Perineuronal nets, inhibitory interneurons and anxiety-related ventral hippocampal neuronal oscillations are altered by early life adversity
Open accessAbstract
BACKGROUND: In humans, accumulated adverse experiences during childhood increase the risk of anxiety disorders and attention-deficit hyperactivity disorder. In rodents, the ventral hippocampus (vHIP) is associated with anxiety regulation, and lesion of this region alters both anxiety-like behavior and activity levels. Neuronal oscillations in the vHIP of the theta frequency range (4–12 Hz) have been implicated in anxious states and derive in part from the activity of inhibitory interneurons in the hippocampus, some of which are enwrapped with perineuronal nets (PNNs), extracellular matrix structures that regulate plasticity. Here we sought to investigate the associations among early life stress-induced anxiety and hyperactivity with vHIP neuronal oscillations, inhibitory interneurons and PNNs in mice. METHODS: We used repeated maternal separation with early weaning (MSEW) to model accumulated early life adversity in mouse offspring and studied the underlying behavioral and cellular level changes in the vHIP associated with early life adversity. RESULTS: We found increased anxiety-like behavior and activity levels in MSEW adult males, along with increased theta power and enhanced theta-gamma coupling in the vHIP. MSEW mice showed reduced intensity of parvalbumin as well as increased PNN intensity around parvalbumin+ interneurons in the vHIP. We further observed that MSEW increased OTX2, a transcription factor promoting PNN development, in the choroid plexus where it is produced, as well as in parvalbumin+ interneurons, where it is sequestered. CONCLUSION: These findings raise the possibility of causal links among parvalbumin+ interneurons, PNNs, OTX2, and MSEW-induced anxiety and hyperactivity.
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Written from the paper’s full text.
TL;DR
Maternal separation with early weaning (MSEW) in male mice increased anxiety-like behavior and activity and altered ventral hippocampal oscillations, including greater theta power in a novel environment and enhanced theta-gamma coupling in familiar and novel environments. MSEW also reduced PV+ and SST+ interneuron densities in the ventral dentate gyrus and increased perineuronal net and OTX2 labeling around PV+ cells, suggesting links among interneurons, PNNs, OTX2, and MSEW-induced anxiety/hyperactivity.
Key findings
- MSEW adult males showed increased anxiety-like behavior in the elevated plus maze: lower percentage of open-arm entries in cohorts 1 and 2, and more time in closed arms in cohort 1. MSEW males also showed greater locomotion in a novel arena, with larger distance covered and increased percentage of time moving. No measurable anxiety-like changes were observed in MSEW females.
- In ventral hippocampus (vHIP) LFP recordings, MSEW males showed no differences in theta (4–12 Hz), beta (12–20 Hz), or gamma (30–80 Hz) power in a familiar environment, but greater theta-gamma phase-amplitude coupling. In a novel environment, MSEW males showed significantly greater theta power and alpha/beta power, with no delta or gamma power differences, and again enhanced theta-gamma coupling.
- MSEW reduced PV+ and SST+ interneuron densities in the ventral dentate gyrus (vDG), with no changes in CA1 or CA3; PV intensity within PV+ neurons in vDG was also reduced. There was no overall difference in GAD67+ cell density, no change in CR+ density, and no differences in DCX+ immature neuron or Ki67+ proliferating cell densities.
- PV+ cells in the vDG of MSEW mice had significantly greater WFA intensity, while vCA1 WFA intensity and overall WFA+ cell density were not different. MSEW increased OTX2 immunofluorescence intensity in the choroid plexus and in PV+/WFA+ cells in the vDG, but not in PV+/WFA− cells.
Methods
- Twenty litters of C57BL/6J mice from two breeding cohorts were assigned at P2 to non-handled control or MSEW: maternal separation for 4 h daily from P2–P5 and 8 h daily from P6–P16, with weaning at P17 versus normal weaning at P21. Behavior testing occurred at P60–P70.
- Behavior included anxiety and activity testing; histochemistry stained for doublecortin, Ki67, calretinin, PV, SST, OTX2, c-fos, and WFA. Cell counts/densities were analyzed in vHIP dentate gyrus, CA1, and CA3; WFA and OTX2 intensities were measured around PV+ cells using confocal images and ImageJ.
- LFP recordings were made from vHIP CA1 after electrode implantation (3.3 mm posterior, 3.45 mm lateral, 4.2 mm depth). One week after surgery, mice underwent familiar and novel environment sessions; power spectra used movement segments at 4–15 cm/s with a minimum of 5 seconds of movement, while phase-amplitude coupling included all animals. Statistical tests were unpaired two-tailed Student’s t-tests or Mann-Whitney U tests after Levene’s test.
Limitations
- The paper states that no anxiety-like changes were observed in MSEW females, that not all male mice were adversely affected by MSEW, and that causal links among PV+ interneurons, PNNs, OTX2, and MSEW-induced anxiety/hyperactivity remain speculative and require future work. It also states that the exact role of SST+ interneurons and whether altered PV intensity drives or results from altered oscillations need further investigation.
- Evident from the text: subsequent cellular and electrophysiological studies focused on males only; there was no direct manipulation of PV+ cells, PNNs, or OTX2 to test causality; and main-text reporting references tables for statistical values rather than providing exact effect sizes or group sample sizes.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 92 cited sources checked · 0 supported · 0 flagged
- Findingown data
SST+ interneuron density in the CA1 and CA3 regions showed no differences in MSEW mice.
“while the CA1 and CA3 regions showed no differences in this measure (Fig 4D’–D’’).”
Quote in the paperNot a substantial claim - Findingown data
The density of PV+ interneurons in MSEW mice was significantly reduced in the ventral DG compared to controls.
“the density of PV+ interneurons in MSEW mice was significantly reduced in the ventral DG (vDG) compared to controls (Fig 4B)”
Quote in the paperSubstantial claim - Findingown data
MSEW male mice exhibited greater locomotion in a novel testing arena, covering a larger distance.
“MSEW male mice exhibited greater locomotion in a novel testing arena in that they covered a larger distance (Fig 2A)”
Quote in the paperNot a substantial claim - Findingown data
In a novel environment, MSEW mice showed significantly greater alpha/beta power compared to controls.
“as well as alpha/beta power (Fig 3L) compared to controls.”
Quote in the paperSubstantial claim - Findingown data
In a novel environment, gamma power was not different between MSEW and control mice.
“Delta (Fig S2B) and gamma power (Fig 3M) were not different between groups.”
Quote in the paperNot a substantial claim
- Findingown data
There was no overall difference in the density of cells stained with the pan-interneuron marker GAD67 between MSEW and control mice.
“there was no overall difference in the density of cells stained with the pan-interneuron marker GAD67 (Fig S5B).”
Quote in the paperSubstantial claim - Findingown data
In a novel environment, delta power was not different between MSEW and control mice.
“Delta (Fig S2B) and gamma power (Fig 3M) were not different between groups.”
Quote in the paperNot a substantial claim - Findingown data
The density of PV+ interneurons in the CA1 and CA3 remained unaltered in MSEW mice.
“while the density in the CA1 and CA3 remained unaltered (Fig 4B’–B’’).”
Quote in the paperSubstantial claim - Findingown data
MSEW did not alter gamma power in a familiar environment.
“When tested in a familiar environment, no differences were observed between MSEW and control groups in theta (4–12Hz), beta (12–20Hz) or gamma (30–80 Hz) power (Fig 3D–F).”
Quote in the paperNot a substantial claim - Findingown data
In a novel environment, amplitude of gamma oscillations was significantly modulated by the phase of theta oscillations in MSEW mice compared to controls.
“Phase amplitude coupling analysis showed that amplitude of gamma oscillations was also significantly modulated by the phase of theta oscillations in MSEW mice in a novel environment when compared to controls (Fig 3N–O).”
Quote in the paperSubstantial claim - Findingown data
MSEW male mice showed an increase in the percentage of time spent moving during the duration of test.
“as well as an increase in the percentage of time spent moving during the duration of test (Fig 2B).”
Quote in the paperNot a substantial claim - Findingown data
MSEW did not alter beta power in a familiar environment.
“When tested in a familiar environment, no differences were observed between MSEW and control groups in theta (4–12Hz), beta (12–20Hz) or gamma (30–80 Hz) power (Fig 3D–F).”
Quote in the paperSubstantial claim - Findingown data
MSEW male mice in cohort 2 made significantly lower percent entries into the open arms.
“MSEW mice from cohort 2 also displayed greater anxiety in the EPM as they made significantly lower percent entries into the open arms (Fig 1D)”
Quote in the paperSubstantial claim - Findingown data
SST+ interneuron density was significantly reduced in the vDG of MSEW mice.
“SST+ interneuron density was also significantly reduced in the vDG of MSEW mice (Fig 4D)”
Quote in the paperSubstantial claim - Findingown data
MSEW did not alter theta power in a familiar environment.
“When tested in a familiar environment, no differences were observed between MSEW and control groups in theta (4–12Hz), beta (12–20Hz) or gamma (30–80 Hz) power (Fig 3D–F).”
Quote in the paperSubstantial claim - Findingown data
No measurable changes in anxiety-like behavior were observed in MSEW female mice compared to same sex controls.
“No measurable changes in anxiety-like behavior were observed in MSEW female mice compared to same sex controls (Fig S1).”
Quote in the paperNot a substantial claim - Findingown data
In a novel environment, MSEW mice showed significantly greater theta power compared to controls.
“When tested in a novel environment, MSEW mice showed significantly greater theta power (Fig 3K)”
Quote in the paperSubstantial claim - Findingown data
PV intensity within PV+ neurons of the vDG was reduced in MSEW mice.
“PV intensity within PV+ neurons of the vDG was also reduced (Fig. S5A)”
Quote in the paperSubstantial claim - Findingown data
MSEW male mice in cohort 1 spent significantly more time in the closed arms.
“MSEW mice in cohort 1 also spent significantly more time in the closed arms (Fig 1C).”
Quote in the paperSubstantial claim - Findingown data
MSEW did not alter delta power in a familiar environment.
“Additionally, delta (1–4 Hz) power was not altered (Fig S2A).”
Quote in the paperNot a substantial claim - Findingown data
No differences were observed in the amount of time spent in the open or closed arms between MSEW and control male mice in cohort 2.
“although no differences were observed in the amount of time spent in the open or closed arms between groups (Fig 1E).”
Quote in the paperNot a substantial claim - Findingown data
In a familiar environment, MSEW male mice displayed greater modulation of gamma oscillations by theta phase.
“By contrast, phase amplitude coupling analysis in the familiar environment showed that MSEW male mice displayed greater modulation of gamma oscillations by theta phase (Fig 3G–H).”
Quote in the paperSubstantial claim - Findingown data
No significant change in density was observed in the CR+ subpopulation in either the DG, CA1 or CA3 regions.
“No significant change in density was observed in the CR+ subpopulation in either the DG, CA1 or CA3 regions (Fig 4F–F’’).”
Quote in the paperNot a substantial claim - Findingown data
MSEW mice showed increased intensity of OTX2 in PV+/WFA+ cells in the vDG.
“Similar to the choroid plexus, MSEW mice showed increased intensity of OTX2 in PV+/WFA+ cells (Fig 6D)”
Quote in the paperSubstantial claim - Findingown data
No differences in the percentage of PV+ or SST+ cells co-labeled with c-fos in the DG or CA1 were observed between MSEW and control mice.
“No differences in the percentage of PV+ or SST+ cells co-labeled with c-fos in the DG or CA1 were observed (Fig 4H–H’, 4J–J’’)”
Quote in the paperSubstantial claim - Findingown data
The overall density of WFA+ cells in either the vDG or vCA1 was not affected between groups.
“The overall density of WFA+ cells in either region was also not affected between groups (Fig 5F,H).”
Quote in the paperNot a substantial claim - Findingown data
In the GCL of the vDG, PV+ cells in MSEW mice had significantly greater WFA intensity compared to controls.
“In the GCL of the vDG, we observed that PV+ cells in MSEW mice had significantly greater WFA intensity (Fig 5E) compared to controls.”
Quote in the paperSubstantial claim - Findingown data
PV+/WFA- cells showed no increase in OTX2 intensity in MSEW mice.
“while PV+/WFA- cells showed no such increase (Fig 6E).”
Quote in the paperSubstantial claim - Findingown data
No differences were detected in DCX+ immature neuron densities between MSEW and control mice.
“No differences were detected in DCX+ or Ki67+ cell densities between MSEW and control mice (Fig S3A, S3B).”
Quote in the paperSubstantial claim - Findingown data
SST+ and CR+ interneurons were not found to be encapsulated by WFA+ PNNs.
“SST+ and CR+ interneurons were not found to be encapsulated by WFA+ PNNs (Fig 5C–D).”
Quote in the paperNot a substantial claim - Findingown data
MSEW mice showed a significant increase in immunofluorescence intensity of OTX2 in the choroid plexus compared to controls.
“MSEW mice showed a significant increase in immunofluorescence intensity of OTX2 when compared to controls in the choroid plexus where it is produced (Fig 6B).”
Quote in the paperSubstantial claim - Findingown data
No differences were detected in Ki67+ proliferating cell densities between MSEW and control mice.
“No differences were detected in DCX+ or Ki67+ cell densities between MSEW and control mice (Fig S3A, S3B).”
Quote in the paperSubstantial claim - Findingown data
No differences were observed in the percentage of PV+ cells that were WFA+ in the vCA1 or the vDG between control and MSEW mice.
“No differences were observed in the percentage of PV+ cells that were WFA+ in the vCA1 or the vDG, between control and MSEW mice (Fig S4).”
Quote in the paperNot a substantial claim - Findingown data
Within each study, not all mice were adversely affected by MSEW.
“while overall significant differences in behavior were observed in 2 separate cohorts of male mice, within each study it was clear that not all mice were adversely affected by MSEW.”
Quote in the paperNot a substantial claim - Findingown data
No significant differences in intensity of WFA was observed between groups in the vCA1.
“However, no significant differences in intensity of WFA was observed between groups in the vCA1 (Fig 5G).”
Quote in the paperNot a substantial claim - Findingown data
MSEW mice showed a reduction in PV+ interneuron densities in the hippocampus.
“The reduction in PV+ interneuron densities we observed in the MSEW hippocampus is likely due to decreased PV protein levels rather than loss of neurons given our data on PV expression and GAD67+ cell densities, as well as previous studies showing reductions in PV protein levels due to early life adversity in the mPFC of juvenile mice (68; 69).”
Quote in the paperSubstantial claim - Findingown data
MSEW mice showed an increase in alpha/beta frequency oscillation power in the vHIP.
“We observed an increase in alpha/beta frequency oscillation power in the vHIP of MSEW mice, which could be related to decreased SST+ interneuron intensities and possibly activity of this cell type.”
Quote in the paperSubstantial claim - Findingown data
We did not observe differences in DCX+ and Ki67+ cell densities between control and MSEW mice.
“While we did not observe differences in DCX+ and Ki67+ cell densities between control and MSEW mice, postsynaptic connections of new neurons to other cell types may be altered.”
Quote in the paperSubstantial claim - Findingown data
MSEW mice showed increased intensities of WFA labelled PNNs around PV+ interneurons.
“Our findings reporting increased intensities of WFA labelled PNNs around PV+ interneurons suggest altered plasticity of PV+ cells as PNNs have been known to regulate synaptic and cellular plasticity of the cells they encapsulate (45) and digestion of PNNs around PV+ cells has been shown to reduce the fast spiking properties and excitability of PV+ cells (73)”
Quote in the paperSubstantial claim - Findingown data
OTX2, PNNs and PV+ interneurons are affected by MSEW.
“The data presented here further indicate that OTX2, PNNs and PV+ interneurons are affected by MSEW and these changes may participate in altering neuronal oscillations underlying anxiety and hyperactivity.”
Quote in the paperSubstantial claim - Findingown data
MSEW mice showed an increase in intensity of labeling of OTX2 in the choroid plexus.
“Our findings showed an increase in intensity of labeling of OTX2 in the choroid plexus suggesting an increase in OTX2 production in MSEW mice.”
Quote in the paperSubstantial claim - Findingown data
MSEW mice displayed increases in OTX2 labeling intensity in PV+ PNN+ cells in the vHIP.
“Our observations showed that MSEW mice displayed increases in OTX2 labeling intensity in PV+ PNN+ cells in the vHIP.”
Quote in the paperSubstantial claim - Premisecitation
Accumulation of multiple bouts of early life stress exposure is most damaging in terms of long-term psychiatric problems.
“but the preponderance of evidence, including a recent large study, indicates that the accumulation of multiple bouts of early life stress exposure is most damaging in terms of long-term psychiatric problems (7–10).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [7] Dunn, 2018, What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: Recency, accumulation, or sensitive periods?, Psychol Med source
Not checked in the free run.
- cites [8] Schalinski, 2019, Environmental adversities and psychotic symptoms: The impact of timing of trauma, abuse, and neglect, Schizophr Res source
Not checked in the free run.
- cites [9] Bjorkenstam, 2016, Childhood adversity and psychiatric disorder in young adulthood: An analysis of 107,704 Swedes, J Psychiatr Res source
Not checked in the free run.
- cites [10] Copeland, 2018, Association of childhood trauma exposure with adult psychiatric disorders and functional outcomes, JAMA Netw Open source
Not checked in the free run.
- Premisecitation
In humans, increased self-reported anxiety during threat is associated with increased theta rhythm in the anterior hippocampus.
“in humans, increased self-reported anxiety during threat is associated with increased theta rhythm in the anterior hippocampus (21)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Cornwell, 2012, Distinct contributions of human hippocampal theta to spatial cognition and anxiety, Hippocampus source
Not checked in the free run.
- Premisecitation
Early life trauma reduces PNN expression in the basolateral amygdala.
“early life trauma has been shown to reduce PNN expression in the basolateral amygdala (31)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Santiago, 2018, Early life trauma increases threat response of peri-weaning rats, reduction of axo-somatic synapses formed by parvalbumin cells and perineuronal net in the basolateral nucleus of amygdala, J Comp Neurol source
Not checked in the free run.
- Premisecitation
PNN degradation reduces theta frequency synchrony between brain regions involved in fear memory.
“as well as reduce theta frequency synchrony between brain regions involved in fear memory (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Thompson, 2018, Removal of perineuronal nets disrupts recall of a remote fear memory, Proc Natl Acad Sci U S A source
Not checked in the free run.
- Premisecitation
Early weaning by itself results in increased anxiety in both mice and rats.
“Early weaning by itself results in increased anxiety in both mice and rats (50;51).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
The lack of an increase in anxiety among female rodents subjected to early life stress is consistent with several other studies.
“The lack of an increase in anxiety among female rodents subjected to early life stress is consistent with several other studies (reviewed in 52)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Murthy, 2018, Early life stress in rodents: Animal models of illness or resilience?, Front Behav Neurosci source
Not checked in the free run.
- Premisecitation
The combination of early weaning with maternal separation results in increased hyperactivity in mice.
“The combination of early weaning with maternal separation also results in increased hyperactivity in mice (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] George, 2010, Maternal separation with early weaning: A novel mouse model of early life neglect, BMC Neurosci source
Not checked in the free run.
- Premisecitation
OTX2 is not synthesized in the vHIP.
“Since previous studies have shown that OTX2 is not synthesized in the vHIP (46)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Spatazza, 2013, Choroid plexus-derived OTX2 homeoprotein constrains adult cortical plasticity, Cell Rep source
Not checked in the free run.
- Interpretationreasoning
PV+/PNN+ cells in the vHIP sequester OTX2 in greater amounts after MSEW.
“our findings suggest that PV+/PNN+ cells in the vHIP sequester OTX2 in greater amounts after MSEW.”
Quote in the paperSubstantial claim - Interpretationcitation
MSEW-induced increased vHIP theta power in a novel environment is consistent with reports showing increased theta power and increased coherence between the mPFC and vHIP during heightened states of anxiety.
“Our data showing increased vHIP theta power in the novel environment are consistent with reports showing increased theta power and increased coherence between the mPFC and vHIP during heightened states of anxiety (20).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Adhikari, 2010, Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety, Neuron source
Not checked in the free run.
- Interpretationown data
Early life adversity produces altered neuronal oscillations in the vHIP of adult male mice.
“Taken together, our findings show that early life adversity produces altered neuronal oscillations in the vHIP of adult male mice”
Quote in the paperSubstantial claim - Interpretationown data
Enhanced theta-phase-gamma-amplitude coupling in MSEW mice in either environmental setting indicates an inherent alteration to the electrophysiological profile.
“Additionally, enhanced theta-phase-gamma-amplitude coupling in MSEW mice when in either environmental setting indicates an inherent alteration to the electrophysiological profile.”
Quote in the paperSubstantial claim - Interpretationreasoning
The decrease in PV+ cell density in the vDG of MSEW mice is due to reduced expression of PV, as opposed to a loss of interneurons due to cell death.
“suggesting that the decrease in cell density was due to reduced expression of PV, as opposed to a loss of interneurons due to cell death.”
Quote in the paperSubstantial claim - Interpretationown data
MSEW-induced decreases in densities of PV+ and SST+ interneurons are not due to cell death.
“It is likely that MSEW-induced decreases in densities of PV+ and SST+ interneurons are not due to cell death because there was no overall difference in the density of cells stained with the pan-interneuron marker GAD67 (Fig S5B).”
Quote in the paperSubstantial claim - Interpretationown data
Overt differences in the population of PV+ or SST+ interneurons activated are not likely the cause of altered neuronal oscillations and behavior.
“indicating that overt differences in the population of PV+ or SST+ interneurons activated are not likely the cause of altered neuronal oscillations and behavior.”
Quote in the paperSubstantial claim - Interpretationown data
Cellular changes in interneurons may be causally linked to the electrophysiological and behavioral alterations induced by MSEW.
“and further demonstrate cellular changes in interneurons that may be causally linked to the electrophysiological and behavioral alterations.”
Quote in the paperSubstantial claim - Premisecitation
PNNs regulate synaptic and cellular plasticity of the cells they encapsulate.
“Our findings reporting increased intensities of WFA labelled PNNs around PV+ interneurons suggest altered plasticity of PV+ cells as PNNs have been known to regulate synaptic and cellular plasticity of the cells they encapsulate (45) and digestion of PNNs around PV+ cells has been shown to reduce the fast spiking properties and excitability of PV+ cells (73)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] Sorg, 2016, Casting a wide net: Role of perineuronal nets in neural plasticity, J Neurosci source
Not checked in the free run.
- Interpretationown data
The reduction in PV+ interneuron densities observed in the MSEW hippocampus is likely due to decreased PV protein levels rather than loss of neurons.
“The reduction in PV+ interneuron densities we observed in the MSEW hippocampus is likely due to decreased PV protein levels rather than loss of neurons given our data on PV expression and GAD67+ cell densities, as well as previous studies showing reductions in PV protein levels due to early life adversity in the mPFC of juvenile mice (68; 69).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [68] Grassi-Oliveira, 2016, Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines, Psychoneuroendocrinology source
Not checked in the free run.
- cites [69] Holland, 2014, Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males, Neurosci Lett source
Not checked in the free run.
- Premisecitation
Disconnecting PV cell activity from the fast spiking inhibitory network in the hippocampus reduces both theta power and theta-gamma coupling.
“In fact, disconnecting PV cell activity from the fast spiking inhibitory network in the hippocampus reduces both theta power and theta-gamma coupling (23)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Wulff, 2009, Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons, Proc Natl Acad Sci U S A source
Not checked in the free run.
- Premisecitation
GABAergic interneurons, especially the PV+ subtype, play an important role in the regulation of neuronal oscillations in the brain.
“GABAergic interneurons, especially the PV+ subtype, play an important role in the regulation of neuronal oscillations in the brain (24–27) and have also been implicated in neuropsychiatric disease (66; 67).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [24] Stark, 2013, Inhibition-induced theta resonance in cortical circuits, Neuron source
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- cites [25] Amilhon, 2015, Parvalbumin interneurons of hippocampus tune population activity at theta frequency, Neuron source
Not checked in the free run.
- cites [26] Ferguson, 2015, Network models provide insights into how oriens-lacunosum-moleculare and bistratified cell interactions influence the power of local hippocampal CA1 theta oscillations, Front Syst Neurosci source
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- cites [27] Huh, 2016, Excitatory inputs determine phase-locking strength and spike-timing of CA1 stratum oriens/alveus parvalbumin and somatostatin interneurons during intrinsically generated hippocampal theta rhythm, J Neurosci source
Not checked in the free run.
- Premisecitation
New neurons may be involved in modulating neuronal oscillations in the hippocampus.
“New neurons may be involved in modulating neuronal oscillations in the hippocampus as ablation of neurogenesis destabilizes network activity in vivo (36).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Lacefield, 2012, Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus, Hippocampus source
Not checked in the free run.
- Interpretationreasoning
Increased rhythmic inhibitory inputs to PV+ cells may underlie the increased theta power and theta-gamma coupling observed in MSEW mice.
“These reports along with our data suggest that increased rhythmic inhibitory inputs to PV+ cells may underlie the increased theta power and theta-gamma coupling observed in MSEW mice.”
Quote in the paperSubstantial claim - Interpretationcitation
Increased intensities of WFA labelled PNNs around PV+ interneurons suggest altered plasticity of PV+ cells.
“Our findings reporting increased intensities of WFA labelled PNNs around PV+ interneurons suggest altered plasticity of PV+ cells as PNNs have been known to regulate synaptic and cellular plasticity of the cells they encapsulate (45) and digestion of PNNs around PV+ cells has been shown to reduce the fast spiking properties and excitability of PV+ cells (73)”
Quote in the paperSubstantial claim - Interpretationown data
The increase in OTX2 labeling intensity in the choroid plexus suggests an increase in OTX2 production in MSEW mice.
“Our findings showed an increase in intensity of labeling of OTX2 in the choroid plexus suggesting an increase in OTX2 production in MSEW mice.”
Quote in the paperSubstantial claim - Premisecitation
OTX2 specifically accumulates in PV+ cells through exogenous transfer from the choroid plexus, the region where it is produced.
“Additionally, OTX2 has been shown to specifically accumulate in PV+ cells through exogenous transfer from the choroid plexus, the region where it is produced (35; 46).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [35] Sugiyama, 2008, Experience-dependent transfer of OTX2 homeoprotein into the visual cortex activates postnatal plasticity, Cell source
Not checked in the free run.
- cites [46] Spatazza, 2013, Choroid plexus-derived OTX2 homeoprotein constrains adult cortical plasticity, Cell Rep source
Not checked in the free run.
- Interpretationreasoning
The results are consistent with an OTX2-mediated mechanism of action for modulating PNNs and hence, PV+ cell plasticity in the vHIP.
“Our results are consistent with an OTX2-mediated mechanism of action for modulating PNNs and hence, PV+ cell plasticity in the vHIP.”
Quote in the paperSubstantial claim - Interpretationown data
These changes (OTX2, PNNs and PV+ interneurons affected by MSEW) may participate in altering neuronal oscillations underlying anxiety and hyperactivity.
“The data presented here further indicate that OTX2, PNNs and PV+ interneurons are affected by MSEW and these changes may participate in altering neuronal oscillations underlying anxiety and hyperactivity.”
Quote in the paperSubstantial claim
- May combine two claims. 15
- Classified as probably not a substantial claim. 49
May combine two claims.
Findingown dataMSEW male mice in cohort 1 showed increased anxiety in the EPM with significantly lower percentage of entries into the open arms.
“MSEW mice in cohort 1 showed increased anxiety in the EPM with significantly lower percentage of entries into the open arms (Fig 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMSEW mice show increased theta power and theta-gamma coupling.
“These reports along with our data suggest that increased rhythmic inhibitory inputs to PV+ cells may underlie the increased theta power and theta-gamma coupling observed in MSEW mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChildhood maltreatment substantially increases the risk of developing neuropsychiatric conditions in adulthood, including anxiety and mood disorders.
“Childhood maltreatment is known to substantially increase the risk of developing neuropsychiatric conditions in adulthood, including anxiety and mood disorders (1–3).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Heim, 2010, Neurobiological and psychiatric consequences of child abuse and neglect, Dev Psychobiol source
Not checked in the free run.
- cites [2] Fuller-Thomson, 2014, Establishing a link between attention deficit disorder/attention deficit hyperactivity disorder and childhood physical abuse, J Aggress Maltreat Trauma source
Not checked in the free run.
- cites [3] Gallo, 2018, Gender differences in the effects of childhood maltreatment on adult depression and anxiety: A systematic review and meta-analysis, Child Abuse Negl source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationChildhood maltreatment increases susceptibility to both ADHD and excessive anxiety.
“Attention-deficit hyperactivity disorder (ADHD) is often comorbid with anxiety disorders in adults and childhood maltreatment has been shown to increase susceptibility to both ADHD and excessive anxiety (5).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Mao, 2014, Comorbidities in adult attention-deficit/hyperactivity disorder: A practical guide to diagnosis in primary care, Postgrad Med source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMore than 50% of diagnosed cases of anxiety disorders and clinical depression occur in individuals who have experienced early life adversity.
“In fact, more than 50% of diagnosed cases of anxiety disorders and clinical depression occur in individuals who have experienced early life adversity (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Li, 2016, Maltreatment in childhood substantially increases the risk of adult depression and anxiety in prospective cohort studies: Systematic review, meta-analysis, and proportional attributable fractions, Psychol Med source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOptogenetic or pharmacological stimulation of the vHIP increases anxiety-like behavior.
“while optogenetic or pharmacological stimulation of the region has the opposite effect (16–18).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [16] Bast, 2001, Hyperactivity, decreased startle reactivity, and disrupted prepulse inhibition following disinhibition of the rat ventral hippocampus by the GABA(A) receptor antagonist picrotoxin, Psychopharmacology source
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- cites [17] Felix-Ortiz, 2013, BLA to vHPC inputs modulate anxiety-related behaviors, Neuron source
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- cites [18] Padilla-Coreano, 2016, Direct ventral hippocampal-prefrontal input is required for anxiety-related neural activity and behavior, Neuron source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDecreases in theta power in the vHIP occur after anxiolytic drug administration.
“with decreases in theta power in the vHIP occurring after anxiolytic drug administration (19)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] McNaughton, 2000, Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety, J Affect Disord source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPV+ interneurons are the main effectors of intrinsic theta rhythm in the hippocampus.
“Optogenetic studies on the hippocampus have shown that parvalbumin (PV)+ interneurons are the main effectors of intrinsic theta rhythm”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Amilhon, 2015, Parvalbumin interneurons of hippocampus tune population activity at theta frequency, Neuron source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIncreases in theta power in the vHIP and mPFC as well as theta synchrony between vHIP and mPFC occur during anxious states.
“and increases in theta power in the vHIP and mPFC as well as theta synchrony between the vHIP and mPFC during anxious states (20).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Adhikari, 2010, Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety, Neuron source
Not checked in the free run.
May combine two claims.
PremisecitationMSEW increases both anxiety levels and hyperactivity in adulthood.
“This developmental manipulation has been shown to increase both anxiety levels and hyperactivity in adulthood (11), suggesting it has strong translational validity”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] George, 2010, Maternal separation with early weaning: A novel mouse model of early life neglect, BMC Neurosci source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe anterior hippocampus in humans is considered analogous to the vHIP in rodents.
“a region that is considered analogous to the vHIP in rodents (22).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Fanselow, 2010, Are the dorsal and ventral hippocampus functionally distinct structures?, Neuron source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBilateral lesions of the vHIP reduce anxiety-like behavior in rodents.
“bilateral lesions of this area have been shown to reduce anxiety-like behavior in rodents (13–15)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [13] Bannerman, 1999, Double dissociation of function within the hippocampus: A comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions, Behav Neurosci source
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- cites [14] Bannerman, 2003, Ventral hippocampal lesions affect anxiety but not spatial learning, Behav Brain Res source
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- cites [15] Weeden, 2015, The role of the ventral dentate gyrus in anxiety-based behaviors, Neurobiol Learn Mem source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEnriched environment rearing reduces PNNs in the cerebellum.
“enriched environment rearing reduces PNNs in the cerebellum (32)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Foscarin, 2011, Experience-dependent plasticity and modulation of growth regulatory molecules at central synapses, PLoS One source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSST+ interneurons modulate the entrainment of intrinsic theta by controlling external inputs to the hippocampus.
“while somatostatin (SST)+ interneurons modulate the entrainment of intrinsic theta by controlling external inputs to the hippocampus (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Amilhon, 2015, Parvalbumin interneurons of hippocampus tune population activity at theta frequency, Neuron source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPNNs are linked to OTX2.
“PNNs have been linked to the transcription factor orthodenticle homeobox protein 2 (OTX2) (35)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Sugiyama, 2008, Experience-dependent transfer of OTX2 homeoprotein into the visual cortex activates postnatal plasticity, Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn adults, OTX2 is produced in the choroid plexus, released into the CSF and accumulates in PV+ cells where it facilitates PNN formation.
“In adults, OTX2 is produced in the choroid plexus, released into the CSF and accumulates in PV+ cells where it facilitates PNN formation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAdult-generated neurons form connections with PV+ inhibitory interneurons.
“Additionally, adult-generated neurons also form connections with PV+ inhibitory interneurons (38; 39).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [38] Song, 2013, Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus, Nat Neurosci source
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- cites [39] Drew, 2016, Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons, Hippocampus source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPNN degradation reduces PV+ interneuron activity.
“PNN degradation has been shown to reduce PV+ interneuron activity (29)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Lensjo, 2017, Removal of perineuronal nets unlocks juvenile plasticity through network mechanisms of decreased inhibition and increased gamma activity, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPNNs limit plasticity and are responsible for the closure of the critical period for ocular dominance in the visual cortex.
“PNNs are thought to limit plasticity and are responsible for the closure of the critical period for ocular dominance in the visual cortex (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Beurdeley, 2012, OTX2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationEarly life adversity reduces the production of new neurons in the dentate gyrus.
“Some previous studies have reported that early life adversity reduces the production of new neurons in the dentate gyrus (37)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Mirescu, 2004, Early life experience alters response of adult neurogenesis to stress, Nat Neurosci source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationAdult-generated neurons in the hippocampus modulate neuronal oscillations; their elimination by focal irradiation or transgenic means increases rhythmic firing.
“Studies have shown that adult-generated neurons in the hippocampus have the ability to modulate neuronal oscillations in that their elimination by focal irradiation or by transgenic means increases rhythmic firing (36).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Lacefield, 2012, Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus, Hippocampus source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEnriched environment rearing increases PNNs in the CA2 region of the hippocampus.
“but increases them in the CA2 region of the hippocampus (33)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Carstens, 2016, Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPNNs are involved in the plasticity and activity of inhibitory interneurons.
“PNNs are involved in the plasticity and activity of inhibitory interneurons (45).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Sorg, 2016, Casting a wide net: Role of perineuronal nets in neural plasticity, J Neurosci source
Not checked in the free run.
May combine two claims.
PremisecitationThe vHIP is functionally distinct from the dHIP and has been implicated in anxiety regulation.
“The vHIP was analyzed separately as it is functionally distinct from the dHIP and has been implicated in anxiety regulation (22).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Fanselow, 2010, Are the dorsal and ventral hippocampus functionally distinct structures?, Neuron source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe left hemisphere has been specifically shown to be affected in MSEW mice.
“Placement of electrode was in the left hemisphere as this hemisphere has been specifically shown to be affected in MSEW mice (42).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Duque, 2012, Neuroanatomical changes in a mouse model of early life neglect, Brain Struct Funct source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOTX2 produced in the choroid plexus binds to PNNs in the visual cortex where it facilitates the expression of PNNs.
“OTX2 produced in the choroid plexus binds to PNNs in the visual cortex where it facilitates the expression of PNNs (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Beurdeley, 2012, OTX2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationWomen are more susceptible to anxiety and depressive disorders than men.
“and surprising given that women are more susceptible to anxiety and depressive disorders than men (53).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Altemus, 2014, Sex differences in anxiety and depression clinical perspectives, Front Neuroendocrinol source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitationc-fos is an immediate early gene used as a proxy for neuronal activation.
“Mice were perfused 2h after the EPM test to allow for maximal accumulation of the protein products of c-fos, an immediate early gene used as a proxy for neuronal activation, in interneurons (44).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Peng, 2005, Temporal patterns of fos expression in the dentate gyrus after spontaneous seizures in a mouse model of temporal lobe epilepsy, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBehavioral tasks can modulate phase amplitude coupling, which has been implicated in sensory integration, memory processes, and attentional selection.
“Behavioral tasks can modulate phase amplitude coupling which has been implicated in sensory integration, memory processes, and attentional selection previously (54–56).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [54] Lisman, 1995, Storage of 7 +/- 2 short-term memories in oscillatory subcycles, Science source
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- cites [55] Lisman, 2005, The theta/gamma discrete phase code occuring during the hippocampal phase precession may be a more general brain coding scheme, Hippocampus source
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- cites [56] Schroeder, 2009, Low-frequency neuronal oscillations as instruments of sensory selection, Trends Neurosci source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTheta-phase gamma-amplitude coupling in the amygdala has been implicated in periods of heightened anxiety.
“and in the amygdala has been implicated in periods of heightened anxiety (58).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Stujenske, 2014, Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala, Neuron source
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PremisecitationThe involvement of PV+ interneurons in theta-gamma coupling has been previously established.
“While the involvement of PV+ interneurons in theta-gamma coupling has been previously established (23)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Wulff, 2009, Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons, Proc Natl Acad Sci U S A source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased theta-gamma coupling has been associated with greater dysfunctional attention/arousal behaviors in ADHD children.
“Increased theta-gamma coupling has been associated with greater dysfunctional attention/arousal behaviors in ADHD children (59).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] Kim, 2015, Relationship between theta-phase gamma-amplitude coupling and attention-deficit/hyperactivity behavior in children, Neurosci Lett source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTheta-phase gamma-amplitude coupling in the dorsal hippocampus has been implicated in cognitive function.
“Specifically, theta-phase gamma-amplitude coupling in the dorsal hippocampus has been implicated in cognitive function (57)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57] Tort, 2009, Theta-gamma coupling increases during the learning of item-context associations, Proc Natl Acad Sci U S A source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAdult hippocampal neurogenesis has been implicated in some anxiety- and depression-related behaviors.
“Adult neurogenesis in the hippocampus has been implicated in some anxiety- and depression-related behaviors (60; 61).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [60] Sahay, 2007, Adult hippocampal neurogenesis in depression, Nat Neurosci source
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- cites [61] Hill, 2015, Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors, Neuropsychopharmacology source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMaternal separation stress reduced adult neurogenesis in the rat hippocampus in previous work.
“Previous work showed maternal separation stress reduced adult neurogenesis in the rat hippocampus (37; 62–64), although other studies failed to show this (65).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [37] Mirescu, 2004, Early life experience alters response of adult neurogenesis to stress, Nat Neurosci source
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- cites [62] Hulshof, 2011, Maternal separation decreases adult hippocampal cell proliferation and impairs cognitive performance but has little effect on stress sensitivity and anxiety in adult Wistar rats, Behav Brain Res source
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- cites [63] Leslie, 2011, Impact of early adverse experience on complexity of adult-generated neurons, Transl Psychiatry source
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- cites [64] Korosi, 2012, Early-life stress mediated modulation of adult neurogenesis and behavior, Behav Brain Res source
Not checked in the free run.
May combine two claims.
Interpretationown datavHIP theta-gamma coupling is inherently enhanced in MSEW mice compared to controls, occurring in both familiar and novel environments, but increases in theta and alpha/beta power are observed only when MSEW mice are in a novel environment.
“These data suggest vHIP theta-gamma coupling is inherently enhanced in MSEW mice compared to controls, occurring in both familiar and novel environments, but increases in theta and alpha/beta power are observed only when MSEW mice are in a novel environment.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationDigestion of PNNs around PV+ cells reduces the fast spiking properties and excitability of PV+ cells.
“Our findings reporting increased intensities of WFA labelled PNNs around PV+ interneurons suggest altered plasticity of PV+ cells as PNNs have been known to regulate synaptic and cellular plasticity of the cells they encapsulate (45) and digestion of PNNs around PV+ cells has been shown to reduce the fast spiking properties and excitability of PV+ cells (73)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [73] Balmer, 2016, Perineuronal nets enhance the excitability of fast-spiking neurons, eNeuro source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExperimentally induced theta bursts reduce PV expression in other brain regions.
“Along these lines, it is worth noting that experimentally induced theta bursts reduce PV expression in other brain regions (70; 71), raising the possibility that the changes we observed in PV intensity are the result of, as opposed to being responsible for, the altered electrophysiological profile observed with MSEW.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [70] Mix, 2015, Reduction in cortical parvalbumin expression due to intermittent theta-burst stimulation correlates with maturation of the perineuronal nets in young rats, Dev Neurobiol source
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- cites [71] Mix, 2010, Continuous and intermittent transcranial magnetic theta burst stimulation modify tactile learning performance and cortical protein expression in the rat differently, Eur J Neurosci source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSST+ interneurons are responsible for preferentially driving beta (15-30 Hz) frequency oscillations in other brain regions.
“SST+ interneurons on the other hand have been demonstrated to indirectly contribute to the entrainment of theta oscillations in the hippocampus (25) and are responsible for preferentially driving beta (15–30 Hz) frequency oscillations in other brain regions (72).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Chen, 2017, Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations, Neuron source
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Classified as probably not a substantial claim.
PremisecitationInterneurons modulate neuronal circuitry controlling hippocampal neurogenesis and the activity of new neurons in vivo.
“Immature neurons project to interneurons in the DG and reports have documented the role of interneurons in modulating neuronal circuitry controlling hippocampal neurogenesis, as well as the activity of new neurons in vivo (38;39).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [38] Song, 2013, Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus, Nat Neurosci source
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- cites [39] Drew, 2016, Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons, Hippocampus source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationImmature neurons project to interneurons in the dentate gyrus.
“Immature neurons project to interneurons in the DG and reports have documented the role of interneurons in modulating neuronal circuitry controlling hippocampal neurogenesis, as well as the activity of new neurons in vivo (38;39).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [38] Song, 2013, Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus, Nat Neurosci source
Not checked in the free run.
- cites [39] Drew, 2016, Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons, Hippocampus source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSST+ interneurons indirectly contribute to the entrainment of theta oscillations in the hippocampus.
“SST+ interneurons on the other hand have been demonstrated to indirectly contribute to the entrainment of theta oscillations in the hippocampus (25) and are responsible for preferentially driving beta (15–30 Hz) frequency oscillations in other brain regions (72).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Amilhon, 2015, Parvalbumin interneurons of hippocampus tune population activity at theta frequency, Neuron source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGABAergic interneurons, especially the PV+ subtype, have been implicated in neuropsychiatric disease.
“GABAergic interneurons, especially the PV+ subtype, play an important role in the regulation of neuronal oscillations in the brain (24–27) and have also been implicated in neuropsychiatric disease (66; 67).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [66] Fee, 2017, Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: Cortical microcircuit and therapeutic perspectives, Biol Psychiatry source
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- cites [67] Rajkowska, 2007, GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression, Neuropsychopharmacology source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSome other studies failed to show that maternal separation stress reduces adult neurogenesis in the rat hippocampus.
“Previous work showed maternal separation stress reduced adult neurogenesis in the rat hippocampus (37; 62–64), although other studies failed to show this (65).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Oomen, 2009, Opposite effects of early maternal deprivation on neurogenesis in male versus female rats, PLoS One source
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Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe increase in alpha/beta frequency oscillation power in the vHIP of MSEW mice could be related to decreased SST+ interneuron intensities and possibly activity of this cell type.
“We observed an increase in alpha/beta frequency oscillation power in the vHIP of MSEW mice, which could be related to decreased SST+ interneuron intensities and possibly activity of this cell type.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationPV+ interneurons appear to be the main generators of intrinsic theta oscillations in the hippocampus.
“PV+ interneurons appear to be the main generators of intrinsic theta oscillations in the hippocampus (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Stark, 2013, Inhibition-induced theta resonance in cortical circuits, Neuron source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPNN degradation reduces PV+ interneuron activity and alters gamma and theta range neuronal oscillations in rats.
“PNN degradation also reduces PV+ interneuron activity and alters gamma and theta range neuronal oscillations in rats (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Lensjo, 2017, Removal of perineuronal nets unlocks juvenile plasticity through network mechanisms of decreased inhibition and increased gamma activity, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOTX2 is a transcription factor known to be important in the regulation of the critical period of plasticity in the visual cortex of developing mice.
“Orthodenticle homeobox protein 2 (OTX2) is a transcription factor known to be important in the regulation of the critical period of plasticity in the visual cortex of developing mice (46) and its expression coincides with the maturation of PV+ cells and the closure of the critical period (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Spatazza, 2013, Choroid plexus-derived OTX2 homeoprotein constrains adult cortical plasticity, Cell Rep source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPNN degradation reduces theta synchrony between the amygdala and the association visual cortex.
“PNN degradation has also been shown to reduce theta synchrony between the amygdala and the association visual cortex; brain regions involved in fear memory recall (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Thompson, 2018, Removal of perineuronal nets disrupts recall of a remote fear memory, Proc Natl Acad Sci U S A source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationContinual binding of OTX2 to PNNs is necessary for synaptic stability in the adult visual cortex.
“Continual binding of OTX2 to PNNs has been shown to be necessary for synaptic stability in the adult visual cortex and blocking OTX2 uptake into PV+ cells in adults has been demonstrated to reduce PNN expression and reinstate juvenile levels of plasticity (28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Beurdeley, 2012, OTX2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOTX2 expression coincides with the maturation of PV+ cells and the closure of the critical period.
“Orthodenticle homeobox protein 2 (OTX2) is a transcription factor known to be important in the regulation of the critical period of plasticity in the visual cortex of developing mice (46) and its expression coincides with the maturation of PV+ cells and the closure of the critical period (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Sugiyama, 2008, Experience-dependent transfer of OTX2 homeoprotein into the visual cortex activates postnatal plasticity, Cell source
Not checked in the free run.
May combine two claims.
Interpretationown dataEarly life adversity results in an altered electrophysiological profile in the vHIP in adulthood, which is associated with an increase in anxiety and hyperactivity.
“These findings are the first to report that early life adversity results in an altered electrophysiological profile in the vHIP in adulthood, which is associated with an increase in anxiety and hyperactivity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMaturation of PNNs around PV+ cells in the visual cortex coincides with the closure of the critical period for the development of binocular vision.
“In fact, the maturation of PNNs around PV+ cells in the visual cortex coincides with the closure of the critical period for the development of binocular vision; degradation of PNNs has been shown to reopen this critical period in the visual cortex (74; 75).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDegradation of PNNs reopens the critical period for the development of binocular vision in the visual cortex.
“In fact, the maturation of PNNs around PV+ cells in the visual cortex coincides with the closure of the critical period for the development of binocular vision; degradation of PNNs has been shown to reopen this critical period in the visual cortex (74; 75).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
PremisecitationBlocking OTX2 uptake into PV+ cells in adults reduces PNN expression and reinstates juvenile levels of plasticity.
“Continual binding of OTX2 to PNNs has been shown to be necessary for synaptic stability in the adult visual cortex and blocking OTX2 uptake into PV+ cells in adults has been demonstrated to reduce PNN expression and reinstate juvenile levels of plasticity (28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Beurdeley, 2012, OTX2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
Not checked in the free run.
The paper relies on this without support.
No previous studies have investigated the electrophysiological profile of rodents that display increased anxious behavior after early life adversity.
“Despite these associations, the electrophysiological profile of rodents that display increased anxious behavior after early life adversity has not been studied.”
The paper relies on this without support.
No previous studies have investigated whether PNNs and OTX2 are altered in PV+ cells of the hippocampus after early life adversity.
“No previous studies have investigated whether PNNs and OTX2 are altered in PV+ cells of the hippocampus after early life adversity.”
The paper relies on this without support.
No previous studies have investigated whether changes in inhibitory interneurons, PNNs and adult-generated neurons occur in association with early life stress-induced alterations in neuronal oscillations and anxiety-like behavior.
“Despite these compelling associations, no previous studies have investigated whether changes in inhibitory interneurons, PNNs and adult-generated neurons occur in association with early life stress-induced alterations in neuronal oscillations and anxiety-like behavior.”
The paper relies on this without support.
The study is the first to report enhanced theta-gamma coupling in the vHIP in the context of early life adversity and anxiety/hyperactivity.
“our study is the first to report enhanced theta-gamma coupling in the vHIP in the context of early life adversity and anxiety/hyperactivity.”
The paper relies on this without support.
No previous studies have investigated how early life adversity impacts PNNs.
“However, no previous studies have investigated how early life adversity impacts PNNs and our findings raise the possibility that increased PNNs around PV+ cells may drive the increase in theta oscillations, as well as elevated anxiety and hyperactivity observed in MSEW mice.”
The paper relies on this without support.
These findings are the first to report that early life adversity results in an altered electrophysiological profile in the vHIP in adulthood, which is associated with an increase in anxiety and hyperactivity.
“These findings are the first to report that early life adversity results in an altered electrophysiological profile in the vHIP in adulthood, which is associated with an increase in anxiety and hyperactivity.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Early life stress in mice increases PNNs surrounding PV+ inhibitory interneurons in the hippocampus.
“Early life stress in mice has been shown to increase PNNs surrounding PV+ inhibitory interneurons in the hippocampus (Murthy et al., 2019).”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Murthy et al., 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Prior study of early-life adversity and PNNs is both cited and denied
MinorThe introduction cites a study reporting that early-life trauma reduces PNN expression, but the discussion says no previous studies have investigated how early-life adversity impacts PNNs.
“However, no previous studies have investigated how early life adversity impacts PNNs”
“early life trauma has been shown to reduce PNN expression in the basolateral amygdala (31)”
The citation lists haven’t been fetched yet
References 76 · Cited by 118
- Authors
- Murthy, S., Kane, G. A., Katchur, N. J., Lara Mejia, P. S., Obiofuma, G., Buschman, T. J., McEwen, B. S., & Gould, E.
- Affiliations
- Princeton University (US)
- Rockefeller University (US)
- Corresponding author
- Gould, Elizabeth
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 85
- Issue
- 12
- Pages
- 1011-1020
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6590696
- OpenAlex
- W2922370863
- Semantic Scholar
- 31600db1e628899452e99af4abe62cc696946959
- Cited by
- 118
- References
- 76
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 19 · 2023: 16 · 2022: 20 · 2021: 16 · 2020: 19 · 2019: 5
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH117459-01)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- perineuronal nets, inhibitory interneurons, parvalbumin, anxiety, childhood adversity, maternal separation, ventral hippocampus, theta oscillations, theta-gamma coupling, hyperactivity, Otx2, choroid plexus, extracellular matrix, childhood stress
- MeSH terms
- Animals, Anxiety, Extracellular Matrix, Female, Hippocampus, Interneurons, Male, Maternal Deprivation, Mice, Inbred C57BL, Neural Pathways, Neurons, Brain Waves
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