A prefrontal–paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice
Open accessAbstract
Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience. Yamamuro et al. show that juvenile social isolation disrupts prefrontal neurons projecting to the paraventricular thalamus and associated prefrontal somatostatin interneurons, and thereby impairs sociability in adulthood.
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TL;DR
In male mice, juvenile social isolation (p21–35) prevents adult recruitment of medial prefrontal cortex neurons projecting to posterior paraventricular thalamus (mPFC→pPVT) during social exposure, and manipulating this circuit bidirectionally alters sociability. The same isolation reduces mPFC→pPVT excitability and increases inhibitory drive from low-threshold spiking somatostatin interneurons, while activating mPFC→pPVT neurons rescues adult sociability deficits.
Key findings
- Juvenile social isolation (jSI) reduced adult sociability in the 3-chamber test compared with group-housed (GH) mice (two-tailed t-test, t36=2.154, *P=0.038, n=20 GH, n=18 jSI), and mPFC→pPVT neurons were activated by a novel mouse in GH but not jSI mice.
- Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adult GH mice reduced sociability without affecting motor activity, anxiety-related behavior, or natural food preference; optogenetic activation of mPFC→pPVT projections was reinforcing and increased sociability.
- Adult jSI mice showed reduced intrinsic excitability of mPFC→pPVT neurons and increased spontaneous inhibitory postsynaptic currents, with a significant decrease in the sEPSC/sIPSC frequency ratio; these effects emerged in adulthood, not at p35.
- mPFC Chrna2+ LTS-SST interneurons showed increased excitability after jSI, and eDREADD activation of these interneurons in GH mice reduced sociability; chemogenetic or optogenetic activation of mPFC→pPVT neurons rescued sociability deficits in adult jSI mice, including a rescue sustained 24 hours after repeated stimulation.
Methods
- Male C57Bl/6 wildtype, Chrna2-Cre, PV-Cre, and SST-Cre mice were used; jSI mice were isolated from weaning at p21 for two weeks, re-grouped at p35, and behaviorally tested at 10–15 weeks old.
- Circuit activity was measured with fiber photometry (GCaMP6f), c-Fos mapping, chemogenetic (iDREADD/eDREADD) and wireless optogenetic (eNpHR3.0/ChR2) manipulations, in vivo electrophysiology, and whole-cell patch-clamp recordings in mPFC and pPVT.
- Behavior included the 3-chamber sociability test, milkshake preference test, elevated plus maze, and open field; analyses used t-tests, 2-way ANOVAs, and paired tests as indicated.
Limitations
- The paper states that no statistical methods were used to pre-determine sample sizes, data collection and analysis were not performed blind to conditions, and data distribution was assumed normal but not formally tested.
- The study used male mice only, so sex differences or female sociability are not addressed (evident from the Methods).
- Some mechanistic conclusions rely on correlational circuit changes plus acute manipulations; the paper notes future studies are needed to reveal how different mPFC projection populations influence subcortical social networks.
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0 of 14 cited sources checked · 0 supported · 0 flagged
- Findingown data
CNO injection in mCherry-expressing control mice produces no significant behavioral differences compared to saline injection.
“CNO injection in mCherry-expressing control mice produced no significant differences in behavior compared to saline injection (Fig.2F).”
Quote in the paperSubstantial claim - Findingown data
Optogenetic suppression of mPFC->pPVT projection terminals in the pPVT reduces sociability in adult group-housed mice.
“This manipulation, which partly reduced the activity of neurons in the pPVT (Extended Data Fig.4A–C), led to reduced sociability (Fig. 3C) without impacting anxiety-related or motor behaviors (Extended Data Fig.4F).”
Quote in the paperSubstantial claim - Findingown data
There were no light-induced behavioral effects in mCherry-expressing control mice in optogenetic suppression experiments.
“There were no light-induced behavioral effects in mCherry-expressing control mice (Fig. 3D, Extended Data Fig.4G).”
Quote in the paperSubstantial claim - Findingown data
Optogenetic activation of mPFC->pPVT projections within the social-interaction zone increases sociability in adult group-housed mice.
“We found that optogenetic activation of mPFC->pPVT projections within the social-interaction zone led to an increase in sociability, whereas activation of mPFC->pPVT projections within the object-interaction zone reduced sociability (Fig.4E–H).”
Quote in the paperSubstantial claim - Findingown data
In adult male mice that underwent juvenile social isolation, mPFC->pPVT projection neurons are not more robustly activated by a novel mouse than by a novel object.
“mPFC->pPVT neurons expressing the calcium indicator GCaMP6f were more robustly activated after introduction of a novel mouse than after introduction of a novel object in adult GH mice, but not in jSI mice (Fig.1E–G)”
Quote in the paperSubstantial claim
- Findingown data
Optogenetic suppression of mPFC->pPVT projection terminals in the pPVT does not impact natural food preference.
“Importantly, this manipulation did not impact natural food preference (Fig.3E,F), suggesting that the observed sociability deficits are not a result of general impairments in natural reward-related behaviors.”
Quote in the paperSubstantial claim - Findingown data
Chemogenetic suppression of pPVT neuron activity reduces sociability.
“Chemogenetic suppression of pPVT neuron activity also reduced sociability (Extended Data Fig.3).”
Quote in the paperSubstantial claim - Findingown data
In adult group-housed male mice, mPFC->pPVT projection neurons are more robustly activated after introduction of a novel mouse than after introduction of a novel object.
“mPFC->pPVT neurons expressing the calcium indicator GCaMP6f were more robustly activated after introduction of a novel mouse than after introduction of a novel object in adult GH mice, but not in jSI mice (Fig.1E–G)”
Quote in the paperSubstantial claim - Findingcitation
In male mice, juvenile social isolation for two weeks immediately after weaning (p21-35) reduces sociability in adulthood compared with group-housed mice.
“Juvenile social isolation reduces sociability in adulthood, but the neural circuit mechanisms are poorly understood.”
- Also stated in: § Juvenile social isolation impairs activation of mPFC->pPVT projection neurons upon social exposure in adulthood · plain
“Adult jSI mice displayed reduced sociability, compared to adult mice that were group-housed (GH) throughout their life, in the 3-chamber test as previously reported5,11 (Extended Data Fig.2).”
- Also stated in: § Introduction · hedged
“In mice, juvenile social isolation (jSI) immediately following weaning for two weeks (21–35 days after birth: p21–35), but not during a later period, leads to decreased sociability in adulthood, suggesting the juvenile period is a sensitive period for the establishment of adult social behavior 5.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Makinodan, M., Rosen, K. M., Ito, S. & Corfas, G. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337, 1357–1360 (2012). source
Not checked in the free run.
- cites [11] Bicks, L. K. et al. Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior. Nat. Commun. 11, 1003 (2020). source
Not checked in the free run.
- Also stated in: § Juvenile social isolation impairs activation of mPFC->pPVT projection neurons upon social exposure in adulthood · plain
- Findingown data
There is a trend towards a decrease in spontaneous excitatory postsynaptic currents (sEPSCs) in mPFC->pPVT neurons from adult jSI mice compared with adult group-housed mice.
“In addition, there was a trend towards a decrease in spontaneous excitatory post synaptic currents (sEPSCs) in adult jSI mice compared with adult GH mice.”
Quote in the paperNot a substantial claim - Findingown data
The effect of optogenetic activation in an empty corral zone quickly disappears after termination of light stimulation.
“This effect quickly disappeared after termination of light stimulation (Fig.4I–K).”
Quote in the paperNot a substantial claim - Findingown data
Optogenetic activation of mPFC->pPVT projections in one of two empty corral interaction zones is sufficient to increase time spent in that zone.
“Furthermore, optogenetic activation of mPFC->pPVT projections in one of two empty corral interaction zones was sufficient to increase time spent in that zone.”
Quote in the paperSubstantial claim - Findingown data
Juvenile social isolation leads to reduced intrinsic excitability of mPFC->pPVT neurons in adulthood.
“Patch-clamp slice recordings of mPFC->PVT neurons from adult jSI mice revealed a reduction of intrinsic excitability (Fig.5A–D) and a significant increase in spontaneous inhibitory post synaptic currents (sIPSCs) compared with adult GH mice.”
Quote in the paperSubstantial claim - Findingown data
Optogenetic activation of mPFC->pPVT projections within the object-interaction zone reduces sociability in adult group-housed mice.
“We found that optogenetic activation of mPFC->pPVT projections within the social-interaction zone led to an increase in sociability, whereas activation of mPFC->pPVT projections within the object-interaction zone reduced sociability (Fig.4E–H).”
Quote in the paperSubstantial claim - Findingown data
Chemogenetic suppression of mPFC->pPVT neuron activity in adult group-housed mice reduces sociability in the 3-chamber test.
“Suppression of mPFC->pPVT neuron activity through clozapine N-oxide (CNO) treatment in adult GH mice reduced sociability in the 3-chamber test, with no impact on motor activity or measurements of anxiety-related behavior (Fig.2E).”
Quote in the paperSubstantial claim - Findingown data
There are no differences in paired pulse ratio (PPR) of evoked EPSCs in pPVT neurons between juvenile-social-isolation and group-housed mice.
“While both groups showed comparable levels of monosynaptic excitatory connectivity (Extended Data Fig.7B,C), jSI mice showed smaller normalized amplitude of evoked EPSCs compared to GH mice (Extended Data Fig.7D), with no differences in paired pulse ratio (PPR) (Extended Data Fig.7E).”
Quote in the paperNot a substantial claim - Findingown data
The paired pulse ratio (PPR) of optically-evoked inhibitory responses from LTS-SST interneurons to mPFC->pPVT neurons is reduced in juvenile-social-isolation mice compared to group-housed mice.
“The amplitude of optically-evoked responses, normalized to the amplitude of the response evoked by the lowest light intensity level for each cell, was comparable between jSI and GH groups, but the paired pulse ratio (PPR) was reduced in jSI mice compared to GH mice (Fig.6E,F), suggesting changes in presynaptic mechanisms of inhibitory neurotransmitter release caused by jSI.”
Quote in the paperSubstantial claim - Findingown data
Whole-cell patch-clamp recordings from mPFC Chrna2+ LTS-SST interneurons show an increase in intrinsic excitability in adult Chrna2-Cre driver mice that had undergone juvenile social isolation versus group-housed mice.
“Whole-cell patch-clamp recordings from mPFC Chrna2+LTS-SST interneurons showed an increase in intrinsic excitability in adult Chrna2-Cre driver mice that had undergone jSI vs GH mice (Fig.6B,C).”
Quote in the paperSubstantial claim - Findingown data
Juvenile-social-isolation mice show smaller normalized amplitude of evoked EPSCs in pPVT neurons compared to group-housed mice.
“While both groups showed comparable levels of monosynaptic excitatory connectivity (Extended Data Fig.7B,C), jSI mice showed smaller normalized amplitude of evoked EPSCs compared to GH mice (Extended Data Fig.7D), with no differences in paired pulse ratio (PPR) (Extended Data Fig.7E).”
Quote in the paperSubstantial claim - Findingown data
The effects of juvenile social isolation on mPFC->pPVT neurons are not detected at the end of isolation at p35 but emerge in adulthood.
“Of note, we did not detect any effect of jSI at the end of isolation on p35; rather, the effects of jSI only emerged in adulthood (Fig.5).”
Quote in the paperSubstantial claim - Findingown data
All patched mPFC->pPVT neurons receive robust monosynaptic input from LTS-SST interneurons.
“Results indicated that all patched mPFC->pPVT neurons receive robust monosynaptic input from LTS-SST interneurons (Fig.6D).”
Quote in the paperSubstantial claim - Findingown data
pPVT neurons themselves show little vulnerability to juvenile social isolation.
“In contrast to mPFC->pPVT neurons, pPVT neurons themselves showed little vulnerability to jSI (Extended Data Fig.5M–R).”
Quote in the paperNot a substantial claim - Findingown data
Repeated optogenetic activation of mPFC->pPVT terminals during social investigation leads to a rescue effect sustained 24 hours after the final day of optogenetic stimulation.
“We found that this intervention leads to a rescue effect that is sustained 24 hours after the final day of optogenetic stimulation (Fig.8E,F, Extended Data Fig.9F,G).”
Quote in the paperSubstantial claim - Findingown data
Juvenile social isolation leads to a significant decrease in the ratio of sEPSC/sIPSC frequency (E/I ratio) in mPFC->pPVT neurons from adult jSI mice compared with adult group-housed mice.
“Together, these changes contributed to a significant decrease in the ratio of sEPSC/sIPSC frequency (E/I ratio, an indicator of overall ‘drive’) in mPFC->PVT neurons from adult jSI mice compared with adult GH mice(Fig.5E–G).”
Quote in the paperSubstantial claim - Findingown data
The amplitude of optically-evoked responses from LTS-SST interneurons to mPFC->pPVT neurons, normalized to the lowest light intensity response, is comparable between juvenile-social-isolation and group-housed groups.
“The amplitude of optically-evoked responses, normalized to the amplitude of the response evoked by the lowest light intensity level for each cell, was comparable between jSI and GH groups, but the paired pulse ratio (PPR) was reduced in jSI mice compared to GH mice (Fig.6E,F), suggesting changes in presynaptic mechanisms of inhibitory neurotransmitter release caused by jSI.”
Quote in the paperNot a substantial claim - Findingown data
CNO injection in mCherry-expressing control juvenile-social-isolation mice produces no CNO-dependent behavioral effect.
“CNO injection in mCherry-expressing control jSI mice produced no CNO-dependent behavioral effect (Fig.7F).”
Quote in the paperSubstantial claim - Findingown data
Other mPFC neurons projecting to nucleus accumbens or contralateral mPFC show no deficits in excitability or synaptic drive in jSI mice.
“In contrast, other mPFC neurons projecting to nucleus accumbens or contralateral mPFC showed no deficits in excitability or synaptic drive in jSI mice (Extended Data Fig.5A–L, Extended Data Fig.6D–I), suggesting that mPFC->pPVT neurons and the associated inhibitory circuits are particularly vulnerable to jSI.”
Quote in the paperSubstantial claim - Findingown data
mCherry-expressing control juvenile-social-isolation mice do not show any light-induced behavioral effects in optogenetic activation experiments.
“mCherry-expressing control jSI mice did not show any light-induced behavioral effects (Fig.8D, Extended Data Fig.9E).”
Quote in the paperSubstantial claim - Findingown data
The majority of patched pPVT neurons show evoked responses to optogenetic activation of ChR2-expressing mPFC->pPVT neurons.
“The majority of patched pPVT neurons showed evoked responses (73.3%: 22/30cells for GH, 68.8%: 22/32cells for jSI).”
Quote in the paperSubstantial claim - Findingcitation
In mPFC of Chrna2-Cre mice, 90.61±4.210% (n=6 mice) of Chrna2-Cre+ cells show SST immunoreactivity.
“To selectively manipulate LTS-SST interneurons, we used Chrna2-Cre mice13 in which 90.61+/−4.210% (n=6 mice) of mPFC Chrna2-Cre+cells show SST immunoreactivity (Fig.6A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Hilscher, M. M., Leao, R. N., Edwards, S. J., Leao, K. E. & Kullander, K. Chrna2-martinotti cells synchronize layer 5 type A pyramidal cells via rebound excitation. PLoS Biol. 15, e2001392 (2017). source
Not checked in the free run.
- Findingown data
Miniature IPSCs of mPFC->pPVT neurons are not impacted by juvenile social isolation.
“As miniature IPSCs of mPFC->pPVT neurons were not impacted by jSI (Extended Data Fig.6A–C), the increased inhibitory drive is likely driven by an action potential-dependent increase in inhibitory neuron activity.”
Quote in the paperSubstantial claim - Findingcitation
There is no change in inhibitory drive in mPFC neurons projecting to contralateral PFC or nucleus accumbens in juvenile-social-isolation mice versus group-housed mice.
“Importantly, Chrna2+LTS-SST interneurons were previously shown to selectively target deep-layer pyramidal neurons that typically project to sub-cortical targets but not to callosal projection neurons or intratelencephalic neurons13; consistent with this finding, we observed no change in inhibitory drive in mPFC neurons projecting to the contralateral PFC (mPFC->cPFC) or nucleus accumbens (mPFC->NA”
Quote in the paperNot a substantial claim - Findingown data
Both group-housed and juvenile-social-isolation groups show comparable levels of monosynaptic excitatory connectivity from mPFC->pPVT neurons to pPVT neurons.
“While both groups showed comparable levels of monosynaptic excitatory connectivity (Extended Data Fig.7B,C), jSI mice showed smaller normalized amplitude of evoked EPSCs compared to GH mice (Extended Data Fig.7D), with no differences in paired pulse ratio (PPR) (Extended Data Fig.7E).”
Quote in the paperNot a substantial claim - Findingown data
A subclass of deep-layer SST-expressing low-threshold spiking (LTS) interneurons shows increased excitability in adult jSI mice compared with group-housed mice.
“We thus screened sub-types of mPFC interneurons expressing somatostatin (SST)12 and parvalbumin11, and found that a subclass of deep-layer SST-expressing low-threshold spiking (LTS) interneurons showed increased excitability in adult jSI mice compared with GH mice (Extended Data Fig. 8).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12] Nigro, M. J., Hashikawa, Y. & Rudy, B. Diversity and connectivity of layer 5 somatostatin-expressing interneurons in the mouse barrel cortex. J. Neurosci. 38, 1622–1633 (2018). source
Not checked in the free run.
- cites [11] Bicks, L. K. et al. Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior. Nat. Commun. 11, 1003 (2020). source
Not checked in the free run.
- Findingown data
Optogenetic suppression decreased action potential of mPFC->pPVT projection neurons upon optogenetic stimulation.
“Representative trace showing decreased action potential of mPFC->pPVT projection neurons upon optogenetic stimulation”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
Bath application of CNO significantly decreases membrane potential of pPVT neurons.
“bath application of CNO significantly decreases membrane potential of pPVT neurons”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
jSI mice showed reduced sociability scores vs GH mice in a 3 chamber task.
“jSI mice showed reduced sociability scores vs GH mice in a 3 chamber task”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
No significant differences in spike threshold between jSI and GH for PFC->NAc neurons.
“No significant differences in spike threshold between jSI and GH”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
Control mCherry+ mice showed no difference in sociability score as a result of CNO vs SAL treatment.
“Control mCherry+ mice showed no difference in sociability score”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
jSI mice showed reduced social interaction in a 3 chamber task.
“reduced social interaction (two-way RM ANOVA, housing (GH/jSI) × stimulus (social/object) interaction F1,36 = 7.042, *P=0.012”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
CNO-treated iDREADD+ mice showed disrupted behavior in 3 chamber sociability task.
“disrupted behavior in 3 chamber sociability task”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
CNO-treated iDREADD+ mice showed reduced sociability scores vs SAL.
“CNO-treated iDREADD+ mice showed reduced sociability, revealed by reduced sociability scores vs. SAL”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
Chemogenetic suppression of pPVT neuron activity reduces sociability in adult group-housed mice.
“Chemogenetic suppression of pPVT neuron activity reduces sociability in adult group-housed mice.”
Quote in the paperSubstantial claim - Findingown data
No significant differences in sEPSC frequency between jSI and GH for pPVT neurons.
“sEPSC frequency (two tailed t-test, t39=0.356, P=0.724, n=20 cells from 8 biologically independent GH mice, n=21 cells from 9 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
The posterior paraventricular thalamus (pPVT) showed significant c-Fos induction in social groups compared with both object and homecage groups.
“the posterior PVT (pPVT) showed significant c-Fos induction in social groups compared with both object and homecage groups.”
Quote in the paperNot a substantial claim - Findingown data
No differences in spike frequency between jSI and GH for PFC->NAc neurons.
“Input-output curves showed no differences in spike frequency between jSI and GH mice”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
jSI mice showed no difference in elevated plus maze.
“they showed no difference in an independent anxiety task (elevated plus maze (EPM: two tailed t-test, t38=0.926, P=0.360”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
No significant differences in sEPSC frequency between jSI and GH for PFC->NAc neurons.
“No significant differences in (D) sEPSC frequency (two tailed t-test, t48=0.308, P=0.760, n=23 cells from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
No differences in spike frequency between jSI and GH for mPFC->cPFC neurons.
“Input-output curve showing no differences in spike frequency”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
No significant differences in sEPSC amplitude between jSI and GH for pPVT neurons.
“or sEPSC amplitude (two tailed t-test, t39=0.636, P=0.529, n=20 cells from 8 biologically independent GH mice, n=21 cells from 9 biologically independent jSI mice) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
jSI mice showed reduced time in center during open field test.
“jSI mice showed reduce time in center during open field test”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
mPFC->pPVT neurons show preferential c-Fos induction by social exposure.
“Representative images showing preferential c-Fos induction in mPFC->pPVT neurons by social exposure”
Quote in the paperSubstantial claim - Findingown data
jSI mice showed no difference in distance traveled during the open field test.
“jSI mice showed no difference in distance traveled during the open field test”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
Control mCherry+ mice showed no difference in investigation time as a result of CNO vs SAL treatment.
“or investigation time (two-way RM ANOVA, housing (GH/jSI) × stimulus (social/object) interaction F1,14 = 0.352, P=0.563, effect of drug F1,14 = 0.024, P=0.880, effect of stimulus F1,14 = 8.630, *P=0.011, n=8 biologically independent mice) as a result of CNO vs. SAL treatment.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
A majority of pPVT neurons received a monosynaptic input from mPFC.
“A majority of pPVT neurons received a monosynaptic input from mPFC.”
Quote in the paperSubstantial claim - Findingown data
Optogenetic activation of mPFC->pPVT axons is blocked by DNQX.
“optogenetic activation of mPFC->pPVT axons blocked by DNQX”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
jSI group shows reduced spike frequency at 200pA and −100pA for SST-LTS cells.
“jSI group shows reduced spike frequency at 200pA and −100pA”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
Juvenile social isolation increases excitability of mPFC low-threshold spiking (LTS)-SST interneurons in adulthood.
“Juvenile social isolation increases excitability of mPFC low-threshold spiking (LTS)-SST interneurons in adulthood.”
Quote in the paperSubstantial claim - Findingown data
mEPSC frequency was significantly lower in jSI mice compared to GH mice for mPFC->pPVT neurons.
“mEPSC frequency was significantly lower in jSI mice compared to GH mice”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
Normalized eEPSC amplitude was lower in jSI mice than GH mice.
“Normalized eEPSC amplitude was lower in jSI mice than GH mice”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
No significant differences in sEPSC/IPSC frequency from pPVT neurons between jSI and GH.
“No significant differences in sEPSC/IPSC frequency from pPVT neurons”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
sIPSC frequency was significantly higher in jSI mice compared to GH mice for pPVT neurons.
“sIPSC frequency was significantly higher in jSI mice compared to GH mice”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
There were no significant differences in PPR at a 500-ms interval between jSI and GH.
“There were no significant differences in PPR at a 500-ms interval”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
jSI group shows decreased excitability in L5/6 SST-AD type at 100pA.
“The jSI group shows decreased excitability in (F) L5/6 SST-AD type at 100pA”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Findingown data
No differences in sIPSC amplitude between jSI and GH for pPVT neurons.
“no differences in sIPSC amplitude”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
- Interpretationown data
Juvenile social experience is necessary for mPFC->pPVT neurons to be fully recruited during social exploration in adulthood.
“demonstrating that juvenile social experience is necessary for mPFC->pPVT neurons to be fully recruited during social exploration in adulthood.”
- Also stated in: § Abstract · plain
“We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex (mPFC) neurons projecting to the posterior paraventricular thalamus (pPVT) during social exposure in adulthood.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Interpretationown data
mPFC->pPVT projection activity is causally linked to social behavior.
“Collectively, these results demonstrate a causal link between mPFC->pPVT projection activity and social behavior.”
Quote in the paperSubstantial claim - Interpretationown data
The study sheds light on a previously unrecognized role of mPFC->PVT projections in naturalistic (unconditioned) social processing in addition to their known function in Pavlovian conditioning and extinction.
“Our study sheds light on a previously unrecognized role of mPFC->PVT projections in naturalistic (unconditioned) social processing in addition to their known function in Pavlovian conditioning and extinction 15–18.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [15] Otis, J. M. et al. Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature 543, 103–107 (2017). source
Not checked in the free run.
- cites [16] Campus, P. et al. The paraventricular thalamus is a critical mediator of top-down control of cue-motivated behavior in rats. eLife 8, e49041 (2019). source
Not checked in the free run.
- cites [17] Do-Monte, F. H., Quinones-Laracuente, K. & Quirk, G. J. A temporal shift in the circuits mediating retrieval of fear memory. Nature 519, 460–463 (2015). source
Not checked in the free run.
- cites [18] Penzo, M. A. et al. The paraventricular thalamus controls a central amygdala fear circuit. Nature 519, 455–459 (2015). source
Not checked in the free run.
- Interpretationown data
mPFC->pPVT neurons and the associated inhibitory circuits are particularly vulnerable to juvenile social isolation.
“In contrast, other mPFC neurons projecting to nucleus accumbens or contralateral mPFC showed no deficits in excitability or synaptic drive in jSI mice (Extended Data Fig.5A–L, Extended Data Fig.6D–I), suggesting that mPFC->pPVT neurons and the associated inhibitory circuits are particularly vulnerable to jSI.”
Quote in the paperSubstantial claim - Interpretationcitation
mPFC->pPVT neurons are well-positioned to provide top-down control of brain networks.
“Given that the PVT projects to various reward-associated areas including the NAc, bed nucleus of the stria terminalis, and central amygdala through collateralized projections 10,14, mPFC->pPVT neurons are well-positioned to provide top-down control of brain networks.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The emergence of deficits in adulthood suggests they may be caused by a mismatch between the juvenile-social-isolation mouse's adult social environment and adaptations resulting from experience during development.
“The finding that these deficits are not observed immediately after the isolation period but only emerge in adulthood suggests that the deficits may be caused by a mismatch between the jSI mouse’s adult social environment and adaptations resulting from experience during development.”
Quote in the paperSubstantial claim - Premisecitation
The PVT projects to various reward-associated areas including the NAc, bed nucleus of the stria terminalis, and central amygdala through collateralized projections.
“Given that the PVT projects to various reward-associated areas including the NAc, bed nucleus of the stria terminalis, and central amygdala through collateralized projections 10,14, mPFC->pPVT neurons are well-positioned to provide top-down control of brain networks.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Kirouac, G. J. Placing the paraventricular nucleus of the thalamus within the brain circuits that control behavior. Neurosci. Biobehav. Rev. 56, 315–329 (2015). source
Not checked in the free run.
- cites [14] Dong, X., Li, S. & Kirouac, G. J. Collateralization of projections from the paraventricular nucleus of the thalamus to the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain Struct. Funct. 222, 3927–3943 (2017). source
Not checked in the free run.
- Interpretationown data
The increased inhibitory drive onto mPFC->pPVT neurons induced by juvenile social isolation is likely driven by an action potential-dependent increase in inhibitory neuron activity.
“As miniature IPSCs of mPFC->pPVT neurons were not impacted by jSI (Extended Data Fig.6A–C), the increased inhibitory drive is likely driven by an action potential-dependent increase in inhibitory neuron activity.”
Quote in the paperSubstantial claim - Interpretationown data
Juvenile social isolation causes changes in presynaptic mechanisms of inhibitory neurotransmitter release from LTS-SST interneurons to mPFC->pPVT neurons.
“The amplitude of optically-evoked responses, normalized to the amplitude of the response evoked by the lowest light intensity level for each cell, was comparable between jSI and GH groups, but the paired pulse ratio (PPR) was reduced in jSI mice compared to GH mice (Fig.6E,F), suggesting changes in presynaptic mechanisms of inhibitory neurotransmitter release caused by jSI.”
Quote in the paperSubstantial claim - Interpretationown data
The enduring neurophysiological deficits in mPFC->pPVT neurons and LTS-SST interneurons are likely the cause of the sociability deficit and reduced activation of mPFC->pPVT neurons during social exploration in juvenile-social-isolation mice.
“Collectively, these experiments demonstrate that jSI leads to enduring neurophysiological deficits in mPFC->pPVT neurons and in LTS-SST interneurons, which are likely to be the cause of the sociability deficit and reduced activation of mPFC->pPVT neurons during social exploration in jSI mice.”
Quote in the paperSubstantial claim - Interpretationown data
Juvenile social isolation causes a lasting reduction in evoked excitatory synaptic transmission onto pPVT neurons.
“These findings suggest that jSI causes a lasting reduction in evoked excitatory synaptic transmission onto pPVT neurons.”
Quote in the paperSubstantial claim
- The quote only partly states this claim. 9
- May combine two claims. 22
- Classified as probably not a substantial claim. 39
The quote only partly states this claim.
Findingown dataJuvenile social isolation leads to a significant increase in spontaneous inhibitory postsynaptic currents (sIPSCs) in mPFC->pPVT neurons compared with adult group-housed mice.
“Patch-clamp slice recordings of mPFC->PVT neurons from adult jSI mice revealed a reduction of intrinsic excitability (Fig.5A–D) and a significant increase in spontaneous inhibitory post synaptic currents (sIPSCs) compared with adult GH mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataChemogenetic suppression of mPFC->pPVT neuron activity in adult group-housed mice does not affect motor activity or anxiety-related behavior.
“Suppression of mPFC->pPVT neuron activity through clozapine N-oxide (CNO) treatment in adult GH mice reduced sociability in the 3-chamber test, with no impact on motor activity or measurements of anxiety-related behavior (Fig.2E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOptogenetic suppression of mPFC->pPVT projection terminals in the pPVT does not impact anxiety-related or motor behaviors.
“This manipulation, which partly reduced the activity of neurons in the pPVT (Extended Data Fig.4A–C), led to reduced sociability (Fig. 3C) without impacting anxiety-related or motor behaviors (Extended Data Fig.4F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataeDREADD-mediated activation of mPFC LTS-SST interneurons in group-housed mice reduces sociability without impacting motor activity or anxiety-related behavior.
“Consistent with these results, excitatory (e)DREADD-mediated activation of mPFC LTS-SST interneurons in GH mice (which recapitulates the physiological deficit seen in jSI mice) was sufficient to reduce sociability without impacting motor activity or anxiety-related behavior (Fig.6G–J).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataChemogenetic activation of mPFC->pPVT projection neurons in adult juvenile-social-isolation mice acutely rescues sociability deficits without impacting motor activity or anxiety-related behavior.
“We found that chemogenetic activation of mPFC->pPVT projection neurons expressing eDREADD through CNO treatment could acutely rescue sociability deficits in the adult jSI mice without impacting motor activity or anxiety-related behavior (Fig.7A–E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOptogenetic activation of mPFC projection terminals in the pPVT acutely rescues sociability deficits in juvenile-social-isolation mice without impacting anxiety-related or motor behaviors.
“We found that this stimulation treatment acutely rescued sociability deficits in jSI mice (Fig.8C), without impacting anxiety-related or motor behaviors (Extended Data Fig.9D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMice with optogenetic suppression showed no differences in motor activity or anxiety-related behaviors between ON and OFF sessions.
“Mice with optogenetic suppression showed no differences in motor activity or anxiety-related behaviors between ON and OFF sessions”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sIPSC frequency between jSI and GH for mPFC->cPFC neurons.
“(K) sIPSC frequency (two tailed t-test, t36=0.758, P=0.454, n=20 cells from 8 biologically independent GH mice, n=18 cells from 8 biologically independent jSI mice,)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sEPSC amplitude between jSI and GH for mPFC->cPFC neurons.
“sEPSC amplitude (two tailed t-test, t36=1.370, P=0.179, n=20 cells from 8 biologically independent GH mice, n=18 cells from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sEPSC amplitude between jSI and GH for PFC->NAc neurons.
“sEPSC amplitude (two tailed t-test, t48=0.305, P=0.762, n=27 cells from 8 biologically independent GH mice, n=23 cells from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sEPSC frequency between jSI and GH for mPFC->cPFC neurons.
“sEPSC frequency (two tailed t-test, t36=0.847, P=0.403, n=20 cells from 8 biologically independent GH mice, n=18 cells from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sIPSC amplitude between jSI and GH for PFC->NAc neurons.
“sIPSC amplitude (two tailed t-test, t48=0.852, P=0.398, n=27 cells from 8 biologically independent GH mice, n=23 cells, from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataOptogenetic suppression of mPFC->pPVT projection terminals does not change motor activity or anxiety-related behaviors in group-housed mice.
“Optogenetic suppression of mPFC->pPVT projection terminals does not change motor activity or anxiety-related behaviors in group-housed mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingown dataNo differences in spike frequency between jSI and GH for pPVT neurons.
“Input-output curve showing no differences in spike frequency”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataControl mCherry+ mice showed no difference in motor activity or anxiety-related behaviors between light ON and OFF sessions.
“Control mCherry+ mice showed no difference in motor activity or anxiety-related behaviors between light ON and OFF sessions”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataControl mCherry+ mice showed no difference in motor activity or anxiety-related behaviors.
“Control mCherry+ mice showed no difference in motor activity or anxiety-related behaviors”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sIPSC frequency between jSI and GH for PFC->NAc neurons.
“(E) sIPSC frequency (two tailed t-test, t48=0.879, P=0.384, n=27 cells from 8 biologically independent GH mice, n=23 cells from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataIn vivo recordings of pPVT neurons showed light-induced decreased firing in 11 out of 57 cells (19%), increased firing in 9 out of 57 cells (16%), or no change in 37 out of 57 cells (65%) upon yellow light delivery over mPFC->pPVT projection terminals expressing halorhodopsin NpHR3.
“Distribution of pPVT neurons showing light-induced decreased firing (11 out of 57 cells from 4 biologically independent mice, 19%), increased firing (9 out of 57 cells from 4 biologically independent mice, 16%), or no change (37 out of 57 cells from 4 biologically independent mice, 65%).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in spike threshold between jSI and GH for pPVT neurons.
“spike threshold (two tailed t-test, t59=0.376, P=0.708, n=26 cells from 8 biologically independent GH mice, n=35 cells from 9 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sEPSC/IPSC frequency ratio between jSI and GH for mPFC->cPFC neurons.
“or (L) sEPSC/IPSC frequency (two tailed t-test, t36=0.147, P=0.884, n=20 cells from 8 biologically independent GH mice, n=18 cells from 8 biologically independent jSI mice) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
The quote only partly states this claim.
Findingown dataNo significant differences in spike threshold between jSI and GH for mPFC->cPFC neurons.
“No significant differences in spike threshold”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in sIPSC amplitude between jSI and GH for mPFC->cPFC neurons.
“sIPSC amplitude (two tailed t-test, t36=0.493, P=0.625, n=20 cells from 8 biologically independent GH mice, n=18 cells from 8 biologically independent jSI mice)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataJuvenile social isolation does not change excitability, nor E/I input ratio of PFC->NAc neurons, mPFC->cPFC neurons, or pPVT neurons in adulthood.
“Juvenile social isolation does not change excitability, nor E/I input ratio of PFC->NAc neurons, mPFC->cPFC neurons, or pPVT neurons in adulthood.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataiDREADD+ mice showed no differences in motor activity or anxiety-related behaviors as a result of CNO vs SAL treatment.
“iDREADD+ mice showed no differences in motor activity or anxiety-related behaviors”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingown dataNo significant differences in sEPSC/sIPSC frequency ratio between jSI and GH for PFC->NAc neurons.
“or (F) sEPSC/sIPSC frequency ratio (two tailed t-test, t48=1.767, P=0.084, n=27 cells from 8 biologically independent GH mice, n=23 cells from 8 biologically independent jSI mice) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataControl mCherry+ jSI mice showed no difference in motor activity or anxiety-related behaviors between ON and OFF sessions.
“Control mCherry+ jSI mice showed no difference in motor activity or anxiety-related behaviors between ON and OFF sessions”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mEPSC amplitude for mPFC->NAc neurons between jSI and GH.
“or mEPSC amplitude (two tailed t-test, t38=0.495, P=0.624) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataChR2+jSI mice showed no differences in motor activity or anxiety-related behaviors between ON and OFF sessions.
“ChR2+jSI mice showed no differences in motor activity or anxiety-related behaviors between ON and OFF sessions”
Quote in the paperSubstantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mIPSC frequency for mPFC->NAc neurons between jSI and GH.
“There were no significant differences in mIPSC frequency (two tailed t-test, t38=0.066, P=0.948)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mIPSC amplitude for mPFC->NAc neurons between jSI and GH.
“or mIPSC amplitude (two tailed t-test, t38=0.455, P=0.652) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mEPSC amplitude for mPFC->pPVT neurons between jSI and GH.
“no significant differences in mEPSC amplitude”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mIPSC amplitude for mPFC->pPVT neurons between jSI and GH.
“or mIPSC amplitude (two tailed t-test, t37=0.303, P=0.764) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
The quote only partly states this claim.
Findingown datajSI group shows decreased excitability in L2/3 SST-AD type at 100pA.
“and (G) L2/3 SST-AD type at 100pA”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere was no difference in mono/polysynaptic ratio between GH and jSI mice.
“There was no difference in mono/polysynaptic ratio”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mIPSC frequency for mPFC->pPVT neurons between jSI and GH.
“There were no significant differences in mIPSC frequency (two tailed t-test, t37=0.101, P=0.920)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mEPSC frequency for mPFC->NAc neurons between jSI and GH.
“There were no significant differences in mEPSC frequency (two tailed t-test, t38=0.002, P=0.998)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNo significant differences in mIPSC amplitude for mPFC->cPFC neurons between jSI and GH.
“or mIPSC amplitude (two tailed t-test, t35=1.579, P=0.123) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingown dataNo significant differences in mEPSC frequency for mPFC->cPFC neurons between jSI and GH.
“There were no significant differences in mEPSC frequency (two tailed t-test, t35=1.559, P=0.128)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingown dataNo significant differences in mIPSC frequency for mPFC->cPFC neurons between jSI and GH.
“There were no significant differences in mIPSC frequency (two tailed t-test, t35=0.247, P=0.807)”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Findingown dataOptogenetic stimulation of mPFC->pPVT projection terminals does not change motor activity or anxiety-related behaviors in adult jSI mice.
“Optogenetic stimulation of mPFC->pPVT projection terminals does not change motor activity or anxiety-related behaviors in adult jSI mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSST-QFS type show comparable excitability between 2 groups at 100pA.
“SST-QFS type show comparable excitability between 2 groups at 100pA”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingown dataNo significant differences in mEPSC amplitude for mPFC->cPFC neurons between jSI and GH.
“or mEPSC amplitude (two tailed t-test, t35=1.275, P=0.211) between jSI and GH.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Data distribution was assumed to be normal but this was not formally tested.
May combine two claims.
Interpretationown dataActivation of mPFC->pPVT projections is reinforcing and is sufficient to increase sociability during social investigation.
“Altogether, these experiments demonstrate that activation of mPFC->pPVT projections is reinforcing, and is sufficient to increase sociability during social investigation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataJuvenile social isolation leads to enduring neurophysiological deficits in mPFC->pPVT neurons and in LTS-SST interneurons.
“Collectively, these experiments demonstrate that jSI leads to enduring neurophysiological deficits in mPFC->pPVT neurons and in LTS-SST interneurons, which are likely to be the cause of the sociability deficit and reduced activation of mPFC->pPVT neurons during social exploration in jSI mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMice with unvalidated viral expression or equipment failure during behavior were excluded from analysis.
“If their viral expression could not be validated or when there was equipment failure during behavior, mice were excluded from the analysis.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationChrna2+ LTS-SST interneurons selectively target deep-layer pyramidal neurons that typically project to sub-cortical targets but not callosal projection neurons or intratelencephalic neurons.
“Importantly, Chrna2+LTS-SST interneurons were previously shown to selectively target deep-layer pyramidal neurons that typically project to sub-cortical targets but not to callosal projection neurons or intratelencephalic neurons13; consistent with this finding, we observed no change in inhibitory drive in mPFC neurons projecting to the contralateral PFC (mPFC->cPFC) or nucleus accumbens (mPFC->NA”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Hilscher, M. M., Leao, R. N., Edwards, S. J., Leao, K. E. & Kullander, K. Chrna2-martinotti cells synchronize layer 5 type A pyramidal cells via rebound excitation. PLoS Biol. 15, e2001392 (2017). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe study identifies a pair of mPFC excitatory and inhibitory neuron populations required for normal adult sociability that are affected by social experience during the juvenile period.
“Overall, our study identifies a pair of mPFC excitatory and inhibitory neuron populations required for normal adult sociability which are affected by social experience during juvenile period (Fig.8G).”
- Also stated in: § Abstract · boosted
“Our study identifies a pair of specific mPFC excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · boosted
May combine two claims.
Interpretationown datamPFC->pPVT neurons and associated LTS-SST interneurons are sensitive to experience-dependent modulation.
“As mPFC->pPVT neurons and associated LTS-SST interneurons are sensitive to experience-dependent modulation, they are promising targets for treatments of social behavior deficits associated with psychiatric disorders that use non-invasive brain modulation techniques such as transcranial magnetic stimulation and/or transcranial direct current stimulation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRecordings in which series resistance exceeded 25MΩ were rejected.
“Recordings in which series resistance exceeded 25MΩ were rejected.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRecordings were discarded when series and membrane resistance changed by more than 20%.
“Series and membrane resistance was continuously monitored, and recordings were discarded when these measurements changed by > 20%.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataFor photometry, GCaMP6 signal levels in all animals were confirmed higher than the autofluorescence channel before behavior testing, and optic fiber placement was confirmed accurate after testing.
“For photometry validation, we confirmed prior to behavior testing that GCaMP6 signal levels in all animals are higher than the signal change in the autofluorescence channel). After behavior testing we confirmed that optic fiber placement was accurate.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenFor wireless optogenetics validation, accuracy of cannula placement was confirmed in all mice.
“For wireless optogenetics validation, accuracy of cannula placement was confirmed in all mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.
Study design and conductown dataBehavioral experiments with CNO and optogenetic stimulation were counterbalanced.
“Mice received CNO and saline (SAL) in a counterbalanced fashion with 1 week of wash out time between treatments.”
- Also stated in: § Behavior Testing · plain
“All experiments were counterbalanced with respect to whether mice received optogenetic stimulation/inhibition on the first day of testing or second day of testing and there was a 24-hour interval between ON and OFF sessions.”
Quote in the paperNot a substantial claim- Also stated in: § Behavior Testing · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSubjects (mice) were randomly assigned into study groups.
“Subjects (mice) were randomly assigned into study groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData collection and analysis were not performed blind to the conditions of the experiments.
“Data collection and analysis were not performed blind to the conditions of the experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenReplication studies confirmed our results in all experiments.
“Replication studies confirmed our results in all experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationNo statistical methods were used to pre-determine sample sizes but sample sizes are similar to those reported in previous publications.
“No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications11,28.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Bicks, L. K. et al. Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior. Nat. Commun. 11, 1003 (2020). source
Not checked in the free run.
- cites [28] Carta, I., Chen, C. H., Schott, A. L., Dorizan, S. & Khodakhah, K. Cerebellar modulation of the reward circmuitry and social behavior. Science 363, eaav0581 (2019). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor all studies, independent animals were used as replicates.
“For all studies, independent animals were used as replicates.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenTo limit the impact of disynaptic excitation, paired pulse ratio was determined as a ratio of the amplitude of EPSC2 to the amplitude of EPSC1.
“To limit the impact of disynaptic excitation, paired pulse ratio was determined as a ratio of the amplitude of EPSC2 to the amplitude of EPSC1.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor chemogenetics, 10 μM CNO was bath applied to cells that exhibited at least 5 minutes of stable baseline recording.
“For chemogenetics, 10 μM CNO was bath applied to cells that exhibited at least 5 minutes of stable baseline recording.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenTo isolate monosynaptic connections, eEPSCs were recorded in the presence of TTX (1 μM), 4-AP (100 μM) and picrotoxin (100 μM).
“To isolate monosynaptic connections, eEPSCs were recorded in the presence of TTX (1 μM), 4-AP (100 μM) and picrotoxin (100 μM).”
Quote in the paperSubstantial claim
The authors state this as an assumption.
Data distribution was assumed to be normal but this was not formally tested.
“Data distribution was assumed to be normal but this was not formally tested.”
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?
mPFC-to-PVT activity is impaired during social interactions following 2 weeks of adolescent social isolation, and activation of this circuit rescued isolation-induced social deficits.
“mPFC-to-PVT activity is impaired during social interactions following 2 weeks of adolescent social isolation, and activation of this circuit rescued isolation induced social deficits [166].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [166]
In rodents, depending on the duration of juvenile social isolation, increased or decreased sociability in adulthood has been reported, suggesting that adolescence is a sensitive period for establishing social behavior later in life.
“In rodents, depending on the duration of juvenile social isolation, increased or decreased sociability in adulthood has been reported, suggesting that adolescence is a sensitive period for establishing social behavior later in life (Yamamuro et al., 2020; Yamamuro et al., 2018; Makinodan et al., 2012; Rivera-Irizarry et al., 2020).”
From Oxytocin neurons mediate the effect of social isolation via the VTA circuits (2022) · cites this paper as Yamamuro et al., 2020
Two weeks of social isolation after weaning altered the pathway from the medial PFC to the posterior paraventricular thalamus, leading to decreased sociability in adult mice.
“Recently, it was reported that 2 weeks of social isolation after weaning altered the pathway from the medial PFC to the posterior paraventricular thalamus, leading to decreased sociability in adult mice (Yamamuro et al., 2020).”
From Oxytocin neurons mediate the effect of social isolation via the VTA circuits (2022) · cites this paper as Yamamuro et al., 2020
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.
Social versus object c-Fos comparison is not significant
MajorThe Results state that mPFC neurons projecting to pPVT were activated more by a novel mouse than by a novel object. The corresponding social-versus-object comparison is reported as P=0.056, above the paper's stated P<0.05 threshold.
“both the posterior part of the paraventricular nucleus of thalamus (pPVT), which relays signals to various components of the classical reward circuitry10, and mPFC deep-layer neurons projecting to the pPVT were activated by exposure to a novel mouse compared with novel-object exposure”
“Social vs object P=0.056”
LTS-SST excitability is described in opposite directions
MinorThe Results say juvenile isolation increases the excitability of LTS-SST interneurons, whereas the Extended Data Fig. 8 caption says the jSI group has reduced spike frequency for those cells.
“a subclass of deep-layer SST-expressing low-threshold spiking (LTS) interneurons showed increased excitability in adult jSI mice compared with GH mice”
“jSI group shows reduced spike frequency at 200pA and −100pA”
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- Authors
- Yamamuro, K., Bicks, L. K., Leventhal, M. B., Kato, D., Im, S., Flanigan, M. E., Garkun, Y., Norman, K. J., Caro, K., Sadahiro, M., Kullander, K., Akbarian, S., Russo, S. J., & Morishita, H.
- Affiliations
- Nara Medical University (JP)
- Icahn School of Medicine at Mount Sinai (US)
- Uppsala University (SE)
- Corresponding author
- Morishita, Hirofumi
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2020-08-31
- Volume
- 23
- Issue
- 10
- Pages
- 1240-1252
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7898783
- OpenAlex
- W3082986453
- Semantic Scholar
- 3abd777340feb7eb6211bf6ead2a7a88d5e5d4f5
- Cited by
- 169
- References
- 31
- Citations by year
- 2026: 17 · 2025: 31 · 2024: 34 · 2023: 22 · 2022: 37 · 2021: 24 · 2020: 4
- FWCI
- 23.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- MEXT | Japan Society for the Promotion of Science
- Naito Foundation
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (T32MH966785, R01MH118297, R01MH119523)
- Simons Foundation (610850)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- medial prefrontal cortex, somatostatin interneurons, social behavior deficits, chemogenetic manipulation, optogenetic stimulation
- MeSH terms
- Animals, Behavior, Animal, Interneurons, Male, Neural Pathways, Neurons, Social Behavior, Social Isolation, Prefrontal Cortex, Midline Thalamic Nuclei, Optogenetics
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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.
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