Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons
Open accessAbstract
Neuromodulatory control by oxytocin is essential to a wide range of social, parental and stress-related behaviours. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels and with genetic alterations of the oxytocin receptor (OXTR). Thirty years ago, Mühlethaler et al. found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision.
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OTR and V1aR are classic neuromodulators, mediating both short- and long-term changes in neural and hence behavioral outcomes.
“OTR and V1aR are classic neuromodulators, mediating both short- and long-term changes in neural and hence behavioral outcomes (Owen et al., 2013).”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Owen et al., 2013
Oxytocin modulates neural activity by affecting excitatory/inhibitory balance and improves signal-to-noise ratio by stimulating fast spiking parvalbumin interneuron activity.
“Oxytocin is thought to modulate neural activity by affecting the excitatory/inhibitory balance and also seems to improve the signal-to-noise ration by stimulating fast spiking parvalbumin inter-neuron activity (Owen et al. 2013).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Owen et al. 2013
Oxytocin can increase processing efficiency at the neuronal level by optimizing signal-to-noise during cell firing.
“Together with recent findings showing that OT can increase processing efficiency at the neuronal level by optimizing signal-to-noise during cell firing43”
From Intranasal oxytocin enhances connectivity in the neural circuitry supporting social motivation and social perception in children with autism (2016) · cites this paper as [43]
In ASD, oxytocin may not only enhance neural activity to preferred stimuli but also improve communication among brain regions involved in social motivation and perception.
“these results show that in ASD, OT may not only serve to enhance neural activity to “preferred” stimuli, but also improve communication among brain regions involved in social motivation and perception.”
From Intranasal oxytocin enhances connectivity in the neural circuitry supporting social motivation and social perception in children with autism (2016) · cites this paper as [43]
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“, 1979) and there 430 certainly is an excellent literature on cortical neuropeptide signaling (Crawley, 1985; Férézou et al., 2007; 431 Gallopin et al., 2006; Gomtsian et al., 2018; Hamilton et al., 2013; Liu et al., 2018; Mena et al., 2013; Mitre 432 et al., 2018; Owen et al., 2013; Rossier and Chapouthier, 1982; Wil…”
BackgroundOxytocin transforms firing mode of CA2 hippocampal neurons
Tirko, N. N., Eyring, K. W., Carcea, I., Mitre, M., Chao, M. V., Froemke, R. C., & Tsien, R. W. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.008 · Cited by 157 · see citing works
“Additionally, OXTR stimulation of CA2 inhibitory neuron firing might dampen the initially strong GABAergic transmission in CA2 (Piskorowski and Chevaleyre, 2013) via activity-dependent synaptic depression (Figure 8H; Owen et al., 2013; Marlin et al., 2015; Oettl et al., 2016).”
InfluentialSmith, C. J. W., Poehlmann, M. L., Li, S., Ratnaseelan, A. M., Bredewold, R., & Veenema, A. H. (2017) · Brain Structure and Function · doi:10.1007/s00429-016-1260-7 · Cited by 143 · see citing works
Oxytocin signaling in the medial amygdala is required for sex discrimination of social cues
Yao, S., Bergan, J., Lanjuin, A., & Dulac, C. (2017) · eLife · doi:10.7554/elife.31373 · Cited by 151 · see citing works
“…documented to increase neuronal firing rates, mainly, though not exclusively in fast-spiking interneurons, resulting in lower background activity and enhanced information transfer in cortical and non-cortical circuits (Owen et al., 2013; Marlin et al., 2015; Oettl et al., 2016; Xiao et al., 2017).”
BackgroundOwen, S. F., Berke, J. D., & Kreitzer, A. C. (2018) · Cell · doi:10.1016/j.cell.2018.01.005 · Cited by 146 · see citing works
Oxytocin-Augmented Social Cognitive Skills Training in Schizophrenia
Davis, M. C., Green, M. F., Lee, J., Horan, W. P., Senturk, D., Clarke, A. D., & Marder, S. R. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.68 · Cited by 149 · see citing works
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Oxytocin׳s role in anxiety: A critical appraisal
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Effects of MDMA and intranasal oxytocin on social and emotional processing
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Interplay between Oxytocin and Sensory Systems in the Orchestration of Socio-Emotional Behaviors
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“A C1 C2 AON piriform cortex MC MC GC OSN = OTR expression B CA1 CA3 entorhinal cortex + oxytocin = GABA Figure 4 B Auditory system IC Aud Ctx MG DC Tz SOc inner year IO A Visual system SC LGThalamus Visual cortex pigment epitheliumretina Figure 3 trigeminal ganglion SpTN STN Somatosensory system SS Ctx PAG Cg Ctx NTS…”
InfluentialNeural Circuits for Social Cognition: Implications for Autism
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Cortical variability in the sensory-evoked response in autism
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Oxytocin mediates entrainment of sensory stimuli to social cues of opposing valence
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Is birth a critical period in the pathogenesis of autism spectrum disorders?
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“…in the generation of cortical rhythms (Stark et al., 2013; Schlingoff et al., 2014), signal processing (Atallah et al., 2012; Lee et al., 2012; Lovett-Barron et al., 2012; Owen et al., 2013; Sachidhanandam et al., 2013), and control of epileptic discharges (Ledri et al., 2014; Ladas et al., 2015).”
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“As observed in the hippocampus (Sala et al., 2011; Owen et al., 2013) and the infralimbic medial prefrontal cortex (Ninan, 2011), OXTR may contribute to signal-tonoise processing throughout the entire neocortex by regulating excitatory and inhibitory balance during post-natal development.”
BackgroundOxytocin receptors modulate a social salience neural network in male prairie voles
Johnson, Z. V., Walum, H., Xiao, Y., Riefkohl, P. C., & Young, L. J. (2017) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.10.009 · Cited by 113 · see citing works
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Estrus-Cycle Regulation of Cortical Inhibition
Clemens, A. M., Lenschow, C., Beed, P. S., Li, L., Sammons, R. P., Naumann, R. K., Wang, H., Schmitz, D., & Brecht, M. (2019) · Current Biology · doi:10.1016/j.cub.2019.01.045 · Cited by 111 · see citing works
Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake
Ryan, P. J., Ross, S. I., Campos, C., Derkach, V. A., & Palmiter, R. D. (2017) · Nature Neuroscience · doi:10.1038/s41593-017-0014-z · Cited by 113 · see citing works
Endocannabinoid Signaling in the Control of Social Behavior
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Oxytocin in learning and addiction: From early discoveries to the present
Sarnyai, Z., & Kovács, G. L. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.11.019 · Cited by 106 · see citing works
Social Decision-Making and the Brain: A Comparative Perspective
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From Autism to Eating Disorders and More: The Role of Oxytocin in Neuropsychiatric Disorders
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Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection
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“This conclusion is supported by other studies in different brain areas: the auditory cortex, piriform cortex, hypothalamus, and hippocampus [51, 52].”
BackgroundResultLin, Y.-T., & Hsu, K. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.10.003 · Cited by 97 · see citing works
Oxytocin and Parental Behaviors
Yoshihara, C., Numan, M., & Kuroda, K. O. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_11 · Cited by 102 · see citing works
Insular function in autism: Update and future directions in neuroimaging and interventions
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Adaptations for social cognition in the primate brain
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“For example, OT applied to hippocampus in rats enhances signal-to-noise ratio of neurons by increasing spike probability while simultaneously decreasing spontaneous background activity [129], potentially providing a foundation for enhanced learning and memory.”
BackgroundOxytocin and vasopressin in the rodent hippocampus
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Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons
Ripamonti, S., Ambrozkiewicz, M. C., Guzzi, F., Gravati, M., Biella, G. R., Bormuth, I., Hammer, M., Tuffy, L. P., Sigler, A., Kawabe, H., et al. (2017) · eLife · doi:10.7554/elife.22466 · Cited by 82 · see citing works
“…publications reporting that, in rat, Oxt acutely activates interneurons located in the stratum pyramidale and modulates fast-spiking interneurons, thus enhancing inhibitory synaptic transmission in the hippocampus (Mühlethaler et al., 1984, 1983; Owen et al., 2013; Zaninetti and Raggenbass, 2000).”
BackgroundResultOxytocin 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
Neuroscience: The hard science of oxytocin
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GABAergic interneurons: The orchestra or the conductor in fear learning and memory?
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“Nevertheless, it is now clear that, similar to excitatory PNs, inhibitory interneurons exhibit diverse forms of synaptic potentiation and depression in response to artificial stimulation (Cohen et al., 2016; Huang et al., 2013; Mahanty and Sah, 1998; Owen et al., 2013; Pelkey et al., 2005; Woodin et al., 2003), raisin…”
BackgroundOxytocin Modulation of Neural Circuits
Mitre, M., Minder, J. L., Morina, E., Chao, M. V., & Froemke, R. C. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_7 · Cited by 76 · see citing works
CA2 beyond social memory: Evidence for a fundamental role in hippocampal information processing
Lehr, A. B., Kumar, A., Tetzlaff, C., Hafting, T., Fyhn, M., & Stöber, T. M. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.020 · Cited by 74 · see citing works
“In both regions, oxytocin receptor activation increases their excitability (Owen et al., 2013; Tirko et al., 2018).”
Olazábal, D. E., & Alsina‐Llanes, M. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.04.006 · Cited by 72 · see citing works
Oxytocin promotes prefrontal population activity via the PVN-PFC pathway to regulate pain
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Control of response reliability by parvalbumin-expressing interneurons in visual cortex
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Oxytocin and Serotonin Brain Mechanisms in the Nonhuman Primate
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“Moreover, amygdala, hippocampus, and prefrontal cortex have also been found to be influenced by OT in experiments on rodents (Viviani et al., 2011; Knobloch et al., 2012; Owen et al., 2013; Nakajima et al., 2014).”
BackgroundAssociation of Social Support With Brain Volume and Cognition
Salinas, J., O’Donnell, A., Kojis, D. J., Pase, M., DeCarli, C. S., Rentz, D., Berkman, L., Beiser, A., & Seshadri, S. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.21122 · Cited by 53 · see citing works
Neuropeptide diversity and the regulation of social behavior in New World primates
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“OTR and V1aR are classic neuromodulators, mediating both 490 short- and long-term changes in neural and hence behavioral out491 comes (Owen et al., 2013).”
Oxytocin and Rodent Models of Addiction
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Zebrafish oxytocin neurons drive nocifensive behavior via brainstem premotor targets
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Oxytocin: Parallel Processing in the Social Brain?
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- Authors
- Owen, S. F., Tuncdemir, S. N., Bader, P. L., Tirko, N. N., Fishell, G., & Tsien, R. W.
- Affiliations
- Stanford Medicine (US)
- New York University (US)
- Corresponding author
- Tsien, Richard W.
- Venue
- Nature
- Published
- 2013-08
- Volume
- 500
- Issue
- 7463
- Pages
- 458-462
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5283693
- OpenAlex
- W2008069212
- Cited by
- 339
- References
- 36
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 21 · 2023: 26 · 2022: 22 · 2021: 28 · 2020: 21 · 2019: 23 · 2018: 35 · 2017: 35 · 2016: 33 · 2015: 37 · 2014: 26 · 2013: 7
- FWCI
- 51.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Mental Health (F31MH084430, MH071739, MH064070, R01MH071739, R37MH071739)
- National Institute of Neurological Disorders and Stroke (NS024067, R01NS024067, R01NS074785)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- oxytocin, hippocampus, fast-spiking interneurons, signal-to-noise ratio, neuromodulation, synaptic depression, pyramidal neurons, cholecystokinin, channelrhodopsin-2, autism spectrum disorder, oxytocin receptor, inhibitory interneurons
- MeSH terms
- Action Potentials, Animals, Brain, Cholecystokinin, Glycine, Hippocampus, Interneurons, Neural Pathways, Synaptic Transmission, Oxytocin, Rhodopsin, Synapses, Threonine, Pyramidal Cells, Receptors, Oxytocin, Excitatory Postsynaptic Potentials, Feedback, Physiological, Mice, Rats
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