RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles
Open accessAbstract
Oxytocin modulates many aspects of social cognition and behaviors, including maternal nurturing, social recognition and bonding. Natural variation in oxytocin receptor (OXTR) density in the nucleus accumbens (NAcc) is associated with variation in alloparental behavior, and artificially enhancing OXTR expression in the NAcc enhances alloparental behavior and pair bonding in socially monogamous prairie voles. Furthermore, infusion of an OXTR antagonist into the NAcc inhibits alloparental behavior and partner preference formation. However, antagonists can promiscuously interact with other neuropeptide receptors. To directly examine the role of OXTR signaling in social bonding, we used RNA interference to selectively knockdown, but not eliminate, OXTR in the NAcc of female prairie voles and examined the impact on social behaviors. Using an adeno-associated viral vector expressing a short hairpin RNA (shRNA) targeting Oxtr mRNA, we reduced accumbal OXTR density in female prairie voles from juvenile age through adulthood. Females receiving the shRNA vector displayed a significant reduction in alloparental behavior and disrupted partner preference formation. These are the first direct demonstrations that OXTR plays a critical role in alloparental behavior and adult social attachment, and suggest that natural variation in OXTR expression in this region alone can create variation in social behavior.
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Oxytocin, dopamine, and vasopressin regulate neural circuits responsible for generating bonds in animals and humans.
“Here, we provide an overview of the roles of oxytocin, dopamine, and vasopressin in regulating neural circuits responsible for generating bonds in animals and humans alike.”
From The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives (2023) · cites this paper as [15]
The Introduction (page unavailable) links oxytocin signaling in the nucleus accumbens and dopamine D2 signaling in the striatum to pair-bond formation in prairie voles. It also discusses oxytocin-related social behavior in humans, but does not establish that all three substances—including vasopressin—regulate bond-forming neural circuits in both animals and humans. (LLM, conf=0.87)
Experimental — accuracy not yet measuredViral knockdown of OXTRs within the NAc of voles disrupts partner preference formation and alloparental behavior; increasing OXTR expression in the NAc facilitates pair bonding and maternal care.
“Additionally, viral knockdown of OXTRs within the NAc of voles disrupts partner preference formation and alloparental behavior; however, pair bonding and maternal care are facilitated when OXTR expression in the NAc is increased, suggesting a direct role of NAc OXTRs in driving affiliative behavior [15,140].”
From The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives (2023) · cites this paper as [15]
The Discussion (page not provided) reports that viral OXTR knockdown in the nucleus accumbens reduced alloparental behavior and disrupted partner preference formation. The Introduction reports that increased OXTR expression facilitated partner preference, and, when administered to juveniles, increased alloparental behavior. It does not establish increased maternal care, which is distinct from care of others’ young. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn contrast to nonmonogamous species, prairie voles have high densities of oxytocin receptors in nucleus accumbens, and oxytocin signaling in the accumbens during mating is essential for partner preference formation.
“In contrast to nonmonogamous species, prairie voles have high densities of oxytocin receptors in nucleus accumbens, and oxytocin signaling in the accumbens during mating is essential for partner preference formation”
From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Keebaugh et al. 2015
The Introduction states that prairie voles have higher nucleus accumbens oxytocin-receptor density than nonmonogamous vole species and that an accumbens receptor antagonist prevents mating-induced partner preferences. The Results show that receptor knockdown eliminated partner preference in females that had mated. Neither finding establishes that signaling specifically during mating is essential; the Methods also note that partner preferences can form without mating. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIncreasing OXTR density in the nucleus accumbens using viral-vector mediated gene transfer facilitates partner preference formation.
“Increasing OXTR density in the NAcc using viral-vector mediated gene transfer facilitates partner preference formation, while decreasing OXTR density in the same region using RNA interference inhibits such bonding (37–39).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [38]
Decreasing OXTR density in the nucleus accumbens using RNA interference inhibits partner preference formation.
“Increasing OXTR density in the NAcc using viral-vector mediated gene transfer facilitates partner preference formation, while decreasing OXTR density in the same region using RNA interference inhibits such bonding (37–39).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [38]
Differences in pair bonding behavior are mediated by OXTR variation.
“and OXTR variation mediates individual differences in pair bonding behaviors (37–39).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [38]
Blockade of endogenous OTR (and other neuromodulatory receptor) signaling in the NAc inhibits pair bond formation and other forms of social behavior in prairie voles and other rodents.
“blockade of endogenous OTR (and other neuromodulatory receptor) signaling in the NAc inhibits pair bond formation and other forms of social behavior in prairie voles and other rodents”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as Keebaugh et al., 2015
Viral-mediated small interfering RNA knockdown of OXTR in the nucleus accumbens of prairie voles inhibits partner preference, while overexpressing NAcc OXTR enhances partner preference formation.
“Viral-mediated small interfering RNA knockdown of OXTR in NAcc of prairie voles inhibits partner preference (138), while overexpressing NAcc OXTR enhances partner preference formation (139).”
From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [138]
The density of NAc OXTR correlates with preferences for an individual.
“Furthermore, OXTR signaling in the NAc plays a critical role for the formation of a preference for an individual, and the density of NAc OXTR correlates with such preferences 27–29.”
From Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles (2022) · cites this paper as [28]
OXTR signaling in the nucleus accumbens plays a critical role for the formation of a preference for an individual.
“Furthermore, OXTR signaling in the NAc plays a critical role for the formation of a preference for an individual, and the density of NAc OXTR correlates with such preferences 27–29.”
From Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles (2022) · cites this paper as [28]
Experimentally increasing or decreasing OXTR expression in the prairie vole nucleus accumbens modulated partner preference behavior.
“experimentally increasing9 or decreasing10 OXTR expression in the prairie vole nucleus accumbens modulated partner preference behavior”
From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [10]
Increased OXTR gene expression is associated with increased oxytocin binding.
“and that increased OXTR gene expression is associated with increased oxytocin binding”
From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [10]
Animal models demonstrate that OXTR expression levels directly modulate social behavior.
“animal models demonstrating that OXTR expression levels directly modulate social behavior9,10”
From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [10]
Knock-down of the oxytocin receptor inhibited social attachment and parental care.
“knock-down of the OT receptor inhibited social attachment and parental care (Keebaugh et al., 2015)”
From Long-term oxytocin administration enhances the experience of attachment (2017) · cites this paper as Keebaugh et al., 2015
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References 67 · Cited by 150
- Authors
- Keebaugh, A. C., Barrett, C. E., Laprairie, J. L., Jenkins, J. J., & Young, L. J.
- Affiliations
- Emory University (US)
- Spelman College (US)
- Corresponding author
- Young, Larry J.
- Venue
- Social Neuroscience
- Publisher
- Informa UK Limited
- Published
- 2015-05-07
- Volume
- 10
- Issue
- 5
- Pages
- 561-570
- ISSN
- 1747-0919 (ISSN-L)
- 1747-0927
- PMC
- PMC4618772
- OpenAlex
- W2094583910
- Cited by
- 150
- References
- 67
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 12 · 2023: 15 · 2022: 20 · 2021: 16 · 2020: 7 · 2019: 5 · 2018: 20 · 2017: 13 · 2016: 16 · 2015: 7
- FWCI
- 30.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Social Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (NIH RO1MH096983)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Human-Animal Interaction Studies
- Keywords
- oxytocin receptor, nucleus accumbens, Microtus ochrogaster, social attachment, parental care, pair bonding, mate preferences, social monogamy, RNAi knockdown, adeno-associated virus vectors, shRNA, female social behavior
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Autoradiography, Arvicolinae, Female, Genetic Vectors, Humans, Nucleus Accumbens, Object Attachment, Pair Bond, Parents, RNA, Messenger, Transduction, Genetic, Transfection, Receptors, Oxytocin, RNA Interference, RNA, Small Interfering, Green Fluorescent Proteins, HEK293 Cells
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