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Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment
Open accessAbstract
Background Oxytocin (OXT) modulates several aspects of social behavior. Intranasal OXT is a leading candidate for treating social deficits in autism spectrum disorder (ASD) and common genetic variants in the human oxytocin receptor (OXTR) are associated with emotion recognition, relationship quality and ASD. Animal models have revealed that individual differences in Oxtr expression in the brain drive social behavior variation. Our understanding of how genetic variation contributes to brain OXTR expression is very limited. Methods We investigated Oxtr expression in monogamous prairie voles, which have a well characterized OXT system. We quantified brain region-specific levels of Oxtr mRNA and OXTR protein with established neuroanatomical methods. We used pyrosequencing to investigate allelic imbalance of Oxtr mRNA, a molecular signature of polymorphic genetic regulatory elements. We performed next-generation sequencing to discover variants in and near the Oxtr gene. We investigated social attachment using the partner preference test. Results Our allelic imbalance data demonstrates that genetic variants contribute to individual differences in Oxtr expression, but only in particular brain regions, including the nucleus accumbens (NAcc), where OXTR signaling facilitates social attachment. Next-generation sequencing identified one polymorphism in the Oxtr intron, near a putative cis-regulatory element, explaining 74% of the variance in striatal Oxtr expression specifically. Males homozygous for the high expressing allele display enhanced social attachment. Discussion Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression and provide novel insights into how non-coding polymorphisms in the OXTR might influence individual differences in human social cognition and behavior
Overview
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Written from the paper’s full text.
TL;DR
In prairie voles, non-coding variation in the oxytocin receptor gene predicts brain-region-specific Oxtr expression and OXTR density, especially in the nucleus accumbens. An intronic SNP, NT213739, explains at least 74% of the variance in NAcc OXTR density and is associated with mating-induced partner preference formation in males.
Key findings
- Oxtr allelic imbalance was strongest in striatal regions: in heterozygous voles, the T-allele transcript was 3–5 times more prevalent than the C-allele in NAcc (cDNA ratio 3.16; gDNA threshold 1.11) and CP (cDNA ratio 5.24; gDNA threshold 1.13), with a lesser effect in amygdala (cDNA ratio 1.19; gDNA threshold 1.14).
- Sequencing 70 kb around Oxtr in 45 voles identified 967 SNPs; 15 SNPs in linkage disequilibrium spanning 30 kb were associated with NAcc OXTR density at P=1.06×10−15, adjusted R²=0.78.
- The intronic SNP NT213739 was robustly associated with NAcc OXTR density across independent samples (all P-values <4×10−10; adjusted R²≥74%) and with Oxtr mRNA levels; it was not associated with insular cortex OXTR density.
- In the partner preference test, C/C males spent significantly more time huddling with the partner than the stranger, whereas C/T and T/T males failed to display a partner preference.
Methods
- Prairie voles from a laboratory breeding colony were used for brain-region-specific measures of Oxtr mRNA and OXTR protein via in situ hybridization and autoradiography, with sample sizes including N=31 for autoradiography and N=31 for in situ hybridization.
- Allelic imbalance was assayed by pyrosequencing in animals heterozygous for the 3′UTR SNP NT204321 (minor allele frequency 0.33); next-generation sequencing of 70 kb surrounding Oxtr was performed in 45 voles, followed by genotyping of NT213739 in additional samples (n=35 and n=31).
- Associations between genetic markers and brain data used linear regression with Bonferroni correction, factor analysis for brain-region covariation, and PLINK/SEQ for SNP–autoradiography associations; social attachment was assessed with the partner preference test.
Limitations
- The paper states that the genotype–phenotype relationships do not implicate NT213739 above other SNPs in perfect LD spanning 30 kb, and that larger samples of more genetically diverse animals, including wild-caught specimens, may be needed to break the haplotype structure and identify the functional SNP.
- The paper notes that cross-species comparisons of putative regulatory elements should be interpreted cautiously because transcription factor binding sites may differ between species.
- Evident from the text: the study reports strong associations but does not perform direct functional validation such as ChIP-seq, chromosome conformation capture, or in vitro transcription assays; the behavioral sample size for the partner preference test is not stated in the provided text.
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40 Not checked yet · 26 Own result · 8 Own interpretation · 4 Own method · 1 Supported so far · 1 Partly supported · 1 No basis given · accuracy not yet measured
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In the paper
“Amongst the 45 voles we sequenced, we identified 967 SNPs with a read depth no lower than 100 reads, a quality score of at least 1000, and for which all were variable in our sample.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“In heterozygous animals for this SNP, we found significant allelic imbalance in NAcc (cDNA: 3.16, gDNA threshold: 1.11), caudate putamen (CP) (cDNA: 5.24, gDNA threshold: 1.13) and to a lesser degree, amygdala (Amyg) (cDNA: 1.19, gDNA threshold: 1.14).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“We performed a second factor analysis in an additional sample (N=85) (Table 1b) and this analysis, like the first one, revealed two factors explaining most of the variance.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plainn = 85- Asserted: passes — The authors put it forward as true.
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In the paper
“Due to linkage disequilibrium, 15 SNPs spanning a 30 kb region were associated with NAcc OXTR density with the same, minimal P-value (P=1.06×10−15, adjusted R2=0.78), which is a remarkable effect size for a genotype-phenotype relationship.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“The allelic imbalance was pronounced in the two striatal sub-regions, NAcc and CP, with the T-allele transcript being 3–5 times more prevalent than the C-allele in the same animals in these regions (Figure 1d).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“In all of our relatively small samples, NT213739 was strongly associated with NAcc expression (all P-values<4×10−10).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“One SNP in the 3’ untranslated region (minor allele frequency 33%), heretofore referred to as NT204321 based on the position of this nucleotide on a sequenced prairie vole bacterial artificial clone (58) (DP001215.2), was identified using this method.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
What the sources say
- Not checked yetcites [58] Mouse, 2012, An encyclopedia of mouse DNA elements (Mouse ENCODE), Genome Biol source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Our analysis revealed two factors together explaining the majority of variance (58%).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plaincorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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In the paper
“As expected based on previous experiments, the NAcc and caudate putamen (CP) exhibited more individual variation in OXTR density than other brain regions (Figure 1a–c).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“Only one SNP overlapped with strong signatures of transcriptional function, a SNP occurring at nucleotide 213739 (NT213739, minor allele frequency: 0.32) (Figure 3b).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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- Probably not a substantial claim. 19
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“OXTR is distributed throughout the brain of many vertebrates and, importantly, the pattern of OXTR distribution is diverse between species (32, 33).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
- Partly supportedcites [33] Freeman, 2014, The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta), Psychoneuroendocrinology sourceExperimental — accuracy not yet measured
The Discussion (Comparison to OXTR expression in other primate species; page not provided) describes distinct OXTR distributions among primates and rodents, supporting the species-difference claim. The Results (In situ hybridization confirms OXTR expression; page not provided) detect a consistent signal in only five macaque brain areas, so the paper does not establish that OXTR is distributed throughout the brain of many vertebrates. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42–46).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
- Not checked yetcites [42] Bendesky, 2011, Genetic contributions to behavioural diversity at the gene-environment interface, Nat Rev Genet source
- Supportedcites [43] Linnen, 2013, Adaptive evolution of multiple traits through multiple mutations at a single gene, Science source
The passage on Agouti promoters (section labeled Abstract; page unavailable) links promoter regions to adaptive coat-color traits in Sand Hills mice. It concludes that cis-regulatory changes are among the mechanisms involved in their color adaptation, supporting the cited statement as a general example. (LLM, conf=0.88)
- Not checked yetcites [44] Oleksiak, 2002, Variation in gene expression within and among natural populations, Nat Genet source
- Supportedcites [45] Cretekos, 2008, Regulatory divergence modifies limb length between mammals, Genes Dev source
The Abstract reports that replacing a mouse limb enhancer with a bat enhancer increased Prx1 expression and produced significantly longer forelimbs. It concludes that changes in noncoding regulatory sequences can contribute to evolutionary morphological differences. (LLM, conf=0.94)
- Not checked yetcites [46] Hammock, 2005, Microsatellite instability generates diversity in brain and sociobehavioral traits, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“OXTR binding in the NAcc was almost perfectly correlated with the first factor and binding in the insular cortex (Ins) was close to perfectly correlated with Factor 2.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plaincorrelationaln = 85- Asserted: passes — The authors put it forward as true.
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In the paper
“After genotyping additional voles (Sample 2 n=35, Sample 3 n=31) for NT213739, we confirmed the SNP was robustly associated with OXTR density in the NAcc but not in the Ins (Figure 4a).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
boostedcorrelationaln = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“Factor 1 strongly reflects co-variability in a set of regions involved in reward processing (NAcc, CP, and olfactory tubercle) while the second factor reflects covariation between cortical and subcortical regions that have relatively uniform levels of OXTR density (Table 1a).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
boostedcorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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In the paper
“The effect was marked, such that OXTR density values in the NAcc between homozygous animals of the two genotypes did not overlap at all while heterozygous animals displayed an intermediate phenotype.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“Similarly, the effect size of this association was very large in all samples (adjusted R2≥74%), strongly suggesting that NT213739 explains at least 74% of the variance in NAcc expression of OXTR in prairie voles.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“Allelic imbalance is strongest in the striatum and genotype-OXTR associations are most robust in this region.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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In the paper
“There was a significant effect of genotype on partner preference formation, with C/C voles spending significantly more time huddling with the partner than the stranger, while C/T and T/T males failed to display a partner preference (Figure 5).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“Single nucleotide polymorphisms (SNPs) in noncoding regions of the human OXTR have been associated with pair bonding behaviors (19), parenting (1), face recognition skills (20), and autism (21).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [19] Walum, 2012, Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior, Biol Psychiatry source
- Not checked yetcites [1] Rilling, 2014, The biology of mammalian parenting and its effect on offspring social development, Science source
- Not checked yetcites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
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In the paper
“Some individuals have heterogeneous responses to OXT (22, 23), which may involve interaction with OXTR genetic polymorphisms (24–27).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [22] Bartz, 2011, Social effects of oxytocin in humans: Context and person matter, Trends Cogn Sci
- Not checked yetcites [23] Olff, 2013, The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences, Psychoneuroendocrinology source
- Not checked yetcites [24] Marsh, 2012, The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype, Psychopharmacology source
- Not checked yetcites [25] Montag, 2013, An interaction between oxytocin and a genetic variation of the oxytocin receptor modulates amygdala activity toward direct gaze: Evidence from a pharmacological imaging genetics study, Eur Arch Psychiatry Clin Neurosci source
- Not checked yetcites [26] Chen, 2015, Genetic modulation of oxytocin sensitivity: A pharmacogenetic approach, Transl Psychiatry source
- Not checked yetcites [27] Feng, 2015, A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans, Genes Brain Behav source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“OXTR affects a range of social behaviors in animals including maternal nurturing and bonding (1, 2), social reward and gregariousness (3, 4), social recognition (5), and pair bonding in monogamous species (6–8).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [1] Rilling, 2014, The biology of mammalian parenting and its effect on offspring social development, Science source
- Not checked yetcites [2] Numan, 2016, Neural mechanisms of mother-infant bonding and pair bonding: Similarities, differences, and broader implications, Horm Behav source
- Not checked yetcites [3] Dolen, 2013, Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin, Nature source
- Not checked yetcites [4] Goodson, 2009, Mesotocin and nonapeptide receptors promote estrildid flocking behavior, Science source
- Not checked yetcites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
- Not checked yetcites [7] Goodson, 2012, Evolving nonapeptide mechanisms of gregariousness and social diversity in birds, Horm Behav source
- Not checked yetcites [8] Johnson, 2015, Neural networks involved in social attachment and pair bonding, Curr Opin Behav Sci source
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In the paper
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28–31).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [28] Loth, 2014, Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events, Biol Psychiatry source
- Not checked yetcites [29] Lucas-Thompson, 2013, Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress, Horm Behav source
- Not checked yetcites [30] Smearman, 2015, Social stress and the oxytocin receptor gene interact to predict antisocial behavior in an at-risk cohort, Dev Psychopathol source
- Not checked yetcites [31] Thompson, 2011, Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls, Psychoneuroendocrinology source
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“OXTR is often enriched within regions of crucial behavioral circuits such as the mesolimbic reward (MLR) network and social decision making network and appears to modulate these networks to generate species-specific social strategies such as monogamous social attachments (32) and social gregarity (7).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Any differences in mRNA levels between alleles occur in the same nuclear environment, where both alleles should be affected equally by environmental, hormonal or epigenetic factors, unless cis-REs proximal to the alleles are variable.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Allelic imbalance is commonly observed in a tissue-specific manner (51, 52).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In prairie voles, a microsatellite in the 5’ flanking region of the vasopressin receptor gene (Avpr1a) containing cis-REs has been shown to have functional influence over species differences and individual variation in Avpr1a expression and is associated with variation in social behavior (47, 48).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [47] Donaldson, 2013, The relative contribution of proximal 5′ flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior, PLoS Genet source
- Not checked yetcites [48] Johnson, 2005, Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics, Pharmacol Ther source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Comparisons of ~1500 bp of 5’ flanking regions from the Oxtr gene reveal only a few SNPs and 99% homology between the species (63).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [63] Young, 1997, The 5′ flanking region of the monogamous prairie vole oxytocin receptor gene directs tissue-specific expression in transgenic mice, Ann N Y Acad Sci source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Amongst the 45 voles we sequenced, we identified 967 SNPs with a read depth no lower than 100 reads, a quality score of at least 1000, and for which all were variable in our sample.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Transgenic mice carrying a reporter gene driven by 5 kb of the prairie vole Oxtr 5’ flanking sequence express the reporter in the brain in a pattern resembling prairie voles (64), suggesting the sequence may suffice for some aspects of brain region-specific expression.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [64] Harony-Nicolas, 2014, Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation, Psychoneuroendocrinology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Polymorphic cis-REs have been shown to influence CTCF binding (71, 72) and DNA looping (73).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [71] Paredes, 2013, Allele-specific transcriptional activity of the variable number of tandem repeats in 5′ region of the DRD4 gene is stimulus specific in human neuronal cells, Genes Brain Behav source
- Not checked yetcites [72] Visser, 2015, Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter, Hum Mol Genet source
- Not checked yetcites [73] Dekker, 2013, Exploring the three-dimensional organization of genomes: Interpreting chromatin interaction data, Nat Rev Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“and accumulates rare SNPs in cases of ASD (62).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [62] Young, 1996, Species differences in central oxytocin receptor gene expression: Comparative analysis of promoter sequences, J Neuroendocrinol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“One role of CTCF is to act as a spatial organizer, aiding DNA looping to permit cis-RE-promoter interactions required for gene transcription (60).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [60] Mizumoto, 1997, A genomic element within the third intron of the human oxytocin receptor gene may be involved in transcriptional suppression, Mol Cell Endocrinol source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together these data suggest that NT213739 is strongly associated with transcriptional variation of the Oxtr gene and tightly linked to a cis-RE.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
hedgedcorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, DNA methylation of OXTR in humans may be mediated by an intronic SNP (67).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [67] Insel, 1993, Gonadal steroids have paradoxical effects on brain oxytocin receptors, J Neuroendocrinol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this manner cis-REs appear to contribute exquisite control over OXTR and through this process, influence behavioral diversity in prairie voles.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (75) involved in reward processing and implicated in numerous human psychiatric disorders including depression (76), addiction (77), and schizophrenia (78).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [75] Russo, 2013, The brain reward circuitry in mood disorders, Nat Rev Neurosci source
- Not checked yetcites [76] Luscher, 2011, Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling, Neuron source
- Not checked yetcites [77] Abi-Dargham, 2014, Schizophrenia: Overview and dopamine dysfunction, J Clin Psychiatry source
boosted- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Additionally, the human intron may contain other cis-REs (61)”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [61] Liu, 2015, Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals, Human Genome Variation source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We here demonstrate that genetic variation in the Oxtr exerts robust control over individual diversity in Oxtr expression and OXTR density in the prairie vole brain and that this influence on expression occurs in a region-specific manner.”
- Also stated in: § Discussion · boosted
“Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Discussion · boosted
In the paper
“We note that such comparisons should be made with the understanding that transcription factor binding sites may differ between species (70).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [70] Verlaan, 2009, Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease, Am J Hum Genet source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis-RE, and associated with face recognition abilities (20) and ASD diagnosis (21).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
- Not checked yetcites [21] LoParo, 2015, The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis, Mol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (68, 69).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [68] Bale, 1995, Regulation of oxytocin receptor messenger ribonucleic acid in the ventromedial hypothalamus by testosterone and its metabolites, Endocrinology source
- Not checked yetcites [69] Odom, 2007, Tissue-specific transcriptional regulation has diverged significantly between human and mouse, Nat Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Regarding the factor analyses, to determine how many factors to extract we used the “nFactors” package in R and the factor extraction decisions were based on the eigenvalues-greater-than-one rule, parallel analysis, the optimal coordinates method and acceleration factor.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > MATERIALS AND METHODS > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“DNA methylation of Oxtr differs between brain regions in rodents (65, 66).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [65] Beery, 2016, Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats, Horm Behav source
- Not checked yetcites [66] Reiner, 2015, Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype, J Psychiatr Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Associations between genetic information and brain data were examined using linear regression with Bonferroni corrections for multiple comparisons.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > MATERIALS AND METHODS > Statistical analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“and others have reported associations with endophenotypes of ASD (20, 82, 83), including structural variability in brain regions relevant to social cognition (80, 84).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
- Not checked yetcites [82] Lerer, 2008, Association between the oxytocin receptor (OXTR) gene and autism: Relationship to Vineland Adaptive Behavior Scales and cognition, Mol Psychiatry source
- Not checked yetcites [83] Inoue, 2010, Association between the oxytocin receptor gene and amygdalar volume in healthy adults, Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The neural mechanisms by which non-coding SNPs in OXTR influence behavior have not yet been explored.
“Despite these many associations with human social behavior and disorders, the neural mechanisms by which non-coding SNPs in the OXTR could influence behaviors has yet to be explored.”
The authors state this as an assumption.
Correlations between OXTR densities across brain regions can be explained by unobserved latent variables, possibly reflecting transcriptional processes.
“We hypothesize that correlations between OXTR densities from different brain regions can be explained by unobserved variables, possibly reflecting transcriptional processes giving rise to the patterns of correlation.”
The paper relies on this without support.
Mouse ENCODE signatures of transcriptional activity in the Oxtr region indicate homologous cis-regulatory elements in prairie vole.
“we investigated their homology with regions of the mouse Oxtr gene that overlap with signatures of functional activity occurring within neural tissues where OXTR is expressed in the mouse (59).”
The paper relies on this without support.
Candidate gene polymorphisms usually explain only 1–10% of behavioral phenotype variance in behavioral genetic studies.
“Behavioral genetic studies typically report that 1–10% of the variance in behavioral phenotype is explained by candidate gene polymorphisms.”
The authors state this as an assumption.
OXTR density lies closer to genotype than behavior does in biological terms.
“We presume that OXTR density is biologically more proximate to genotype than behavior”
The authors state this as an assumption.
Behavioral genetic studies usually involve many additional contributors to behavioral variation.
“and in typical behavioral genetic studies many more variables are contributing to behavioral variation.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“These genetic variations may also influence social behavior, as male C/C prairie voles display enhanced social attachment as compared to C/T and T/T animals [71].”
From The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives (2023) · cites this paper as [71]
In the citing paper
“it is well known from non-human animal work that the striatum and regions within the midbrain are highly populated with oxytocin receptors.44, 45”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [45]
In the citing paper
“Furthermore, individual differences in the density of OXTR in the NAcc in prairie voles have now been shown to be mediated by a single nucleotide polymorphism (SNP) in a regulatory region of the OXTR gene (22)”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [22]
In the citing paper
“and individuals with high NAcc OXTR show enhanced social attachment (22)”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [22]
In the citing paper
“However, it is important to note that OXTR polymorphisms in the prairie vole robustly predict individual differences in OTR density in the NAc as well as pair bonding behavior (King et al., 2016).”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as King et al., 2016
In the citing paper
“Finally, site-specific OTR blockade does not likely reflect natural intra- and interspecific variation in levels of region-specific OTR expression and signaling (King et al., 2016).”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as King et al., 2016
In the citing paper
“Partner preference formation in male prairie voles is predicted by a natural genetic polymorphism in the OTR gene (Oxtr) that robustly influences the density of OTR binding in the NAc”
From Oxytocin and Social Relationships: From Attachment to Bond Disruption (2017) · cites this paper as King et al. 2016
In the citing paper
“Our results in prairie voles reveal that OTR density in the striatum, which is robustly predicted by polymorphisms in the OTR gene (King et al. 2016), is indicative of resilience to early-life social isolation with respect to later life bonding.”
From Oxytocin and Social Relationships: From Attachment to Bond Disruption (2017) · cites this paper as King et al. 2016
In the citing paper
“This variation in OXTR density in the NAcc is determined by genetic variation in the Oxtr gene (144), which in turn predicts how early-life nurturing experience affects laterlife bonding ability (143).”
From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [144]
In the citing paper
“In prairie voles, for instance, such sequence variation determines individual variation in striatal oxytocin receptor density [12]”
From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [12]
In the citing paper
“This variation in brain receptor distribution is determined by sequence variation in the receptor genes [12,13].”
From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [12]
In the citing paper
“Importantly, our group has recently demonstrated that the density of OTR variability between individuals within the prairie vole species in the ventral striatum is the result of gene polymorphisms in the OTR gene (King et al. 2016).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as King et al. 2016
Citations
Cites
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“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (74) involved in reward processing and implicated in numerous human psychiatric disorders, including depression (75), addiction (76), and schizophrenia (77).”
Cited by
Sorted by citations
Oxytocin, Neural Plasticity, and Social Behavior
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“A reduction or upregulation in the availability of the oxytocin or vasopressin receptors can reflect both heritable genetic variation (King et al., 2016; Baker et al., 2017) and/or epigenetic tuning (Okhovat et al.”
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“Also in prairie voles, polymorphisms in Oxtr predict OTR xpression in the nucleus accumbens (NAc) and individual variaion in pair bonding (King et al., 2016).”
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“Furthermore, individual differences in the density of OXTR in the NAcc in prairie voles have now been shown to be mediated by a single nucleotide polymorphism (SNP) in a regulatory region of the OXTR gene (22), and individuals with high NAcc OXTR show enhanced social attachment (22) and resilience to early life stress…”
BackgroundSelf-citationOxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities
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“Partner preference formation in male prairie voles is predicted by a natural genetic polymorphism in the OTR gene (Oxtr) that robustly influences the density of OTR binding in the NAc (King et al. 2016).”
BackgroundSelf-citationEarly nurture epigenetically tunes the oxytocin receptor
Perkeybile, A. M., Carter, C. S., Wroblewski, K. L., Puglia, M. H., Kenkel, W. M., Lillard, T. S., Karaoli, T., Gregory, S. G., Mohammadi, N., Epstein, L., et al. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.08.037 · Cited by 160
Overview of human oxytocin research
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Oxytocin receptors modulate a social salience neural network in male prairie voles
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“Finally, site-specific OTR blockade does not likely reflect natural intra- and interspecific variation in levels of region-specific OTR expression and signaling (King et al., 2016).”
Self-citationOxytocin pathways in the intergenerational transmission of maternal early life stress
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“Moreover, a highly relevant study in rodents recently showed that a polymorphism in the Oxtr gene explains a large proportion of variance in accumbal OTR expression, which is known to be functionally relevant for attachment formation and parenting (King et al., 2015).”
BackgroundGenetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression
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“S3A, W = 77, p = 0.98) or NT213739 genotype (Additional file 1: Fig.”
BackgroundResultInfluentialOxytocin receptor is not required for social attachment in prairie voles
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“known from non-human animal work that the striatum and regions within the midbrain are highly populated with oxytocin receptors (Insel and Shapiro, 1992; King et al., 2015).”
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Epigenetic modification of OXT and human sociability
Haas, B. W., Filkowski, M. M., Cochran, R. N., Denison, L., Ishak, A., Nishitani, S., & Smith, A. K. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602809113 · Cited by 91
“Although mounting data strongly support the role of OXTR in the phenotypic expression of sociability in humans (5, 6) and animals (7), the roles of other oxytocin pathway genes has received relatively little attention.”
BackgroundOxytocin receptor dynamics in the brain across development and species
Vaidyanathan, R., & Hammock, E. A. D. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22403 · Cited by 86
Long-term oxytocin administration enhances the experience of attachment
Bernaerts, S., Prinsen, J., Berra, E., Bosmans, G., Steyaert, J., & Alaerts, K. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.01.010 · Cited by 90
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The neurobiological reward system in Prolonged Grief Disorder (PGD): A systematic review
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The Monogamy Paradox: What Do Love and Sex Have to Do With It?
Carter, C. S., & Perkeybile, A. M. (2018) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2018.00202 · Cited by 87
“The individual differences seen in sociality in this species have been associated with genetic variation in the Oxtr, which influences variation in receptor protein expression (King et al., 2016).”
Pohl, T. T., Young, L. J., & Bosch, O. J. (2019) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2017.12.011 · Cited by 83
Self-citationIntegrative pathways linking close family ties to health: A neurochemical perspective.
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Loth, M. K., & Donaldson, Z. R. (2020) · Endocrinology · doi:10.1210/endocr/bqaa223 · Cited by 80
“Finally, individual differences in OXTR levels in the NAc are also tied to variation in bond formation within male prairie voles (40).”
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“In prairie voles, one non-coding polymorphism in the Oxtr (SNP2) explains the variance in OXTR expression in particular brain regions [61].”
BackgroundZhubi, A., Chen, Y., Guidotti, A., & Grayson, D. R. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.02.003 · Cited by 79
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Oxytocin and sex differences in behavior
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“DOI: 10.7554/eLife.22170 1 of 25 of OXT and/or its cognate receptor are not necessarily lethal; however, they may disrupt both physi- ological and psychological responses such as stress and social behaviors (King et al., 2016; Bosch et al., 2005).”
BackgroundInfluentialImproving the precision of intranasal oxytocin research
Winterton, A., Westlye, L. T., Steen, N. E., Andreassen, O. A., & Quintana, D. S. (2020) · Nature Human Behaviour · doi:10.1038/s41562-020-00996-4 · Cited by 65
Oxytocin as Treatment for Social Cognition, Not There Yet
Erdozain, A. M., & Peñagarikano, O. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00930 · Cited by 62
“Specifically, a certain single SNP in the OXTR gene modulated OXTR expression in the nucleus accumbens, a structure widely implicated in the processing of reward, and correlated with the propensity of the animals to form social attachments (28).”
BackgroundSparapani, S., Millet-Boureima, C., Oliver, J., Mu, K., Hadavi, P., Kalostian, T., Ali, N., Avelar, C. M., Bardies, M., Barrow, B., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9010089 · Cited by 64
The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives
Blumenthal, S. A., & Young, L. J. (2023) · Biology · doi:10.3390/biology12060844 · Cited by 59
“These genetic variations may also influence social behavior, as male C/C prairie voles display enhanced social attachment as compared to C/T and T/T animals [71].”
BackgroundSelf-citationMadrid, J. E., Parker, K. J., & Ophir, A. G. (2020) · Advances in the study of behavior · doi:10.1016/bs.asb.2020.02.001 · Cited by 55
“This result in males is consistent with other laboratory research showing that polymorphisms in non-coding regions in the prairie vole oxytocin gene, oxtr, predict OTR density in the NAcc and individual variation in laboratory pair bonding (King et al., 2016).”
ResultSippel, L. M., Han, S., Watkins, L. E., Harpaz‐Rotem, I., Southwick, S. M., Krystal, J. H., Olff, M., Sherva, R., Farrer, L. A., Kranzler, H. R., et al. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.07.008 · Cited by 63
“Among voles, genetic variation in nonencoding regions of OXTR contribute to OXTR transcription levels, oxytocin receptor density, and individual differences in social cognition and behavior (King et al., 2016).”
BackgroundCircuits for social learning: a unified model and application to autism spectrum disorder
DeMayo, M. M., Young, L. J., Hickie, I. B., Song, Y. J. C., & Guastella, A. J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.034 · Cited by 52
“In humans, oxytocin receptors are dense within the striatum, offering a mechanism through which genetic oxytocin receptor pathways influence striatal connectivity (King et al., 2016; Loth et al., 2014).”
BackgroundSelf-citationImaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
Hernandez, L. M., Lawrence, K. E., Padgaonkar, N. T., Inada, M., Hoekstra, J. N., Lowe, J. K., Eilbott, J., Jack, A., Aylward, E., Gaab, N., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0750-9 · Cited by 54
Evolution of affiliation: patterns of convergence from genomes to behaviour
Fischer, E. K., Nowicki, J. P., & O’Connell, L. A. (2019) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2018.0242 · Cited by 46
Flattery, C. N. R., Ross, A. P., Sahu, S. P., Siegel, E. R., Dooyema, J. M., Cree, M. A., Stopa, E. G., Young, L. J., Rilling, J. K., Albers, H. E., et al. (2018) · American Journal of Primatology · doi:10.1002/ajp.22875 · Cited by 53
Self-citationBaribeau, D. A., Dupuis, A., Paton, T., Scherer, S. W., Schachar, R. J., Arnold, P. D., Szatmári, P., Nicolson, R., Georgiades, S., Crosbie, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-10821-0 · Cited by 51
How does oxytocin modulate human behavior?
Yao, S., & Kendrick, K. M. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02898-1 · Cited by 61
“Indeed, more social individuals, or those exposed to social enrichment, tend to have higher basal OT concentrations [18, 19] and receptor expression density in brain reward areas within species may also re fl ect individual levels of sociality [17, 20 – 22].”
Horie, K., Inoue, K., Nishimori, K., & Young, L. J. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.08.023 · Cited by 46
“Recent research has focused on understanding how genes, neuronal modulators, receptors, and circuits regulate social bond formation and maintenance, which may have translational implications for improving quality of life in certain psychiatric disorders such as autism, PTSD, and depression (Modi et al., 2015; Arai et…”
BackgroundSelf-citationInoue, K., Ford, C. L., Horie, K., & Young, L. J. (2022) · Journal of Comparative Neurology · doi:10.1002/cne.25382 · Cited by 45
“However, no Oxtr mRNA-positive cells were detected in the SNR in voles of either genotype (Figure 7g,h), suggesting that OXTR binding in the SNR is on projections from another brain area, most likely the striatum, where Oxtr expression is genotype dependent (King et al., 2016) (Figure 7).”
BackgroundResultInfluentialSelf-citationTranslational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry
Ford, C. L., & Young, L. J. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.11.007 · Cited by 46
“In prairie voles, for instance, such sequence variation determines individual variation in striatal oxytocin receptor density [12], which predicts resiliency to early life neglect with respect to adult social bonding [14].”
BackgroundSelf-citationAdditive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism
Hernandez, L. M., Krasileva, K., Green, S. A., Sherman, L. E., Ponting, C., McCarron, R., Lowe, J. K., Geschwind, D. H., Bookheimer, S. Y., & Dapretto, M. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.209 · Cited by 43
Witchey, S. K., Fuchs, J., & Patisaul, H. B. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.06.007 · Cited by 45
“OT is synthesized primarily by the paraventricular (PVN) and supraoptic nuclei (SON) and released in multiple areas of the mesolimbic dopamine system and other brain nuclei that play a role in food intake, social recognition, mate choice, anxiety, empathy, parental care and other socioemotional behaviors (Caldwell, 20…”
BackgroundSocial experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles
Borie, A. M., Agezo, S., Lunsford, P., Boender, A. J., Guo, J.-D., Zhu, H., Berman, G. J., Young, L. J., & Liu, R. C. (2022) · Current Biology · doi:10.1016/j.cub.2022.01.014 · Cited by 39
Self-citationA precision medicine approach to oxytocin trials
Andari, E., Hurlemann, R., & Young, L. J. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_29 · Cited by 40
“Importantly, our group has recently demonstrated that the density of OTR variability between individuals within the prairie vole species in the ventral striatum is the result of gene polymorphisms in the OTR gene (King et al. 2016).”
BackgroundSelf-citationReuter, M., Montag, C., Altmann, S., Bendlow, F., Elger, C. E., Kirsch, P., Becker, A. J., Schoch, S., Simon, M., Weber, B., et al. (2016) · Social Neuroscience · doi:10.1080/17470919.2016.1214174 · Cited by 38
Brain functional networks associated with social bonding in monogamous voles
López-Gutiérrez, M. F., Gracia-Tabuenca, Z., Ortiz, J. J., Camacho, F., Young, L. J., Paredes, R. G., Díaz, N. F., Portillo, W., & Alcauter, S. (2021) · eLife · doi:10.7554/elife.55081 · Cited by 42
“Variation in OXT receptor density in the NAcc relates to partner preference in prairie voles (King et al., 2016).”
BackgroundSelf-citationComparative role of reward in long-term peer and mate relationships in voles
Goodwin, N. L., Lopez, S., Lee, N. S., & Beery, A. K. (2018) · Hormones and Behavior · doi:10.1016/j.yhbeh.2018.10.012 · Cited by 35
“Because of these selective social relationships, prairie voles have been hailed as an emerging model organism for the translational study of human social deficits in disorders such as autism spectrum disorder and schizophrenia (King et al., 2016; Lim et al., 2005; McGraw and Young, 2010; Modi and Young, 2012; Sadino a…”
MethodOxytocin, vasopressin and social behavior in the age of genome editing: a comparative perspective
Boender, A. J., & Young, L. J. (2020) · Hormones and Behavior · doi:10.1016/j.yhbeh.2020.104780 · Cited by 30
Self-citationRogers Flattery, C. N., Coppeto, D. J., Inoue, K., Rilling, J. K., Preuss, T. M., & Young, L. J. (2022) · Brain Structure and Function · doi:10.1007/s00429-021-02369-7 · Cited by 31
Self-citationSex differences in the reward value of familiar mates in prairie voles
Vahaba, D. M., Halstead, E. R., Donaldson, Z. R., Ahern, T. H., & Beery, A. K. (2022) · Genes Brain & Behavior · doi:10.1111/gbb.12790 · Cited by 29
“Oxtr genotype at the intronic locus NT213739 has been associated with both oxytocin receptor binding density within the nucleus accumbens, and preference behaviors.(24,37) We asked whether oxytocin receptor genotype was associated with oxytocin receptor binding density and social behavior in animals from the present s…”
BackgroundResultHelping behavior in prairie voles: a model of empathy and the importance of oxytocin
Kitano, K., Yamagishi, A., Horie, K., Nishimori, K., & Sato, N. (2022) · iScience · doi:10.1016/j.isci.2022.103991 · Cited by 31
“Oxytocin works as a hormone and as a neurotransmitter, which is involved in a variety of sociality, such as nurturing, familiarity, empathy, and social attachment (Bosch and Neumann, 2012; Decety et al., 2016; Insel, 2010; King et al., 2016; Rodrigues et al., 2009; Young and Wang, 2004).”
Partner Loss in Monogamous Rodents: Modulation of Pain and Emotional Behavior in Male Prairie Voles
Osako, Y., Nobuhara, R., Arai, Y.-C. P., Tanaka, K., Young, L. J., Nishihara, M., Mitsui, S., & Yuri, K. (2017) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000524 · Cited by 31
“Indeed, recent work has shown that a polymorphism in the Oxtr gene leads to alteration in oxytocin receptor density and also robustly predicts OXTR expression in the brain as well as pair-bonding behavior (57).”
Self-citationSmith, A. L., Freeman, S. M., Barnhart, T. E., Abbott, D. H., Ahlers, E. O., Kukis, D. L., Bales, K. L., Goodman, M. M., & Young, L. J. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.04.097 · Cited by 29
Self-citationBridging the gap between rodents and humans: The role of non‐human primates in oxytocin research
Putnam, P. T., Young, L. J., & Gothard, K. M. (2018) · American Journal of Primatology · doi:10.1002/ajp.22756 · Cited by 28
“For example, OXTR density is highly variable among prairie voles and is tightly regulated by genetic polymorphisms in the OXTR gene (King, Walum, Inoue, Eyrich, & Young, 2016).”
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Oxytocin signaling in the treatment of drug addiction: Therapeutic opportunities and challenges
Che, X., Cai, J., Liu, Y., Xu, T., Yang, J., & Wu, C. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107820 · Cited by 28
Role of Oxytocin in Different Neuropsychiatric, Neurodegenerative, and Neurodevelopmental Disorders
Ghazy, A. A., Soliman, O., Elbahnasi, A. I., Alawy, A. Y., Mansour, A. M., & Gowayed, M. A. (2022) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/112_2022_72 · Cited by 27
Ahern, T. H., Olsen, S., Tudino, R., & Beery, A. K. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105209 · Cited by 27
Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes
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Fifty Years of Advances in Neuroendocrinology
Russell, J. A. (2018) · Brain and Neuroscience Advances · doi:10.1177/2398212818812014 · Cited by 26
“From the studies on the importance of differences in oxytocin receptor expression on bonding in voles, an inference was made that in humans actions of oxytocin in the brain on differentially expressed oxytocin receptors might be important in social function, through regulating rewarding aspects of social stimuli (King…”
BackgroundGene expression correlates of social evolution in coral reef butterflyfishes
Nowicki, J. P., Pratchett, M. S., Walker, S. P. W., Coker, D. J., & O'Connell, L. A. (2020) · Proceedings of the Royal Society B: Biological Sciences · doi:10.1098/rspb.2020.0239 · Cited by 23
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Oxytocin receptor is not required for social attachment in prairie volesPreprint
Berendzen, K. M., Sharma, R., Mandujano, M. A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.22.501192 · Cited by 26
“Comparative studies between socially monogamous and non-monogamous vole species revealed striking differences in OxtR expression in brain regions thought to be important for social attachment, and implicated natural variation within species in specific aspects of pair bonding and attachment behaviors (Heinrichs et al.…”
BackgroundResultEvolutionary diversity as a catalyst for biological discovery
JOHNSON, Z. V., & YOUNG, L. J. (2018) · Integrative Zoology · doi:10.1111/1749-4877.12339 · Cited by 25
Self-citationLee, M., Lindo, J., & Rilling, J. K. (2022) · Genes Brain & Behavior · doi:10.1111/gbb.12783 · Cited by 27
“sity, which, in turn, predicted relevant social behaviors such as mating preference.(43) Overlap between OXTR mRNA expression and receptor density has also been found in primate species such as titi monkey(58) and rhesus macaque.”
BackgroundDuclot, F., Sailer, L. L., Koutakis, P., Wang, Z., & Kabbaj, M. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.11.022 · Cited by 20
Kobylinska, L. (2019) · Acta Endocrinologica (Bucharest) · doi:10.4183/aeb.2019.16 · Cited by 20
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“Furthermore, males with a genetic polymorphism leading to reduced oxytocin receptor expression in the NAcc display impairments in pair bond formation [31].”
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“Interestingly, OTR SNPs have also been associated with interindividual variability in OTR expression in specific brain areas, such as the nucleus accumbens in prairie voles (King et al., 2016).”
BackgroundSelectivity and Sociality: Aggression and Affiliation Shape Vole Social Relationships
Lee, N. S., & Beery, A. K. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.826831 · Cited by 25
The neurobiology of parenting and infant-evoked aggression
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Genetics of Interactive Behavior in Silver Foxes (Vulpes vulpes)
Nelson, R. M., Temnykh, S. V., Johnson, J. L., Kharlamova, A. V., Vladimirova, A. V., Gulevich, R. G., Shepeleva, D. V., Oskina, I. N., Acland, G. M., Rönnegård, L., et al. (2016) · Behavior Genetics · doi:10.1007/s10519-016-9815-1 · Cited by 21
Clinical potential of oxytocin in autism spectrum disorder: current issues and future perspectives
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“Variations in the Oxtr gene are associated with social recognition (Skuse et al., 2014), attachment and pair-bonding affiliative behavior (Walum et al., 2012; King et al., 2016), empathy (Rodrigues et al., 2009), and social interactions (Murakami et al., 2011) in humans and animal models.”
InfluentialInoue, Y., Miwa, H., Hori, K., Kaneko, R., Morimoto, Y., Koike, E., Asami, J., Kamijo, S., Yamada, M., Hoshino, M., et al. (2022) · eNeuro · doi:10.1523/eneuro.0423-21.2022 · Cited by 18
“The authors suggested that these SNPs might overlap with cis-regulatory elements in the intron (King et al., 2016).”
BackgroundResting state brain networks in the prairie vole
Ortiz, J. J., Portillo, W., Paredes, R. G., Young, L. J., & Alcauter, S. (2018) · Scientific Reports · doi:10.1038/s41598-017-17610-9 · Cited by 18
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“While the role played by OXT in the ventral striatum has been deeply investigated (King et al., 2016), its role in the dorsal striatum has received far less attention.”
BackgroundLove and longevity: A Social Dependency Hypothesis
Horn, A. J., & Carter, C. S. (2021) · Comprehensive Psychoneuroendocrinology · doi:10.1016/j.cpnec.2021.100088 · Cited by 23
“[129, 130], social communication [131], social attachments [62,132], and seasonal behavioral changes that enable enhanced thermoregulatory abilities, for example as is seen in some species of birds (e.”
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Staes, N., Guevara, E. E., Helsen, P., Eens, M., & Stevens, J. M. G. (2021) · Journal of Human Evolution · doi:10.1016/j.jhevol.2021.102949 · Cited by 16
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“Individual variation in V1aR and OTR density in prairie voles have been linked to genetic polymorphisms in the respective genes (Hammock & Young, 2005; King et al., 2016).”
BackgroundSelf-citationNeurogenomics of Behavioural Plasticity in Socioecological Contexts
Baker, M. R., Hofmann, H. A., & Wong, R. Y. (2017) · Wiley eBooks · doi:10.1002/9780470015902.a0026839 · Cited by 14
“A more recent study utilised RNA sequencing in and near the oxytocin receptor (Otr) gene and identified noncoding single nucleotide polymorphisms that contribute to differences in Otr expression and social attachment between individuals (King et al., 2015).”
BackgroundClarke, L., Zyga, O., Pineo-Cavanaugh, P. L., Jeng, M., Fischbein, N. J., Partap, S., Katznelson, L. J., & Parker, K. J. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104770 · Cited by 13
Partner separation rescues pair bond-induced decreases in hypothalamic oxytocin neural densities
Fricker, B. A., Roshko, V. C., Jiang, J., & Kelly, A. M. (2023) · Scientific Reports · doi:10.1038/s41598-023-32076-8 · Cited by 15
On the origins of diversity in social behavior
YOUNG, L. J., & ZHANG, Q. (2021) · Japanese Journal of Animal Psychology · doi:10.2502/janip.71.1.4 · Cited by 13
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Father’s care uniquely influences male neurodevelopment
Danoff, J. S., Ramos, E. N., Hinton, T. D., Perkeybile, A. M., Graves, A. J., Quinn, G. C., Lightbody-Cimer, A. R., Gordevičius, J., Milčiūtė, M., Brooke, R. T., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308798120 · Cited by 16
Qin, X., Lin, H., Cao, Y., Wu, R. S. S., Lai, K. P., & Kong, R. Y. C. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.160594 · Cited by 14
Tsukamoto, M., Nagai, L. A., Inoue, K., Kandasamy, L. C., Pires, M. F., Shin, M., Nagasawa, Y., Sambuu, T., Nakai, K., Itohara, S., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.01.518660 · Cited by 9
Self-citation
Metadata
- Authors
- King, L. B., Walum, H., Inoue, K., Eyrich, N. W., & Young, L. J.
- Affiliations
- Emory University (US)
- Corresponding author
- Young, Larry J.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 80
- Issue
- 2
- Pages
- 160-169
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4909578
- OpenAlex
- W2216755319
- Semantic Scholar
- 01a573b667c990664ff2f484a535ecfac25237b4
- Cited by
- 191
- References
- 86
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 16 · 2023: 11 · 2022: 18 · 2021: 24 · 2020: 32 · 2019: 10 · 2018: 18 · 2017: 21 · 2016: 19
- FWCI
- 32.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01MH096983, 1P50MH100023, 5T32GM008605, 5T32DA015040)
- National Institutes of Health Office of Research Infrastructure Programs/OD (P51OD11132)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- oxytocin receptor gene, oxytocin receptor, Microtus ochrogaster, social attachment, brain region-specific gene expression, allelic imbalance, cis-regulatory elements, intronic polymorphism, nucleus accumbens, striatum, mate preferences, monogamy, genetic regulation of gene expression, autism spectrum disorder
- MeSH terms
- Autism Spectrum Disorder, Alleles, Animals, Behavior, Animal, Arvicolinae, Individuality, Nucleus Accumbens, Object Attachment, Polymorphism, Genetic, RNA, Messenger, Social Behavior, Sequence Analysis, DNA, Receptors, Oxytocin
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.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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