Clock-mutant mice.
“and the expression level of PER1 was dampened in Clock−/− mice (Figure S6D).”
Quote in the paperNot a substantial claim - Findingown data
Monocular deprivation in adulthood (P60-P90) significantly reduced visual acuity in Clock-mutant mice.
“but was significantly reduced in Clock−/− mice (Figures 2D–2F).”
Quote in the paperSubstantial claim - Findingown data
Brief monocular deprivation induced amblyopia in PV-Cre control littermates only during the critical period.
“While amblyopia was then induced as expected by brief MD in PV-Cre control littermates only at critical period”
Quote in the paperSubstantial claim - Findingown data
Pvalb expression did not show circadian rhythmicity during development.
“Because Pvalb expression itself did not show circadian rhythmicity during development (Figure 1C)”
Quote in the paperSubstantial claim - Findingown data
Among several neural markers, only Pvalb expression was significantly lower in Clock-mutant mice at both critical-period and adult ages.
“Only the expression of Pvalb was significantly reduced at both critical period and adult ages in Clock−/− mice (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Retinogeniculate axon terminal segregation in the dLGN was normal in Clock-mutant mice.
“eye-specific segregation of retino-geniculate axon terminals in the dorsal lateral geniculate nucleus (dLGN), which is refined earlier postnatally in an activity-dependent manner (Huberman et al., 2008), was also normal in Clock−/− mice (Figures S1C and S1D).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huberman et al., 2008 source
Not checked in the free run.
- Findingown data
Monocular deprivation at P25-P26 strongly reduced deprived-eye acuity in wild-type mice.
“Upon MD during the critical period starting from P25–P26, visual acuity of the deprived eye was significantly reduced (i.e. amblyopia) in Clock+/+ mice, indicating strong plasticity at this age (Figure 2A and 2C).”
Quote in the paperSubstantial claim - Findingown data
Visual acuity was significantly reduced in adult PV-Cre; Bmal1f/f mice.
“but was reduced significantly in adulthood in PV-Cre; Bmal1f/f mice (Figure 7I).”
Quote in the paperSubstantial claim - Findingown data
Diazepam given with monocular deprivation at P25-P26 fully induced amblyopia in Clock-mutant mice.
“Amblyopia was induced fully by diazepam treatment concurrent with MD at P25–P26 in Clock−/− mice (Figures 3A and 3B).”
Quote in the paperSubstantial claim - Findingown data
A 10-day diazepam treatment from P23 to P33 prevented later adult plasticity in Clock-mutant mice.
“Moreover, mimicking a critical period by 10-day injection (P23–P33) of diazepam (Fagiolini and Hensch, 2000) prevented later adult plasticity in Clock−/− mice (Figure 3C).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fagiolini and Hensch, 2000 source
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- Findingown data
Clock expression in mouse V1 lacked rhythmicity at all ages tested.
“Clock expression did not show rhythmicity at any age (Figure 1C)”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data
Soma-enwrapping PNN maturation was slower in Clock-mutant mice.
“The maturation of soma-enwrapping PNNs was also slowed in Clock−/− mice (Figures 4B, 4D, and 4E)”
Quote in the paperSubstantial claim - Findingown data
PV-cell circuits stayed immature in Clock-mutant mice even after P120.
“PV-cell circuits remained immature even at > P120 in Clock−/− mice (Figures S3B and S3C), which was consistent with their prolonged plasticity (Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
Monocular deprivation at typical critical-period ages did not change visual acuity in PV-Cre; Bmal1f/f mice.
“Visual acuity again remained unchanged by MD at typical critical period ages (Figure S7D)”
Quote in the paperSubstantial claim - Findingown data
Conditional Clock deletion made PV-cell circuits and surrounding PNNs significantly immature at critical-period and adult ages.
“Analyses by immunohistochemistry and qRT-PCR again revealed PV-cell circuits and surrounding PNNs to be significantly immature at critical period and adult ages by the conditional deletion of Clock (Figures 7C–7H).”
Quote in the paperSubstantial claim - Findingown data
PER1 showed global circadian rhythmicity, peaking at ZT0 and troughing at ZT12.
“A circadian gene product PER1 globally exhibited circadian rhythmicity with a peak at ZT0 and a trough at ZT12 (Figure S6C)”
Quote in the paperNot a substantial claim - Findingown data
Monocular deprivation in adulthood (P60-P90) usually left visual acuity unchanged in wild-type mice.
“Instead, after MD in adulthood starting from P60–P90, visual acuity remained typically unchanged in Clock+/+ mice”
Quote in the paperSubstantial claim - Findingown data
Dbp expression in Clock-mutant V1 was reduced in proportion to the number of deleted Clock alleles.
“qRT-PCR analyses revealed Dbp expression to be reduced in a dose-dependent manner of Clock deletion (Figure 1E)”
Quote in the paperSubstantial claim - Findingcitation
Genes misregulated in Clock-deleted PV-cells are associated with autism and schizophrenia.
“It has been shown that a set of genes mis-regulated in our Clock-deleted PV-cells are associated with autism (Kcnma1, Nrxn1-3, Prkcb, Slc24a2, Cacna1c, Ptpn11, Htr2a, Abat) and schizophrenia (Cacna1c, Htr2a) (Allen et al., 2008; Basu et al., 2009).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
PV-cell-specific Clock or Bmal1 knockout mice showed delayed critical-period timing even though the SCN master clock remained intact.
“and PV-cell-specific Clock or Bmal1 conditional knock-out mice also exhibited delayed critical period timing despite an intact master clock in the SCN (Figure 7).”
Quote in the paperSubstantial claim - Findingown data
Microarray analysis of PV-cells identified distinct gene sets misregulated in Clock mutants that may underlie immature PV-cell circuits.
“Our PV-cell specific microarray analysis identified unique sets of genes mis-regulated in Clock−/− mice that are potentially responsible for the immature PV-cell circuits.”
Quote in the paperSubstantial claim - Interpretationown data
Clock gene disruption might contribute to mistimed brain plasticity in related mental disorders.
“which may contribute mis-timed brain plasticity in associated mental disorders.”
Quote in the paperSubstantial claim - Premisecitation
Postnatal maturation of cortical inhibitory networks is needed to start the critical period.
“The maturation of cortical inhibitory networks in the postnatal brain is important for initiating this critical period (Fagiolini and Hensch, 2000; Sugiyama et al., 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
The data show circadian clock genes have a developmental function outside the SCN.
“These data demonstrate a developmental role for circadian clock genes outside the suprachiasmatic nucleus”
Quote in the paperSubstantial claim - Premisecitation
Fast-spiking PV-expressing GABA neurons are central to this process.
“One particular GABA cell-type, fast-spiking neurons expressing parvalbumin (PV), is pivotal for this process (Fagiolini et al., 2004; Hensch, 2005).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
Clock genes regulate the start of neocortical critical-period plasticity.
“Here, we show that circadian clock genes control the onset of critical period plasticity in the neocortex.”
Quote in the paperSubstantial claim - Interpretationown data
CLOCK is needed for functional maturation of PV-cell circuits.
“Taken together, CLOCK is important for the functional maturation of PV-cell circuits.”
Quote in the paperSubstantial claim - Interpretationown data
Selective deletion of Clock or Bmal1 in PV-cells reproduces the delayed plasticity onset seen in global Clock mutants.
“These results recapitulate delayed onset of plasticity identified in global Clock−/− mutants by selective deletion of Clock or Bmal1 only from PV-cells.”
Quote in the paperSubstantial claim - Interpretationown data
CLOCK may regulate distinct gene sets that control synaptic events and cellular homeostasis needed for PV-cell maturation and maintenance.
“These results suggest that CLOCK may regulate unique sets of genes controlling synaptic events and cellular homeostasis for the proper maturation and maintenance of PV-cells.”
Quote in the paperSubstantial claim - Premisecitation
Changing the local extracellular environment around cortical PV-cells can alter plasticity timing.
“Direct manipulation of the local extracellular milieu surrounding cortical PV-cells can influence plasticity timing.”
Quote in the paperNot a substantial claim - Interpretationown data
PV-cells contain a functional CLOCK-dependent circadian mechanism.
“indicating a functional CLOCK-mediated circadian machinery within PV-cells.”
Quote in the paperSubstantial claim - Interpretationown data
The subcortical visual pathway looked intact in Clock-mutant mice.
“Taken together, the subcortical visual pathway in Clock−/− mice appeared intact.”
Quote in the paperSubstantial claim - Study design and conductown data
Immunohistology confirmed selective loss of CLOCK in cortical PV-cells at typical critical-period age after conditional Clock deletion.
“Immunohistological analysis confirmed specific loss of CLOCK expression within cortical PV-cells at typical critical period age (Figure 7A).”
Quote in the paperSubstantial claim - Interpretationown data
Clock genes inside PV-cells coordinate their postnatal network maturation and thereby the timing of critical-period plasticity.
“We show that clock genes intrinsic to PV-cells coordinate postnatal maturation of their networks and consequently the onset of critical period plasticity.”
Quote in the paperSubstantial claim - Interpretationcitation
The results point to reduced inhibition in local cortical circuits when CLOCK is absent.
“These data suggested a reduced inhibition within local cortical circuits in the total absence of CLOCK (Hensch et al, 1998).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hensch et al, 1998 source
Not checked in the free run.
- Premisecitation
As PV-cells mature, PNNs of extracellular matrix molecules condense around their cell bodies.
“With PV-cell maturation, perineuronal nets (PNNs) of extracellular matrix molecules condense around their somata”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
The molecular rhythm in mouse V1 develops relatively late compared with the SCN rhythm, which appears around birth.
“This developmental trajectory of molecular rhythm was relatively late compared to that in the SCN which appears perinatally (Shimomura et al., 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shimomura et al., 2001 source
Not checked in the free run.
- Interpretationown data
The Pvalb gene is probably not a direct target of CLOCK:BMAL1 transcription.
“it is unlikely that the Pvalb gene is a direct target of CLOCK:BMAL1-mediated transcription.”
Quote in the paperSubstantial claim - Study design and conductown data
Because PV is not expressed in the SCN, the conditional deletion left CLOCK there intact.
“Importantly in the SCN, PV was not expressed, leaving CLOCK expression intact by our conditional deletion (Figure 7B).”
Quote in the paperSubstantial claim - Interpretationown data
This study showed that circadian clock genes time postnatal brain development.
“In this study, we showed that circadian clock genes time postnatal brain development.”
Quote in the paperSubstantial claim - Premisecitation
Cell-autonomous redox dysregulation from deleting Gclc only in PV-cells is enough to prolong critical-period plasticity.
“Direct cell autonomous redox dysregulation by deletion of the primary antioxidant (glutathione) synthetic enzyme (Gclc) only within PV-cells is sufficient to prolong critical period plasticity (Morishita et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Morishita et al., 2015 source
Not checked in the free run.
- Premisecitation
Intracellular maturation programs, in addition to the local cortical environment, may regulate GABAergic circuit development.
“Intracellular maturational programs in addition to the local cortical milieu may regulate the development of GABAergic circuits (Bartolini et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bartolini et al., 2013 source
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- Interpretationcitation
Such environmental influences during normal development might still affect critical-period plasticity timing through the mechanisms described.
“Thus, these environmental influences even during normal development may still impact timing of critical period plasticity through the mechanisms described here.”
Quote in the paperNot a substantial claim - Premisecitation
Autism and schizophrenia are characterized by impaired PV-cell circuits.
“which are in turn marked by impaired PV-cell circuits (Gogolla et al., 2009; Le Magueresse and Monyer, 2013; Marin, 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
These genes likely affect PV-cell maturation or maintenance rather than earlier processes such as migration.
“It is likely that these genes are involved in maturation and/or maintenance of PV-cell circuits rather than earlier events such as cell migration.”
Quote in the paperSubstantial claim - Interpretationreasoning
The findings suggest a neurodevelopmental link between circadian disruption and mental illness.
“Lastly, our findings offer a neurodevelopmental link between circadian disruption and mental illness.”
Quote in the paperSubstantial claim - Premisecitation
Clock-mutant mice have normal behavioral rhythms under a standard light:dark cycle.
“since Clock−/− mice exhibit normal behavioral rhythms under a conventional light:dark cycle (Debruyne et al., 2006)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Debruyne et al., 2006 source
Not checked in the free run.
- Interpretationcitation
The developmental delay is probably not caused by loss of systemic circadian rhythms.
“The developmental delay observed here is not likely due to loss of systemic circadian rhythms”
Quote in the paperSubstantial claim - Premisecitation
Human linkage studies have linked circadian gene mutations and behavioral changes such as sleep disturbances to psychiatric disorders including autism and schizophrenia.
“Linkage studies in human patients have implicated circadian gene mutations and behavioral changes (e.g. sleep disturbances) in psychiatric disorders, such as autism and schizophrenia (Chemerinski et al., 2002; Wulff et al., 2010)”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
The required clockwork is intrinsic to specific interneurons that are pivotal for critical-period plasticity.
“Moreover, the necessary clockwork is cell-intrinsic to specific interneurons known to play a pivotal role in critical period plasticity (Hensch, 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hensch, 2005 source
Not checked in the free run.
- Premisecitation
Transplanting embryonic GABA neuron precursors into postnatal mouse visual cortex induces an ectopic critical period after enough maturation time.
“Supporting this idea, when embryonic precursors of GABA neurons are transplanted into the postnatal visual cortex of mice, an ectopic critical period is induced once sufficient maturational time has elapsed for the transplanted cells (Southwell et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Southwell et al., 2010 source
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- Premisecitation
Embryonic stem cells, which lack circadian rhythmicity, gain oscillatory machinery during neural differentiation.
“Curiously, embryonic stem cells, which do not exhibit circadian rhythmicity, acquire their oscillatory machinery during neural differentiation (Yagita et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yagita et al., 2010 source
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- May combine two claims. 23
- Classified as probably not a substantial claim. 31
May combine two claims.
Findingown dataDeleting Bmal1 from excitatory neurons did not lower Pvalb expression or delay critical-period plasticity.
“As opposed to PV-cell-specific deletion, the removal of Bmal1 from the more numerous excitatory neuron population neither reduced Pvalb expression nor delayed critical period plasticity (Figures S7C and S7D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDbp, Per1, and Per2 rhythmicity in mouse V1 appeared gradually after eye opening and became fully established by adulthood (P70-P90).
“However, rhythmicity of well-known circadian genes (Dbp, Per1, Per2) gradually emerged with age after eye-opening and was fully established by adulthood (P70–P90) (Figure 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe plastic window in Clock-mutant mice lasted longer than two months, versus less than one month normally, since amblyopia remained inducible after P120.
“Moreover, the peak plastic window in Clock−/− mice was also effectively prolonged in duration (> 2 months) as compared to that of a normal critical period (< 1 month), because amblyopia was still inducible at > P120 in the mutants (Figure S3A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataClock-mutant mice had VEP onset latency and baseline visual acuity similar to age-matched wild-type controls.
“The latency to VEP onset, which is largely determined by retino-geniculate processing, and baseline visual acuity of Clock−/− mice were comparable to those of age-matched Clock+/+ controls (Figures 2C, 2F, and S1A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPV-cell numbers were lower in Clock-mutant mice and in Clock heterozygous mice.
“immunohistological analysis revealed the number of PV-cells to be reduced in Clock−/− mice (Figures 4B and 4C) and also in heterozygous Clock+/− mice (107.08 ± 5.1 cells/mm2 at critical period, P < 0.01 compared to Clock+/+ mice, 4 mice each, t-test).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Clock-mutant mice, mIPSC frequency, but not amplitude, was significantly reduced in layer 4 pyramidal neurons.
“Consistent with these anatomical changes, the frequency (but not amplitude) of miniature inhibitory post-synaptic currents (mIPSCs) was significantly reduced within layer 4 pyramidal neurons (Figures 5G–5I).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationPV-cell Bmal1 deletion caused neither the gross abnormalities of global deletion nor retinocortical transmission deficits.
“which caused neither gross abnormalities associated with global deletion (Bunger et al., 2000; Kondratov et al., 2006) nor deficits in retino-cortical transmission (Figure S1B).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Findingown dataCLOCK was present in over 80% of PV-cells but in smaller fractions of SST-positive (38%) and CR-positive (45%) interneurons.
“CLOCK was expressed in more than 80% of PV-cells, but in only a smaller proportion of other interneuron subtypes (38% and 45% in somatostatin (SST)-and calretinin (CR)-positive interneurons, respectively), suggesting a predominant function for CLOCK in PV-cells (Figures S6A and S6B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSyt2 puncta were also smaller and fewer in Clock-mutant mice.
“Syt2 puncta were also decreased in size and number in Clock−/− mice (Figures 5D–5F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPV-positive puncta on layer 4 pyramidal neurons were smaller and fewer in Clock-mutant mice.
“Detailed analysis further revealed PV-positive puncta onto layer 4 pyramidal neurons to be decreased in size and number in Clock−/− mice (Figures 5A–5C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCritical-period plasticity onset was delayed and then restored by enhancing GABAergic transmission pharmacologically.
“Concomitantly, the onset of critical period plasticity was delayed, but restored by pharmacological enhancement of GABAergic transmission.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCircadian gene oscillations in V1 first appeared after eye opening, and deleting Clock or Bmal1 after PV-cells had formed produced phenotypes similar to constitutive Clock deletion.
“Notably, circadian gene oscillations first emerged in V1 after eye opening, and the delayed deletion of Clock or Bmal1 once PV-cells have already appeared induced similar phenotypes as seen by constitutive Clock deletion.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationExperience-dependent plasticity shapes neural circuits during early postnatal life.
“Neural circuits are shaped by experience-dependent plasticity in early postnatal life (Hensch, 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hensch, 2004 source
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Classified as probably not a substantial claim.
PremisecitationAmblyopia is a lasting visual acuity loss caused by depriving one eye during a restricted developmental period.
“A classic example is the enduring loss of visual acuity, known as amblyopia, upon sensory deprivation of one eye during a limited developmental window (Wiesel, 1982).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wiesel, 1982 source
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May combine two claims.
PremisecitationIn mouse V1, functional PV-cell networks appear after eye opening (after P12) and mature over about three weeks (after P35).
“In mouse primary visual cortex (V1), functional PV-cell networks emerge after eye opening (> postnatal day P12) and mature over three weeks (> P35) (Gonchar et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gonchar et al., 2007
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCircadian clocks affect both everyday biological cycles and the scheduling of other body events beyond the daily cycle.
“Circadian rhythms have been shown to control not only daily biological processes but also the timing of other physiological events outside the diurnal cycle.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Golombek et al., 2014 source
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PremisecitationMost brain regions show circadian rhythmicity through the same oscillatory mechanism.
“Notably, the majority of brain regions exhibit circadian rhythmicity by the same oscillatory machinery (Wakamatsu et al., 2001; Yan et al., 2000).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPNN condensation helps close critical-period plasticity.
“which in turn contributes to closure of critical period plasticity (Beurdeley et al., 2012; Carulli et al., 2010; Pizzorusso et al., 2002).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThis transcriptional loop occurs in nearly all mammalian tissues, not only the SCN.
“This transcriptional loop can be observed not only in the SCN but also in nearly all mammalian tissues (Dibner et al., 2010; Takahashi et al., 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRemoving PNNs or lowering Otx2 uptake reopens plasticity in adult animals.
“In contrast, removing PNNs or reducing Otx2 uptake reopens plasticity in adulthood (Beurdeley et al., 2012; Pizzorusso et al., 2002; Spatazza et al., 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mammals, the SCN houses the central oscillator, which is produced by a CLOCK- and BMAL1-driven transcriptional feedback loop.
“In mammals, the central oscillator is located in the hypothalamic suprachiasmatic nucleus (SCN) and is generated by an auto-regulatory genetic feedback loop driven by the transcription factors CLOCK and BMAL1 (Lowrey and Takahashi, 2011) (Figure 1A).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lowrey and Takahashi, 2011
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PremisecitationCircadian timing mechanisms are linked to seasonal, photoperiod-driven changes in physiology and behavior.
“For example, there is a link between circadian timing mechanisms and seasonal, photoperiodic driven changes in an organism’s physiology and behavior (Golombek et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Golombek et al., 2014 source
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PremisecitationCircadian rhythms are roughly 24-hour biological clocks that drive daily gene expression, physiology, and behavior in most organisms.
“Circadian rhythms are approximately 24-hour biological clocks which drive daily patterns of gene expression, physiology and behavior in most organisms (Dibner et al., 2010; Masri and Sassone-Corsi, 2010; Takahashi et al., 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreasing BDNF or Otx2 to accelerate PV-cell maturation produces precocious plasticity.
“Acceleration of PV-cell maturation by over-expressing non-cell-autonomous factors, such as brain-derived neurotrophic factor (BDNF) or orthodenticle homeobox 2 (Otx2), induces precocious plasticity (Huang et al., 1999; Sugiyama et al., 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataClock genes inside PV-cells are important for PV-cell maturation and for the timing of critical-period plasticity.
“Taken together, intrinsic clock genes within pivotal PV-cells are important for their maturation and subsequent timing of critical period plasticity (Figure S8).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataExcitatory-neuron-specific Bmal1 deletion was confirmed to remove BMAL1 from cortical layers 2/3 and 5/6 but not the SCN.
“We confirmed restricted loss of BMAL1 expression from excitatory neurons in cortical layers 2/3 and 5/6, and not in the SCN (Figures S7A and S7B).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationVEP recordings were performed using standard techniques in mice.
“VEPs were recorded under nembutal/chlorprothixene anesthesia using standard techniques in mice (Fagiolini and Hensch, 2000; Porciatti et al., 1999).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRNA quality was assessed with a BioAnalyzer before microarray analysis.
“RNA quality was assessed on a 2100 BioAnalyzer (Agilent Technologies).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCumulative distributions of two groups were compared with two-sample Kolmogorov-Smirnov test.
“Two-sample Kolmogorov-Smirnov test (K-S test) was used to compare the cumulative distributions of two groups.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCircadian gene oscillation in mouse V1 appeared alongside PV-cell maturation, which disruption of the molecular clock slowed anatomically and functionally.
“Circadian gene oscillation in mouse V1 emerged in register with PV-cell maturation, which was anatomically and functionally slowed by disruption of the molecular clock.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationPCR genotyping primers were described elsewhere.
“Primers used in this study were described elsewhere (Debruyne et al., 2006; Storch et al., 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenImage data were collected and analyzed with blinding to genotype.
“Image data were collected and analyzed blind to genotypes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn slice recordings, series resistance was monitored closely.
“Series resistance (5–12 MΩ) was closely monitored during recording.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMice were randomly assigned to experimental groups.
“Mice were randomly assigned to the experimental groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationAntibodies against PER1, CLOCK, and BMAL1 were generated as described previously.
“Anti-PER1, anti-CLOCK, and anti-BMAL1 antibodies were made as described previously (Hastings et al., 1999; Lesauter et al., 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCLOCK:BMAL1 transcription targets many genes in different cellular contexts across tissues.
“Because CLOCK:BMAL1-mediated transcription targets a variety of genes in different cellular contexts across tissues (Janich et al., 2011; Marcheva et al., 2010; Paschos et al., 2012; Yu et al., 2013)”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAnimal housing and procedures were approved under Harvard University IACUC guidelines.
“Animal housing and experimental procedures were approved (AEP28-19) following guidelines of the Harvard University Institutional Animal Care and Use Committee.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningFor PV puncta analysis, threshold intensity was optimized across the entire image set to minimize exclusion of low-intensity puncta and fusion of multiple puncta.
“The threshold intensity was optimized for the entire set of images such that exclusion of low-intensity puncta (too high threshold) and fusion of multiple puncta (too low threshold) were minimized.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCircadian rhythms regulate brain redox homeostasis, and circadian gene disruption causes neuronal oxidative damage.
“Circadian rhythms have been shown to regulate redox homeostasis in the brain, and disruption of circadian genes causes neuronal oxidative damage (Musiek et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Musiek et al., 2013 source
Not checked in the free run.
May combine two claims.
PremisecitationCLOCK:BMAL1 levels or activity are tightly tied to circadian oscillations, which pulsed light or sleep deprivation disrupt by suppressing CLOCK:BMAL1 transcription.
“However, it is important to keep in mind that the levels and/or activity of CLOCK:BMAL1 are tightly linked to circadian oscillations, which are disrupted by pulsed-light exposure or sleep deprivation suppressing CLOCK:BMAL1-mediated transcription (Grone et al., 2011; Mongrain et al., 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenMultiple group comparisons used one-way ANOVA with Dunnett's test and two-way ANOVA with Bonferroni's test.
“One-way ANOVA with Dunnett’s multiple comparison test and two-way ANOVA with Bonferroni’s multiple comparison test were used to compare multiple groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenImaging settings were optimized and held constant across all samples within an experiment.
“Imaging settings were optimized and kept constant for the entire set of samples belonging to one experiment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenTwo-group comparisons used two-tailed unpaired t-test or Mann-Whitney test.
“Two-tailed unpaired t-test or Mann-Whiteny test were used to compare between two groups.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenMice were included in deprivation experiments only if their eyelids remained closed for the entire deprivation period.
“The integrity of the suture was checked daily and mice were used only if the eyelids remained closed throughout the duration of the deprivation period.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor PV-cell and WFA analysis, a manual threshold was set per image to include PV somata of all intensities and exclude background.
“A threshold for PV-cell somata was manually set for each image, such that all PV-cell somata of different signal intensity were included and various background signals across images properly excluded.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenMicroarray raw data were normalized by quantile normalization with background subtraction using GenomeStudio and analyzed with GeneSpring GX 11.
“The raw data were normalized by quantile normalization method with background subtraction using GenomeStudio Software (Illumina) and analyzed using GeneSpring GX 11 (Agilent Technologies).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRecordings were discarded if series resistance changed by more than 15%.
“And recording was discarded if series resistance changed by >15%.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationFast-spiking PV-cells are highly metabolically active, rich in mitochondria, and especially vulnerable to redox dysregulation, leading to oxidative stress and PNN loss.
“Notably, fast-spiking PV-cells are highly metabolically active with a hallmark of abundant mitochondrial molecules (Plessy et al., 2008) and are particularly vulnerable to redox dysregulation as compared to other neuronal types, resulting in their enhanced oxidative stress and loss of PNNs (Cabungcal et al., 2013a,b).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Plessy et al., 2008 source
Not checked in the free run.
- cites Cabungcal et al., 2013a,b
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNormality of data was tested with Shapiro-Wilk test.
“Shapiro-Wilk test was used for normality.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe degree of eye-specific axon overlap in dLGN was quantified using a multi-threshold protocol previously described.
“The degree of contralateral and ipsilateral eye axon overlap in dLGN was quantified using a multi-threshold protocol as previously described (Schafer et al., 2012; Torborg and Feller, 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Schafer et al., 2012 source
Not checked in the free run.
- cites Torborg and Feller, 2004
Not checked in the free run.
The paper relies on this without support.
The function of circadian clocks outside the SCN, especially their connection to higher-order cortical information processing, is not well understood.
“However, the purpose of circadian clocks outside the SCN, especially their link to higher-order functions such as information processing in the cerebral cortex remains poorly understood.”
Claims other papers make about this one
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Maturation of inhibitory circuits, in particular mediated by PVBCs, is necessary for the expression of early competitive plasticity.
“the maturation of inhibitory circuits, in particular mediated by PVBCs, is necessary for the expression of this early competitive plasticity”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [589]
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Hippocampal GABAergic Inhibitory Interneurons
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Reh, R. K., Dias, B. G., Nelson, C. A., Kaufer, D., Werker, J. F., Kolb, B., Levine, J. D., & Hensch, T. K. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820836117 · Cited by 492 · see citing works
Self-citationDo, K. Q., Cuenod, M., & Hensch, T. K. (2015) · Schizophrenia Bulletin · doi:10.1093/schbul/sbv065 · Cited by 158 · see citing works
Self-citationGenome-Wide Target Analyses of Otx2 Homeoprotein in Postnatal Cortex
Sakai, A., Nakato, R., Ling, Y., Hou, X., Hara, N., Iijima, T., Yanagawa, Y., Kuwano, R., Okuda, S., Shirahige, K., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00307 · Cited by 30 · see citing works
- Authors
- Kobayashi, Y., Ye, Z., & Hensch, T. K.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Corresponding author
- Hensch, Takao K.
- ORCID
- Hensch, Takao K.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 86
- Issue
- 1
- Pages
- 264-275
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4392344
- OpenAlex
- W2034312395
- Semantic Scholar
- 511b3e87ae9914544eb40fd7de570bee6b62a933
- Cited by
- 99
- References
- 75
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 12 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 20 · 2016: 8 · 2015: 5
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (P50MH094271)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- clock genes, critical period plasticity, visual cortex development, parvalbumin interneurons, GABAergic neurotransmission, monocular deprivation, visual acuity, clocks, Bmal1, synaptic development
- MeSH terms
- Adenosine Triphosphatases, Age Factors, Animals, Animals, Newborn, Circadian Rhythm, Evoked Potentials, Visual, gamma-Aminobutyric Acid, Functional Laterality, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Parvalbumins, Sensory Deprivation, Visual Acuity, Visual Cortex, Gene Expression Regulation, Developmental, Mice, CLOCK Proteins, ARNTL Transcription Factors, Period Circadian Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
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