Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The hippocampal CA2 region is essential for social memory

Nature volume 508, pages 88–92 (2014)Cite this article

Subjects

Abstract

The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when1. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output2. Genetic lesions of EC (ref. 3) and hippocampal dentate gyrus (ref. 4), CA3 (ref. 5) and CA1 (ref. 6) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output7. Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory—the ability of an animal to remember a conspecific—with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genetic targeting of the CA2 subfield using the Amigo2-Cre mouse line.
Figure 2: Genetically targeted tracing of the CA2 circuit.
Figure 3: Electrophysiological verification of CA2 inactivation with TeNT.
Figure 4: Inactivation of CA2 impairs social memory.

Similar content being viewed by others

References

  1. Squire, L. R. & Wixted, J. T. The cognitive neuroscience of human memory since H.M. Annu. Rev. Neurosci. 34, 259–288 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van Strien, N. M., Cappaert, N. L. & Witter, M. P. The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nature Rev. Neurosci. 10, 272–282 (2009)

    Article  CAS  Google Scholar 

  3. Suh, J., Rivest, A. J., Nakashiba, T., Tominaga, T. & Tonegawa, S. Entorhinal cortex layer III input to the hippocampus is crucial for temporal association memory. Science 334, 1415–1420 (2011)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149, 188–201 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nakashiba, T., Young, J. Z., McHugh, T. J., Buhl, D. L. & Tonegawa, S. Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning. Science 319, 1260–1264 (2008)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Tsien, J. Z., Huerta, P. T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996)

    Article  CAS  PubMed  Google Scholar 

  7. Chevaleyre, V. & Siegelbaum, S. A. Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop. Neuron 66, 560–572 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lorente de Nó, R. Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J. Psychol. Neurol. 46, 113–177 (1934)

    Google Scholar 

  9. Franklin, K. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic, 2007)

    Google Scholar 

  10. Lein, E. S., Callaway, E. M., Albright, T. D. & Gage, F. H. Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J. Comp. Neurol. 485, 1–10 (2005)

    Article  CAS  PubMed  Google Scholar 

  11. Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, S. E. et al. RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc. Natl Acad. Sci. USA 107, 16994–16998 (2010)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cui, Z., Gerfen, C. R. & Young, W. S. III. Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus. J. Comp. Neurol. 521, 1844–1866 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kohara, K. et al. Cell type-specific genetic and optogenetic tools reveal hippocampal CA2 circuits. Nature Neurosci. 10.1038/nn.3614. (2013)

  15. Wall, N. R., De La Parra, M., Callaway, E. M. & Kreitzer, A. C. Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron 79, 347–360 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rowland, D. C. et al. Transgenically targeted rabies virus demonstrates a major monosynaptic projection from hippocampal area CA2 to medial entorhinal layer II neurons. J. Neurosci. 33, 14889–14898 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neurosci. 8, 1263–1268 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. Hargreaves, E. L., Rao, G., Lee, I. & Knierim, J. J. Major dissociation between medial and lateral entorhinal input to dorsal hippocampus. Science 308, 1792–1794 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Hensler, J. G. Serotonergic modulation of the limbic system. Neurosci. Biobehav. Rev. 30, 203–214 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. Pan, W. X & McNaughton, N. The supramammillary area: its organization, functions and relationship to the hippocampus. Prog. Neurobiol. 74, 127–166 (2004)

    Article  PubMed  Google Scholar 

  21. Young, W. S., Li, J., Wersinger, S. R. & Palkovits, M. The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy. Neuroscience 143, 1031–1039 (2006)

    Article  CAS  PubMed  Google Scholar 

  22. Wersinger, S. R., Ginns, E. I., O’Carroll, A. M., Lolait, S. J. & Young, W. S. III. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry 7, 975–984 (2002)

    Article  CAS  PubMed  Google Scholar 

  23. DeVito, L. M. et al. Vasopressin 1b receptor knock-out impairs memory for temporal order. J. Neurosci. 29, 2676–2683 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stevenson, E. L. & Caldwell, H. K. The vasopressin 1b receptor and the neural regulation of social behavior. Horm. Behav. 61, 277–282 (2012)

    Article  CAS  PubMed  Google Scholar 

  25. Kogan, J. H., Frankland, P. W. & Silva, A. J. Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10, 47–56 (2000)

    Article  CAS  PubMed  Google Scholar 

  26. Ferguson, J. N. et al. Social amnesia in mice lacking the oxytocin gene. Nature Genet. 25, 284–288 (2000)

    Article  CAS  PubMed  Google Scholar 

  27. Brennan, P. A. & Zufall, F. Pheromonal communication in vertebrates. Nature 444, 308–315 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Corkin, S. What’s new with the amnesic patient H.M.? Nature Rev. Neurosci. 2, 153–160 (2002)

    Article  ADS  CAS  Google Scholar 

  29. Benes, F. M., Kwok, E. W., Vincent, S. L. & Todtenkopf, M. S. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol. Psychiatry 44, 88–97 (1998)

    Article  CAS  PubMed  Google Scholar 

  30. Meyer-Lindenberg, A., Domes, G., Kirsch, P. & Heinrichs, M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nature Rev. Neurosci. 12, 524–538 (2011)

    Article  CAS  Google Scholar 

  31. Heintz, N. GENSAT Brain Atlas of gene expression in EGFP Transgenic Mice http://www.gensat.org (2003)

    Google Scholar 

  32. Lein, E. S. ISH Data: Allen Brain Atlas: Mouse Brain http://mouse.brain-map.org/ (2007)

    Google Scholar 

  33. de Jong, P. J. BAC Clones Distribution Center – BACPAC Resources Center https://bacpac.chori.org/ (2000)

    Google Scholar 

  34. Warming, S., Costantino, N., Court, D. L., Jenkins, N. A. & Copeland, N. G. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res. 33, e36 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gong, S. et al. Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs. J. Neurosci. 27, 9817–9823 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nature Neurosci. 13, 133–140 (2010)

    Article  CAS  PubMed  Google Scholar 

  37. Wickersham, I. R., Sullivan, H. A. & Seung, H. S. Production of glycoprotein-deleted rabies viruses for monosynaptic tracing and high-level gene expression in neurons. Nature Protocols 5, 595–606 (2010)

    Article  CAS  PubMed  Google Scholar 

  38. Watabe-Uchida, M., Zhu, L., Ogawa, S. K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873 (2012)

    Article  CAS  PubMed  Google Scholar 

  39. Yamamoto, M. et al. Reversible suppression of glutamatergic neurotransmission of cerebellar granule cells in vivo by genetically manipulated expression of tetanus neurotoxin light chain. J. Neurosci. 23, 6759–6767 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jiao, Y. et al. A simple and sensitive antigen retrieval method for free-floating and slide-mounted tissue sections. J. Neurosci. Methods 93, 149–162 (1999)

    Article  CAS  PubMed  Google Scholar 

  41. Boulanger, L. M. et al. Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase. J. Neurosci. 15, 1532–1544 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Takeda, K. et al. WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum. Mol. Genet. 10, 477–484 (2001)

    Article  CAS  PubMed  Google Scholar 

  43. Rasband, W. S. Image J. http://imagej.nih.gov/ij/ (1997)

  44. Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature Protocols 1, 848–858 (2006)

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bielsky, I. F., Hu, S., Szegda, K. L., Westphal, H. & Young, L. J. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 29, 483–493 (2004)

    Article  CAS  PubMed  Google Scholar 

  46. Yang, M. & Crawley, J. N. Simple behavioral assessment of mouse olfaction. Curr. Protocols Neurosci. 84, 8.24.1–8.24.12 (2009)

    Google Scholar 

Download references

Acknowledgements

We thank T. R. Reardon for providing the rabies virus; J. Kupferman and F. Lema for experimental assistance; and C. Denny, Z. Donaldson, R. Hen, J. Gordon, J. Basu and M. Russo for discussions and comments on the manuscript. This work was supported by a Ruth L. Kirschstein F30 National Research Service Award from the National Institute of Mental Health (F.L.H.) and the Howard Hughes Medical Institute (S.A.S.).

Author information

Authors and Affiliations

  1. Department of Neuroscience, Kavli Institute, College of Physicians and Surgeons, Columbia University 1051 Riverside Drive, New York, 10032, New York, USA

    Frederick L. Hitti & Steven A. Siegelbaum

  2. Department of Pharmacology, Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University 1051 Riverside Drive, New York, 10032, New York, USA

    Steven A. Siegelbaum

Authors
  1. Frederick L. Hitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven A. Siegelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.L.H. planned and performed the experiments, analysed the data and wrote the manuscript. S.A.S. oversaw the overall execution of the project, contributed to the experimental design and the interpretation of the data, provided financial support and helped write the manuscript.

Corresponding author

Correspondence to Steven A. Siegelbaum.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Generation of Amigo2-Cre mouse line.

λ Red-mediated homologous recombination with galK positive and negative selection was used to make seamless changes to the bacterial artificial chromosome (BAC). PCR cassettes are shown in orange, and Amigo2 locus is shown in blue. The PCR cassette contained two homology arms (H1, 58 nucleotides; H2, 62 nucleotides) that flanked the galactose kinase (galK) cassette. The homology arms flanked the Amigo2 start codon. Recombination followed by positive selection was used to obtain the galK integrate. Recombination of the modified BAC with a PCR cassette containing the Cre open reading frame (ORF) and poly(A) (PA) flanked by the same homology arms yielded the final BAC used to generate the transgenic line.

Extended Data Figure 2 Amigo2-Cre mice express Cre in a genetically defined population of CA2 PNs.

Coronal sections of hippocampus from Amigo2-Cre mice injected in dorsal hippocampus with a Cre-dependent AAV to express YFP (shown in green) in CA2. a, Coronal section of ventral hippocampus (about 2.8 mm caudal to bregma; see Fig. 54 of ref. 9 for a reference image) showing CA2 axons (green) from dorsal CA2. Note absence of YFP from ventral CA2 neurons (RGS14 stain in red). b, 97.22 ± 0.46% of YFP+ cells (n = 4 mice, 2,948 cells) express the CA2 marker PCP4 (red). c, 98.45 ± 0.33% of YFP+ cells (n = 4 mice, 2,870 cells) express the CA2 marker STEP (red). d, Almost no YFP+ cells (0.17 ± 0.13%; n = 4 mice, 2,870 cells) express the CA1 marker WFS1 (red). e–g, Magnification of boxed area in b, showing YFP signal (e), PCP4 staining (f) and a merge of the two (g). h–j, Magnification of boxed area in c, showing YFP signal (h), STEP staining (i) and a merge of the two (j). k–m, Magnification of boxed area in d, showing YFP signal (k), WFS1 staining (l) and a merge of the two (m). Nissl stain shown in blue. Scale bars, 400 μm (a–d); 100 μm (e–m).

Extended Data Figure 3 Amigo2-Cre mice express Cre in RGS14+ CA2 PNs but not in GABA+ inhibitory neurons.

Cre+ neurons expressing YFP (shown in green) co-label with RGS14 staining (shown in red), but do not co-label with GABA staining (shown in red in separate images). a, Reproduction of section −1.06 mm shown in Fig. 1b. b, e, Magnification of boxed area in a. c, RGS14 staining of section shown in b. d, Merge of b and c, showing YFP and RGS14 co-labelling. f, GABA staining of section shown in e. g, Merge of e and f, showing no overlap of GABA and YFP. h, Reproduction of section −1.46 mm shown in Fig. 1b. i, l, Magnification of boxed area in h. j, RGS14 staining of section shown in i. k, Merge of i and j, demonstrating YFP and RGS14 co-labelling. m, GABA staining of section shown in l. n, Merge of l and m, showing no overlap of GABA and YFP. o, Reproduction of section −2.18 mm shown in Fig. 1b. p, s, Magnification of boxed area in o. q, RGS14 staining of section shown in p. r, Merge of p and q, demonstrating YFP and RGS14 co-labelling. t, GABA staining of section shown in s. u, Merge of s and t, showing no overlap of GABA and YFP. Scale bars, 200 μm. Nissl stain shown in blue.

Extended Data Figure 4 Specificity of the pseudotyped rabies virus.

a, b, No labelled cells were observed (n = 3 mice) after injection of the (EnvA)SAD-ΔG-mCherry virus when TVA was not expressed in CA2. b, Magnification of boxed area in a. Rabies labelling would have appeared in magenta; Nissl stain shown in green. Scale bars, 200 μm.

Extended Data Figure 5 Inactivation of CA2 does not alter locomotor activity or anxiety-like behaviour.

a, There was no significant difference (P = 0.31, two-tailed unpaired Student’s t-test) between CA2-YFP and CA2-TeNT groups in the distance travelled in the open field (OF) test (YFP, 53.14 ± 4.62 m, n = 8; TeNT, 47.04 ± 3.70 m, n = 10). b, There was also no significant difference (P = 0.55, two-tailed unpaired Student’s t-test) between the groups in the number of rearing events recorded during the OF session (YFP, 378.0 ± 17.36, n = 8; TeNT, 354.7 ± 30.99, n = 10). c, d, Inactivation of CA2 did not alter anxiety-like behaviour measured in the elevated plus maze (EPM). The number of open arm entries was not significantly different (P > 0.99, two-tailed unpaired Student’s t-test) between the groups (YFP, 14.00 ± 1.46, n = 8; TeNT, 14.00 ± 1.54, n = 10). Additionally, the time spent in the open arms (YFP, 163.7 ± 10.43 s, n = 8; TeNT, 155.1 ± 16.38 s, n = 10) did not differ significantly (P = 0.68, two-tailed unpaired Student’s t-test) between the groups. Results are means ± s.e.m.

Extended Data Figure 6 Spatial learning and memory assayed with the Morris water maze task is unaltered by CA2 inactivation.

a, Diagram of the experimental design. On days 1 and 2 mice were trained to find a platform with a visible flag. On days 3–7 mice were trained to find a hidden platform located in the southwest quadrant of the water maze. Spatial memory was assayed on day 8 with the platform removed. Reversal training was conducted on days 9–13 with the platform now hidden in the northwest quadrant. Spatial memory of the novel location was tested on day 14. b, Path length to the platform was not altered significantly by CA2 inactivation (two-way repeated-measures ANOVA: treatment × time F(11,770) = 0.67, P = 0.77; time F(11,770) = 21.87, P < 0.0001; treatment F(1,70) = 2.85, P = 0.10). c, Latency to find the platform did not differ significantly between the two groups (two-way repeated-measures ANOVA: treatment × time F(11,770) = 0.78, P = 0.66; time F(11,770) = 25.23, P < 0.0001; treatment F(1,70) = 2.84, P = 0.10). YFP, n = 8; TeNT, n = 10. d, Spatial memory during the probe trial was unaffected by CA2 inactivation. The percentage of time spent in the target quadrant (YFP, 33.00 ± 2.66%; TeNT, 38.6 ± 4.79%) was not significantly different between the two groups (P = 0.36, two-tailed unpaired Student’s t-test). e, Spatial memory after reversal training was unaffected by CA2 inactivation. There was no significant difference between the groups in the percentage of time spent in the target quadrant during the probe trial after reversal training (YFP, 36.38 ± 5.75%; TeNT, 36.40 ± 2.92%; P > 0.99, two-tailed unpaired Student’s t-test). Results are means ± s.e.m.

Extended Data Figure 7 Contextual fear-conditioning memory and auditory fear-conditioning memory are unaffected by inactivation of CA2.

a, Diagram of the experimental design. Delay fear conditioning was employed to test hippocampus-dependent contextual fear memory and amygdala-dependent auditory fear memory. b, There was no significant difference in percentage freezing between the groups (two-way repeated-measures ANOVA: treatment × day F(4,68) = 0.31, P = 0.87; treatment F(1,17) = 0.13, P = 0.73; day F(4,68) = 100.8, P < 0.0001; YFP, n = 11; TeNT, n = 8). Before training on day 1, neither group showed a fear response to context A (YFP, 2.45 ± 1.06%; TeNT, 0.75 ± 0.49%) or to the tone (YFP, 3.09 ± 1.31%; TeNT, 1.63 ± 0.84%). On day 2 after training, robust fear responses to context A were measured in both groups (YFP, 24.09 ± 2.88%; TeNT, 26.00 ± 4.10%). Both groups showed low levels of freezing on day 3 in novel context B (YFP, 6.55 ± 1.52%; TeNT, 4.00 ± 0.87%), demonstrating context specificity of the fear memory and a lack of fear generalization. Both groups showed robust freezing to the tone on day 3 (YFP, 35.82 ± 4.93%; TeNT, 34.63 ± 3.96%), demonstrating intact auditory fear memory. c, Freezing data plotted in 30-s bins. Shaded areas represent tone presentation. Red line represents shock delivery. Left: two-way repeated-measures ANOVA revealed no significant difference between groups in freezing on day 1 (treatment × time F(6,102) = 1.135, P = 0.3474; treatment F(1,17) = 1.116, P = 0.3056; time F(6,102) = 6.348, P < 0.0001). Middle: two-way repeated-measures ANOVA revealed no significant difference between groups in freezing on day 2 (treatment × time F(9,153) = 0.9741, P = 0.4637; treatment F(1,17) = 0.1326, P = 0.7203; time F(9,153) = 6.335, P < 0.0001). Right: two-way repeated-measures ANOVA revealed no significant difference between groups in freezing on day 3 (treatment × time F(7,119) = 0.2490, P = 0.9716; treatment F(1,17) = 0.6517, P = 0.4307; time F(7,119) = 50.87, P < 0.0001). Results are means ± s.e.m.

Extended Data Figure 8 Object recognition memory and preference for novelty is preserved in CA2-TeNT animals.

a, Diagram of the experimental design for the novel-object-recognition task. b, The groups did not differ significantly in exploration of object 1 (YFP, 16.75 ± 1.57 s; TeNT, 19.60 ± 2.24 s) or object 2 (YFP, 16.50 ± 1.97 s; TeNT, 15.90 ± 1.66 s) averaged over the course of the first four trials (two-way ANOVA: treatment × object F(1,32) = 0.80, P = 0.38; object F(1,32) = 1.05, P = 0.31; treatment F(1,32) = 0.34, P = 0.56; YFP, n = 8; TeNT, n = 10). c, Both groups explored the novel object (YFP, 21.23 ± 2.37 s; TeNT, 24.37 ± 2.81 s) more than the familiar object (YFP, 7.41 ± 0.92 s; TeNT, 8.57 ± 1.48 s). Statistical analysis revealed a significant effect of object, but not CA2 inactivation or interaction of the two (two-way ANOVA: treatment × object F(1,28) = 0.22, P = 0.64; object F(1,28) = 48.46, P < 0.0001; treatment F(1,28) = 1.02, P = 0.32). Multiple comparison testing revealed a significant difference between exploration of the novel object compared with exploration of the old object for both the YFP group (P = 0.0002) and the TeNT group (P < 0.0001). d, Diagram of the experimental design for another variation of the novel-object-recognition task. e, The groups did not differ significantly in time spent exploring object 1 (YFP, 21.50 ± 2.31 s; TeNT, 22.18 ± 3.57 s) or object 2 (YFP, 22.02 ± 2.23 s; TeNT, 22.36 ± 2.81 s) during trial 1 of day 4 (two-way ANOVA: treatment × object F(1,44) = 0.004, P = 0.95; object F(1,44) = 0.02, P = 0.90; treatment F(1,44) = 0.03, P = 0.85; YFP, n = 12; TeNT, n = 12). f, Both groups explored the novel object (YFP, 21.49 ± 1.91 s; TeNT, 22.73 ± 1.82 s) more than the familiar object (YFP, 13.74 ± 1.83 s; TeNT, 16.53 ± 1.64 s). Statistical analysis revealed a significant effect of object, but not CA2 inactivation or interaction of the two (two-way ANOVA: treatment × object F(1,44) = 0.18, P = 0.67; object F(1,44) = 15.02, P = 0.0004; treatment F(1,44) = 1.25, P = 0.27). Multiple comparison testing revealed a significant difference between exploration of the novel object compared with exploration of the old object for both the YFP group (P = 0.008) and the TeNT group (P = 0.02). Results are means ± s.e.m.

Extended Data Figure 9 Olfaction is unaffected by CA2 inactivation.

a, There was no significant difference between the groups in latency to find a buried food pellet (YFP, 63.93 ± 8.22 s, n = 15; TeNT, 67.06 ± 9.42 s, n = 16; P = 0.81, two-tailed unpaired Student’s t-test). b, There was no significant difference between the groups (YFP, n = 15; TeNT, n = 14) in performance on the olfactory habituation/dishabituation task (two-way repeated-measures ANOVA: treatment × trial F(11,297) = 0.933, P = 0.51; treatment F(1,27) = 0.08, P = 0.78; trial F(11,297) = 60.21, P < 0.0001). Results are means ± s.e.m.

Extended Data Table 1 Electrophysiological properties of Cre+ neurons
Full size table

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hitti, F., Siegelbaum, S. The hippocampal CA2 region is essential for social memory. Nature 508, 88–92 (2014). https://doi.org/10.1038/nature13028

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature13028

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing