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Cited by 292Neuroendocrine regulation and behaviorMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

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Hippocampal oxytocin receptors are necessary for discrimination of social stimuli

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Raam, Tara, McAvoy, Kathleen M., Besnard, Antoine, Veenema, Alexa H., Sahay, Amar·2017·Nature Communications
DOI 10.1038/s41467-017-02173-0PMC PMC5722862
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Abstract

Oxytocin receptor (Oxtr) signaling in neural circuits mediating discrimination of social stimuli and affiliation or avoidance behavior is thought to guide social recognition. Remarkably, the physiological functions of Oxtrs in the hippocampus are not known. Here we demonstrate using genetic and pharmacological approaches that Oxtrs in the anterior dentate gyrus (aDG) and anterior CA2/CA3 (aCA2/CA3) of mice are necessary for discrimination of social, but not non-social, stimuli. Further, Oxtrs in aCA2/CA3 neurons recruit a population-based coding mechanism to mediate social stimuli discrimination. Optogenetic terminal-specific attenuation revealed a critical role for aCA2/CA3 outputs to posterior CA1 for discrimination of social stimuli. In contrast, aCA2/CA3 projections to aCA1 mediate discrimination of non-social stimuli. These studies identify a role for an aDG-CA2/CA3 axis of Oxtr expressing cells in discrimination of social stimuli and delineate a pathway relaying social memory computations in the anterior hippocampus to the posterior hippocampus to guide social recognition.

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Figures

Fig. 1 Characterization of Oxtr expression in anterior hippocampus. a Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in anterior DG by FISH (n = 4 males, 3 females). Asterisk (*) denotes Oxtr+/Gad1+ interneuron. Arrowhead (>) denotes Oxtr+/GAD1− mossy cell. Scale bar, 100 μm. Inset scale bar, 50 μm. b Quantification of Gad1 and Oxtr colocalization for males and females, expressed as a percentage of Gad1+ cells over total Oxtr+ cells. c Representative images of low-magnification (left) and high-magnification (right) images of Oxtr, PV, and SST mRNA expression in anterior DG by FISH (n = 4 males, 3 females). Asterisk (*) denotes PV+/Oxtr+ interneuron. Right-facing arrowhead (>) denotes Oxtr+ mossy cell. Upward facing arrowhead (^) denotes Oxtr+/SST+ interneuron. Scale bar, 100 μm. Inset scale bar, 50 μm. d Quantification of Oxtr colocalization with PV and SST, expressed as a percentage of total Oxtr cells. e Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in aCA3proximal by FISH (n = 4 males, 3 females). Scale bar, 100 μm. Inset scale bar, 50 μm. f Quantification of mean Oxtr intensity for CA regions expressed in arbitrary units, normalized for background. g Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in aCA2/CA3distal by FISH (n = 4 males, 3 females). Asterisk (*) denotes Oxtr+/GAD1+ interneuron. Scale bar, 100 μm. Inset scale bar, 50 μm. h Quantification of Gad1 and Oxtr colocalization in aCA2/CA3distal for males and females, expressed as a percentage of Gad1+ cells over Oxtr+ cells. i Representative images of Oxtr, PV, and SST mRNA expression in aCA2/CA3distal by FISH (n = 4 males, 3 females). Asterisk (*) denotes PV+/Oxtr+ interneuron. Scale bar, 50 μm. Inset scale bar, 25 μm. j Quantification of Oxtr colocalization with PV and SST in aCA2/CA3distal, expressed as a percentage of total PV cells (top) or SST cells (bottom). k Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in aCA1 by FISH (n = 4 males, 3 females). Scale bar, 100 μm. Inset scale bar, 50 μm. l Schematic of anterior and posterior hippocampal subregions boundaries
Fig. 1 Characterization of Oxtr expression in anterior hippocampus. a Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in anterior DG by FISH (n = 4 males, 3 females). Asterisk (*) denotes Oxtr+/Gad1+ interneuron. Arrowhead (>) denotes Oxtr+/GAD1− mossy cell. Scale bar, 100 μm. Inset scale bar, 50 μm. b Quantification of Gad1 and Oxtr colocalization for males and females, expressed as a percentage of Gad1+ cells over total Oxtr+ cells. c Representative images of low-magnification (left) and high-magnification (right) images of Oxtr, PV, and SST mRNA expression in anterior DG by FISH (n = 4 males, 3 females). Asterisk (*) denotes PV+/Oxtr+ interneuron. Right-facing arrowhead (>) denotes Oxtr+ mossy cell. Upward facing arrowhead (^) denotes Oxtr+/SST+ interneuron. Scale bar, 100 μm. Inset scale bar, 50 μm. d Quantification of Oxtr colocalization with PV and SST, expressed as a percentage of total Oxtr cells. e Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in aCA3proximal by FISH (n = 4 males, 3 females). Scale bar, 100 μm. Inset scale bar, 50 μm. f Quantification of mean Oxtr intensity for CA regions expressed in arbitrary units, normalized for background. g Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in aCA2/CA3distal by FISH (n = 4 males, 3 females). Asterisk (*) denotes Oxtr+/GAD1+ interneuron. Scale bar, 100 μm. Inset scale bar, 50 μm. h Quantification of Gad1 and Oxtr colocalization in aCA2/CA3distal for males and females, expressed as a percentage of Gad1+ cells over Oxtr+ cells. i Representative images of Oxtr, PV, and SST mRNA expression in aCA2/CA3distal by FISH (n = 4 males, 3 females). Asterisk (*) denotes PV+/Oxtr+ interneuron. Scale bar, 50 μm. Inset scale bar, 25 μm. j Quantification of Oxtr colocalization with PV and SST in aCA2/CA3distal, expressed as a percentage of total PV cells (top) or SST cells (bottom). k Representative low-magnification (left) and high-magnification (right) images of Oxtr and Gad1 mRNA expression in aCA1 by FISH (n = 4 males, 3 females). Scale bar, 100 μm. Inset scale bar, 50 μm. l Schematic of anterior and posterior hippocampal subregions boundariesCC BY · PubMed Central
Fig. 2 Viral recombination of Oxtr in anterior DG hilar neurons impairs discrimination of social, but not non-social, stimuli. a Schematic illustrating viral injection and behavioral testing timeline. b Representative images of Cre and GFP virus infection in aDG. Scale bar, 200 μm. c Representative images and quantifications of cFos immunoreactivity in granule cell layer of aDG (GFP: n = 7, Cre: n = 4). Scale bar, 75 μm. d Behavioral schematic (top) and quantification (bottom) of single object exploration (GFP: n = 11, Cre: n = 6). e Behavioral schematic (top) and quantification (bottom) of novel objection recognition (GFP: n = 11, Cre: n = 6). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). f Behavioral schematic (top) and quantification (bottom) of social exploration test (GFP: n = 11, Cre: n = 6). g Behavioral schematic (top) and quantification (bottom) of social discrimination task (GFP: n = 11, Cre: n = 6). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). All data are displayed as mean ± SEM
Fig. 2 Viral recombination of Oxtr in anterior DG hilar neurons impairs discrimination of social, but not non-social, stimuli. a Schematic illustrating viral injection and behavioral testing timeline. b Representative images of Cre and GFP virus infection in aDG. Scale bar, 200 μm. c Representative images and quantifications of cFos immunoreactivity in granule cell layer of aDG (GFP: n = 7, Cre: n = 4). Scale bar, 75 μm. d Behavioral schematic (top) and quantification (bottom) of single object exploration (GFP: n = 11, Cre: n = 6). e Behavioral schematic (top) and quantification (bottom) of novel objection recognition (GFP: n = 11, Cre: n = 6). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). f Behavioral schematic (top) and quantification (bottom) of social exploration test (GFP: n = 11, Cre: n = 6). g Behavioral schematic (top) and quantification (bottom) of social discrimination task (GFP: n = 11, Cre: n = 6). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). All data are displayed as mean ± SEMCC BY · PubMed Central
Fig. 3 Viral recombination of Oxtr in aCA2/CA3distal impairs discrimination of social, but not non-social, stimuli. a Schematic illustrating viral injection and behavioral testing timeline. b Representative images of Cre and GFP virus infection in aCA2/CA3. Scale bar, 200 μm. c Behavioral schematic (top) and quantification (bottom) of single object exploration (GFP: n = 7, Cre: n = 10). d Behavioral schematic (top) and quantification (bottom) of novel objection recognition (GFP: n = 7, Cre: n = 10). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). e Behavioral schematic (top) and quantification (bottom) of social exploration test (GFP: n = 7, Cre: n = 10). f Behavioral schematic (top) and quantification (bottom) of social discrimination task (GFP: n = 7, Cre: n = 10). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). All data are displayed as mean ± SEM
Fig. 3 Viral recombination of Oxtr in aCA2/CA3distal impairs discrimination of social, but not non-social, stimuli. a Schematic illustrating viral injection and behavioral testing timeline. b Representative images of Cre and GFP virus infection in aCA2/CA3. Scale bar, 200 μm. c Behavioral schematic (top) and quantification (bottom) of single object exploration (GFP: n = 7, Cre: n = 10). d Behavioral schematic (top) and quantification (bottom) of novel objection recognition (GFP: n = 7, Cre: n = 10). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). e Behavioral schematic (top) and quantification (bottom) of social exploration test (GFP: n = 7, Cre: n = 10). f Behavioral schematic (top) and quantification (bottom) of social discrimination task (GFP: n = 7, Cre: n = 10). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). All data are displayed as mean ± SEMCC BY · PubMed Central
Fig. 4 Viral recombination of Oxtr in aCA2/CA3distal impairs population based coding of social stimuli. a Schematic illustrating conceptual design of catFISH using c-fos intronic and full-length mRNA localization as readouts for ensembles of neurons activated at distinct behavioral windows. b Representative images of CA3 pyramidal neurons exhibiting cytoplasmic, nuclear, or cytoplasmic and nuclear localization of c-fos mRNA transcripts. Scale bar, 10 μm. c Schematic illustrating viral injection and behavioral exposure timelines (GFP AA: n = 5, GFP AB: n = 5, Cre AA: n = 5, Cre AB: n = 4). d, f Percent overlap between ensembles of neurons encoding first and second stimulus for CA3proximal (top) and CA3distal (bottom), respectively. e, g Total number of active cells per section for CA3proximal (top) and CA3distal (bottom), respectively. All data are displayed as mean ± SEM
Fig. 4 Viral recombination of Oxtr in aCA2/CA3distal impairs population based coding of social stimuli. a Schematic illustrating conceptual design of catFISH using c-fos intronic and full-length mRNA localization as readouts for ensembles of neurons activated at distinct behavioral windows. b Representative images of CA3 pyramidal neurons exhibiting cytoplasmic, nuclear, or cytoplasmic and nuclear localization of c-fos mRNA transcripts. Scale bar, 10 μm. c Schematic illustrating viral injection and behavioral exposure timelines (GFP AA: n = 5, GFP AB: n = 5, Cre AA: n = 5, Cre AB: n = 4). d, f Percent overlap between ensembles of neurons encoding first and second stimulus for CA3proximal (top) and CA3distal (bottom), respectively. e, g Total number of active cells per section for CA3proximal (top) and CA3distal (bottom), respectively. All data are displayed as mean ± SEMCC BY · PubMed Central
Fig. 5 Optogenetic attenuation of aCA2/CA3distal outputs to aCA1 impairs discrimination of object, but not social stimuli. a Schematic illustrating viral injection, optogenetic implants and behavioral testing timeline. b Representative images of site of injection of eNpHR3.0 virus in aCA2/CA3distal cell bodies (top) and corresponding axon terminals in aCA1 (bottom). Scale bar, 200 μm. c Behavioral schematic (top) and quantification (bottom) of single object exploration (EYFP: n = 9, NpHR: n = 7). d Behavioral schematic (top) and quantification (bottom) of novel objection recognition (EYFP: n = 8, NpHR: n = 8). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. e Behavioral schematic (top) and quantification (bottom) of social exploration test (EYFP: n = 10, NpHR: n = 7). f Behavioral schematic (top) and quantification (bottom) of social discrimination task (EYFP: n = 6, NpHR: n = 6). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. All data are displayed as mean ± SEM
Fig. 5 Optogenetic attenuation of aCA2/CA3distal outputs to aCA1 impairs discrimination of object, but not social stimuli. a Schematic illustrating viral injection, optogenetic implants and behavioral testing timeline. b Representative images of site of injection of eNpHR3.0 virus in aCA2/CA3distal cell bodies (top) and corresponding axon terminals in aCA1 (bottom). Scale bar, 200 μm. c Behavioral schematic (top) and quantification (bottom) of single object exploration (EYFP: n = 9, NpHR: n = 7). d Behavioral schematic (top) and quantification (bottom) of novel objection recognition (EYFP: n = 8, NpHR: n = 8). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. e Behavioral schematic (top) and quantification (bottom) of social exploration test (EYFP: n = 10, NpHR: n = 7). f Behavioral schematic (top) and quantification (bottom) of social discrimination task (EYFP: n = 6, NpHR: n = 6). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. All data are displayed as mean ± SEMCC BY · PubMed Central
Fig. 6 Optogenetic attenuation of aCA2/CA3distal outputs to pCA1 impairs discrimination of social, but not non-social, stimuli. a Schematic illustrating viral injection, optogenetic implants and behavioral testing timeline. b Representative images of site of injection of eNpHR3.0 virus in aCA2/CA3distal cell bodies (top) and corresponding axon terminals in pCA1 (bottom). Scale bars, 200 μm (top) and 500 μm (bottom). c Representative images and quantifications of cFos immunoreactivity in pyramidal layer of pCA1 during optogenetic silencing (EYFP: n = 7, NpHR: n = 7). Scale bar, 100 μm. d Behavioral schematic (top) and quantification (bottom) of single object exploration (EYFP: n = 7, NpHR: n = 7). e Behavioral schematic (top) and quantification (bottom) of novel objection recognition (EYFP: n = 6, NpHR: n = 7). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. f Behavioral schematic (top) and quantification (bottom) of social exploration test (EYFP: n = 6, NpHR: n = 7). g Behavioral schematic (top) and quantification (bottom) of social discrimination task (EYFP: n = 6, NpHR: n = 7). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. All data are displayed as mean ± SEM
Fig. 6 Optogenetic attenuation of aCA2/CA3distal outputs to pCA1 impairs discrimination of social, but not non-social, stimuli. a Schematic illustrating viral injection, optogenetic implants and behavioral testing timeline. b Representative images of site of injection of eNpHR3.0 virus in aCA2/CA3distal cell bodies (top) and corresponding axon terminals in pCA1 (bottom). Scale bars, 200 μm (top) and 500 μm (bottom). c Representative images and quantifications of cFos immunoreactivity in pyramidal layer of pCA1 during optogenetic silencing (EYFP: n = 7, NpHR: n = 7). Scale bar, 100 μm. d Behavioral schematic (top) and quantification (bottom) of single object exploration (EYFP: n = 7, NpHR: n = 7). e Behavioral schematic (top) and quantification (bottom) of novel objection recognition (EYFP: n = 6, NpHR: n = 7). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. f Behavioral schematic (top) and quantification (bottom) of social exploration test (EYFP: n = 6, NpHR: n = 7). g Behavioral schematic (top) and quantification (bottom) of social discrimination task (EYFP: n = 6, NpHR: n = 7). Quantifications are displayed as Habituation (trials 1–3), Test (trial 4), and discrimination ratio (trial 4). Laser was on during trial 4 only. All data are displayed as mean ± SEMCC BY · PubMed Central

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Metadata

Authors
Raam, T., McAvoy, K. M., Besnard, A., Veenema, A. H., & Sahay, A.
Affiliations
  • Harvard University (US)
  • Michigan State University (US)
  • Broad Institute (US)
Corresponding author
Sahay, Amar
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-12-08
Volume
8
Issue
1
Pages
2001-2001
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02173-0
PMC
PMC5722862
OpenAlex
W2772417881
Cited by
292
References
70
Citations by year
2026: 25 · 2025: 35 · 2024: 26 · 2023: 33 · 2022: 48 · 2021: 40 · 2020: 34 · 2019: 25 · 2018: 26
FWCI
33.27
Type
journal article
Language
en
Update notices
correction (2018-02-02)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ellison Medical Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health
  • Harvard Stem Cell Institute
  • National Institute on Aging (RF1AG048908)
  • National Institute of Mental Health (R01MH104175, R01MH111729)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
oxytocin receptor, hippocampus, social recognition, CA1, population coding, social memory, optogenetic manipulation
MeSH terms
Animals, Behavior, Animal, Discrimination, Psychological, Hippocampus, Male, Mice, Inbred C57BL, Neural Pathways, Neurons, Social Behavior, Receptors, Oxytocin, Mice, Knockout, Models, Animal, Mice, Optogenetics

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