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Cited by 180Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Dopamine regulates aversive contextual learning and associated in vivo synaptic plasticity in the Hippocampus

Open access
Broussard, John I., Yang, Kechun, Levine, Amber T., Tsetsenis, Theodoros, Jenson, Daniel, Cao, Fei, Garcia, Isabella, Arenkiel, Benjamin R. +3 more·2016·Cell Reports
DOI 10.1016/j.celrep.2016.01.070PMC PMC4772154
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Abstract

Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP) underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.

AI snapshot

Written from the paper’s full text.

TL;DR

In an inhibitory avoidance task, IA training produced CA3-CA1 synaptic potentiation in mouse hippocampus, and D1-like dopamine receptor activity was required for long-term memory retention and associated plasticity. Sparse midbrain dopaminergic terminals innervate CA1, and blocking D1-like receptors prevented training-induced increases in AMPA/NMDA ratio and in vivo fEPSP slope.

Key findings

  • Midbrain dopaminergic innervation of hippocampus was sparse but present: GFP-positive CA1 terminals were 0.83% ± 0.03 in Slc6a3ires-cre/+ mice vs 0.09% ± 0.004 in WT, n = 5 and 3; Ruby-Red/TH double-positive terminals were 93 ± 2%, n = 6.
  • The D1-like antagonist SCH 23390 (0.05 mg/kg) impaired 24 h IA long-term memory without impairing short-term memory at 1 h or 3 h; intra-CA1 SCH also reduced approach latency vs saline (p < 0.05, n = 7,9). The D1-like agonist SKF 81297 enhanced retention 72 h after a 0.4 mA footshock (p < 0.05, n = 10,32), while the β2-adrenergic antagonist timolol did not impair learning (p < 0.01, n = 10,10).
  • IA training increased the CA1 AMPA/NMDA ratio at 1.5 h: 0.59 ± 0.06 control vs 0.93 ± 0.06 after IA, n = 12,6, p < 0.01; the ratio returned to baseline by 24 h. Dentate granule cell AMPA/NMDA ratios did not differ after IA.
  • In vivo CA1 fEPSP slope increased after IA training (F(41,328) = 5.065, p < 0.01), and SCH blocked this training-induced increase (F(41,246) = 1.35, p > 0.05), whereas timolol did not (F(41,164) = 1.98, p < 0.01). SCH also blocked IA-induced increases in the AMPA/NMDA ratio.

Methods

  • Adult wild-type C57BL/6J and Slc6a3ires-cre/+ (DAT-cre) mice were used; midbrain DA areas were injected with AAV-EF1a-DIO-synaptophysin:GFP or :RFP, followed by immunohistochemistry for TH to label dopaminergic terminals.
  • Inhibitory avoidance training used a light/dark chamber with a single 2 s footshock; retention was tested at 1, 3, 24, or 72 h. Drugs included SCH 23390, SKF 81297, and timolol given i.p. or SCH infused bilaterally above CA1.
  • Synaptic plasticity was assessed ex vivo as AMPA/NMDA ratios from CA1 pyramidal neurons or dentate granule cells, and in vivo as fEPSP slopes from CA1 stratum radiatum in freely moving mice with contralateral Schaffer collateral stimulation. Statistical analysis used repeated measures ANOVA and t-tests, with significance at p < 0.05.

Limitations

  • Stated: the paper notes an “imperfect match” between learning and in vivo fEPSP LTP because the fEPSP rose slowly over approximately 30 min; it also states that short-term memory after D1-like inhibition may involve smaller components of dorsal hippocampus or other brain areas, which is speculative.
  • Stated: dopaminergic innervation of CA1 is sparse, and the authors acknowledge that DA signaling from noradrenergic innervation may contribute, although their β2-adrenergic antagonist results did not significantly influence memory retention in their paradigms.
  • Evident from the text: the pharmacological approach uses D1-like receptor drugs rather than receptor-subtype-specific or circuit-specific manipulations, and the study does not directly measure dopamine release in the hippocampus during IA training.

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

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2016.01.070

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Direct hippocampal infusions of the D1-like antagonist significantly reduced approach latency compared to saline controls (p<0.05, n=7,9).

    “When tested 24 h later, direct hippocampal infusions of the D1-like antagonist significantly reduced approach latency compared to saline controls (Fig. 3D): p < 0.05, unpaired t-test, n = 7,9.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.
  • Findingown data

    Inhibition of D1-like dopamine receptors prevents the training-induced enhancement of ex vivo LTP induction.

    “Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction.”
    • Also stated in: § Inhibiting D1-like dopamine receptors prevented IA learning and synaptic plasticity · plain
      “The D1-like receptor inhibitor, SCH, at doses that inhibited learning (0.05 mg/kg, Figs. 3B, Fig S4) also inhibited IA-induced increases in the AMPA/NMDA ratio (Fig. 7A-C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.
  • Findingown data

    IA training did not change the AMPA/NMDA ratio in dentate granule cells at 1.5 h after footshock (0.77 ± 0.06 vs 0.63 ± 0.07, n=10,11, p>0.05).

    “We recorded the AMPA/NMDA ratio of granule cells in the dentate gyrus 1.5 h after the footshock and found no difference relative to walk-through controls (Fig. 4G,H): 0.77 ± 0.06 in control vs. 0.63 ± 0.07 at 1.5 h after footshock, n = 10, 11, p > 0.05 unpaired t test.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Inhibition of D1-like dopamine receptors impairs memory of the IA task.

    “Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction.”
    • Also stated in: § Dopamine regulated acquisition of inhibitory avoidance memories · plain
      “In summary, the D1/D5 antagonist, at a dose that did not influence approach latency during training and did not impair short-term memory, inhibited long-term memory retention in this IA task.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.
  • Findingown data

    There was no difference in AMPA/NMDA ratio in dentate granule cells between footshock and no-footshock groups 1 d after training (0.70 ± 0.10 vs 0.57 ± 0.06, n=5,7, p>0.05).

    “Similarly, 1 d after training and following testing of memory retention, there was no difference between the footshock and the no-footshock groups (Fig. 4I,J): 0.70 ± 0.10 in control vs. 0.57 ± 0.06 at 1 d after training, n = 5, 7, p > 0.05 unpaired t test.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    24 h after training, control mice injected with saline significantly delayed entering the dark (previously shocked) side, whereas SCH-treated mice did not delay at three different shock intensities.

    “24 h after training (i.e., footshock), control mice injected with saline significantly delayed entering the dark (previously shocked) side (Fig. 3B, black bars). On the contrary, the latency to approach the dark (shocked) side was not delayed in SCH-treated mice at three different shock intensities (Fig. 3B, red bars).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.

  • May combine two claims.

    Findingown data

    SCH (0.05 mg/kg) did not impair short-term memory (STM) because approach latency remained similar to controls at 1 h and 3 h after shock training.

    “This dose of SCH (0.05 mg/kg, i.p.) also did not impair short-term memory (STM) because approach latency remained similar to controls at 1 h and 3 h after the shock training (Fig. 3C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.

  • May combine two claims.

    Findingown data

    Only the higher doses of SCH (0.2, 0.1 mg/kg) slowed the approach latency during training; the lowest dose (0.05 mg/kg) did not slow the initial approach.

    “Only the higher doses of SCH slowed the approach latency during training (Fig. S2): p < 0.01, n = 4-8. Therefore, we used the lowest dose of SCH (0.05 mg/kg) that did not slow the initial approach of mice to the dark side of the light/dark chamber (Fig. S2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.

  • May combine two claims.

    Findingown data

    No cell bodies were labeled in the locus coeruleus, verifying that the labeling arose from the midbrain not the locus coeruleus.

    “We inspected the locus coeruleus and found punctate terminals, but no cell bodies labeled (Fig. 1J), verifying that the labeling arose from the midbrain not the locus coeruleus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GFP-positive terminals were found throughout the CA1 region of Cre-positive mice, and this expression was significantly greater relative to Cre-negative mice (0.83% ± 0.03, n=5 vs 0.09% ± 0.004, n=3).

    “GFP-positive terminals were also found throughout the CA1 region of Cre-positive mice (Fig. 1F,H). This expression was significantly greater relative to Cre-negative mice (Fig. 1G): 0.83% ± 0.03, n = 5 for Slc6a3ires-cre/+; 0.09% ± 0.004, n = 3 for WT (Fig. 1I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was virtually no green fluorescence in the cerebellum (0.003%) and no GFP fluorescence in the hypothalamus of injected mice.

    “To test the specificity of Slc6a3ires-cre/+ expression, we checked the cerebellum of injected Slc6a3irescre/+ mice and found virtually no green fluorescence in the cerebellum (0.003%, data not shown). Likewise, there was no GFP fluorescence in the hypothalamus, which is near to the midbrain DA areas (Fig. S1A,B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was nearly complete co-localization between Synaptophysin-Ruby-Red and TH (93 ± 2%, n=6), confirming that the synaptic terminals are dopaminergic and originate from the midbrain.

    “We observed nearly complete co-localization between the Synaptophysin-Ruby-Red and TH (Fig. 2A,B), confirming that the synaptic terminals are dopaminergic and originate from the midbrain: Ruby-Red/TH double positive terminals, 93 ± 2%, n = 6.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    At early times after IA training with D1-like receptors inhibited, short-term memory was observed without global indications of LTP by fEPSPs or AMPA/NMDA ratios.

    “at early times after IA training with D1-like receptors inhibited, short-term memory was observed without global indications of LTP by fEPSPs or AMinPA/NMDA ratios.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The in vivo fEPSP and ex vivo AMPA/NMDA ratio are valid indicators of LTP.
    • Rests on an assumption: The D1-like antagonist SCH 23390 selectively inhibits D1-like receptors.

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

    Premisecitation

    Drugs of abuse, such as nicotine and methylphenidate, recruit dopaminergic neurotransmission to influence synaptic plasticity within the hippocampus.

    “Also, there is functional evidence that indicates that drugs of abuse, such as nicotine (Tang and Dani, 2009; Zhang et al., 2010) and methylphenidate (Jenson et al., 2015), recruit dopaminergic neurotransmission to influence synaptic plasticity within the hippocampus.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Tang and Dani, 2009

      Not checked in the free run.

    • cites Zhang et al., 2010 source

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    • cites Jenson et al., 2015 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Dopaminergic neurotransmission in the hippocampus during specific time points in the retention interval is important for successful consolidation of long-term memories.

    “Dopaminergic neurotransmission in the hippocampus during specific time points in the retention interval also seem to be important for successful consolidation of long-term memories (Rossato et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rossato et al., 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    D1 and D5 receptors are important for controlling spike timing dependent plasticity within the hippocampus.

    “Physiological evidence demonstrated that D1 and D5 receptors are important for controlling spike timing dependent plasticity within the hippocampus (Yang and Dani, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yang and Dani, 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Dopaminergic projections originating primarily from the midbrain project directly to the hippocampus.

    “Earlier evidence indicated that dopaminergic projections originating primarily from the midbrain (including the VTA, substantia nigra, and retrorubral field) project directly to the hippocampus (Gasbarri et al., 1994a; Gasbarri et al., 1996; Gasbarri et al., 1994b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gasbarri et al., 1994a

      Not checked in the free run.

    • cites Gasbarri et al., 1996 source

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    • cites Gasbarri et al., 1994b

      Not checked in the free run.

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

    Premisecitation

    There is controversy about the source of dopaminergic innervation in the hippocampus.

    “Despite this evidence, there is currently some controversy about the source of dopaminergic innervation in the hippocampus (Smith and Greene, 2012), suggesting that significant dopaminergic neurotransmission is the result of extra-synaptic volume transmission from other sources (Agnati et al., 1995; Borgkvist et al., 2012), such as the locus coeruleus (Walling et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smith and Greene, 2012

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The D1/D5 antagonist, at a dose that did not influence approach latency during training and did not impair short-term memory, inhibited long-term memory retention in the IA task.

    “In summary, the D1/D5 antagonist, at a dose that did not influence approach latency during training and did not impair short-term memory, inhibited long-term memory retention in this IA task.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.

  • May combine two claims.

    Premisecitation

    Optical stimulation of dopaminergic fibers in the VTA or locally in the hippocampus in mice exploring novel environments enhanced hippocampal reactivation and improved spatial learning and memory.

    “Optical stimulation of these dopaminergic fibers in the VTA or locally in the hippocampus in mice exploring novel environments enhanced hippocampal reactivation and improved spatial learning and memory (McNamara et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McNamara et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivation of the VTA with local infusion of TTX inhibited the nicotine effect, demonstrating that the required dopamine signal originated, at least in part, from the midbrain.

    “Inactivation of the VTA with local infusion of TTX inhibited this effect, demonstrating that the required dopamine signal originated, at least in part, from the midbrain (Tang and Dani, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tang and Dani, 2009

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Baseline fEPSP recordings were required to remain stable over the 30-min period on the day before (−1 d) and the day of IA training (0 d) to justify continuation of the multi-day in vivo recording paradigm.

    “These baseline recordings of synaptic responses were required to remain stable over the 30-min period on the day before (−1 d) and the day of IA training (0 d) to justify continuation of the multi-day in vivo recording paradigm (Fig. 5C).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Nicotine can cause in vivo hippocampal long-term synaptic plasticity, and this effect required local activation of DA receptors.

    “It was shown that nicotine can cause in vivo hippocampal long-term synaptic plasticity, and this effect required local activation of DA receptors (Tang and Dani, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tang and Dani, 2009

      Not checked in the free run.

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

    Premisecitation

    This subpopulation of DA neurons projects to the medial prefrontal cortex and the medial shell of the nucleus accumbens.

    “Anatomically, this subpopulation of DA neurons projects to the medial prefrontal cortex and the medial shell of the nucleus accumbens (Lammel et al., 2011; Lammel et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lammel et al., 2011 source

      Not checked in the free run.

    • cites Lammel et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Injections were localized to the midbrain and no fluorescence was found in the hypothalamus or from the cell bodies in the locus coeruleus, which precludes noradrenergic neurons as the source of the labeling observed in the hippocampus.

    “Injections were localized to the midbrain and no fluorescence was found in the hypothalamus or from the cell bodies in the locus coeruleus (Fig. 1J), which precludes noradrenergic neurons as the source of the labeling that we observed in the hippocampus.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    L-LTP is thought to be a molecular mechanism underlying mnemonic consolidation in CA1 synapses.

    “is thought to be a molecular mechanism underlying mnemonic consolidation in CA1 synapses”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Frey et al., 1993 source

      Not checked in the free run.

    • cites Huang et al., 2013 source

      Not checked in the free run.

    • cites Huang and Kandel, 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DA was important for long-term retention at 6 h, but not at 20 min in a different behavioral task.

    “DA was important for long-term retention at 6 h, but not at 20 min in a different behavioral task (O'Carroll et al., 2006)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O'Carroll et al., 2006

      Not checked in the free run.

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

    Interpretationown data

    D1-like receptor activity in the CA1 was necessary for retention of long-term, but not short-term IA memory.

    “An interesting concept was that D1-like receptor activity in the CA1 was necessary for retention of long-term, but not short-term IA memory.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The D1-like antagonist SCH 23390 selectively inhibits D1-like receptors.

  • May combine two claims.

    Premisecitation

    The D1-like antagonist SCH does not block early LTP produced by tetanization, but does block late phase LTP.

    “The D1-like antagonist, SCH, does not block early LTP produced by tetanization, but does block late phase LTP (Swanson-Park et al., 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Swanson-Park et al., 1999 source

      Not checked in the free run.

    • Rests on an assumption: The D1-like antagonist SCH 23390 selectively inhibits D1-like receptors.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Without D1-like activity, a high percentage of the dorsal CA1 is not contributing to the memory process needed to retain information for days.

    “without D1-like activity a high percentage of the dorsal CA1 is not contributing to the memory process needed to retain information for days.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The D1-like antagonist SCH 23390 selectively inhibits D1-like receptors.

  • Classified as probably not a substantial claim.

    Premisecitation

    L-LTP requires protein synthesis.

    “a phenomenon that requires protein synthesis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Frey et al., 1993 source

      Not checked in the free run.

    • cites Huang et al., 2013 source

      Not checked in the free run.

    • cites Huang and Kandel, 1995

      Not checked in the free run.

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

    Premisecitation

    Hippocampal dopaminergic activity influences long-term but not short-term memory retention in appetitive tasks.

    “hippocampal dopaminergic activity was shown to influence long-term but not short-term memory retention in appetitive tasks (Bethus et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bethus et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hippocampal slice recordings, weaker stimulation protocols can be enhanced by D1-like receptor activation and blocked by D1-like receptor antagonists or catecholaminergic depletion.

    “In hippocampal slice recordings it has been shown that weaker stimulation protocols can be enhanced by D1-like receptor activation and blocked by D1-like receptor antagonists or catecholaminergic depletion (Otmakhova and Lisman, 1996; Yang and Dani, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Otmakhova and Lisman, 1996

      Not checked in the free run.

    • cites Yang and Dani, 2014

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

    Premisecitation

    L-LTP is typically produced by stimulating the Schaffer collaterals with high frequency trains that increase the slope of the fEPSP.

    “L-LTP is typically produced by stimulating the Schaffer collaterals with high frequency trains that increase the slope of the fEPSP (Frey and Morris, 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Frey and Morris, 1997

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In the synaptic tagging and capture hypothesis, learning signals such as the novel IA context and subsequent association with a footshock could cause upregulation of plasticity proteins that stabilizes learning-induced synaptic change.

    “In the synaptic tagging and capture hypothesis, learning signals, such as the novel IA context and subsequent association with a footshock, could cause upregulation of plasticity proteins that stabilizes learning-induced synaptic change (Frey and Morris, 1997, 1998).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Frey and Morris, 1997

      Not checked in the free run.

    • cites Frey and Morris, 1998

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  • May combine two claims.

    Interpretationreasoning

    DA D1-like receptor activity modulates and regulates hippocampal CA1 synaptic plasticity, associated learning, and long-term memory arising from an aversive contextual task.

    “In summary, DA D1-like receptor activity modulates and regulates hippocampal CA1 synaptic plasticity, associated learning, and long-term memory arising from an aversive contextual task.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The in vivo fEPSP and ex vivo AMPA/NMDA ratio are valid indicators of LTP.
    • Rests on an assumption: The D1-like antagonist SCH 23390 selectively inhibits D1-like receptors.
31 of 31

  • The paper relies on this without support.

    The D1-like receptor antagonist SCH 23390 at the doses used acts selectively on D1-like dopamine receptors.

    “To test the hypothesis that DA regulates acquisition of IA memory, we injected groups of animals with SCH 23390 (SCH), a D1/D5 receptor antagonist, prior to footshock training (Fig 3A).”

  • The paper relies on this without support.

    The D1-like receptor agonist SKF 81297 at 0.9 mg/kg acts selectively on D1-like dopamine receptors.

    “Acting opposite to the D1-like antagonist, the D1-like agonist, SKF 81297 (0.9 mg/kg), enhanced IA retention 72 h after a moderate (0.4 mA) footshock (Fig. 3F): p < 0.05, n = 10, 32.”

  • The paper relies on this without support.

    The β2-adrenergic receptor antagonist Timolol at the doses used acts selectively on β2-adrenergic receptors.

    “In order to test whether β-adrenergic (norepinephrine, NE) neurotransmission was important for learning the IA task, we injected two doses (10 mg/kg and 20 mg/kg, i.p.) of the β2-adrenergic antagonist, Timolol (Tim), prior to IA training.”

  • The paper relies on this without support.

    The in vivo fEPSP and ex vivo AMPA/NMDA ratio are valid indicators of LTP.

    “The hippocampal synaptic potentiation indicated in vivo by the fEPSPs or ex vivo by the AMPA/NMDA ratios correlated with the long-term memory tested 24 to 72 h later.”

  • The paper relies on this without support.

    The D1-like antagonist SCH 23390 selectively inhibits D1-like receptors.

    “When D1Rs were inhibited, in vivo the global fEPSP did not change during IA training”
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?

  • DA release in the hippocampus promotes spatial memory, reward-associated memory, novel-object recognition and memory consolidation.

    “DA release in the hippocampus promotes spatial memory, rewardassociated memory, novel-object recognition and memory consolida­ tion (Broussard et al., 2016; Kempadoo et al., 2016; Mamad et al., 2017; McNamara et al., 2014; Rosen et al., 2015; Rossato et al., 2009; Takeuchi et al., 2016).”

    From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Broussard et al., 2016

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(41, 328) = 5.065reported p < .01 · recomputed p < .001

    “F (41, 328) = 5.065, p < .01”

  • ConsistentF(41, 246) = 1.03reported p > .05 · recomputed p = .428

    “F(41, 246) = 1.03, p > .05”

  • ConsistentF(41, 164) = 0.94reported p > .05 · recomputed p = .579

    “F (41,164) = 0.94, p > .05”

3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Methods say all injections preceded training, but one followed it

    Minor

    The Experimental Procedures say all animals were injected before IA training, whereas the Results describe a group given SCH 23390 after training.

  • Different D1-like agonists named in Results and Methods

    Minor

    The Results identify the agonist as SKF 81297, while the Experimental Procedures identify it as SKF 82197. The paper gives two different drug names for the IA-training injections.

  • Footshock-memory result points to the anatomy figure

    Minor

    The memory-retention result calls Figure 2 a previous experiment, but the paper describes Figure 2 as showing labeled hippocampal terminals and TH staining, not an IA memory experiment.

3 of 3

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Related

Authors
Broussard, J. I., Yang, K., Levine, A. T., Tsetsenis, T., Jenson, D., Cao, F., Garcia, I., Arenkiel, B. R., Zhou, F.-M., De Biasi, M., & Dani, J. A.
Affiliations
  • Baylor College of Medicine (US)
  • University of Pennsylvania (US)
Corresponding author
Dani, John A.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2016-03
Volume
14
Issue
8
Pages
1930-1939
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2016.01.070
PMC
PMC4772154
OpenAlex
W2280257738
Semantic Scholar
b093282c5794dc6e89223c37eb4e476ba498d699
Cited by
180
References
59
Citations by year
2026: 9 · 2025: 30 · 2024: 16 · 2023: 22 · 2022: 16 · 2021: 18 · 2020: 19 · 2019: 8 · 2018: 13 · 2017: 14 · 2016: 15
FWCI
10.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Mental Health (MH067119, R01MH067119)
  • National Institute on Drug Abuse (DA09411, DA017173, DA021194, R01DA017173, R01DA009411, R01DA036572, R01DA021194)
  • National Institute of Neurological Disorders and Stroke (NS 21229, R37NS021229, R01NS021229)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
dopamine, D1-like receptors, hippocampus, synaptic plasticity, long-term potentiation, passive avoidance, aversive memory, contextual learning, dopaminergic innervation
MeSH terms
Action Potentials, Animals, Avoidance Learning, Benzazepines, Conditioning, Psychological, Dopamine, Electrodes, Learning, Mesencephalon, Mice, Inbred C57BL, Microtomy, Synaptic Transmission, Synapses, Receptors, Dopamine D1, Long-Term Potentiation, Pyramidal Cells, Tissue Culture Techniques, Mice, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Memory, Long-Term

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 2026-10-10.

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

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 ›

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