Parallel social information processing circuits are differentially impacted in autism
Open accessPublished version of a preprint
Abstract
Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons in male mice, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next use novel multiple feature selection tools in Fmr1-KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are enriched in parvocellular compared with magnocellular oxytocin neurons. Taken together, these results provide the first evidence that oxytocin-pathway-specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.
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Written from the paper’s full text.
TL;DR
Magnocellular and parvocellular oxytocin neurons form parallel social information processing streams in male mice. Parvocellular, but not magnocellular, oxytocin neurons are selectively required for peer-peer social reward learning and are enriched for autism risk genes and FMRP targets.
Key findings
- In the PVN of male mice, 66% (952 ± 69) of oxytocinergic neurons were magnocellular and 34% (488 ± 25) parvocellular; magnocellular neurons were predominantly rostral and parvocellular neurons caudal.
- Electrophysiological clustering matched anatomical classification: two k-means clusters corresponded 100% (18/18) with shoulder-based classification and 94% (17/18) with FluoroGold labeling; 4-AP reduced latency and increased action potential duration in magnocellular but not parvocellular OT neurons.
- scRNA-seq of 194 collected OT neurons (146 passed QC) identified two transcriptional clusters; cluster 1 was 72.8% FG+ (magnocellular) and cluster 2 was 100% FG− (parvocellular). Differential expression found 181 genes at 0.1% FDR, including magnocellular-enriched Calb1 and Kcnmb4 and parvocellular-enriched Reln and Cnr1.
- Fmr1 KO mice showed impaired peer-peer social CPP but normal cocaine CPP and alloparent CPP. NAc-projecting OT neurons were parvocellular (9/9; mean probability 92.8 ± 2.7%), and conditional Fmr1 deletion in NAc or OT neurons impaired social CPP, whereas Calb1-IRES-Cre::cdFmr1 KO mice were not impaired. ASD risk genes and FMRP targets were enriched in parvocellular relative to magnocellular OT neurons; schizophrenia risk genes were not enriched (p = 0.98).
Methods
- Male mice (3–7 weeks; P30–40 for anatomy) were used with OT-2A-Flp::fdGFP, Fmr1 KO, conditional Fmr1 KO, and Calb1-IRES-Cre lines. Magnocellular OT neurons were labeled by i.v. FluoroGold; NAc projections were mapped with retrobeads and viral injections.
- Electrophysiology used whole-cell current clamp in acute PVN slices, with post-hoc neurobiotin labeling and blind FG classification; k-means clustering was trained on electrophysiological features.
- scRNA-seq used FACS-enriched OT neurons and modified SMART-Seq2, followed by UMAP, Monocle2 differential expression, and hypergeometric gene set enrichment. Behavior used social, cocaine, and alloparent conditioned place preference assays.
Limitations
- The paper states that FluoroGold labeling has a non-zero false-negative rate and that FG− cells within the magnocellular transcriptional cluster may reflect technical artifact from acidic pH during dissociation/FACS rather than a biological subtype.
- The paper states that no exclusively magnocellular OT projection was identified, so Calb1-IRES-Cre manipulation also knocked down Fmr1 in non-OTergic Calb1-expressing neurons elsewhere in the brain.
- Evident from the text: experiments were conducted only in male mice, anatomical quantification used n = 3 mice, electrophysiology used n = 9 and n = 6 mice, and scRNA-seq analyzed 146 cells, so sex-specific and broader generalizability remain untested.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 48 cited sources checked · 0 supported · 0 flagged
- Findingown data
Autism risk genes are enriched in parvocellular compared to magnocellular oxytocin neurons.
“autism risk genes are enriched in parvocellular compared to magnocellular oxytocin neurons”
Quote in the paperSubstantial claim - Findingown data
Unsupervised k-means clustering on electrophysiological features yields two clusters that correspond completely (100%, 18 of 18) with qualitative Sh classification.
“The resulting best fit to this data are two clusters (Figure S2), which corresponded completely (100%, 18 of 18 OT neurons) with the qualitative magnocellular or parvocellular categorization based on the presence or absence of a shoulder in the electrophysiological trace (Figure 2P)”
Quote in the paperSubstantial claim - Findingown data
Parvocellular OT neurons are concentrated in the caudal division of the PVN.
“parvocellular OT neurons are concentrated in the caudal division of the PVN”
Quote in the paperSubstantial claim - Findingown data
AP duration is longer in FG+ versus FG- OT neurons.
“as well as longer in FG+ versus FG- OT neurons (Figure 2I)”
Quote in the paperNot a substantial claim - Findingown data
Oxt+ neurons in the rostral portion of the PVN were specifically colocalized with Calb1 and not Cnr1 mRNA.
“Oxt+ neurons in the rostral portion of the PVN were specifically colocalized with Calb1 and not Cnr1 mRNA (Figure 4D)”
Quote in the paperNot a substantial claim
- Findingown data
Silhouette analysis of UMAP embedding yielded a best fit of 2 clusters.
“This calculation yielded a best fit of 2 clusters, which are plotted in Figure 3C”
Quote in the paperSubstantial claim - Findingown data
18 differentially expressed genes were identified as potentially contributing to the electrophysiological signature of magnocellular and parvocellular OT neurons.
“18 differentially expressed genes were identified as potentially contributing to the electrophysiological signature of magnocellular and parvocellular OT neurons (Figure S3)”
Quote in the paperSubstantial claim - Findingown data
The two clusters correspond in 94% (17 of 18) with FG labeling classification.
“and in 94% (17 of 18 OT neurons) when defined by FG labeling, (Figure 2Q)”
Quote in the paperSubstantial claim - Findingown data
Two distinct transcriptional subtypes of OT neurons were identified using high-resolution full-length sequencing.
“these studies identify two distinct transcriptional subtypes of OT neurons using high-resolution full-length sequencing techniques, in samples enriched for OT neurons by molecular techniques”
Quote in the paperSubstantial claim - Findingown data
Fmr1 KO mice show significant impairment in peer-peer social CPP compared to wildtype.
“These results demonstrate a significant impairment in peer-peer social CPP (sCPP) in Fmr1 KO mice compared to wildtype (WT; Figures 5A-D, Figure S4)”
Quote in the paperSubstantial claim - Findingown data
Calb1 and Kcnmb4 are enriched for expression in the magnocellular OT neuronal population.
“the calcium-binding protein Calbindin (Calb1) and a large conductance calcium-activated potassium channel subunit (Kcnmb4), both enriched for expression in the magnocellular OT neuronal population (Figure 4B)”
Quote in the paperSubstantial claim - Findingown data
Application of 4-AP has no effect on latency in parvocellular (Sh-) OT neurons.
“but had no effect on latency in parvocellular (Sh-) OT neurons (Figures 2K,L,N,O)”
Quote in the paperSubstantial claim - Findingown data
Electrophysiological and anatomical classification systems show near perfect agreement (94%; 17 of 18 OT neurons).
“demonstrate near perfect agreement of electrophysiological and anatomical classification systems (94%; 17 of 18 OT neurons)”
Quote in the paperSubstantial claim - Findingown data
AP duration is longer in Sh+ compared to Sh- OT neurons.
“AP duration (Figure 2G) is longer in Sh+ compared to Sh- OT neurons (Figure 2H)”
Quote in the paperSubstantial claim - Findingown data
Within the magnocellular cluster, FG- neurons are evenly distributed across mitochondrial density measurements.
“within the magnocellular cluster, where FG+ neurons (purple circles) dominate, the FG- neurons (green circles) are evenly distributed across mitochondrial density measurements (Figure 3G)”
Quote in the paperSubstantial claim - Findingown data
Magnocellular OT neurons are predominantly localized to the rostral division of the PVN.
“magnocellular OT neurons are predominantly localized to the rostral division of the PVN”
Quote in the paperSubstantial claim - Findingown data
Reln and Cnr1 are significantly enriched in parvocellular OT neurons.
“the extracellular matrix serine protease Reelin (Reln) and the cannabinoid receptor 1 (Cnr1) genes, both significantly enriched in parvocellular OT neurons (Figure 4C)”
Quote in the paperSubstantial claim - Findingown data
181 genes have significant differential expression between magnocellular and parvocellular OT cells.
“we identified 181 genes (Table S1) with significant (0.1% FDR; Monocle2; BH-corrected) differential expression (DE) between magnocellular and parvocellular OT cells (Figure 4A)”
Quote in the paperSubstantial claim - Findingown data
Latency to first AP is longer in FG+ compared to FG- OT neurons.
“as well in FG+ compared to FG- OT neurons when neurons are grouped by FG labeling (Figure 2F)”
Quote in the paperSubstantial claim - Findingown data
In more caudal sections, Oxt+ neurons colocalized with Cnr1 and not Calb1.
“in more caudal sections Oxt+ neurons colocalized with Cnr1 and not Calb1 (Figure 4E)”
Quote in the paperSubstantial claim - Findingown data
Fmr1 KO mice exhibit no significant impairment in filial attachments.
“our finding that Fmr1 KO mice exhibit no significant impairment in filial attachments (Figures 5I-L)”
Quote in the paperSubstantial claim - Findingown data
Latency to first AP is longer in Sh+ compared to Sh- OT neurons.
“latency to first AP is longer in Sh+ compared to Sh- OT neurons (Figure 2E)”
Quote in the paperSubstantial claim - Findingown data
Magnocellular neurons had a greater ratio of mitochondrial reads to genomic reads than parvocellular neurons.
“magnocellular neurons had a greater ratio of mitochondrial reads to genomic reads than that of parvocellular neurons (Figure 3G)”
Quote in the paperSubstantial claim - Findingown data
Acute knockdown of Fmr1 in adolescence is sufficient to recapitulate peer-peer sCPP impairments seen in the constitutive Fmr1 KO.
“acute knockdown of Fmr1 in adolescence is sufficient to recapitulate peer-peer sCPP impairments seen in the constitutive Fmr1 KO”
Quote in the paperSubstantial claim - Findingown data
Alzheimer's Disease had only a single differentially expressed gene (Lhx5) among OT cells.
“Moreover, Alzheimer’s Disease had only a single differentially expressed gene (Lhx5)”
Quote in the paperSubstantial claim - Findingown data
NAc-projecting OT neurons belong to the parvocellular cluster with a mean probability of 92.8 ± 2.7%.
“NAc-projecting OT neurons belong to the parvocellular cluster with a mean probability of 92.8 ± 2.7%”
Quote in the paperSubstantial claim - Findingnone given
Calb1 is a discriminatory marker of magnocellular compared to parvocellular OT neurons.
“our discovery that Calb1 is a discriminatory marker of magnocellular compared to parvocellular OT neurons”
Quote in the paperSubstantial claim - Findingown data
The probability for NAc-projecting OT neurons is similar to probabilities for FG- neurons and Sh- neurons.
“This is similar (H(2) = 0.762, p = 0.6833; Kruskal Wallis test) to the probabilities for FG- neurons and Sh- neurons (87.2 ± 8.9%; Figure 2Q, and 96 ± 1.9%; Figure 2P) respectively”
Quote in the paperSubstantial claim - Findingown data
All RtB labeled, OT positive neurons recorded (9 of 9) exhibited a parvocellular electrophysiological phenotype.
“All RtB labeled, OT positive neurons recorded (9 of 9) exhibited a parvocellular electrophysiological phenotype by latency to first AP, AP duration, 4-AP sensitivity (Figures 6C-J)”
Quote in the paperSubstantial claim - Findingown data
sCPP was not impaired in Calb1-IRES-Cre::cdFmr1 KO mice.
“sCPP was not impaired in Calb1-IRES-Cre::cdFmr1 KO mice (Figures 7I-L)”
Quote in the paperSubstantial claim - Findingown data
Impaired sCPP was observed in cdFmr1 KO mice injected with CAV2-Cre-GFP, but not CAV2-GFP.
“we observed impaired sCPP in cdFmr1 KO mice injected with CAV2-Cre-GFP, but not CAV2-GFP (Figures 7A-D)”
Quote in the paperSubstantial claim - Findingown data
Type II Diabetes risk genes were completely absent amongst differentially expressed genes in OT cells.
“and Type II Diabetes risk genes were completely absent amongst differentially expressed genes in OT cells (Figure 8D,E).”
Quote in the paperSubstantial claim - Findingown data
Schizophrenia risk genes that were differentially expressed in OT neuronal subtypes were not significantly enriched in either magnocellular or parvocellular OT neurons (p = 0.98).
“While a handful of Schizophrenia risk genes were differentially expressed in OT neuronal subtypes, these were not significantly enriched in either magnocellular or parvocellular OT neurons (p = 0.98, Figure 8C).”
Quote in the paperSubstantial claim - Findingown data
The NAc receives an exclusively parvocellular OTergic projection.
“the NAc receives an exclusively parvocellular OTergic projection (Figure S5)”
Quote in the paperSubstantial claim - Findingown data
OT neurons in both the rostral and caudal PVN express FMRP.
“Since OT neurons in both the rostral and caudal PVN (Figure S7) express FMRP”
Quote in the paperSubstantial claim - Findingown data
10 of the 12 differentially expressed genes in the intersection of the ASD risk gene and FMRP binding partner groups were also enriched in parvocellular cells.
“Additionally, 10 of the 12 differentially expressed genes in the intersection of the 2 groups (Dlgap2, Cnr1, Pacs1, Tanc2, Anks1b, Slc6a1, Synj1, Tspan7, Camk2b, Stxbp1, Fbxo11, Foxp1; Figures 8A,B, individually labeled genes; Figure S7) were also enriched in parvocellular cells.”
Quote in the paperSubstantial claim - Findingown data
The magnocellular subtype of OT neuron is not involved in the pathogenesis of ASD.
“we found no evidence to support the view that the magnocellular subtype of OT neuron is involved in the pathogenesis of ASD.”
Quote in the paperSubstantial claim - Premisecitation
Only the hypothalamus exhibits the exaggerated protein synthesis phenotype seen in Fmr1 KO mice.
“only the hypothalamus, where OT neurons reside, exhibits the exaggerated protein synthesis phenotype seen in Fmr1 KO mice (Qin et al., 2005)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Qin et al., 2005 source
Not checked in the free run.
- Premisecitation
Social behavioral abnormalities seen in constitutive knockout mice are not recapitulated following deletion of Pten in OT neurons.
“social behavioral abnormalities seen in constitutive knockout mice are not recapitulated following deletion of Pten in OT neurons (Clipperton-Allen et al., 2016)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Clipperton-Allen et al., 2016 source
Not checked in the free run.
- Premisecitation
FMRP regulates roughly 20% of ASD susceptibility genes.
“FMRP, the protein product of FMR1, regulates roughly 20% of ASD susceptibility genes (Darnell et al., 2011; Driesche et al., 2019)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Darnell et al., 2011 source
Not checked in the free run.
- cites Driesche et al., 2019
Not checked in the free run.
- Interpretationown data
Normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior.
“normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior”
Quote in the paperSubstantial claim - Premisecitation
NAc, dRph, and VTA receive direct or indirect projections from hypothalamic OT neurons.
“the nucleus accumbens (NAc), dorsal raphe nucleus (dRph), and ventral tegmental area (VTA) receive direct or indirect projections from hypothalamic OT neurons (Beier et al., 2015; Dölen et al., 2013; Hung et al., 2017; Nardou et al., 2019)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Oxytocin neurons are comprised of magnocellular and parvocellular subtypes.
“oxytocin (OT) neurons are comprised of magnocellular and parvocellular subtypes (Gurdjian, 1927)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gurdjian, 1927 source
Not checked in the free run.
- Interpretationown data
Oxytocin pathway specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.
“oxytocin pathway specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies”
Quote in the paperSubstantial claim - Interpretationown data
Electrophysiological parameters can be used to build a mathematical model to predict magnocellular and parvocellular OT cell identity.
“these electrophysiological parameters can be used to build a mathematical model to predict magnocellular and parvocellular OT cell identity (Figure 2P-Q)”
Quote in the paperSubstantial claim - Interpretationown data
Cluster 1 cells are magnocellular OT neurons.
“we deduce that cluster 1 cells are magnocellular, while cluster 2 cells are parvocellular OT neurons (Figure 3E-F)”
Quote in the paperSubstantial claim - Interpretationown data
The electrophysiological signature of magnocellular and parvocellular neurons applies specifically to the subset of these cells that are oxytocinergic.
“These results demonstrate that the electrophysiological signature of magnocellular and parvocellular neurons applies specifically to the subset of these cells that are oxytocinergic (Figure 2D-O)”
Quote in the paperSubstantial claim - Interpretationown data
It is unlikely that changes in locomotor activity could account for the observed differences in sCPP.
“since aCPP and cCPP were not different (Figures 5E-L), it is unlikely that changes in locomotor activity could account for the observed differences in sCPP (Figures 5A-D)”
Quote in the paperSubstantial claim - Premisecitation
The Fmr1 KO mouse model has established construct validity for ASD.
“the Fmr1 KO mouse model, which has established construct validity for the disease (Bakker et al., 1994)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bakker et al., 1994
Not checked in the free run.
- Interpretationown data
These results establish a set of discriminating molecular identifiers which can distinguish between magnocellular and parvocellular OT neuronal subtypes.
“These results are the first to establish a set of discriminating molecular identifiers which can distinguish between magnocellular and parvocellular OT neuronal subtypes”
Quote in the paperSubstantial claim - Interpretationreasoning
It is unlikely that diminished cell health or quality accounts for the FG- cells in the magnocellular cluster.
“it is unlikely that diminished cell health or quality accounts for this finding”
Quote in the paperSubstantial claim - Interpretationown data
Cluster 2 cells are parvocellular OT neurons.
“we deduce that cluster 1 cells are magnocellular, while cluster 2 cells are parvocellular OT neurons (Figure 3E-F)”
Quote in the paperSubstantial claim - Interpretationown data
FG- cells in the magnocellular cluster represent a technical artifact, rather than a biologically significant subcategory of magnocellular neuron.
“consistent with our interpretation that FG- cells in this cluster represent a technical artifact, rather than a biologically significant subcategory of magnocellular neuron”
Quote in the paperSubstantial claim - Interpretationreasoning
False negative magnocellular neurons are represented in the FG- population of cluster 1.
“these false negative magnocellular neurons would be represented in the FG- population of cluster 1”
Quote in the paperNot a substantial claim - Interpretationown data
These studies are the first to establish a transcriptional signature for classifying magnocellular and parvocellular OT neuronal subtypes.
“these studies are the first to establish a transcriptional signature for classifying magnocellular and parvocellular OT neuronal subtypes”
Quote in the paperSubstantial claim - Premisecitation
Intravenous injections of the BBB impermeable retrograde tracer FluoroGold into the lateral tail vein enable selective labeling of magnocellular but not parvocellular OT neurons.
“intravenous (i.v.) injections of the BBB impermeable retrograde tracer FluoroGold (FG) into the lateral tail vein enables selective labeling of magnocellular but not parvocellular OT neurons (Merchenthaler, 1991)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Merchenthaler, 1991 source
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- Premisecitation
Only magnocellular OT neurons send axonal projections outside the blood-brain barrier to the posterior pituitary.
“only magnocellular OT neurons send axonal projections outside of the blood-brain barrier (BBB) to the posterior pituitary (van den Pol, 2012)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites van den Pol, 2012 source
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- Premisecitation
Changes in locomotor activity are unlikely to account for differences in sCPP across a variety of experimental manipulations.
“Previously, we have shown that changes in locomotor activity are unlikely to account for differences in sCPP across a variety of experimental manipulations (Dölen et al., 2013; Nardou et al., 2019)”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
The pathogenesis of social impairments in ASD can be better understood using the framework of 'pathoclisis', whereby subtype-specific differences render a specific neuronal population vulnerable to genetic lesion.
“Our current findings provide evidence that the pathogenesis of social impairments in ASD can be better understood using the framework of ‘pathoclisis’ (Klatzo, 2003), whereby subtype-specific differences render a specific neuronal population vulnerable to genetic lesion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Klatzo, 2003
Not checked in the free run.
- Premisecitation
Intranasal OT targets magnocellular but not parvocellular OT neurons.
“likely because intranasal OT targets magnocellular but not parvocellular OT neurons (Dölen, 2015; Leng and Ludwig, 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Dölen, 2015
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- cites Leng and Ludwig, 2016 source
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- Premisecitation
Previously parvocellular OT neurons had only been directly implicated in non-social functions.
“previously parvocellular OT neurons had only been directly implicated in non-social functions (e.g. feeding, yawning, erection, cardiovascular function, pain (Althammer and Grinevich, 2017; Eliava et al., 2016; Melis et al., 1986; Petersson, 2002; Valassi et al., 2008))”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Parvocellular OT has a critical role in the pathogenesis of ASD.
“the current studies have identified a critical role of parvocellular OT in the pathogenesis of ASD.”
Quote in the paperSubstantial claim - Premisecitation
No brain region has been identified that receives an exclusively magnocellular OTergic projection.
“To date we have yet to identify a brain region that receives an exclusively magnocellular OTergic projection (Hung et al., 2017)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hung et al., 2017 source
Not checked in the free run.
- Interpretationown data
These studies identify the first social function directly encoded by parvocellular OT neurons.
“these studies identify the first social function directly encoded by this subtype of OT neuron”
Quote in the paperSubstantial claim - Interpretationown data
Previous reports that hysteresis plays an important role in the pathogenesis of social impairments in ASD do not generalize across etiologies.
“suggest that previous reports that hysteresis plays an important role in the pathogenesis of social impairments in ASD (Orefice et al., 2019), do not generalize across etiologies”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Orefice et al., 2019 source
Not checked in the free run.
- Interpretationreasoning
Subtype specific expression of FMRP itself is unlikely to account for selective enrichment of ASD risk genes and FMRP binding partners in parvocellular OT neurons.
“these results indicate that subtype specific expression of FMRP itself is unlikely to account for selective enrichment of ASD risk genes and FMRP binding partners in parvocellular OT neurons.”
Quote in the paperSubstantial claim - Interpretationreasoning
Parvocellular OT neurons are directly implicated in the pathogenesis of a peer-peer social reward learning behavior that has clear face validity for social impairments that define ASD.
“and directly implicate these neurons in the pathogenesis of a peer-peer social reward learning behavior that has clear face validity for social impairments that define ASD.”
Quote in the paperSubstantial claim - Interpretationreasoning
Fmr1 has an ongoing requirement in regulating these behaviors.
“these results demonstrate an ongoing requirement of Fmr1 in regulating these behaviors”
Quote in the paperSubstantial claim - Interpretationown data
Filial social behaviors are governed by mechanisms distinct from those governing peer-peer social interactions.
“Here we provide evidence that these filial social behaviors (Figure S8, Left) are governed by mechanisms distinct from those governing peer-peer social interactions (Figure S8, Right).”
Quote in the paperSubstantial claim - Interpretationown data
Previous reports implicating the cerebellum in the pathogenesis of social impairments in the Tsc1 KO model of ASD do not generalize across ASD.
“these results suggest that previous reports implicating the cerebellum in the pathogenesis of social impairments in the Tsc1 KO model of ASD (Kelly et al., 2020; Tsai et al., 2012) do not generalize across ASD”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Clinical trials examining core symptoms of ASD have failed to consistently demonstrate efficacy of intranasal OT treatment.
“Clinical trials examining core symptoms of ASD have failed to consistently demonstrate efficacy of intranasal OT treatment (Anagnostou et al., 2012; Dadds et al., 2014; Guastella et al., 2015; Hollander et al., 2007)”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Fmr1 in OT neurons projecting to the NAc specifically is required for peer-peer social reward learning.
“these results demonstrate that Fmr1 in OT neurons projecting to the NAc specifically, is required for peer-peer social reward learning”
Quote in the paperSubstantial claim - Interpretationown data
The lack of sCPP impairment in Calb1-IRES-Cre::cdFmr1 KO mice is consistent with the selective requirement of Fmr1 in parvocellular OT neurons for peer-peer social reward learning.
“consistent with the selective requirement of Fmr1 in parvocellular OT neurons for peer-peer social reward learning”
Quote in the paperSubstantial claim - Interpretationreasoning
Parvocellular OT neurons are the appropriate therapeutic target for correcting social impairments in ASD.
“Rather, our findings implicate the parvocellular OT neurons as the appropriate therapeutic target for correcting social impairments in ASD.”
Quote in the paperSubstantial claim - Study design and conductown data
Limiting the power calculation to a balanced design results in 96.94% power for an FDR of 0.001 to observe 181 genes with a significant two-fold change.
“Limiting the power calculation to a balanced design by using only enough magnocellular cells to match the reduced number of parvocellular cells (thereby disregarding the observed ratio of cell types), results in 96.94% power for and FDR of 0.001 to observe 181 genes with a significant two-fold change (log2 Magno/Parvo ≥1 or log2 Magno/Parvo ≤−1).”
Quote in the paperNot a substantial claim - Premisecitation
Activation of systemic OT receptors in the adrenal cortex suppresses cortisol release.
“whose activation suppresses cortisol release (Chiodera and Legros, 1981; Legros et al., 1984; de Oliveira et al., 2007; Stachowiak et al., 1995)”
Quote in the paperSubstantial claim0 of 3 sources checked - Study design and conductown data
There is 99.84% power to observe 181 genes with a significant two-fold change in gene expression.
“Based on these calculations, there is 99.84% power (probability of true positives) to observe 181 genes with a significant two-fold change (log2 Magno/Parvo ≥1 or log2 Magno/Parvo ≤−1) in gene expression.”
Quote in the paperNot a substantial claim - Premisecitation
The only study to date that has examined the therapeutic potential of intranasal OT specifically in the Fragile X population found a correlation between improvements in a measure of social anxiety and decreased serum cortisol levels.
“Moreover, the only study to date that has examined the therapeutic potential of intranasal OT specifically in the Fragile X population (Hall et al., 2012), found a correlation between improvements in a measure of social anxiety (a syndromic symptom that is seen more frequently in Fragile X than ASD (Thurman et al., 2014)) and decreased serum cortisol levels (Hall et al., 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Intranasally delivered OT reaches systemic OT receptors in the adrenal cortex.
“Since intranasally delivered OT also reaches systemic OT receptors in the adrenal cortex (Hammock and Levitt, 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hammock and Levitt, 2013
Not checked in the free run.
- May combine two claims. 25
- Classified as probably not a substantial claim. 19
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataApplication of 4-AP reduces the latency to first AP and increases AP duration in magnocellular (Sh+) OT neurons.
“Application of the voltage-gated K+ channel blocker 4-AP (5 mM; Figures 2J,M) reduced the latency to first AP and increased AP duration in magnocellular (Sh+) OT neurons”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth WT and Fmr1 KO mice exhibit significant alloparent CPP.
“as well alloparent CPP (aCPP) (Figures 5I-L, S4)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data72.8% of cells in cluster 1 were FG positive, while cluster 2 contained only FG negative cells (100%) across all three replicates.
“72.8% of cells in cluster 1 were FG positive (FG+), while cluster 2 contained only cells that were FG negative (FG-; 100%) across all three replicates (Figure S3)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the PVN, 66% (952 ± 69 neurons) of OTergic neurons are magnocellular, while 34% (488 ± 25 neurons) are parvocellular.
“in the PVN, 66% (952 ± 69 neurons) of OTergic neurons are magnocellular, while 34% (488 ± 25 neurons) of OTergic neurons are parvocellular (Figure 1G)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong Sh+ OT neurons, 91% were FG+, and 100% of Sh- neurons were FG-.
“among Sh+ OT neurons 91% were FG+, and 100% of Sh- neurons were FG- (Figure 2S)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth WT and Fmr1 KO mice exhibit significant cocaine CPP.
“while both WT and Fmr1 KO mice exhibit significant cocaine CPP (cCPP) (Figures 5E-H)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the sampled neurons, 61% were Sh+ and 39% were Sh-.
“61% of sampled neurons were Sh+, and 39% were Sh-”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmong FG+ neurons, 100% were Sh+, and 88% of FG- neurons were Sh-.
“100% of FG+ neurons were Sh+ and 88% of FG- neurons were Sh- (Figure 2T)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the sampled neurons, 56% were FG+ and 44% were FG-.
“56% of sampled neurons were FG+ and 44% were FG- (Figure 2R)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPeer-peer, but not filial social attachments are disrupted in the Fmr1 KO.
“Specifically, peer-peer, but not filial social attachments are disrupted in the Fmr1 KO (Figure 5).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datasCPP was absent in OT-2A-Flp::cdFmr1 KO, while WT animals injected with rgAAV-fdCre exhibited normal social reward learning.
“sCPP was absent in OT-2A-Flp::cdFmr1 KO, while WT animals injected with rgAAV-fdCre exhibited normal social reward learning”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe current studies provide validation of 8 of the 14 characteristics identified as distinguishing between magnocellular and parvocellular OT neurons, having discovered 2 of these characteristic features here.
“In the current studies, we took a comprehensive approach to provide validation of 8 of the 14 characteristics identified as distinguishing between magnocellular and parvocellular OT neuron, having discovered 2 of these characteristic features here (Figure S8, Center; Figures 1–4, 8).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataASD risk genes and FMRP binding partners are significantly enriched in parvocellular relative to magnocellular OT neurons.
“In both cases, genes were significantly enriched in parvocellular relative to magnocellular neurons (Figures 8A,B; Tables S3 and S4).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMonogenic mutation of FMR1 is still the most common identified cause of ASD.
“making monogenic mutation of FMR1, the gene disrupted in Fragile X (Verkerk et al., 1991), still the most common identified cause of the disease (Suhl and Warren, 2015)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Suhl and Warren, 2015
Not checked in the free run.
May combine two claims.
PremisecitationHypothalamic disruptions of OT neurons have been reported in human patients with ASD related disorders and in knockout mice for ASD risk genes including Fmr1, Cntnap2, and Pten.
“hypothalamic disruptions of OT neurons have been reported in human patients with ASD related disorders such as Prader Willi syndrome (Swaab et al., 1995), as well as in knockout mice for ASD risk genes including Fmr1 (Francis et al., 2014), Cntnap2 (Peñagarikano et al., 2015), and Pten (Page et al., 2009)”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEvidence supporting a role for the genes encoding OXT and OXTR in ASD has been controversial.
“evidence supporting a role for the genes encoding OT (OXT) and the OT receptor (OXTR) has been more controversial (Allen-Brady et al., 2009; Ebstein et al., 2009; Hovey et al., 2014; Satterstrom et al., 2020; Willsey et al., 2013; Zhang et al., 2017)”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe etiology of ASD is primarily genetic.
“The etiology of ASD is also primarily genetic (Sullivan et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sullivan et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation50% of males and 20% of females with Fragile X meet full diagnostic criteria for ASD.
“50% of males, and 20% of females with Fragile X meet full diagnostic criteria for ASD (Kaufmann et al., 2017)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kaufmann et al., 2017 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationMagnocellular and parvocellular OT neuronal subtypes can be differentiated by a number of characteristic features.
“magnocellular and parvocellular OT neuronal subtypes can be differentiated by a number of characteristic features (van den Pol, 2012)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites van den Pol, 2012 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationMagnocellular neurons have increased mitochondrial density.
“Previous reports indicate that magnocellular neurons have increased mitochondrial density (Dayanithi et al., 2012; van den Pol, 1982)”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationThe social motivation theory of autism proposes that a primary deficit in peer-peer social reward learning could account for all characteristic behavioral impairments in ASD.
“The social motivation theory of autism proposes that a primary deficit in peer-peer social reward learning could account for all of the characteristic behavioral impairments that define the clinical picture in ASD (Chevallier et al., 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chevallier et al., 2013
Not checked in the free run.
May combine two claims.
Interpretationown dataSocial reward learning impairments in Fmr1 KO mice are domain specific and restricted to peer-peer social attachments.
“these findings support the view that social reward learning impairments in Fmr1 KO mice are domain specific and restricted to peer-peer social attachments”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataSocial reward learning deficits in constitutive Fmr1 KO mice are not the consequence of hysteresis, but rather the ongoing requirement of Fmr1 in parvocellular, but not magnocellular OT neurons.
“Taken together, these anatomical, electrophysiological, and functional genomic data demonstrate that social reward learning deficits seen in constitutive Fmr1 KO mice are not the consequence of hysteresis, but rather the ongoing requirement of Fmr1 in parvocellular, but not magnocellular OT neurons”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningParallel processing enables a single peptide to encode a wide diversity of social behaviors, significantly expanding the network capabilities of the social brain.
“Taken together these results delineate a novel example of parallel processing, which enables a single peptide to encode a wide diversity of social behaviors, significantly expanding the network capabilities of the social brain (Figure S8).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataFmr1 is required in parvocellular OT neurons, but not magnocellular OT neurons, for peer-peer social reward learning.
“Furthermore, in parvocellular OT neurons (Figure 6), but not magnocellular OT neurons (Figure 4) Fmr1 is required for peer-peer social reward learning (Figure 7).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCell type specific vulnerability of parvocellular OT neurons to genetic injury generalizes across multiple ASD etiologies, but is not apparent in unrelated genetic disorders that are not defined by impairments in social behavior.
“These results support the view that cell type specific vulnerability of parvocellular OT neurons to genetic injury generalizes across multiple ASD etiologies, but is not apparent in unrelated genetic disorders that are not defined by impairments in social behavior.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThese findings provide improved face validity for social impairments in the Fmr1 KO mouse model of ASD and additional support for the social motivation theory of autism.
“they provide improved face validity for social impairments in the Fmr1 KO mouse model of ASD, as well as additional support for the social motivation theory of autism”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationResearch into the pathogenesis of ASD has largely focused on understanding unifying biochemical mechanisms based on the hypothesis that ASD is a 'synaptopathy'.
“For more than a decade, research into the pathogenesis of ASD has largely focused on understanding unifying biochemical mechanisms based on the hypothesis that ASD is a ‘synaptopathy’ (Bear et al., 2008; Dölen and Bear, 2009; Grabrucker et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataInjection sites and viral function were confirmed.
“Injection sites and viral function were confirmed as shown in Figure S6.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenCalb1-Cre::cdFmr1KO experiments were done blind, as were a subset of OT-Flp::cdFmr1KO experiments.
“Calb1-Cre::cdFmr1KO experiments were done blind, as were a subset of OT-Flp::cdFmr1KO experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNeurons were targeted and recorded blind to FG labeling status.
“Neurons were targeted and recorded blind to FG labeling status.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningAll OT-Flp mice used in these experiments were heterozygous, leaving one WT copy of the Oxt gene, to control for possible effects of knockin on Oxt gene function.
“Therefore, in order to control for possible effects of knockin on Oxt gene function, all OT-Flp mice used in these experiments were heterozygous, leaving one WT copy of the Oxt gene.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataFor k-means clustering analysis, two clusters were specified, as indicated by the elbow method.
“For k-means clustering analysis, two clusters were specified, as this number of clusters was indicated by the elbow method (Figure S2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenExclusion criteria for sCPP were defined as a pre-conditioning preference score > 1.5 or < 0.5.
“Exclusion criteria for this behavior were defined as a pre-conditioning preference score (timeside1/totaltime2) of > 1.5 or < 0.5.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenChamber assignments were counterbalanced for side and bedding cues in sCPP.
“Chamber assignments were counterbalanced for side and bedding cues.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenInjection sites were confirmed post-hoc by preparing sections containing the NAc.
“Injection sites were confirmed post-hoc by preparing sections (20–50 μm) containing the NAc.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
InterpretationreasoningThe anxiolytic effects of intranasal OT in Fragile X likely reflect indirect activity of OT in the periphery.
“these anxiolytic effects likely reflect indirect activity of OT in the periphery.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll data were subjected to the Shapiro-Wilk normality test and F test to compare variances.
“All data were subjected to the Shapiro-Wilk normality test and F test to compare variances.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNine mice, with a maximum of 4 neurons per animal, were used to cross-validate FG and electrophysiological differentiation of magnocellular and parvocellular neurons.
“Nine mice, with a maximum of 4 neurons per animal were used to cross-validate FG and electrophysiological differentiation of magnocellular and parvocellular neurons.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data146 neurons passed quality assessment.
“146 neurons passed our quality assessment”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
Little is known about the pathogenic mechanisms underlying social behavioral abnormalities in ASD and whether these are the consequence of selective vulnerability of specific cell types to genetic injury.
“at this time little is known about the pathogenic mechanisms underlying social behavioral abnormalities in ASD, and whether these are the consequence of selective vulnerability of specific cell types to genetic injury”
The authors state this as an assumption.
A quantitative analysis of the proportion and distribution of OT neuron subtypes within the PVN in mice has not been carried out to date.
“to date a quantitative analysis of the proportion and distribution of these OT neuron subtypes within the PVN in mice has not been carried out”
The authors state this as an assumption.
The FG tail vein injection labeling technique has a non-zero false negative rate.
“The FG tail vein injection labeling technique, like all labeling techniques, has a non-zero false negative rate.”
The authors state this as an assumption.
Calb1 is also expressed in the Purkinje cells of the cerebellum.
“since Calb1 is also expressed in the Purkinje cells of the cerebellum”
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?
Lewis et al. (2020) used RNA-Seq to characterize the transcriptome of magno- and parvocellular PVN oxytocin neurons to examine common pathways linking oxytocin and ASD-related genes.
“Lewis et al. (2020) recently used RNA-Seq to characterize the transcriptome of magno- and parvocellular PVN oxytocin neurons to examine common pathways linking oxytocin and ASD-related genes.”
From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Lewis et al. 2020
Single-cell transcriptomics studies show that paraventricular oxytocin neurons projecting within the brain that mediate social reward behaviors are disrupted in a mouse model of autism spectrum disorder, and those neurons are enriched for ASD-risk genes.
“Single-cell transcriptomics studies show that PVN OXT neurons projecting within the brain that mediate social reward behaviors are disrupted in a mouse model of ASD, and those neurons are enriched for ASD-risk genes (159).”
From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [159]
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.
Conflicting figure references for clustering training data
MinorThe statistical methods say the electrophysiological clustering algorithm was trained on neurons from Figure 1, whereas the Results say it was trained with electrophysiological data from Figure 2.
“the clustering algorithm was trained only on the values from neurons from Fig. 1.”
“Next, we used unsupervised K-means clustering, trained with electrophysiological data from Figure 2, to provide unbiased quantitative cross validation of our electrophysiological findings (Figure 6K).”
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Self-citationBridging the Gap between Patients and Models
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Self-citationCécile & Oskar Vogt: The significance of their contributions in modern neuroscience
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Self-citationPathophysiological Toolkit; Genes to Circuits
Dölen, G., Malenka, R. C., Perlmutter, J. S., et al. (2015) · Zurich Open Repository and Archive (University of Zurich) · doi:10.5167/uzh-123143 · Cited by 2 · see citing works
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Oxytocin, Neural Plasticity, and Social Behavior
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Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities
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A genetically encoded sensor measures temporal oxytocin release from different neuronal compartments
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Social circuits and their dysfunction in autism spectrum disorder
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Neural circuitry for maternal oxytocin release induced by infant cries
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The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects
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Plasticity of neural connections underlying oxytocin-mediated parental behaviors of male mice
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Oxytocin normalizes altered circuit connectivity for social rescue of the Cntnap2 knockout mouse
Choe, K. Y., Bethlehem, R. A. I., Safrin, M., Dong, H., Salman, E., Li, Y., Grinevich, V., Golshani, P., DeNardo, L. A., Peñagarikano, O., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.11.031 · Cited by 77 · see citing works
The multiple faces of the oxytocin and vasopressin systems in the brain
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Endogenous oxytocin, cortisol, and testosterone in response to group singing
Bowling, D. L., Gahr, J., Ancochea, P. G., Hoeschele, M., Canoine, V., Fusani, L., & Fitch, W. T. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2021.105105 · Cited by 51 · see citing works
Dopamine Dysregulation in Reward and Autism Spectrum Disorder
Blum, K., Bowirrat, A., Sunder, K. R., Thanos, P. K., Hanna, C., Gold, M. S., Dennen, C. A., Elman, I., Murphy, K. T., & Makale, M. T. (2024) · Brain Sciences · doi:10.3390/brainsci14070733 · Cited by 44 · see citing works
Zhao, F., Zhang, H., Wang, P., Cui, W., Xu, K., Chen, D., Hu, M., Li, Z., Geng, X., & Wei, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.919890 · Cited by 42 · see citing works
Berkhout, J. B., Poormoghadam, D., Yi, C., Kalsbeek, A., Meijer, O. C., & Mahfouz, A. E. (2024) · Journal of Neuroendocrinology · doi:10.1111/jne.13367 · Cited by 41 · see citing works
Powell, S. B., & Swerdlow, N. R. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad098 · Cited by 40 · see citing works
Sexual differentiation of neural mechanisms of stress sensitivity during puberty
Wright, E. C., Luo, P. X., Zakharenkov, H. C., Serna Godoy, A., Lake, A. A., Prince, Z. D., Sekar, S., Culkin, H. I., Ramirez, A. V., Dwyer, T., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2306475120 · Cited by 34 · see citing works
Althammer, F., Muscatelli, F., Grinevich, V., & Schaaf, C. P. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02054-1 · Cited by 34 · see citing works
Recording and manipulation of the maternal oxytocin neural activities in mice
Yukinaga, H., Hagihara, M., Tsujimoto, K., Chiang, H.-L., Kato, S., Kobayashi, K., & Miyamichi, K. (2022) · Current Biology · doi:10.1016/j.cub.2022.06.083 · Cited by 33 · see citing works
The paraventricular nucleus of the hypothalamus: a key node in the control of behavioural states
Iremonger, K. J., & Power, E. M. (2025) · The Journal of Physiology · doi:10.1113/jp288366 · Cited by 33 · see citing works
Isaac, J., Karkare, S. C., Balasubramanian, H., Schappaugh, N., Javier, J. L., Rashid, M., & Murugan, M. (2024) · Nature Communications · doi:10.1038/s41467-024-52294-6 · Cited by 32 · see citing works
AMPA Receptor Function in Hypothalamic Synapses
Royo, M., Aznar-Escolano, B., Madrigal, M. P., & Jurado, S. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.833449 · Cited by 29 · see citing works
Gruber, T., Lechner, F., Murat, C., Contreras, R. E., Sanchez-Quant, E., Miok, V., Makris, K., Thuc, O. L., González‐García, I., García-Clavé, E., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113305 · Cited by 28 · see citing works
Arakawa, H. (2021) · Current Research in Neurobiology · doi:10.1016/j.crneur.2021.100011 · Cited by 24 · see citing works
The dopamine hypothesis of autism spectrum disorder: A comprehensive analysis of the evidence
Pavăl, D. (2023) · International review of neurobiology · doi:10.1016/bs.irn.2023.08.009 · Cited by 25 · see citing works
Navigating Central Oxytocin Transport: Known Realms and Uncharted Territories
Parmaksiz, D., & Kim, Y. (2024) · The Neuroscientist · doi:10.1177/10738584241268754 · Cited by 20 · see citing works
Neural cell-types and circuits linking thermoregulation and social behavior
Rogers, J. F., Vandendoren, M., Prather, J. F., Landen, J. G., Bedford, N. L., & Nelson, A. C. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105667 · Cited by 20 · see citing works
Althammer, F., Wimmer, M. C., Krabichler, Q., Küppers, S., Schimmer, J., Fröhlich, H., Dötsch, L., Gruber, T., Wunsch, S., Schubert, T. S., et al. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13217 · Cited by 19 · see citing works
Wang, Y., Xu, H., Chen, S., Chen, J., Zheng, Q., Ma, Y., Zhao, X., Shi, Y., & Xiao, L. (2024) · Advanced Science · doi:10.1002/advs.202310244 · Cited by 17 · see citing works
Neonatal oxytocin gives the tempo of social and feeding behaviors
Muscatelli, F., Matarazzo, V. A., & Chini, B. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1071719 · Cited by 17 · see citing works
Complexity of the Hypothalamic Oxytocin System and its Involvement in Brain Functions and Diseases
Cui, X., & Xiao, L. (2025) · Neuroscience Bulletin · doi:10.1007/s12264-025-01424-1 · Cited by 16 · see citing works
Flexible adjustment of oxytocin neuron activity in mouse dams revealed by microendoscopy
Yaguchi, K., Miyamichi, K., & Tasaka, G. (2024) · Science Advances · doi:10.1126/sciadv.adt1555 · Cited by 16 · see citing works
Oxytocin and the social facilitation of placebo effects
Itskovich, E., Bowling, D. L., Garner, J. P., & Parker, K. J. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01515-9 · Cited by 16 · see citing works
Xing, Y., Zan, C., & Liu, L. (2023) · Frontiers in Neural Circuits · doi:10.3389/fncir.2023.1007755 · Cited by 16 · see citing works
Ghrelin Action in the PVH of Male Mice: Accessibility, Neuronal Targets, and CRH Neurons Activation
Fernández, G., Francesco, P. N. D., Cornejo, M. P., Cabral, A., Aguggia, J. P., Duque, V. J., Sayar, N., Cantel, S., Burgos, J. I., Fehrentz, J., et al. (2023) · Endocrinology · doi:10.1210/endocr/bqad154 · Cited by 15 · see citing works
Selective vulnerability of parvocellular oxytocin neurons in social dysfunction
Tsurutani, M., Goto, T., Hagihara, M., Irie, S., & Miyamichi, K. (2024) · Nature Communications · doi:10.1038/s41467-024-53092-w · Cited by 15 · see citing works
Oxytocin signaling regulates maternally directed behavior during early life
Zelmanoff, D. D., Bornstein, R., Kaufman, M., Dine, J., Wietek, J., Litvin, A., Abraham, S., Cohen, S., Atzmon, A., Porat, I., et al. (2025) · Science · doi:10.1126/science.ado5609 · Cited by 12 · see citing works
Oxytocin and autism: Insights from clinical trials and animal models
Xing, C., & Yu, X. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2025.103015 · Cited by 11 · see citing works
Manjila, S. B., Betty, R., & Kim, Y. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1044736 · Cited by 11 · see citing works
Kong, X., Kang, J., & Liu, K. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.08.006 · Cited by 10 · see citing works
Lake, A. A., & Trainor, B. C. (2024) · Hormones and Behavior · doi:10.1016/j.yhbeh.2024.105487 · Cited by 9 · see citing works
Epigenomic and phenotypic characterization of DEGCAGS syndrome
Karimi, K., Weis, D., Aukrust, I., Hsieh, T., Horackova, M., Paulsen, J., Mendoza‐Londono, R., Dupuis, L., Dickson, M., Lesmann, H., et al. (2024) · European Journal of Human Genetics · doi:10.1038/s41431-024-01702-y · Cited by 9 · see citing works
Sánchez-Lafuente, C. L., Romay-Tallón, R., Allen, J., Johnston, J. N., Kalynchuk, L. E., & Caruncho, H. J. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2022.105267 · Cited by 9 · see citing works
Nasanbuyan, N., Yoshida, M., Inutsuka, A., Takayanagi, Y., Kato, S., Hidema, S., Nishimori, K., Kobayashi, K., & Onaka, T. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.09.015 · Cited by 8 · see citing works
Patwardhan, A., & Choe, K. Y. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102787 · Cited by 7 · see citing works
Wei, F., Zhang, L., Ma, B., Li, W., Deng, X. Y., Zheng, T., Wang, X., & Jing, Y. (2021) · Peptides · doi:10.1016/j.peptides.2021.170659 · Cited by 6 · see citing works
Social processes and social environment during development
Sakurai, T. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.09.016 · Cited by 6 · see citing works
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Deficiency of Shank3 in the nucleus accumbens reveals a loss of social-specific motivation
Folkes, O. M., Donahue, M., Wang, S. E., Negrón-Moreno, P. N., Oo, N. X., Qiao, S.-N., Wang, X., & Jiang, Y. (2025) · Communications Biology · doi:10.1038/s42003-025-08942-8 · Cited by 4 · see citing works
Heralding a new era of oxytocinergic research: New tools, new problems?
Althammer, F. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13333 · Cited by 4 · see citing works
Patwardhan, A., Li, S., Chen, J. A., & Choe, K. Y. (2025) · Journal of Neuroendocrinology · doi:10.1111/jne.70092 · Cited by 2 · see citing works
L’ocytocine, dès la naissance, conditionne le comportement alimentaire et social d’un individu
Muscatelli, F. (2022) · Biologie Aujourd hui · doi:10.1051/jbio/2022017 · Cited by 2 · see citing works
Chrisman, A. N., Sugimoto, C., Butler-Struben, H. M., Minie, V. A., Eagle, A. L., Anderson, D., Duque‐Wilckens, N., Ramos, A., Lewis, Y. I., Archdeacon, S. C., et al. (2026) · Neuropsychopharmacology · doi:10.1038/s41386-026-02352-y · Cited by 1 · see citing works
Zhao, Y., & Xiao, L. (2026) · Brain Structure and Function · doi:10.1007/s00429-026-03105-9 · Cited by 1 · see citing works
Liu, C., Wang, X., Yao, J., Yang, Y. H., Wang, F., Le, Q., Le, Q., Liu, X., Ma, L., & Wang, F. (2026) · Science Advances · doi:10.1126/sciadv.aeb0400 · Cited by 1 · see citing works
Nasanbuyan, N., Yoshida, M., Takayanagi, Y., Itoi, K., & Onaka, T. (2026) · Journal of Neuroendocrinology · doi:10.1111/jne.70228 · Cited by 1 · see citing works
Soumier, A., Lio, G., & Demily, C. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02487-8 · Cited by 1 · see citing works
Parvocellular Oxytocin Neurons and Autism Spectrum Disorders
Sundaram, S. M., & Schwaninger, M. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.01.004 · Cited by 1 · see citing works
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Reciprocal interactions between the oxytocin and somatosensory systems
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New regulators in oxytocin and vasopressin release : role of the endolysosomal two-pore channels
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- Authors
- Lewis, E. M., Stein-O’Brien, G. L., Patino, A. V., Nardou, R., Grossman, C. D., Brown, M., Bangamwabo, B., Ndiaye, N., Giovinazzo, D., Dardani, I., Jiang, C., Goff, L. A., & Dölen, G.
- Affiliations
- Johns Hopkins University (US)
- University of Pennsylvania (US)
- Corresponding author
- Goff, Loyal A.
- Dölen, Gül
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 108
- Issue
- 4
- Pages
- 659-675.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8033501
- OpenAlex
- W3094668538
- Cited by
- 72
- References
- 167
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 14 · 2023: 11 · 2022: 16 · 2021: 10
- FWCI
- 10.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Chan Zuckerberg Initiative
- National Institutes of Health
- National Science Foundation
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, oxytocin neurons, magnocellular neurons, parvocellular neurons, Fmr1 knockout mice, autism risk genes, social information processing, electrophysiology, gene expression profiling
- MeSH terms
- Autism Spectrum Disorder, Animals, Disease Models, Animal, Male, Neurons, Object Attachment, Oxytocin, Social Behavior, Mice, Knockout, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Gene Knock-In Techniques
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.
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