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

The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index; none of the 40 sources its claims cite is checked for support yet.

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

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.

Overview

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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.

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Integrity signals

Registry

Crossref · 10.1523/jneurosci.19-12-05016.1999

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

44 Own result · 23 Not checked yet · 22 Own interpretation · 3 No basis given

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Show all 62 claims

  • It may state two separate claims as one. 27
  • Probably not a substantial claim. 5
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.”
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Metadata

Authors
Radulovic, J., Rühmann, A., Liepold, T., & Spiess, J.
Affiliations
Max Planck Institute of Experimental Medicine (DE)
Venue
The Journal of Neuroscience
Published
1999-06-15
Volume
19
Issue
12
Pages
5016-5025
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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

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