Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner
Open accessAbstract
BACKGROUND: Chronic stress exposure increases the risk of developing various neuropsychiatric illnesses. The behavioral sequelae of stress correlate with dendritic hypertrophy and glutamate-related synaptic remodeling at basolateral amygdala projection neurons (BLA PNs). Yet, though BLA PNs are functionally heterogeneous with diverse corticolimbic targets, it remains unclear whether stress differentially impacts specific output circuits. METHODS: Confocal imaging was used to reconstruct the morphology of mouse BLA PNs with the aid of retrograde tracing and biocytin staining. The synaptic activity in these neurons was measured with in vitro electrophysiology, and anxiety-like behavior of the mice was assessed with the elevated plus maze and open field test. RESULTS: Chronic restraint stress (CRS) produced dendritic hypertrophy across mouse BLA PNs, regardless of whether they did (BLA→dorsomedial prefrontal cortex [dmPFC]) or did not (BLA↛dmPFC) target dmPFC. However, CRS increased the size of dendritic spine heads and the number of mature, mushroom-shaped spines only in BLA↛dmPFC PNs, sparing neighboring BLA→dmPFC PNs. Moreover, the excitatory glutamatergic transmission was also selectively increased in BLA↛dmPFC PNs, and this effect correlated with CRS-induced increases in anxiety-like behavior. Segregating BLA↛dmPFC PNs based on their targeting of ventral hippocampus (BLA/ventral hippocampus) or nucleus accumbens (BLA→nucleus accumbens) revealed that CRS increased spine density and glutamatergic signaling in BLA→ventral hippocampus PNs in a manner that correlated with anxiety-like behavior. CONCLUSIONS: Chronic stress caused BLA PN neuronal remodeling with a previously unrecognized degree of circuit specificity, offering new insight into the pathophysiological basis of depression, anxiety disorders, and other stress-related conditions.
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Written from the paper’s full text.
TL;DR
Chronic restraint stress (CRS) in mice produced generalized dendritic hypertrophy in basolateral amygdala projection neurons (BLA PNs), but synaptic remodeling was circuit-specific. CRS increased mature spine density and glutamatergic transmission selectively in BLA PNs not targeting dmPFC, and specifically in BLA→ventral hippocampus (vHPC) PNs, where these changes correlated with anxiety-like behavior.
Key findings
- CRS increased dendritic length and branch number in both BLA→dmPFC and BLA↛dmPFC PNs, indicating generalized dendritic hypertrophy regardless of dmPFC targeting.
- CRS increased spine head diameter and mushroom spine density only in BLA↛dmPFC PNs, sparing BLA→dmPFC PNs; mEPSC frequency was also significantly higher in BLA↛dmPFC PNs, with no effect on amplitude.
- Among non-dmPFC targets, CRS increased spine density in all three spine types and mEPSC frequency in BLA→vHPC PNs, but not BLA→NAc PNs; BLA→vHPC and BLA→NAc populations showed minimal collateral colabeling (approximately 7%).
- CRS-exposed mice showed heightened anxiety-like behavior (decreased open arm time/entries in elevated plus maze and less center-square time in open field), and mEPSC frequency in BLA↛dmPFC and BLA→vHPC PNs was inversely correlated with open arm and center-square exploration. The increased glutamatergic afferents to BLA→vHPC PNs were absent after acute stress and persisted after 1 week stress-free recovery; no changes in miniature inhibitory postsynaptic currents were observed.
Methods
- Male C57BL/6 mice were subjected to CRS at 50–53 days of age: 2 hours/day for 10 consecutive days; acute stress mice received 1 session; controls were handled and returned to holding room for 10 days.
- RetroBeads were injected into dmPFC, vHPC, or NAc 7–10 days before stress; BLA PNs were recorded with whole-cell patch clamp, filled with biocytin, reconstructed with confocal microscopy and Neurolucida, and analyzed for Sholl, dendrite length, branching, spine density, and spine subtype (thin, mushroom, stubby).
- Excitatory transmission was measured with mEPSCs (TTX 1 μmol/L, picrotoxin 100 μmol/L), paired-pulse evoked EPSCs (50 ms interval), and MK-801 decay of NMDA receptor currents; anxiety-like behavior used elevated plus maze and open field test. Statistics used two-way ANOVA with Bonferroni-corrected t tests, two-tailed t tests, and Kolmogorov-Smirnov comparisons where stated.
Limitations
- The paper states that precisely how the BLA→vHPC circuit is functionally altered by stress to promote anxiety-like behavior remains to be determined, and that future studies are needed to identify factors such as molecular phenotype that render this population stress-responsive.
- The paper notes that BLA→dmPFC PNs were not fully spared because they showed dendritic hypertrophy, and that possible behavioral deficits such as fear extinction and discrimination were not examined; it also raises whether BLA PNs projecting to ventromedial PFC are similarly spared.
- Evident from the text: the study used only male mice; the link between increased glutamatergic transmission and anxiety-like behavior is correlational rather than causal; and the BLA↛dmPFC population was defined as nonfluorescent putative non-dmPFC-projecting cells, which may include other projection targets.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 59 cited sources checked · 0 supported · 0 flagged
- Findingown data
In chronic restraint stress-exposed mice, open arm and center square explorations were significantly and inversely correlated with miniature excitatory postsynaptic current frequency in BLA↛dmPFC projection neurons.
“However, in CRS-exposed mice, the open arm and center square explorations were significantly and inversely correlated with mEPSC frequency (not amplitude) in BLA↛dmPFC, but not BLA→dmPFC, PNs (Figure 4E, G and Supplemental Figure S4).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
In unstressed control mice, spines in BLA→vHPC PNs have notably lower density but larger head size than spines in BLA→NAc PNs.
“Our first observation was that, in unstressed control mice, the spines in BLA→vHPC PNs had notably lower density but larger head size than the spines in the BLA→NAc PNs (Figure 5B–D).”
Quote in the paperNot a substantial claim - Findingown data
CRS does not increase spine density of BLA→NAc PNs.
“CRS significantly increased the spine density of BLA→vHPC PNs, relative to unstressed control mice, and this effect was absent in BLA→NAc PNs (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
When BLA projection neurons were considered as a whole, chronic restraint stress produced a nonsignificant trend for increased spine density.
“When PNs were considered as a whole, i.e., regardless of dmPFC targeting, we observed a nonsignificant trend for increased spine density and a significant increase in spine head diameter after CRS (Supplemental Figure S2A–C).”
Quote in the paperNot a substantial claim - Findingown data
Mice subjected to chronic restraint stress exhibited heightened anxiety-like behavior, indicated by decreased open arm time and entries in the elevated plus maze and less time in the center square in the open field test relative to unstressed control mice.
“Mice subjected to CRS exhibited heightened anxiety-like behavior, as indicated by decreased open arm time and entries in the elevated plus maze and less time in the center square in the open field test relative to unstressed control mice (Figure 4B, C).”
Quote in the paperSubstantial claim
- Findingown data
Paired pulse facilitation was comparable across chronic restraint stress condition and projection neuron targeting population.
“We observed paired pulse facilitation that was comparable across CRS condition and PN targeting population (Figure 3G, H).”
Quote in the paperSubstantial claim - Findingown data
Within each subcategory of spine type, head size was unaltered by chronic restraint stress in either BLA→dmPFC or BLA↛dmPFC projection neuron population.
“Within each subcategory of spine type, head size was unaltered by CRS in either PN population (Supplemental Figure S3).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
CRS slightly but significantly increases spine head size of BLA→vHPC PNs.
“It also slightly but significantly increased the spine head size of BLA→vHPC PNs (Figure 5D).”
Quote in the paperNot a substantial claim - Findingown data
Chronic restraint stress produces dendritic hypertrophy across mouse BLA projection neurons, regardless of whether they target the dmPFC.
“Chronic restraint stress (CRS) produced dendritic hypertrophy across mouse BLA PNs, regardless of whether they did (BLA→dorsomedial prefrontal cortex [dmPFC]) or did not (BLA↛dmPFC) target dmPFC.”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
CRS has no effect on spine type density in BLA→NAc PNs.
“Furthermore, categorization of spine type revealed increased density in all three spine types in BLA→vHPC PNs after CRS (Figure 5E) and no effect in BLA→NAc PNs (Figure 5F).”
Quote in the paperSubstantial claim - Findingown data
When BLA projection neurons were considered as a whole, chronic restraint stress significantly increased spine head diameter.
“When PNs were considered as a whole, i.e., regardless of dmPFC targeting, we observed a nonsignificant trend for increased spine density and a significant increase in spine head diameter after CRS (Supplemental Figure S2A–C).”
Quote in the paperNot a substantial claim - Findingown data
For both BLA→dmPFC and BLA↛dmPFC projection neuron populations, chronic restraint stress significantly increased dendritic length and branch number relative to unstressed control mice.
“For both PN populations, CRS significantly increased dendritic length and branch number in both PN populations, relative to unstressed control mice (Figure 1C–H).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
Chronic restraint stress was associated with a significantly higher density of mushroom spines in BLA↛dmPFC projection neurons.
“Consistent with the increase in head diameter in BLA↛dmPFC PNs, CRS was associated with a significantly higher density of mushroom, but not thin or stubby, spines, whereas no change was evident in BLA→dmPFC PNs for any spine type (Figure 2E, F).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
Chronic restraint stress was not associated with a significantly higher density of thin or stubby spines in BLA↛dmPFC projection neurons.
“Consistent with the increase in head diameter in BLA↛dmPFC PNs, CRS was associated with a significantly higher density of mushroom, but not thin or stubby, spines, whereas no change was evident in BLA→dmPFC PNs for any spine type (Figure 2E, F).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
CRS significantly increases spine density of BLA→vHPC PNs relative to unstressed control mice.
“CRS significantly increased the spine density of BLA→vHPC PNs, relative to unstressed control mice, and this effect was absent in BLA→NAc PNs (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
BLA→vHPC PNs and BLA→NAc PNs are spatially interspersed in a salt-and-pepper manner, with minimal (approximately 7%) collateral colabeling.
“We labeled BLA→vHPC PNs using RetroBeads and differentiated these cells from BLA→NAc PNs, finding that the two cells in the two populations were spatially interspersed in a salt-and-pepper manner, with minimal (approximately 7%) collateral colabeling (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
Chronic restraint stress had no effect on miniature excitatory postsynaptic current amplitude in BLA↛dmPFC projection neurons.
“Although neither the frequency nor amplitude of mEPSCs in BLA→dmPFC PNs differed between CRS-exposed mice and unstressed control mice (Figure 3A–C), CRS produced significantly higher mEPSC frequency in BLA↛dmPFC PNs, with no effect on amplitude (Figure 3D–F).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
Chronic restraint stress produced significantly higher miniature excitatory postsynaptic current frequency in BLA↛dmPFC projection neurons.
“Although neither the frequency nor amplitude of mEPSCs in BLA→dmPFC PNs differed between CRS-exposed mice and unstressed control mice (Figure 3A–C), CRS produced significantly higher mEPSC frequency in BLA↛dmPFC PNs, with no effect on amplitude (Figure 3D–F).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
C57BL/6J mice subjected to chronic restraint stress exhibited significantly increased dendritic length and branch number compared with nonstressed control mice.
“we found that C57BL/6J mice subjected to CRS exhibited significantly increased dendritic length and branch number compared with nonstressed control mice (Supplemental Figure S1A–C).”
Quote in the paperSubstantial claim - Findingown data
Chronic restraint stress produced no change in the density of any spine type in BLA→dmPFC projection neurons.
“Consistent with the increase in head diameter in BLA↛dmPFC PNs, CRS was associated with a significantly higher density of mushroom, but not thin or stubby, spines, whereas no change was evident in BLA→dmPFC PNs for any spine type (Figure 2E, F).”
Quote in the paperSubstantial claim - Findingown data
In unstressed control mice, miniature excitatory postsynaptic current frequency did not correlate with explorations in the open arm or center square in either BLA→dmPFC or BLA↛dmPFC projection neuron population.
“In unstressed control mice, mEPSC frequency did not correlate with explorations in open arm (elevated plus maze) and center square (open field test) in either population (Figure 4D, F).”
Quote in the paperSubstantial claim - Findingown data
CRS does not increase mEPSC frequency in BLA→NAc PNs.
“Finally, electrophysiological recordings indicated a significant CRS-related increase of mEPSC frequency, not amplitude, in BLA→vHPC, not BLA→NAc, PNs (Figure 5G, H), which was inversely correlated with exploration in the open arm in the elevated plus maze and center square in the open field test (Figure 5I–N).”
Quote in the paperSubstantial claim - Findingown data
CRS increases density in all three spine types in BLA→vHPC PNs.
“Furthermore, categorization of spine type revealed increased density in all three spine types in BLA→vHPC PNs after CRS (Figure 5E) and no effect in BLA→NAc PNs (Figure 5F).”
Quote in the paperSubstantial claim - Findingown data
For both BLA→dmPFC and BLA↛dmPFC projection neuron populations, the decay of evoked N-methyl-D-aspartate receptor-mediated currents was indistinguishable between chronic restraint stress-exposed mice and control mice, as demonstrated by similar τ values.
“For both PN populations, the decay of the current was indistinguishable between CRS-exposed mice and control mice, as demonstrated by similar τ values (Figure 3I–L).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Findingown data
In chronic restraint stress-exposed mice, open arm and center square explorations were not correlated with miniature excitatory postsynaptic current frequency in BLA→dmPFC projection neurons.
“However, in CRS-exposed mice, the open arm and center square explorations were significantly and inversely correlated with mEPSC frequency (not amplitude) in BLA↛dmPFC, but not BLA→dmPFC, PNs (Figure 4E, G and Supplemental Figure S4).”
Quote in the paperNot a substantial claim - Findingown data
No changes in miniature inhibitory postsynaptic currents are observed in BLA→vHPC and BLA→NAc PNs following CRS.
“No changes in miniature inhibitory postsynaptic currents were observed in BLA→vHPC and BLA→NAc PNs following CRS (Supplemental Figure S7).”
Quote in the paperNot a substantial claim - Findingown data
Paired ratio of evoked EPSCs and decay of NMDA receptor current by MK-801 are unaffected by stress.
“The absence of an increase in excitatory transmission is unlikely owing to reduced glutamate release probability onto BLA→dmPFC PNs because two measures indicating glutamate release probability, paired ratio of evoked EPSCs and the decay of N-methyl-D-aspartate receptor current by MK-801, were unaffected by stress.”
Quote in the paperSubstantial claim - Findingown data
BLA→dmPFC PNs show the same pronounced dendritic hypertrophy evident in other BLA projection populations examined.
“However, it is important to emphasize that this population was in fact not fully spared the effects of stress, and BLA→dmPFC PNs showed the same pronounced dendritic hypertrophy evident in the other BLA projection populations examined.”
Quote in the paperSubstantial claim - Findingown data
The same set of stress-related changes occurs in BLA PNs targeting the vHPC and not the NAc.
“Subsequent experiments revealed that this same set of stress-related changes occurred in BLA PNs targeting the vHPC and not the NAc.”
Quote in the paperSubstantial claim - Findingown data
Dendritic hypertrophy in BLA→dmPFC PNs is not associated with higher mEPSCs.
“It was surprising that dendritic hypertrophy was not associated with higher mEPSCs in this population, given that the overall number of spines would be expected to be higher even if density per dendritic segment was not.”
Quote in the paperSubstantial claim - Findingown data
Greater stress-induced increases in synaptic transmission at BLA→vHPC PNs correlate with higher levels of anxiety-like behavior.
“Finally, greater stress-induced increases in synaptic transmission at BLA→vHPC PNs were found to correlate with higher levels of anxiety-like behavior.”
Quote in the paperSubstantial claim - Findingown data
The CRS-related increase in mEPSC frequency in BLA→vHPC PNs is inversely correlated with exploration in the open arm in the elevated plus maze and center square in the open field test.
“Finally, electrophysiological recordings indicated a significant CRS-related increase of mEPSC frequency, not amplitude, in BLA→vHPC, not BLA→NAc, PNs (Figure 5G, H), which was inversely correlated with exploration in the open arm in the elevated plus maze and center square in the open field test (Figure 5I–N).”
Quote in the paperSubstantial claim - Findingcitation
The density of immature thin and stubby spines is also increased in BLA→vHPC PNs after stress.
“Notably, the density of immature thin and stubby spines was also increased in BLA→vHPC PNs, which might be associated with the generation of silent synapses following stress (15).”
Quote in the paperNot a substantial claim - Interpretationown data
Chronic restraint stress had a negligible influence on presynaptic glutamate release.
“Thus, CRS had a negligible influence on presynaptic glutamate release, supporting the notion that the preferential increase in mEPSC frequency in BLA↛dmPFC PNs likely reflects the corresponding increase in mature spine density produced by CRS.”
Quote in the paperSubstantial claim - Premisecitation
There is relatively little collateralization of BLA projection neurons to their target regions, suggesting a high degree of projection specificity.
“Notably, there appears to be relatively little collateralization of BLA PNs to these target regions (17), suggesting a high degree of projection specificity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Beyeler, 2016, Divergent routing of positive and negative information from the amygdala during memory retrieval, Neuron source
Not checked in the free run.
- Premisecitation
The ventral hippocampus is a candidate region for the anxiety-related effects of chronic restraint stress given prior evidence implicating this region in anxiety-related behavior.
“The vHPC represents one obvious candidate for these effects given prior evidence implicating this region in anxiety-related behavior (38).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Bannerman, 2014, Hippocampal synaptic plasticity, spatial memory and anxiety, Nat Rev Neurosci source
Not checked in the free run.
- Interpretationown data
Remodeling of BLA↛dmPFC projection neurons after chronic restraint stress is associated with increased glutamatergic transmission onto this population.
“These electrophysiological data demonstrate that remodeling of BLA↛dmPFC PNs after CRS is associated with increased glutamatergic transmission onto this population.”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Premisecitation
The amygdala exhibits profound functional changes as a result of chronic stress that are closely linked to attendant changes in anxiety.
“Moreover, the amygdala exhibits profound functional changes as a result of chronic stress that are closely linked to attendant changes in anxiety (5,6,9–12).”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [5] Luthi, 2014, Pathological circuit function underlying addiction and anxiety disorders, Nat Neurosci source
Not checked in the free run.
- cites [6] Chattarji, 2015, Neighborhood matters: Divergent patterns of stress-induced plasticity across the brain, Nat Neurosci source
Not checked in the free run.
- cites [9] Roozendaal, 2009, Stress, memory and the amygdala, Nat Rev Neurosci source
Not checked in the free run.
- cites [10] Rauch, 2000, Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: A functional MRI study, Biol Psychiatry source
Not checked in the free run.
- cites [11] Maroun, 2013, Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons, Eur J Neurosci source
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- cites [12] Mozhui, 2010, Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability, J Neurosci source
Not checked in the free run.
- Interpretationown data
Heightened anxiety-like behavior resulting from chronic restraint stress is closely associated with increases in glutamatergic transmission onto BLA↛dmPFC projection neurons.
“These data show that heightened anxiety-like behavior resulting from CRS is closely associated with increases in glutamatergic transmission onto BLA↛dmPFC PNs.”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Premisecitation
BLA projection neurons projecting to the ventral hippocampus or nucleus accumbens have been shown to sparsely innervate the dmPFC.
“Moreover, BLA PNs projecting to the vHPC or NAc have been shown to sparsely innervate the dmPFC (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Beyeler, 2016, Divergent routing of positive and negative information from the amygdala during memory retrieval, Neuron source
Not checked in the free run.
- Premisecitation
The BLA is connected through projection neurons to the dmPFC, ventral hippocampus, and nucleus accumbens.
“The BLA is connected through PNs to the dmPFC, ventral hippocampus (vHPC), and various other regions involved in higher-order behavioral processes, including the nucleus accumbens (NAc) (16).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] LeDoux, 2007, The amygdala, Curr Biol source
Not checked in the free run.
- Interpretationown data
The generalized dendritic hypertrophy produced by chronic restraint stress is associated with a preponderance of mature mushroom spines that is restricted to BLA projection neurons that do not target the dmPFC.
“These data show that the generalized dendritic hypertrophy produced by CRS is associated with a preponderance of mature mushroom spines that is restricted to BLA PNs that do not target the dmPFC.”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Interpretationreasoning
The preferential increase in miniature excitatory postsynaptic current frequency in BLA↛dmPFC projection neurons likely reflects the corresponding increase in mature spine density produced by chronic restraint stress.
“Thus, CRS had a negligible influence on presynaptic glutamate release, supporting the notion that the preferential increase in mEPSC frequency in BLA↛dmPFC PNs likely reflects the corresponding increase in mature spine density produced by CRS.”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
- Premisecitation
Chronic stress causes dendritic retraction in the dorsomedial prefrontal cortex and hippocampus.
“in contrast to the stress-induced dendritic retraction seen in other nodes within the corticolimbic system, such as the dorsomedial prefrontal cortex (dmPFC) and hippocampus (13)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Holmes, 2009, Stress-induced prefrontal reorganization and executive dysfunction in rodents, Neurosci Biobehav Rev source
Not checked in the free run.
- Interpretationown data
Functional alterations in BLA→vHPC PNs account for stress-induced anxiety-like behavior.
“The current findings that BLA→vHPC PNs are particularly susceptible to the effects of chronic stress and that functional alterations in these cells account for stress-induced anxiety-like behavior provide an important extension of these prior observations.”
Quote in the paperSubstantial claim- Rests on an assumption: The stress-induced synaptic and morphological changes in BLA→vHPC PNs causally drive stress-induced anxiety-like behavior.
- Interpretationown data
The absence of an increase in excitatory transmission in BLA→dmPFC PNs is unlikely owing to reduced glutamate release probability onto these neurons.
“The absence of an increase in excitatory transmission is unlikely owing to reduced glutamate release probability onto BLA→dmPFC PNs because two measures indicating glutamate release probability, paired ratio of evoked EPSCs and the decay of N-methyl-D-aspartate receptor current by MK-801, were unaffected by stress.”
Quote in the paperSubstantial claim - Interpretationown data
The highly heterogeneous nature of stress effects extends to the level of specific output pathways within limbic structures.
“The findings of the current study, along with earlier work (44), show that the highly heterogeneous nature of stress effects extends to the level of specific output pathways within limbic structures.”
Quote in the paperSubstantial claim - Interpretationreasoning
The BLA→dmPFC pathway may be less susceptible to stress.
“The observation that BLA PNs targeting the dmPFC did not exhibit increases in spine density and excitatory transmission after CRS echoes an earlier report that CRS led to hypotrophy in medial PFC (mPFC) PNs projecting to the entorhinal cortex, but not the BLA (44), and suggests that this pathway may be less susceptible to stress.”
Quote in the paperSubstantial claim - Premisecitation
The effect of stress on neuronal morphology and functions varies across brain regions.
“In recent years, it has become increasingly clear that the effect of stress on neuronal morphology and functions varies across brain regions (53–56).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [53] Sousa, 2012, Disconnection and reconnection: The morphological basis of (mal)adaptation to stress, Trends Neurosci source
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- cites [54] Liston, 2006, Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting, J Neurosci source
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- cites [55] Sheline, 1996, Hippocampal atrophy in recurrent major depression, Proc Natl Acad Sci U S A source
Not checked in the free run.
- cites [56] McEwen, 2016, Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex, Neuropsychopharmacology source
Not checked in the free run.
- Premisecitation
Reciprocal connections between the BLA and mPFC are important for fear extinction, fear discrimination, and other processes requiring the resolution of conflicting information.
“Reciprocal connections between the BLA and mPFC are important for fear extinction, fear discrimination, and other processes requiring the resolution of conflicting information (47–50), and dendritic hypotrophy in mPFC neurons has been linked to stress and alcohol-related deficits in fear extinction (51,52).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [47] Burgos-Robles, 2017, Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment, Nat Neurosci source
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- cites [48] Banks, 2007, Amygdala-frontal connectivity during emotion regulation, Soc Cogn Affect Neurosci source
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- cites [49] Likhtik, 2005, Prefrontal control of the amygdala, J Neurosci source
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- cites [50] Bukalo, 2015, Prefrontal inputs to the amygdala instruct fear extinction memory formation, Sci Adv source
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- Premisecitation
Neuronal and synaptic remodeling in BLA PNs, along with enhanced glutamatergic transmission, has been repeatedly associated with the negative consequence of stress.
“Neuronal and synaptic remodeling in BLA PNs, along with enhanced glutamatergic transmission, has been repeatedly associated with the negative consequence of stress (14,33,34,40), and prevention of these changes is paralleled by a protection against stress-induced increases in anxiety-like behavior (26,41).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [14] Vyas, 2002, Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons, J Neurosci source
Not checked in the free run.
- cites [33] Adamec, 2012, Dendritic morphology of amygdala and hippocampal neurons in more and less predator stress responsive rats and more and less spontaneously anxious handled controls, Behav Brain Res source
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- cites [34] Vyas, 2004, Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior, Neuroscience source
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- cites [40] Mitra, 2008, Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy, Proc Natl Acad Sci U S A source
Not checked in the free run.
- Interpretationown data
Chronic stress significantly alters the morphology and synaptic physiology of amygdala projection neurons in a manner selective to certain output pathways.
“The major finding of the current study was that chronic stress significantly altered the morphology and synaptic physiology of amygdala projection neurons in a manner that was selective to certain output pathways.”
Quote in the paperSubstantial claim
- May combine two claims. 15
- Classified as probably not a substantial claim. 13
May combine two claims.
Findingown dataThe spatial distribution of chronic restraint stress-induced dendritic length increase differed: in BLA→dmPFC projection neurons it was unbiased toward soma/proximal and distal regions, whereas in BLA↛dmPFC projection neurons it was only in distal areas.
“There was a difference in the spatial distribution pattern of hypertrophy, with increased dendritic length unbiased toward both the soma/proximal and distal regions in BLA→dmPFC PNs (Figure 1D) but only in the distal areas in BLA↛dmPFC PNs (Figure 1G).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
May combine two claims.
Findingown dataCRS significantly increases mEPSC frequency, but not amplitude, in BLA→vHPC PNs.
“Finally, electrophysiological recordings indicated a significant CRS-related increase of mEPSC frequency, not amplitude, in BLA→vHPC, not BLA→NAc, PNs (Figure 5G, H), which was inversely correlated with exploration in the open arm in the elevated plus maze and center square in the open field test (Figure 5I–N).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNeither the frequency nor amplitude of miniature excitatory postsynaptic currents in BLA→dmPFC projection neurons differed between chronic restraint stress-exposed mice and unstressed control mice.
“Although neither the frequency nor amplitude of mEPSCs in BLA→dmPFC PNs differed between CRS-exposed mice and unstressed control mice (Figure 3A–C), CRS produced significantly higher mEPSC frequency in BLA↛dmPFC PNs, with no effect on amplitude (Figure 3D–F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe chronic restraint stress-induced increase in spine head diameter was restricted to BLA↛dmPFC projection neurons, with no effect on neighboring BLA→dmPFC cells.
“When segregated into BLA→dmPFC and BLA↛dmPFC PNs, the effects of CRS on spine density were again mild (Figure 2A, B), but the CRS-induced increase in spine head diameter was found to be restricted to BLA↛dmPFC PNs, with no effect on neighboring BLA→dmPFC cells (Figure 2C, D).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
May combine two claims.
Findingown dataChronic restraint stress-induced branch number proliferation emerged only in the soma/proximal regions of BLA→dmPFC projection neurons but both proximally and distally to the soma of BLA↛dmPFC cells.
“However, the branch number proliferation emerged only in the soma/proximal regions of BLA→dmPFC PNs (Figure 1I) but both proximally and distally to the soma of BLA↛dmPFC cells (Figure 1J).”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
May combine two claims.
Findingown dataSholl analysis showed that increased dendritic length after chronic restraint stress was particularly prominent in dendrites proximal to the soma, whereas increased branch number was evident both proximally and distally.
“Sholl analysis showed that increased dendritic length was particularly prominent in dendrites proximal to the soma, whereas increased branch number was evident both proximally and distally (Supplemental Figure S1D, E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMice subjected to repeated restraint stress show dendritic hypertrophy, spine enlargement, and increased synaptic glutamatergic transmission, but only in BLA PNs not projecting to the dmPFC.
“Specifically, mice subjected to repeated restraint stress showed dendritic hypertrophy, spine enlargement, and increased synaptic glutamatergic transmission, but only in BLA PNs not projecting to the dmPFC.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBLA PNs targeting the dmPFC do not exhibit increases in spine density and excitatory transmission after CRS.
“The observation that BLA PNs targeting the dmPFC did not exhibit increases in spine density and excitatory transmission after CRS echoes an earlier report that CRS led to hypotrophy in medial PFC (mPFC) PNs projecting to the entorhinal cortex, but not the BLA (44), and suggests that this pathway may be less susceptible to stress.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationChronic stress exposure increases the risk of developing various neuropsychiatric illnesses.
“Chronic stress exposure increases the risk of developing various neuropsychiatric illnesses.”
- Also stated in: § CONCLUSIONS: · plain
“Maladaptive responses to prolonged stress are associated with the onset and exacerbation of neuropsychiatric diseases, including mood and anxiety disorders (1–4).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] McEwen, 2013, The brain on stress: Vulnerability and plasticity of the prefrontal cortex over the life course, Neuron source
Not checked in the free run.
- cites [2] McEwen, 2015, Mechanisms of stress in the brain, Nat Neurosci source
Not checked in the free run.
- cites [3] Dias-Ferreira, 2009, Chronic stress causes frontostriatal reorganization and affects decision-making, Science source
Not checked in the free run.
- cites [4] de Kloet, 2005, Stress and the brain: From adaptation to disease, Nat Rev Neurosci source
Not checked in the free run.
- Also stated in: § CONCLUSIONS: · plain
Classified as probably not a substantial claim.
Study design and conductnone givenDendrites located at least 20 μm away from the soma and longer than 15 μm were randomly selected for analysis of spine density and head size.
“Dendrites located at least 20 μm away from the soma and longer than 15 μm were randomly selected for analysis of spine density and head size.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNeurons were traced by an independent experimenter blinded to the group.
“Neurons were traced by an independent experimenter blinded to the group.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenTo control reproducibility of RetroBead injection across mice, only mice with amygdala sections containing more than 250 RetroBead-labeled cells/mm2 were included for analysis.
“To control the reproducibility of the RetroBead injection across mice, we included for analysis only mice with amygdala sections (70-μm thickness) containing >250 RetroBead-labeled cells/mm2.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataChronic restraint stress produces robust dendritic hypertrophy in BLA projection neurons, and these effects are generalized regardless of whether the neurons target the dmPFC.
“The main finding from these morphologic analyses is that, replicating prior data, CRS produces robust dendritic hypertrophy in BLA PNs and that these effects are generalized regardless of whether the PNs target the dmPFC.”
Quote in the paperSubstantial claim- Rests on an assumption: Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBLA projection neurons innervating the nucleus accumbens and ventral hippocampus primarily encode information with positive and negative valence, respectively.
“This work has, for instance, proposed that BLA PNs innervating the NAc and vHPC primarily encode information with positive and negative valence, respectively (17,20,22,23).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [17] Beyeler, 2016, Divergent routing of positive and negative information from the amygdala during memory retrieval, Neuron source
Not checked in the free run.
- cites [20] Namburi, 2015, A circuit mechanism for differentiating positive and negative associations, Nature source
Not checked in the free run.
- cites [22] Felix-Ortiz, 2013, BLA to vHPC inputs modulate anxiety-related behaviors, Neuron source
Not checked in the free run.
- cites [23] Stuber, 2011, Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking, Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenOnly neurons that maintained stable membrane potential for at least 20 minutes were included.
“Only neurons that maintained stable membrane potential for at least 20 minutes were included.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHeightened activity within the amygdala is implicated in stress-related emotional abnormalities in humans and animal models.
“Heightened activity within the amygdala, a brain region essential for the regulation of fear and anxiety, has been implicated in stress-related emotional abnormalities in humans and animal models (5–8).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [5] Luthi, 2014, Pathological circuit function underlying addiction and anxiety disorders, Nat Neurosci source
Not checked in the free run.
- cites [6] Chattarji, 2015, Neighborhood matters: Divergent patterns of stress-induced plasticity across the brain, Nat Neurosci source
Not checked in the free run.
- cites [7] Davis, 2010, Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety, Neuropsychopharmacology source
Not checked in the free run.
- cites [8] Etkin, 2007, Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia, Am J Psychiatry source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenProjection neurons were included for analysis only when their dendritic trees were completely filled as evidenced by well-defined ending with no visible terminals on the furthest margins.
“PNs were included for analysis only when their dendritic trees were completely filled as evidenced by well-defined ending with no visible terminals on the furthest margins.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe BLA→vHPC circuit is a critical locus regulating anxiety-like behavior and a principal site underlying stress-induced dysregulation of anxiety.
“Together, these findings identify the BLA→vHPC circuit as a critical locus regulating anxiety-like behavior and a principal site underlying stress-induced dysregulation of anxiety.”
Quote in the paperSubstantial claim- Rests on an assumption: The stress-induced synaptic and morphological changes in BLA→vHPC PNs causally drive stress-induced anxiety-like behavior.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDendritic hypotrophy in mPFC neurons has been linked to stress and alcohol-related deficits in fear extinction.
“Reciprocal connections between the BLA and mPFC are important for fear extinction, fear discrimination, and other processes requiring the resolution of conflicting information (47–50), and dendritic hypotrophy in mPFC neurons has been linked to stress and alcohol-related deficits in fear extinction (51,52).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [51] Izquierdo, 2006, Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice, J Neurosci source
Not checked in the free run.
- cites [52] Holmes, 2012, Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding, Nat Neurosci source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningIncreases in glutamatergic transmission coupled with increased density of mature mushroom spines would be expected to result in stronger excitatory flow into BLA→vHPC PNs after stress.
“Increases in glutamatergic transmission coupled with the increased density of mature mushroom spines would be expected to result in stronger excitatory flow into this neuronal population after stress.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBLA PNs targeting the vHPC are at least one key output pathway that is functionally altered by CRS and linked to stress-induced increases in anxiety-like behavior.
“Taken together, these data identify BLA PNs targeting the vHPC as at least one key output pathway that is functionally altered by CRS and linked to stress-induced increases in anxiety-like behavior (Figure 6).”
Quote in the paperSubstantial claim- Rests on an assumption: The stress-induced synaptic and morphological changes in BLA→vHPC PNs causally drive stress-induced anxiety-like behavior.
May combine two claims.
PremisecitationPhotostimulating BLA PNs targeting the vHPC increases anxiety-like behavior and reduces social interaction.
“Recent optogenetic studies have shown that photostimulating BLA PNs targeting the vHPC increases anxiety-like behavior and reduces social interaction, whereas photosilencing this pathway has the opposite effects, and, conversely, stimulating NAc-targeting BLA PNs promotes reward-seeking (20,22,23,39).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [20] Namburi, 2015, A circuit mechanism for differentiating positive and negative associations, Nature source
Not checked in the free run.
- cites [22] Felix-Ortiz, 2013, BLA to vHPC inputs modulate anxiety-related behaviors, Neuron source
Not checked in the free run.
- cites [23] Stuber, 2011, Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking, Nature source
Not checked in the free run.
- cites [39] Felix-Ortiz, 2014, Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior, J Neurosci source
Not checked in the free run.
May combine two claims.
PremisecitationPrevention of neuronal and synaptic remodeling in BLA PNs and enhanced glutamatergic transmission is paralleled by protection against stress-induced increases in anxiety-like behavior.
“Neuronal and synaptic remodeling in BLA PNs, along with enhanced glutamatergic transmission, has been repeatedly associated with the negative consequence of stress (14,33,34,40), and prevention of these changes is paralleled by a protection against stress-induced increases in anxiety-like behavior (26,41).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [26] Mitra, 2009, Resilience against predator stress and dendritic morphology of amygdala neurons, Behav Brain Res source
Not checked in the free run.
- cites [41] Mitra, 2009, SK2 potassium channel overexpression in basolateral amygdala reduces anxiety, stress-induced corticosterone secretion and dendritic arborization, Mol Psychiatry source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPhotosilencing the BLA→vHPC pathway has effects opposite to photostimulation.
“Recent optogenetic studies have shown that photostimulating BLA PNs targeting the vHPC increases anxiety-like behavior and reduces social interaction, whereas photosilencing this pathway has the opposite effects, and, conversely, stimulating NAc-targeting BLA PNs promotes reward-seeking (20,22,23,39).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [20] Namburi, 2015, A circuit mechanism for differentiating positive and negative associations, Nature source
Not checked in the free run.
- cites [22] Felix-Ortiz, 2013, BLA to vHPC inputs modulate anxiety-related behaviors, Neuron source
Not checked in the free run.
- cites [23] Stuber, 2011, Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking, Nature source
Not checked in the free run.
- cites [39] Felix-Ortiz, 2014, Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior, J Neurosci source
Not checked in the free run.
May combine two claims.
PremisecitationChronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in lateral or central subnuclei of the amygdala.
“Chronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in the BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in the lateral or central subnuclei of the amygdala (3,54,57–61).”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [3] Dias-Ferreira, 2009, Chronic stress causes frontostriatal reorganization and affects decision-making, Science source
Not checked in the free run.
- cites [54] Liston, 2006, Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting, J Neurosci source
Not checked in the free run.
- cites [57] McEwen, 2017, Allostasis and the epigenetics of brain and body health over the life course: The brain on stress, JAMA Psychiatry source
Not checked in the free run.
- cites [58] Turecki, 2016, Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review, Biol Psychiatry source
Not checked in the free run.
- cites [59] Bennett, 2014, Stress and trauma: BDNF control of dendritic-spine formation and regression, Prog Neurobiol source
Not checked in the free run.
- cites [60] Issler, 2014, MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity, Neuron source
Not checked in the free run.
- cites [61] Myers, 2014, Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress, Front Neuroendocrinol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationStimulating NAc-targeting BLA PNs promotes reward-seeking.
“Recent optogenetic studies have shown that photostimulating BLA PNs targeting the vHPC increases anxiety-like behavior and reduces social interaction, whereas photosilencing this pathway has the opposite effects, and, conversely, stimulating NAc-targeting BLA PNs promotes reward-seeking (20,22,23,39).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [20] Namburi, 2015, A circuit mechanism for differentiating positive and negative associations, Nature source
Not checked in the free run.
- cites [22] Felix-Ortiz, 2013, BLA to vHPC inputs modulate anxiety-related behaviors, Neuron source
Not checked in the free run.
- cites [23] Stuber, 2011, Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking, Nature source
Not checked in the free run.
- cites [39] Felix-Ortiz, 2014, Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior, J Neurosci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOptogenetic excitation of BLA→dmPFC PNs increases conditioned fear after extinction.
“Moreover, optogenetic excitation of BLA→dmPFC PNs has been shown to increase conditioned fear after extinction (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Senn, 2014, Long-range connectivity defines behavioral specificity of amygdala neurons, Neuron source
Not checked in the free run.
The paper relies on this without support.
It remains unclear whether the effects of stress are restricted to specific output circuits or manifest more ubiquitously across BLA neurons.
“Despite emerging evidence of the functional and anatomical heterogeneity of BLA output pathways, it remains unclear whether the effects of stress are restricted to specific output circuits or manifest more ubiquitously across BLA neurons.”
The paper relies on this without support.
Within the BLA there is no clear spatial organization of projection neurons based on their primary output target.
“However, within the BLA there is no clear spatial organization of PNs based on their primary output target, and it is only recently, with the advent of new techniques for functional circuit mapping, that the role of specific BLA output pathways has begun to be delineated (17–21).”
The paper relies on this without support.
Nonfluorescent BLA neurons after dmPFC RetroBead injection are putative BLA↛dmPFC projection neurons that do not target the dmPFC.
“This was achieved by injecting red fluorescent RetroBeads into the dmPFC and then biocytin-staining fluorescent (BLA→dmPFC) and nonfluorescent (putative BLA↛dmPFC) PNs in the BLA with the aid of whole-cell patch recording (Figure 1A, B).”
The paper relies on this without support.
The stress-induced synaptic and morphological changes in BLA→vHPC PNs causally drive stress-induced anxiety-like behavior.
“Taken together, these data identify BLA PNs targeting the vHPC as at least one key output pathway that is functionally altered by CRS and linked to stress-induced increases in anxiety-like behavior (Figure 6).”
“The current findings that BLA→vHPC PNs are particularly susceptible to the effects of chronic stress and that functional alterations in these cells account for stress-induced anxiety-like behavior provide an important extension of these prior observations.”
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?
Patients with somatic symptom disorder who underwent BSRP showed significant reductions in depression, anxiety, stress, and physical symptoms compared to controls.
“Similarly, patients with somatic symptom disorder (SSD) who underwent BSRP showed significant reductions in depression, anxiety, stress, and physical symptoms, compared to controls [1,70,71].”
From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [71]
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.
Discussion incorrectly limits dendritic hypertrophy to non-dmPFC-projecting neurons
MinorThe Discussion says dendritic hypertrophy occurred only in BLA neurons that do not project to the dmPFC, but the Results say CRS increased dendritic length and branch number in both populations.
“Specifically, mice subjected to repeated restraint stress showed dendritic hypertrophy, spine enlargement, and increased synaptic glutamatergic transmission, but only in BLA PNs not projecting to the dmPFC.”
“For both PN populations, CRS significantly increased dendritic length and branch number in both PN populations, relative to unstressed control mice (Figure 1C–H).”
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“Moreover, optogenetic excitation of BLA→dmPFC PNs has been shown to increase conditioned fear after extinction (19).”
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Page, C. E., & Coutellier, L. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.07.024 · Cited by 213 · see citing works
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The primary cilia are associated with the axon initial segment in neurons
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- Authors
- Zhang, J.-Y., Liu, T.-H., He, Y., Pan, H.-Q., Zhang, W.-H., Yin, X.-P., Tian, X.-L., Li, B.-M., Wang, X.-D., Holmes, A., Yuan, T.-F., & Pan, B.-X.
- Affiliations
- Nanchang University (CN)
- National Institutes of Health (US)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Pan, Bing-Xing
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 85
- Issue
- 3
- Pages
- 189-201
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6747699
- OpenAlex
- W2871495632
- Semantic Scholar
- a7831cd0a4b0a7b693081d5edd819d85d75738bb
- Cited by
- 183
- References
- 63
- Citations by year
- 2026: 17 · 2025: 33 · 2024: 26 · 2023: 22 · 2022: 27 · 2021: 28 · 2020: 11 · 2019: 18 · 2018: 1
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- National Natural Science Foundation of China (81741759, 81503079, 91332123, 31700916, 81601179)
- Natural Science Foundation of Jiangxi Province (20172BCB22005, 20143ACB21002, KJLD14013, 20161BAB215204)
- National Basic Research Program of China (2014CB846100)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- chronic stress, chronic restraint stress, basolateral amygdala, projection neurons, dendritic spine remodeling, glutamatergic neurotransmission, dorsomedial prefrontal cortex, ventral hippocampus, nucleus accumbens, anxiety-like behavior, depression, dendritic spine morphology
- MeSH terms
- Amygdala, Animals, Behavior, Animal, Dendrites, Electrophysiology, Hypertrophy, Male, Neuronal Plasticity, Restraint, Physical, Stress, Psychological, Microscopy, Confocal, Glutamic Acid, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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