CoChat
Sign Up
Cited by 976Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

The hippocampal CA2 region is essential for social memory

Open access
Hitti, Frederick L., Siegelbaum, Steven A.·2014·Nature
DOI 10.1038/nature13028PMC PMC4000264
Open this paper in CoChat — free account

Abstract

The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when. 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 output. 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 output. 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.

AI snapshot

Written from the paper’s full text.

TL;DR

A newly generated Amigo2-Cre mouse line allowed selective targeting of hippocampal CA2 pyramidal neurons, showing that CA2 receives distinct entorhinal and subcortical inputs and projects mainly within hippocampus. Inactivating CA2 output with tetanus toxin selectively abolished social memory while sparing sociability, spatial memory, contextual/auditory fear memory, anxiety, locomotion, and olfaction.

Key findings

  • The Amigo2-Cre line selectively labeled CA2 pyramidal neurons: 97.38 ± 0.31% of YFP+ cells co-stained for RGS14 (n = 4 mice, 2546 cells), 82.33 ± 2.37% of RGS14+ cells were YFP+ (n = 4 mice, 2992 cells), and only 0.16 ± 0.16% of YFP+ neurons were GABA+ (n = 3 mice, 1539 cells).
  • CA2 inactivation with eGFP-TeNT blocked CA2→CA1 synaptic transmission: light-evoked monosynaptic PSPs in CA1 had mean latency 1.22 ± 0.06 ms (n = 119 observations) in controls, but TeNT co-expression produced little or no synaptic response.
  • CA2-TeNT mice showed a profound social memory deficit: they failed to prefer a novel mouse in the three-chamber social novelty test, showed suppressed social memory in the direct interaction test after a 1-h inter-trial interval, and showed no habituation/dishabituation in the 5-trial social memory assay.
  • CA2 inactivation did not alter sociability, locomotor activity, anxiety-like behavior, Morris water maze spatial memory, contextual fear memory, auditory fear memory, novel object recognition, buried food detection, or olfactory habituation/dishabituation.

Methods

  • Generated an Amigo2-Cre BAC transgenic mouse line, backcrossed to C57BL/6J at least 6 times; only Cre+ males >8 weeks old were used, with Cre-dependent AAVs stereotaxically injected into dorsal hippocampus and experiments performed 2–4 weeks later.
  • Used Cre-dependent YFP for anatomical tracing, EnvA pseudotyped ΔG rabies virus for monosynaptic input mapping, immunohistochemistry/confocal microscopy for cell-type validation, and slice electrophysiology with ChR2 and TeNT to test CA2→CA1 transmission.
  • Compared CA2-YFP controls with CA2-TeNT mice across open field, elevated plus maze, novel object, Morris water maze, fear conditioning, three-chamber sociability/social novelty, direct interaction, 5-trial social memory, buried food, and olfactory habituation/dishabituation tests; statistics used t-tests, 2-way ANOVA, or 2-way RM ANOVA with Holm-Sidak correction, P < 0.05.

Limitations

  • The paper states that the results do not rule out a more general role for CA2 in hippocampal-dependent memory tasks; other hippocampal regions may compensate, or CA2 may be selectively required for more demanding non-social memory tasks.
  • The paper notes that failure to observe vasopressinergic input to CA2 may reflect the rabies tracing system’s inability to label peptidergic inputs; absent CA2 output to supramammillary nucleus may reflect an inhibitory projection, and absent CA2 output to EC layer II may reflect weak connections not detected by anterograde tracing.
  • Evident from the text: only male Cre+ mice were studied, and only dorsal CA2 was targeted; the Amigo2-Cre line also expresses Cre outside CA2 in adult brain and during development, requiring AAV restriction to CA2.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nature13028

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There was no co-staining for a CA1 pyramidal neuron marker in the Amigo2-Cre line.

    “In contrast, there was no co-staining for a CA1 PN marker”
    Quote in the paperSubstantial claim
  • Findingown data

    CA2 pyramidal neurons have no observed extra-hippocampal outputs.

    “We did not observe extra-hippocampal outputs.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Increasing light intensity recruited progressively larger PSPs in CA1 pyramidal neurons.

    “Increasing the light intensity recruited progressively larger PSPs, presumably due to an increase in the number of optically-activated CA2 axons (Fig. 3e, f).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Low intensity illumination focused on CA2 reliably triggered action potentials in CA2 pyramidal neurons expressing ChR2.

    “Low intensity illumination (using 2-ms pulses of 470 nm light at 3 mW·mm−2) focused on CA2 reliably triggered action potentials in CA2 PNs, as seen by the presence of fast action currents in cell-attached patch clamp recordings (Fig. 3a-c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Synaptic inputs to CA2 pyramidal neurons were detected from medial septum and diagonal band, median raphe nucleus, and the supramammillary nucleus of the hypothalamus.

    “synaptic inputs were detected from medial septum and diagonal band (Fig. 2e), median raphe nucleus (Fig. 2f), and the supramammillary nucleus of the hypothalamus (Fig. 2g).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 28
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The electrophysiological properties of YFP+ neurons in the Amigo2-Cre line differed significantly from CA1 pyramidal neurons and largely matched previously reported CA2 pyramidal neuron values.

    “the electrophysiological properties of the YFP+ neurons differed significantly from those of CA1 PNs (Extended Data Table 1) and largely matched the values previously reported for CA2 pyramidal neurons7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Chevaleyre, V. & Siegelbaum, S. A. Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop. Neuron 66, 560–572 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    YFP expression in the Amigo2-Cre line was selective and robust in CA2 pyramidal neurons throughout dorsal hippocampus.

    “We observed selective and robust YFP expression in CA2 PNs throughout dorsal hippocampus9-11”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Franklin, K. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic, 2007)

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

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

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Monosynaptic inputs to CA2 pyramidal neurons include bilateral inputs from CA3 and CA2 and strong unilateral input from lateral and medial entorhinal cortex layer II neurons.

    “Unilateral viral injections revealed bilateral inputs from CA3 and CA2 (Fig. 2a, b) and strong unilateral input from both lateral and medial EC layer II neurons (Fig. 2c, d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Only a minute fraction of YFP+ neurons were also GABA+ (0.16 ± 0.16%; n = 3 mice, 1539 cells), demonstrating specific targeting of CA2 excitatory pyramidal neurons.

    “Only a minute fraction of YFP+ neurons were also GABA+ (0.16 ± 0.16%; n = 3 mice, 1539 cells), demonstrating the specific targeting of CA2 excitatory PNs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CA2 pyramidal neurons project strongly bilaterally to hippocampal CA1, CA2, and CA3, with densest projections in stratum oriens and weaker projections in stratum radiatum.

    “Unilateral viral injections resulted in strong bilateral labeling in hippocampal CA1, CA2, and CA3 regions, with densest projections observed in stratum oriens (SO) and weaker projections detected in stratum radiatum (SR) (Fig. 2h, i).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the 5-trial social memory assay, CA2-TeNT mice showed no significant habituation during four exposures to the stimulus mouse or dishabituation to the novel stimulus mouse.

    “In contrast, the CA2-TeNT group showed no significant habituation during the four exposures to the stimulus mouse or dishabituation to the novel stimulus mouse”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the 5-trial social memory assay, CA2-YFP control mice displayed normal social memory, with habituation during trials 1-4 and dishabituation to a novel animal on trial 5.

    “The CA2-YFP control group of mice displayed normal social memory, as evidenced by a marked habituation (decreased exploration) during trials 1-4 and a striking dishabituation (increased exploration) upon presentation of a novel animal on the fifth trial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the three-chamber social novelty test, CA2-YFP controls demonstrated a significant preference for the novel animal whereas CA2-TeNT mice did not.

    “Multiple comparison testing revealed that the CA2-YFP control group demonstrated a significant preference for the compartment containing the novel animal whereas the CA2-TeNT group did not (Fig. 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Functional inactivation of dorsal CA2 did not alter locomotor activity or anxiety-like behavior.

    “Functional inactivation of dorsal CA2 did not alter locomotor activity or anxiety-like behavior (Extended Data Fig. 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CA2 inactivation did not change hippocampal-dependent contextual fear memory or amygdala-dependent auditory fear memory.

    “Nor was there any change in hippocampal-dependent contextual fear memory or amygdala-dependent auditory fear memory (Extended Data Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CA2 silencing did not alter sociability in the direct interaction test, as exploration times were equal when two different unfamiliar mice were encountered in successive trials.

    “CA2 silencing did not alter sociability as evidenced by the equal exploration times for trials 1 and 2 when a subject mouse encountered two different unfamiliar mice in successive trials (Fig. 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Selective silencing of CA2 did not alter sociability in the three-chamber test; CA2-TeNT and CA2-YFP groups displayed significant and similar preference for the littermate compartment.

    “selective silencing of CA2 did not alter sociability as the CA2-TeNT and CA2-YFP groups displayed a significant and similar preference for the compartment containing the littermate (Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CA2 inactivation had no effect on the ability of mice to detect or discriminate non-social or social odors in the olfactory habituation/dishabituation test.

    “CA2 inactivation also had no effect on the ability of the mice to detect or discriminate either non-social or social odors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The olfactory habituation/dishabituation test validly measures detection and discrimination of social and non-social odors.

  • May combine two claims.

    Findingown data

    CA2 inactivation did not significantly alter hippocampal-dependent spatial memory assessed by the Morris water maze, although there was a trend for CA2-inactivated mice to learn the task more slowly.

    “CA2-inactivation also did not significantly alter hippocampal-dependent spatial memory assessed by the Morris water maze (although there was a trend for the CA2-inactivated mice to learn the task more slowly; Extended Data Fig. 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The social recognition deficit in CA2-TeNT mice was not due to a lack of interest in novelty, as they showed normal preference for a novel object in two protocols.

    “This deficit was not due to a lack of interest in novelty, per se, as the CA2-TeNT mice demonstrated normal preference for a novel object as assayed by two different novel object recognition protocols (Extended Data Fig. 8).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The novel object recognition protocols validly measure interest in novelty.

  • May combine two claims.

    Study design and conductnone given

    The Amigo2-Cre line expresses Cre throughout the brain during early development and in certain limited areas outside CA2 in adult mice.

    “Because this line expresses Cre throughout the brain during early development, as well as in certain limited areas outside of CA2 in the adult”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The failure to observe vasopressinergic input to CA2 from the paraventricular nucleus may reflect an inability of the transsynaptic rabies tracing system to label peptidergic inputs.

    “we failed to observe vasopressinergic input to CA2 from the paraventricular nucleus of the hypothalamus13, which may reflect an inability of the transsynaptic rabies tracing system to label peptidergic inputs15.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The absence of observed CA2 output to entorhinal cortex layer II may be because anterograde tracing failed to detect weak connections.

    “Moreover, we did not observe CA2 output to EC layer II16, perhaps because the anterograde tracing failed to detect weak connections.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The anatomical results generally support previous findings on CA2 connectivity.

    “These anatomical results generally support previous13,14 findings.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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) source

      Not checked in the free run.

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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The absence of observed CA2 output to the supramammillary nucleus suggests this output may represent an inhibitory projection from CA2, as only pyramidal neurons were labeled.

    “We also did not observe CA2 output to the supramammillary nucleus13, suggesting this output may represent an inhibitory projection from CA2 as we selectively labeled PNs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Avpr1b mRNA is strongly expressed in CA2.

    “Previous studies have shown that the mRNA for the vasopressin 1b receptor (Avpr1b) is strongly expressed in CA221”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The input pattern of CA2 suggests a potential role for CA2 in non-spatial hippocampal tasks.

    “suggests a potential role for CA2 in non-spatial hippocampal tasks.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Unconditional deletion of Avpr1b impairs social recognition memory.

    “unconditional deletion of this gene impairs social recognition memory22,23.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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) source

      Not checked in the free run.

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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    CA2 may be selectively required for performance of more demanding non-social memory tasks.

    “Alternatively, CA2 may be selectively required for performance of more demanding non-social memory tasks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Avpr1b mRNA is also expressed outside hippocampus, and its deletion results in changes in non-hippocampal dependent behaviors, including reduced aggression and decreased sociability.

    “However, Avpr1b mRNA is also expressed outside hippocampus21 and its deletion results in changes in non-hippocampal dependent behaviors, including reduced aggression and decreased sociability22,23”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Other regions of hippocampus may be able to compensate for loss of any role CA2 may normally play in performance of the water maze or contextual fear conditioning tasks.

    “Thus, other regions of hippocampus may be able to compensate for loss of any role that CA2 may normally play in performance of the water maze or contextual fear conditioning tasks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The results do not rule out the possibility that CA2 may participate more generally in hippocampal-dependent memory tasks.

    “our results do not rule out the possibility that CA2 may participate more generally in hippocampal-dependent memory tasks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The progressive increase in PSP size with light intensity was presumably due to an increase in the number of optically-activated CA2 axons.

    “Increasing the light intensity recruited progressively larger PSPs, presumably due to an increase in the number of optically-activated CA2 axons (Fig. 3e, f).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cells with a 15% or greater change in series resistance were excluded from analysis.

    “Cells with a 15% or greater change in series resistance were excluded from analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Illumination over stratum oriens, stratum pyramidale, and stratum radiatum activates the CA2 projections to CA1 that course through stratum oriens and stratum radiatum.

    “This provided illumination over stratum oriens (SO), stratum pyramidale (SP), and stratum radiatum (SR) thus activating the CA2 projections to CA1 that course through SO and SR.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted). The quote only partly states this claim.

    Study design and conductown data

    The data met the assumptions of the statistical tests used.

    “Data met assumptions of statistical tests and variance was similar between groups for all metrics measured except for AP duration (Extended Data Table 1), social novelty difference score (Fig. 4b), and direct interaction difference score (Fig. 4c).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For cell counting, the first section examined was randomly chosen.

    “The first section was randomly chosen, and cells were assessed for double labeling in a single optical section taken near the middle of the slice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The Amigo2-Cre line was backcrossed to C57BL/6J a minimum of 6 times before any behavioral or physiological experiments were performed.

    “The line was backcrossed to C57BL/6J a minimum of 6 times before any behavioral or physiological experiments were performed.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    All injections were verified histologically, and no injections were mistargeted, so no subjects were excluded from analysis due to injection failure.

    “All injections were verified histologically. No injections were mistargeted, hence no subjects were excluded from analysis due to injection failure.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Mice older than 8 weeks were injected with virus under stereotactic control into the hippocampus proper to avoid Amigo2-Cre expression in mossy cells of the dentate gyrus.

    “Mice > 8 weeks old were injected with virus under stereotactic control into the hippocampus proper to avoid Amigo2-Cre expression in mossy cells of the dentate gyrus.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Series resistance was always less than 30 MΩ and was monitored and compensated throughout the experiment.

    “Series resistance, which was always less than 30 MΩ, was monitored and compensated throughout the experiment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Half of the mice in each home cage were injected with the YFP virus, while the other half were injected with the TeNT virus.

    “Half of the mice in each home cage were injected with the YFP virus, while the other half were injected with the TeNT virus.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All procedures were approved by the Institutional Animal Care and Use Committee at Columbia University and the New York State Psychiatric Institute.

    “All procedures were approved by the Institutional Animal Care and Use Committee at Columbia University and the New York State Psychiatric Institute.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The experimenter was blind to the treatment groups during behavioral testing.

    “The experimenter was blind to the treatment groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    To test the specificity of the rabies virus, a subset of animals was injected with rabies virus without prior injection of AAVs expressing TVA and G.

    “To test the specificity of the rabies virus, a subset of animals was injected with 360 nl of the (EnvA)SAD-ΔG-mCherry rabies virus without prior injection of AAVs expressing TVA and G.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Sample sizes were chosen based on previous studies.

    “Sample sizes were chosen based on previous studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Variance was similar between groups for all metrics measured except for AP duration, social novelty difference score, and direct interaction difference score.

    “Data met assumptions of statistical tests and variance was similar between groups for all metrics measured except for AP duration (Extended Data Table 1), social novelty difference score (Fig. 4b), and direct interaction difference score (Fig. 4c).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The identity of the treatment groups was revealed only after testing was completed.

    “The identity of the groups was revealed only after testing was completed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Virus aliquots were stored as pairs of coded cryotubes to blind the experimenter and randomize the treatment groups.

    “To blind the experimenter and randomize the treatment groups, virus aliquots were stored as pairs of coded cryotubes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All reward pellets given to the mice one day before the buried food test were consumed.

    “All pellets were consumed.”
    Quote in the paperNot a substantial claim
45 of 45

  • The paper relies on this without support.

    The functional properties and behavioral role of CA2 are largely unknown.

    “Although the CA2 region was first described by Lorente de Nó in 19348 relatively little is known about its functional properties and behavioral role.”

  • The paper relies on this without support.

    The olfactory habituation/dishabituation test validly measures detection and discrimination of social and non-social odors.

    “we used an olfactory habituation/dishabituation test (Extended Data Fig. 9b) and found that CA2 inactivation also had no effect on the ability of the mice to detect or discriminate either non-social or social odors.”

  • The paper relies on this without support.

    The novel object recognition protocols validly measure interest in novelty.

    “the CA2-TeNT mice demonstrated normal preference for a novel object as assayed by two different novel object recognition protocols (Extended Data Fig. 8).”

  • The paper relies on this without support.

    The buried food test validly measures non-social odor detection.

    “CA2-TeNT mice showed no loss in the ability to detect the presence of food buried under a deep layer of cage bedding, a test of non-social odor detection (Extended Data Fig. 9a).”

  • The paper relies on this without support.

    Contextual fear memory is hippocampal-dependent and auditory fear memory is amygdala-dependent.

    “A 3-day delay fear conditioning protocol was employed to test hippocampal-dependent contextual fear memory and amygdala-dependent auditory fear memory.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The dorsal CA2 is the key centre for encoding, consolidation and recall phases of social memory.

    “The dorsal CA2 is the key centre for encoding, consolidation and recall phases of social memory [125–128].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [125]

    The Abstract (page not provided) reports that inactivating dorsal CA2 pyramidal neurons impaired social memory in mice, supporting its importance for social memory. The experiments do not separately establish that dorsal CA2 is the key centre for each of encoding, consolidation, and recall. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Inactivation of CA2 pyramidal neurons selectively impaired social memory while leaving sociability and other forms of memory intact.

    “Using the novel Amigo2-Cre transgenic driver line that targets pyramidal neurons specifically in the CA2 region, it was demonstrated that inactivation of this subregion selectively impaired social memory while leaving sociability and other forms of memory intact [72].”

    From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [72]

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Heintz, N. GENSAT Brain Atlas of gene expression in EGFP Transgenic Mice http://www.gensat.org (2003)
  2. Lein, E. S. ISH Data: Allen Brain Atlas: Mouse Brain http://mouse.brain-map.org/ (2007)
  3. de Jong, P. J. BAC Clones Distribution Center – BACPAC Resources Center https://bacpac.chori.org/ (2000)

Cited by

Sorted by citations

Related

Authors
Hitti, F. L., & Siegelbaum, S. A.
Affiliations
  • Columbia University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Siegelbaum, Steven A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2014-02-23
Volume
508
Issue
7494
Pages
88-92
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature13028
PMC
PMC4000264
OpenAlex
W2011504521
Semantic Scholar
a6576814ff321874b6fa9395eee21393bda3dfe6
Cited by
976
References
44
Citations by year
2026: 77 · 2025: 103 · 2024: 98 · 2023: 113 · 2022: 103 · 2021: 101 · 2020: 67 · 2019: 70 · 2018: 87 · 2017: 53 · 2016: 54 · 2015: 32 · 2014: 17
FWCI
29.01
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of Mental Health (F30MH098633)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
social memory, neural inactivation, transgenic mice, entorhinal cortex, contextual memory, spatial memory, sociability, autism spectrum disorder, schizophrenia, hippocampal subfields
MeSH terms
Animals, Autistic Disorder, Electrophysiology, Female, Male, Memory, Mice, Inbred C57BL, Mice, Transgenic, Schizophrenia, Social Behavior, Space Perception, Synapses, Pyramidal Cells, Integrases, Mice, CA2 Region, Hippocampal

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review