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Cited by 402Memory and Neural MechanismsNeuropeptides and Animal PhysiologyStress Responses and Cortisol

Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2

Open access
Radulovic, Jelena, Rühmann, Andreas, Liepold, Thomas, Spiess, Joachim·1999·The Journal of Neuroscience
DOI 10.1523/jneurosci.19-12-05016.1999PMC PMC6782638
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Abstract

The differential modulation of learning and anxiety by corticotropin-releasing factor (CRF) through CRF receptor subtypes 1 (CRFR1) and 2 (CRFR2) is demonstrated. As learning paradigm, context- and tone-dependent fear conditioning of the mouse was used. Injection of CRF into the dorsal hippocampus before training enhanced learning through CRFR1 as demonstrated by the finding that this effect was prevented by the local injection of the unselective CRFR antagonist astressin, but not by the CRFR2-specific antagonist antisauvagine-30 (anti-Svg-30). In contrast, injection of CRF into the lateral intermediate septum impaired learning through CRFR2, as demonstrated by the ability of antisauvagine-30 to block this effect. When antisauvagine-30 was injected alone into the lateral intermediate septum, learning was enhanced. Such tonic control of learning was not observed when astressin or antisauvagine-30 was injected into the dorsal hippocampus. Injection of CRF after the training into the dorsal hippocampus and the lateral intermediate septum also enhanced and impaired learning, respectively. Thus, it was indicated that CRF acted on memory consolidation. It was concluded that the observed effects reflected changes of associative learning and not arousal, attention, or motivation. Although a dose of 20 pmol human/rat CRF was sufficient to affect learning significantly, a fivefold higher dose was required to induce anxiety by injection into the septum. Immobilization for 1 hr generated a stress response that included the induction of anxiety through septal CRFR2 and the subsequent enhancement of learning through hippocampal CRFR1. The involvement of either receptor subtype was demonstrated by region-specific injections of astressin and antisauvagine-30.

AI snapshot

Written from the paper’s full text.

TL;DR

In male BALB/c mice, hippocampal CRF receptor 1 (CRFR1) enhanced fear conditioning, whereas septal CRFR2 impaired it and mediated CRF-induced anxiety. Immobilization stress reproduced these effects sequentially: septal CRFR2-mediated anxiety at 30 min and hippocampal CRFR1-mediated enhancement of fear learning at 3 hr.

Key findings

  • Intrahippocampal h/rCRF enhanced context- and tone-dependent fear conditioning; this was blocked by the nonselective CRFR antagonist astressin but not by the CRFR2-selective antagonist antisauvagine-30 (anti-Svg-30), implicating CRFR1. Intra-septal h/rCRF impaired conditioning; this was blocked by both astressin and anti-Svg-30, implicating CRFR2.
  • Antagonists alone injected into the lateral intermediate septum enhanced fear conditioning to context and tone, suggesting tonic impairment of learning through septal CRFR2; hippocampal antagonist injections alone had no effect.
  • A dose of 20 pmol h/rCRF was sufficient to affect learning, whereas a fivefold higher dose was required to induce anxiety after septal injection. Septal h/rCRF at 500 ng per mouse reduced open-arm time and entries in the elevated plus-maze, and this was antagonized by astressin and anti-Svg-30.
  • One-hour immobilization stress increased anxiety at 30 min via septal CRFR2 and enhanced fear conditioning at 3 hr via hippocampal CRFR1; astressin injected into the hippocampus prevented the stress-induced enhancement of conditioned fear, and septal astressin or anti-Svg-30 prevented stress-induced anxiety.

Methods

  • Nine-week-old male BALB/c mice were implanted with bilateral cannulae into the lateral ventricles, dorsal hippocampus, or lateral intermediate septum; cannula placement was verified histologically, and only correctly placed mice were analyzed (7–13 mice per group).
  • Context- and tone-dependent fear conditioning used a 3 min context, 30 sec 10 kHz tone, and 2 sec 0.7 mA footshock; freezing was scored 24 hr later as the fear index. Anxiety was assessed with the elevated plus-maze, and stress was 1 hr immobilization.
  • Peptides included h/rCRF, rat urocortin, ovine CRF, h/rCRF(6–33), astressin, and anti-Svg-30; effects were analyzed with ANOVA followed by Bonferroni-Dunn tests.

Limitations

  • The paper states that it is not clear whether the anxiety response is necessary for the subsequent enhancement of learning or whether these responses occur independently. It also notes that in vivo interactions of h/rCRF and urocortin with their receptors differed from in vitro findings, possibly due to partial agonism of rat urocortin toward CRFR1.
  • Evident from the text: the study used only male BALB/c mice and a single immobilization stressor, so generality across sex, strain, and stress type is not established. CRFR1 mediation was inferred from blockade by nonselective astressin and lack of blockade by CRFR2-selective anti-Svg-30, rather than by a CRFR1-selective antagonist.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.19-12-05016.1999

Cites

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Claims the paper makes

0 of 40 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    Injection of CRF into the dorsal hippocampus before training enhanced learning through CRFR1, as shown by blockade with astressin but not antisauvagine-30.

    “Injection of CRF into the dorsal hippocampus before training enhanced learning through CRFR1 as demonstrated by the finding that this effect was prevented by the local injection of the unselective CRFR antagonist astressin, but not by the CRFR2-specific antagonist antisauvagine-30 (anti-Svg-30).”
    • Also stated in: § Modulation of fear conditioning by h/rCRF is restricted to a small time window · plain
      “The enhancement of fear conditioning after i.h.injection of h/rCRF was completely blocked by previous administration of astressin but not antisauvagine-30 (anti-Svg-30) (Fig. 6a)”
    • Also stated in: § CRF enhances fear conditioning through CRFR1 and impairs it through CRFR2 · plain
      “Because the enhancement of fear conditioning by i.h.injection of h /rCRF was prevented by astressin but not anti-Svg-30, it was concluded that this effect was mediated by CRFR1.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.
  • Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    Injection of astressin or antisauvagine-30 alone into the dorsal hippocampus did not affect learning.

    “Such tonic control of learning was not observed when astressin or antisauvagine-30 was injected into the dorsal hippocampus.”
    • Also stated in: § Modulation of fear conditioning by h/rCRF is restricted to a small time window · plain
      “Administration of the CRF receptor antagonists astressin and anti-Svg-30 alone into the hippocampus did not affect fear conditioning”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.
  • Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    Injection of CRF into the lateral intermediate septum impaired learning through CRFR2, as shown by blockade with antisauvagine-30.

    “In contrast, injection of CRF into the lateral intermediate septum impaired learning through CRFR2, as demonstrated by the ability of antisauvagine-30 to block this effect.”
    • Also stated in: § Modulation of fear conditioning by h/rCRF is restricted to a small time window · plain
      “Both astressin and anti-Svg-30 blocked the memory-impairing effects of i.s.injection of h/rCRF (Fig. 6b).”
    • Also stated in: § CRF enhances fear conditioning through CRFR1 and impairs it through CRFR2 · hedged
      “In contrast, the impairment of fear conditioning observed after i.s.application of h /rCRF was mediated by CRFR2, as indicated by the ability of both astressin and anti-Svg-30 to block this effect.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.
  • Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    Injection of antisauvagine-30 alone into the lateral intermediate septum enhanced learning.

    “When antisauvagine-30 was injected alone into the lateral intermediate septum, learning was enhanced.”
    • Also stated in: § Modulation of fear conditioning by h/rCRF is restricted to a small time window · plain
      “Administration of the CRF receptor antagonists astressin and anti-Svg-30 alone into the hippocampus did not affect fear conditioning, whereas their i.s.injection significantly enhanced fear conditioning to context (F (5,42) ϭ 12.089, p Ͻ 0.001) and tone (F (5,42) ϭ 11.664, p Ͻ 0.001).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.
  • Findingown data

    The strongest enhancement of fear conditioning after intracerebroventricular injection was observed with h/rCRF.

    “The strongest effect was observed after intracerebroventricular injection of h/rCRF.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    Injection of CRF after training into the dorsal hippocampus enhanced learning, and into the lateral intermediate septum impaired learning.

    “Injection of CRF after the training into the dorsal hippocampus and the lateral intermediate septum also enhanced and impaired learning, respectively.”
    • Also stated in: § Modulation of fear conditioning by h/rCRF is restricted to a small time window · plain
      “i.h.administration of h/rCRF immediately after the training also enhanced acquisition of context-dependent (F (5,48) ϭ 9.568, p Ͻ 0.001) and tonedependent fear (F (5,48) ϭ 9.344, p Ͻ 0.001) (Fig. 5a).”
    • Also stated in: § Modulation of fear conditioning by h/rCRF is restricted to a small time window · plain
      “Context-dependent fear was impaired by i.s.injection of h/rCRF before and immediately after the training, whereas injection 1 hr after the training was ineffective.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    A dose of 20 pmol human/rat CRF was sufficient to affect learning significantly, but a fivefold higher dose was required to induce anxiety by injection into the septum.

    “Although a dose of 20 pmol human/rat CRF was sufficient to affect learning significantly, a fivefold higher dose was required to induce anxiety by injection into the septum.”
    • Also stated in: § h/rCRF induces anxious behavior through septal CRFR2 but not hippocampal CRFR1 · plain
      “The dose of h /rCRF modulating fear conditioning did not affect plus-maze behavior (Fig. 7), as evaluated by time spent, number of entries, and distance crossed on the open and closed arms of an elevated plus-maze.However, i.s.injection of 500 ng h /rCRF per mouse significantly reduced the time spent (F (4,45) ϭ 4.32, p Ͻ 0.01) (Fig. 7a) and the number of entries (F (4,45) ϭ 4.11, p Ͻ 0.01) (Fig.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    Immobilization for 1 hr generated a stress response that included induction of anxiety through septal CRFR2 and subsequent enhancement of learning through hippocampal CRFR1.

    “Immobilization for 1 hr generated a stress response that included the induction of anxiety through septal CRFR2 and the subsequent enhancement of learning through hippocampal CRFR1.”
    • Also stated in: § h/rCRF mediates stress-induced enhancement of fear conditioning through hippocampal CRFR1 and stressinduced anxiety through septal CRFR2 · plain
      “In mice subjected to 1 hr immobilization stress, fear conditioning to context ((F 3,40 ϭ 7.134, p Ͻ 0.01) and tone (F 3,40 ϭ 6.795, p Ͻ 0.01) was significantly increased 3 hr after termination of the stress when compared with nonstressed controls (Fig. 8a).”
    • Also stated in: § h/rCRF mediates stress-induced enhancement of fear conditioning through hippocampal CRFR1 and stressinduced anxiety through septal CRFR2 · plain
      “Astressin and anti-SVG-30 completely prevented stress-induced anxiety when given by i.s.injection (Fig. 9c,d) but not by i.h.injection (data not shown) before the immobilization stress.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Findingown data

    Enhancement of freezing by i.h. injection of h/rCRF was demonstrated only for fear-conditioned mice, not for mice receiving peptide without a shock.

    “Enhancement of freezing by i.h.injection of h/rCRF was demonstrated only for fear-conditioned mice, but not for mice receiving peptide without a shock (Fig. 2a)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Locomotor activity and shock response did not differ between mice injected with CRF-like peptides and control mice injected with aCSF.

    “The locomotor activities and the activity burst in response to the shock of mice injected with CRF-like peptides did not differ from the values of control mice injected with aCSF (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The minimally required dose for modulation of fear conditioning after local administration of h/rCRF was 25 ng per injection site (50 ng total), a dose ineffective after intracerebroventricular injection.

    “The minimally required dose for modulation of fear conditioning after local administration of h /rCRF was 25 ng per injection site [a total of 50 ng (10 pmol) per mouse], a dose ineffective after intracerebroventricular injection of h /rCRF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    i.h. administration of h/rCRF enhanced context-dependent and tone-dependent fear, whereas i.s. administration impaired them, in a dose-dependent manner.

    “Subsequent experiments demonstrated that i.h.administration of h/rCRF enhanced context-dependent (F (3,35) ϭ 9.726, p Ͻ 0.001) and tone-dependent fear (F (3,35) ϭ 9.456, p Ͻ 0.001) (Fig. 3a), whereas i.s.administration of h/rCRF impaired context-dependent (F (3,31) ϭ 8.120, p Ͻ 0.001) (Fig. 4a) and tone-dependent fear (F (3,31) ϭ 7.724, p Ͻ 0.001) (Fig. 4b) in a dose-dependent manner.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Findingown data

    The enhancement of fear conditioning after i.h. injection of h/rCRF was completely blocked by previous administration of astressin but not antisauvagine-30.

    “The enhancement of fear conditioning after i.h.injection of h/rCRF was completely blocked by previous administration of astressin but not antisauvagine-30 (anti-Svg-30) (Fig. 6a), a peptidic antagonist recently developed in our laboratory (Ru ¨hmann et al., 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rühmann et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Administration of astressin and anti-Svg-30 alone into the hippocampus did not affect fear conditioning, whereas their i.s. injection significantly enhanced fear conditioning to context and tone.

    “Administration of the CRF receptor antagonists astressin and anti-Svg-30 alone into the hippocampus did not affect fear conditioning, whereas their i.s.injection significantly enhanced fear conditioning to context (F (5,42) ϭ 12.089, p Ͻ 0.001) and tone (F (5,42) ϭ 11.664, p Ͻ 0.001).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Findingown data

    Astressin and anti-Svg-30 applied by i.s. injection completely antagonized anxiety induced by i.s. injection of h/rCRF without affecting baseline anxiety levels.

    “Astressin and anti-Svg-30 applied by i.s.injection completely antagonized anxiety induced by i.s.injection of h/rCRF (Fig. 7a,b), without affecting baseline anxiety levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Astressin and anti-SVG-30 completely prevented stress-induced anxiety when given by i.s. injection but not by i.h. injection before the immobilization stress.

    “Astressin and anti-SVG-30 completely prevented stress-induced anxiety when given by i.s.injection (Fig. 9c,d) but not by i.h.injection (data not shown) before the immobilization stress.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Findingown data

    i.s. injection of 500 ng h/rCRF per mouse significantly reduced the time spent and the number of entries on the open arms without affecting locomotor activity.

    “However, i.s.injection of 500 ng h /rCRF per mouse significantly reduced the time spent (F (4,45) ϭ 4.32, p Ͻ 0.01) (Fig. 7a) and the number of entries (F (4,45) ϭ 4.11, p Ͻ 0.01) (Fig. 7b) on the open arms without affecting locomotor activity (data not shown), as revealed by the total distance crossed in 5 min.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CRF-injected mice exhibited strong freezing to the context and tone used as conditioned stimuli, but this fear response did not generalize to a novel context.

    “The specific action of CRF on learning was also supported by the observation that CRF-injected mice exhibited strong freezing to the context and tone used as conditioned stimuli, but this fear response did not generalize to a novel context.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Exposure of mice to immobilization stress produced transiently increased anxiety after 30 min that disappeared after 1 hr, followed by enhanced acquisition of conditioned fear after 3 hr.

    “Exposure of mice to immobilization stress produced sequential changes in anxiety and learning, as shown by a transiently increased anxiety after 30 min that disappeared after 1 hr, followed by enhanced acquisition of conditioned fear after 3 hr.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The stress-induced increase of anxiety and fear conditioning could be fully prevented by septal and hippocampal CRFR antagonists, respectively.

    “The stress-induced increase of anxiety and fear conditioning could be fully prevented by septal and hippocampal CRFR antagonists, respectively, which under nonstress conditions did not affect either behavior by themselves.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Immobilization stress increases endogenous CRF activity in the brain areas studied.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    A role of CRFR2 and a relationship between CRFR1- and CRFR2-mediated behaviors of the brain CRF system have not been established.

    “So far, a role of CRFR2 and a relationship between CRFR1-and CRFR2-mediated behaviors of the brain CRF system have not been established.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

    The observed effects reflected changes of associative learning and not arousal, attention, or motivation.

    “It was concluded that the observed effects reflected changes of associative learning and not arousal, attention, or motivation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CRF and Ucn exert their biological activity by binding to two types of CRF receptors, CRFR1 and CRFR2, which show distinct distribution patterns in specific brain areas.

    “CRF and Ucn exert their biological activity by binding to two types of CRF receptors (CRFRs), CRFR1 (Chen et al., 1993;Chang et al., 1993;Vita et al., 1993;Dautzenberg et al., 1998) and CRFR2 (L ovenberg et al., 1995;Perrin et al., 1995;Stenzel et al., 1995;K ishimoto et al., 1995), which show distinct distribution patterns in specific brain areas (Chalmers et al., 1995).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chen et al., 1993

      Not checked in the free run.

    • cites Lovenberg et al., 1995

      Not checked in the free run.

    • cites Chalmers et al., 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher doses of CRF typically induce anxiety, whereas displacement of CRF from its binding protein even by high doses of CRF-BP ligands enhances learning without affecting anxiety.

    “Interestingly, higher doses of CRF typically induce anxiety, whereas displacement of CRF from its binding protein even by high doses of CRF-BP ligands enhances learning without affecting anxiety (Dunn and Berridge, 1990;Behan et al., 1995).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dunn and Berridge, 1990

      Not checked in the free run.

    • cites Behan et al., 1995

      Not checked in the free run.

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

    Premisecitation

    CRF and Ucn are widely distributed throughout the CNS of rodents and humans, where they affect numerous behaviors such as locomotor activity, anxiety, food intake, and learning.

    “In addition, CRF and the novel CRF-like peptide urocortin (Ucn) are widely distributed throughout the C NS of rodents and humans (Olschowka et al., 1982;Cummings et al., 1983;Vaughan et al., 1995;Kozicz et al., 1998), where they affect numerous behaviors such as locomotor activity, anxiety, food intake, and learning (Sutton et al., 1982;Dunn and Berridge, 1990;De Souza, 1995).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Olschowka et al., 1982

      Not checked in the free run.

    • cites Vaughan et al., 1995

      Not checked in the free run.

    • cites Dunn and Berridge, 1990

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The hippocampus is required for context-dependent and tone-dependent fear conditioning.

    “The hippocampus appears to be required for context-dependent (Kim and Fanselow, 1992;Phillips and LeDoux, 1992) and tonedependent fear conditioning (Maren et al., 1997)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kim and Fanselow, 1992

      Not checked in the free run.

    • cites Phillips and LeDoux, 1992

      Not checked in the free run.

    • cites Maren et al., 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The lateral septum mediates the impairment of conditioned fear responses and the enhancement of anxious behaviors.

    “whereas the lateral septum mediates the impairment of conditioned fear responses (Thomas and Yadin, 1980;Yadin and Thomas, 1981; Garcia and Jaffard, 1996) and the enhancement of anxious behaviors (Menard and Treit, 1996).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Thomas and Yadin, 1980

      Not checked in the free run.

    • cites Yadin and Thomas, 1981

      Not checked in the free run.

    • cites Garcia and Jaffard, 1996

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Fear conditioning was tonically impaired by septal CRFR2 but not by hippocampal CRFR1.

    “Thus, these antagonists exhibited an effect opposite to the one of h /rCRF and suggested that fear conditioning was tonically impaired by septal CRFR2 but not by hippocampal CRFR1.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Interpretationreasoning

    Post-training i.h. injection of h/rCRF increases fear conditioning, and this effect excludes attentional, motivational, or arousal effects.

    “The effect of post-training i.h.injection of h/rCRF to increase fear conditioning excluded the possibility that the observed effect was caused by attentional, motivational, or arousal effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Control experiments demonstrated that the effects were specifically mediated through the dorsal hippocampus and lateral intermediate septum but not through neighboring brain areas or lateral ventricles.

    “Control experiments demonstrated that these effects were specifically mediated through the dorsal hippocampus and lateral intermediate septum but not through the neighboring brain areas or lateral ventricles.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The hippocampus and lateral intermediate septum play an important role in associative learning.

  • May combine two claims.

    Premisecitation

    High levels of CRFR2α mRNA but not CRFR1 mRNA or CRFR1 protein were found in the lateral intermediate septum.

    “In agreement with this observation, high levels of CRFR2␣ mRNA but not CRFR1 mRNA (Chalmers et al., 1995) or CRFR1 protein (Radulovic et al., 1998a) were found in the lateral intermediate septum.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chalmers et al., 1995

      Not checked in the free run.

    • cites Radulovic et al., 1998a

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent study reported impairment of tone-dependent fear conditioning after neurotoxic and electrolytic lesions of the dorsal hippocampus.

    “It should be mentioned, however, that a recent study reported impairment of tone-dependent fear conditioning after neurotoxic and electrolytic lesions of the dorsal hippocampus (Maren et al., 1997), a region used for CRF-like peptide injections in our experiments.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maren et al., 1997

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Enhanced associative learning of tone-dependent fear through hippocampal CRFR1 could result from activation of hippocampal pathways to the amygdala.

    “Enhanced associative learning of tone-dependent fear through hippocampal CRFR1 could result from activation of hippocampal pathways to the amygdala (Henke, 1990), a brain region identified as being crucial for acquisition of fear responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Henke, 1990 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Enhancement of tone-dependent fear contrasted with the common view that the hippocampal formation does not play a role in acquisition of tone-dependent fear.

    “However, enhancement of tonedependent fear, generally believed to be mediated by different neuronal circuits, contrasted with the common view that the hippocampal formation does not play a role in acquisition of tone-dependent fear.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The high density of glucocorticoid receptors and almost restricted distribution of mineralocorticoid receptors was demonstrated in the lateral septum and hippocampus.

    “Consistently, the high density of glucocorticoid receptors and almost restricted distribution of mineralocorticoid receptors was demonstrated in the lateral septum and hippocampus (Reul and De Kloet, 1985).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Reul and De Kloet, 1985

      Not checked in the free run.

30 of 30

  • The authors state this as an assumption.

    The hippocampus and lateral intermediate septum play an important role in associative learning.

    “These two regions, which contain different amounts of CRFR1, CRFR2, and CRF-BP, are assumed to play an important role in associative learning.”

  • The authors state this as an assumption.

    Ucn may be the putative ligand for CRFR2.

    “The observation that h/rCRF was more effective than Ucn in enhancing or impairing fear conditioning was surprising in view of the assumption that Ucn may be the putative ligand for CRFR2 and the finding that Ucn binds under defined conditions with higher affinity than h/rCRF to both CRFR1 and CRFR2 (Vaughan et al., 1995).”

  • The paper relies on this without support.

    Immobilization stress increases endogenous CRF activity in the brain areas studied.

    “The stress-induced increase of anxiety and fear conditioning could be fully prevented by septal and hippocampal CRFR antagonists, respectively, which under nonstress conditions did not affect either behavior by themselves.”
3 of 3

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?

  • LS injections of agonists of the type 2 corticotropin-releasing factor receptor (Crfr2) have resulted in increased anxiety.

    “For example, LS injections of agonists of the type 2 corticotropin-releasing factor receptor (Crfr2) have resulted in increased anxiety (Radulovic et al., 1999; Bakshi et al., 2002; Henry et al., 2006).”

    From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Radulovic et al., 1999

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.

  • Fear-conditioning result is attributed to the anatomical figure

    Minor

    The text cites Figure 1a for the context-dependent fear-conditioning result, but the Figure 1 caption identifies it as showing injection-site anatomy. The Figure 2 caption identifies panel a as the context-dependent fear-conditioning result.

  • Intracaudate panel has conflicting labels

    Minor

    The results refer to panels 3c and 3d for the cortical and striatal injections, respectively, whereas the Figure 3 caption labels the intracaudate panel e.

2 of 2

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Authors
Radulovic, J., Rühmann, A., Liepold, T., & Spiess, J.
Affiliations
Max Planck Institute of Experimental Medicine (DE)
ORCID
Liepold, Thomas
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
1999-06-15
Volume
19
Issue
12
Pages
5016-5025
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.19-12-05016.1999
PMC
PMC6782638
OpenAlex
W1633118497
Cited by
402
References
55
Citations by year
2026: 3 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 11 · 2020: 6 · 2019: 8 · 2018: 5 · 2017: 11 · 2016: 8 · 2015: 13 · 2014: 14 · 2013: 15 · 2012: 14
FWCI
15.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Max-Planck-Gesellschaft
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
corticotropin-releasing factor, CRF1 receptor, CRF receptor 2, fear conditioning, memory consolidation, anxiety, dorsal hippocampus, astressin, antisauvagine-30, restraint stress, stress response, associative learning
MeSH terms
CRF Receptor, Type 1, Acoustic Stimulation, Animals, Anxiety, Behavior, Animal, Brain Chemistry, Conditioning, Psychological, Corticotropin-Releasing Hormone, Dose-Response Relationship, Drug, Fear, Hippocampus, Male, Mice, Inbred BALB C, Peptide Fragments, Septal Nuclei, Stress, Psychological, Receptors, Corticotropin-Releasing Hormone, Neuroprotective Agents, Maze Learning, Mice

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 ›

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