A Cortical Circuit for Sexually Dimorphic Oxytocin-Dependent Anxiety Behaviors

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 Sep 20

PMID 27641503

Citations 109

Authors

Kun Li

Miho Nakajima

Ines Ibanez-Tallon

Nathaniel Heintz

Affiliations

Soon will be listed here.

Abstract

The frequency of human social and emotional disorders varies significantly between males and females. We have recently reported that oxytocin receptor interneurons (OxtrINs) modulate female sociosexual behavior. Here, we show that, in male mice, OxtrINs regulate anxiety-related behaviors. We demonstrate that corticotropin-releasing-hormone-binding protein (CRHBP), an antagonist of the stress hormone CRH, is specifically expressed in OxtrINs. Production of CRHBP blocks the CRH-induced potentiation of postsynaptic layer 2/3 pyramidal cell activity of male, but not female, mice, thus producing an anxiolytic effect. Our data identify OxtrINs as critical for modulation of social and emotional behaviors in both females and males and reveal a molecular mechanism that acts on local medial prefrontal cortex (mPFC) circuits to coordinate responses to OXT and CRH. They suggest that additional studies of the impact of the OXT/OXTR and CRHBP/CRH pathways in males and females will be important in development of gender-specific therapies.

Citing Articles

Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.

Lin Y, Luo X, Wang F, Cai H, Lin Y, Kang D Biol Sex Differ. 2025; 16(1):3.

PMID: 39833961 PMC: 11744935. DOI: 10.1186/s13293-025-00684-w.

Continuous cell type diversification throughout the embryonic and postnatal mouse visual cortex development.

Gao Y, van Velthoven C, Lee C, Thomas E, Bertagnolli D, Carey D bioRxiv. 2025; .

PMID: 39829740 PMC: 11741437. DOI: 10.1101/2024.10.02.616246.

To Attack or Not: A Neural Circuit Coding Sexually Dimorphic Aggression.

Xin Q, Hu H Neurosci Bull. 2025; .

PMID: 39752045 DOI: 10.1007/s12264-024-01345-5.

Prefrontal cortical circuits in social behaviors: an overview.

Cao W, Li H, Luo J J Zhejiang Univ Sci B. 2024; 25(11):941-955.

PMID: 39626878 PMC: 11634449. DOI: 10.1631/jzus.B2300743.

Inhibitory gamma-aminobutyric acidergic neurons in the anterior cingulate cortex participate in the comorbidity of pain and emotion.

Guan L, Qiu M, Li N, Zhou Z, Ye R, Zhong L Neural Regen Res. 2024; 20(10):2838-2854.

PMID: 39314159 PMC: 11826466. DOI: 10.4103/NRR.NRR-D-24-00429.

References

Westphal N, Seasholtz A . CRH-BP: the regulation and function of a phylogenetically conserved binding protein. Front Biosci. 2005; 11:1878-91. DOI: 10.2741/1931. View

Penagarikano O, Lazaro M, Lu X, Gordon A, Dong H, Lam H . Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med. 2015; 7(271):271ra8. PMC: 4498455. DOI: 10.1126/scitranslmed.3010257. View

Laryea G, Arnett M, Muglia L . Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders. Behav Sci (Basel). 2012; 2(2):135-71. PMC: 3471213. DOI: 10.3390/bs2020135. View

Rilling J, Young L . The biology of mammalian parenting and its effect on offspring social development. Science. 2014; 345(6198):771-6. PMC: 4306567. DOI: 10.1126/science.1252723. View

Kunwar P, Zelikowsky M, Remedios R, Cai H, Yilmaz M, Meister M . Ventromedial hypothalamic neurons control a defensive emotion state. Elife. 2015; 4. PMC: 4379496. DOI: 10.7554/eLife.06633. View

Ventura A, Meissner A, Dillon C, McManus M, Sharp P, Van Parijs L . Cre-lox-regulated conditional RNA interference from transgenes. Proc Natl Acad Sci U S A. 2004; 101(28):10380-5. PMC: 478580. DOI: 10.1073/pnas.0403954101. View

Dolen G, Darvishzadeh A, Huang K, Malenka R . Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature. 2013; 501(7466):179-84. PMC: 4091761. DOI: 10.1038/nature12518. View

Altemus M, Sarvaiya N, Epperson C . Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol. 2014; 35(3):320-30. PMC: 4890708. DOI: 10.1016/j.yfrne.2014.05.004. View

Shrestha P, Mousa A, Heintz N . Layer 2/3 pyramidal cells in the medial prefrontal cortex moderate stress induced depressive behaviors. Elife. 2015; 4. PMC: 4566133. DOI: 10.7554/eLife.08752. View

10.

MacDonald K, Feifel D . Oxytocin's role in anxiety: a critical appraisal. Brain Res. 2014; 1580:22-56. DOI: 10.1016/j.brainres.2014.01.025. View

11.

Rubenstein E, Wiggins L, Lee L . A Review of the Differences in Developmental, Psychiatric, and Medical Endophenotypes Between Males and Females with Autism Spectrum Disorder. J Dev Phys Disabil. 2015; 27(1):119-139. PMC: 4490156. DOI: 10.1007/s10882-014-9397-x. View

12.

Insel T . Translating Oxytocin Neuroscience to the Clinic: A National Institute of Mental Health Perspective. Biol Psychiatry. 2016; 79(3):153-4. DOI: 10.1016/j.biopsych.2015.02.002. View

13.

Scott N, Prigge M, Yizhar O, Kimchi T . A sexually dimorphic hypothalamic circuit controls maternal care and oxytocin secretion. Nature. 2015; 525(7570):519-22. DOI: 10.1038/nature15378. View

14.

Owen S, Tuncdemir S, Bader P, Tirko N, Fishell G, Tsien R . Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature. 2013; 500(7463):458-62. PMC: 5283693. DOI: 10.1038/nature12330. View

15.

Insel T . The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron. 2010; 65(6):768-79. PMC: 2847497. DOI: 10.1016/j.neuron.2010.03.005. View

16.

Nakajima M, Gorlich A, Heintz N . Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell. 2014; 159(2):295-305. PMC: 4206218. DOI: 10.1016/j.cell.2014.09.020. View

17.

Labermaier C, Kohl C, Hartmann J, Devigny C, Altmann A, Weber P . A polymorphism in the Crhr1 gene determines stress vulnerability in male mice. Endocrinology. 2014; 155(7):2500-10. DOI: 10.1210/en.2013-1986. View

18.

Smoller J . The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders. Neuropsychopharmacology. 2015; 41(1):297-319. PMC: 4677147. DOI: 10.1038/npp.2015.266. View

19.

Pfaff D, McEwen B . Actions of estrogens and progestins on nerve cells. Science. 1983; 219(4586):808-14. DOI: 10.1126/science.6297008. View

20.

Iwasaki-Sekino A, Mano-Otagiri A, Ohata H, Yamauchi N, Shibasaki T . Gender differences in corticotropin and corticosterone secretion and corticotropin-releasing factor mRNA expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala in response to footshock stress or.... Psychoneuroendocrinology. 2008; 34(2):226-237. DOI: 10.1016/j.psyneuen.2008.09.003. View