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Cited by 147Neuropeptides and Animal PhysiologyStress Responses and CortisolNeurotransmitter Receptor Influence on Behavior

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The Effect of Lateral Septum Corticotropin-Releasing Factor Receptor 2 Activation on Anxiety Is Modulated by Stress

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Henry, Brook, Vale, Wylie, Markou, Athina·2006·The Journal of Neuroscience
DOI 10.1523/jneurosci.1494-06.2006PMC PMC6674509
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Abstract

Corticotropin-releasing factor (CRF), a 41 amino acid peptide, mediates endocrine, autonomic, and behavioral responses to stress. Whereas the CRF 1 receptor appears to contribute to anxiety associated with stress, the role of the CRF 2 receptor remains unclear and may depend on drug dose, brain location, or testing environment. Results involving treatments with selective CRF 2 receptor agonists or antagonists and the behavior of CRF 2 receptor knock-out mice suggest both anxiogenic and anxiolytic effects of CRF 2 receptor activation. The present study tested the hypothesis that the effect of CRF 2 receptor activation on anxiety depends on the stress level of the animal. The selective CRF 2 receptor agonist urocortin 2 was infused into the lateral septum of mice under low- or high-stress (30 min of immobilization) testing conditions, and then behavior in the light–dark box, open-field, and novel-object tests was assessed. In the low-stress environment, 240 pmol of septal urocortin 2 increased anxiety, but lower doses (0.48, 4.8, and 48 pmol) did not have consistent effects. However, in the high-stress condition, 48 pmol of septal urocortin 2 significantly increased anxiety compared with control in wild-type but not CRF 2 receptor knock-out mice in the light–dark box. Septal administration of the relatively selective CRF 2 antagonist astressin-2B, but not the CRF 1- selective antagonist antalarmin, blocked the anxiogenic effects of urocortin 2. Urocortin 2 infusion into the medial septum or lateral ventricle did not affect anxiety measures. These results indicate that the effect of septal CRF 2 receptor activation on anxiety is dependent on stress level.

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Figures

Figure 1 Histological verification of the cannula injector placements. Cannula placement was verified after each experiment with the infusion of methylene blue dye as shown in the lateral ( b ) and medial ( c ) septum. Scale bars, 500 𝛍 m. a is an illustration of the septum showing successful cannula placements in the intermediate lateral septum (filled circles) and placements excluded from data analyses (open circles). d illustrates the central amygdala region targeted for antalarmin infusion, with an example section shown in e . LS, Lateral septum; MS, medial septum; LV, lateral ventricle; cc, corpus callosum; aca, anterior commissure, IC internal capsule; OP, optic tract; CEA, central nucleus of the amygdala; BLA, basolateral amygdala.
Figure 1 Histological verification of the cannula injector placements. Cannula placement was verified after each experiment with the infusion of methylene blue dye as shown in the lateral ( b ) and medial ( c ) septum. Scale bars, 500 𝛍 m. a is an illustration of the septum showing successful cannula placements in the intermediate lateral septum (filled circles) and placements excluded from data analyses (open circles). d illustrates the central amygdala region targeted for antalarmin infusion, with an example section shown in e . LS, Lateral septum; MS, medial septum; LV, lateral ventricle; cc, corpus callosum; aca, anterior commissure, IC internal capsule; OP, optic tract; CEA, central nucleus of the amygdala; BLA, basolateral amygdala.CC-BY-NC-SA · From the PDF
Image 2
CC-BY-NC-SA · From the PDF
Figure 4 Effect of septal urocortin 2 on anxiety is dependent on stress. Effect of septal urocortin 2 (48 pmol) in ICR mice treated with no stress or 30 min of immobilization stress on the following: a , latency to enter the light side of the light- dark box (seconds); b , total time spent in the light side of the light- dark box (seconds); c , locomotion in the open field (total square entries); d , percentage time in the center of the open field; e , locomotion in the open field with a novel object (total square entries; and f , percentage time spent in the center with a novel object. Transitions in the light- dark box and percentage center entries in open-field and novelobject tests are not shown. This dose of urocortin 2 had no effect on anxiety-like behavior in the low-stress condition but significantly increased anxiety-like behavior compared with vehicle in the light- dark box, open-field, and novel-object tests when combined with 30 min of immobilization stress. There was no difference in locomotion between vehicle- and peptide-treated mice in the stress condition. Data are presented as mean ± SEM. ** p < 0.01;*** p < 0.001.
Figure 4 Effect of septal urocortin 2 on anxiety is dependent on stress. Effect of septal urocortin 2 (48 pmol) in ICR mice treated with no stress or 30 min of immobilization stress on the following: a , latency to enter the light side of the light- dark box (seconds); b , total time spent in the light side of the light- dark box (seconds); c , locomotion in the open field (total square entries); d , percentage time in the center of the open field; e , locomotion in the open field with a novel object (total square entries; and f , percentage time spent in the center with a novel object. Transitions in the light- dark box and percentage center entries in open-field and novelobject tests are not shown. This dose of urocortin 2 had no effect on anxiety-like behavior in the low-stress condition but significantly increased anxiety-like behavior compared with vehicle in the light- dark box, open-field, and novel-object tests when combined with 30 min of immobilization stress. There was no difference in locomotion between vehicle- and peptide-treated mice in the stress condition. Data are presented as mean ± SEM. ** p < 0.01;*** p < 0.001.CC-BY-NC-SA · From the PDF
Figure 5 Septal urocortin 2 increased anxiety when combined with stress in CRF 2 receptor wild-type mice on a mixed C57BL/ 6 × 129 background. Effect of septal urocortin 2 (vehicle or 0.48, 4.8, or 48 pmol) in CRF 2 receptor wild-type mice treated with no stress or 30 min of immobilization stress on the following: a , latency to enter the light side of the light- dark box (seconds); b , total time spent in the light side of the light- dark box (seconds); c , locomotion in the open field (total square entries); d , percentage of time in the center of the open field; e , locomotion in the open field with a novel object (total square entries); and f , percentage of time spent in the center with a novel object. Transitions in the light- dark box and percentage of center entries in the open-field andnovel-object tests are not shown. Urocortin 2 did not affect anxiety-like behavior in the no-stress condition at any dose tested. In the stress condition, 48 pmol of urocortin 2 increased anxiety-like behavior in the light- dark box and novel-object tests; the 4.8 pmol dose increased anxiety in the novel-object test in the stress condition but not the no-stress condition. Data are presented as mean ± SEM. *** p < 0.001.
Figure 5 Septal urocortin 2 increased anxiety when combined with stress in CRF 2 receptor wild-type mice on a mixed C57BL/ 6 × 129 background. Effect of septal urocortin 2 (vehicle or 0.48, 4.8, or 48 pmol) in CRF 2 receptor wild-type mice treated with no stress or 30 min of immobilization stress on the following: a , latency to enter the light side of the light- dark box (seconds); b , total time spent in the light side of the light- dark box (seconds); c , locomotion in the open field (total square entries); d , percentage of time in the center of the open field; e , locomotion in the open field with a novel object (total square entries); and f , percentage of time spent in the center with a novel object. Transitions in the light- dark box and percentage of center entries in the open-field andnovel-object tests are not shown. Urocortin 2 did not affect anxiety-like behavior in the no-stress condition at any dose tested. In the stress condition, 48 pmol of urocortin 2 increased anxiety-like behavior in the light- dark box and novel-object tests; the 4.8 pmol dose increased anxiety in the novel-object test in the stress condition but not the no-stress condition. Data are presented as mean ± SEM. *** p < 0.001.CC-BY-NC-SA · From the PDF
Image 5
CC-BY-NC-SA · From the PDF
Figure 7 CRF 2 antagonist astressin-2B blocked the effect of urocortin 2 and stress on anxiety. Effect of septal CRF 2 receptor antagonist astressin-2B (24, 96, or 192 pmol) administered 10 min before urocortin 2 (48 pmol) in CRF 2 receptor wild-type mice treated with no stress or 30 min of immobilization stress on the following: a , latency to enter the light side of the light- dark box (seconds); b , total time spent in the light side of the light- dark box (seconds); c , locomotionintheopenfield(totalsquareentries); d , percentage of time in the center of the open field; e , locomotion in the open field with a novel object (total square entries); and f , percentage of time spent in the center with a novel object. Transitions in the light- dark box and percentage of center entries in the open-field and novel-object tests are not shown. Astressin-2B decreased anxiety-like behavior in the light- dark box, openfield, and novel-object tests in the stress condition but had little effect in the no-stress condition. In the light- dark box, 24 and 96 pmolofastressin-2Bdecreasedtheanxiogeniceffectofurocortin2inthestressconditionbuthadnoeffectinvehicle-treatedmice, whereasthe192pmoldosereducedanxietyinallstressedmice,decreasingthelatencytoenterthelightsideofthelight- darkbox ( a ) and increasing time spent in the light side ( b ). In the open field, 24 pmol of astressin-2B decreased the anxiogenic effect of urocortin 2 but had no effect in vehicle-treated mice in the stress condition ( d ). In the novel-object test, 24 and 96 pmol of the antagonist inhibited the anxiogenic effect of urocortin 2 but had no significant effect in vehicle-treated mice ( f ), whereas 192 pmol decreased anxiety in both groups. Data are presented as mean ± SEM. * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 7 CRF 2 antagonist astressin-2B blocked the effect of urocortin 2 and stress on anxiety. Effect of septal CRF 2 receptor antagonist astressin-2B (24, 96, or 192 pmol) administered 10 min before urocortin 2 (48 pmol) in CRF 2 receptor wild-type mice treated with no stress or 30 min of immobilization stress on the following: a , latency to enter the light side of the light- dark box (seconds); b , total time spent in the light side of the light- dark box (seconds); c , locomotionintheopenfield(totalsquareentries); d , percentage of time in the center of the open field; e , locomotion in the open field with a novel object (total square entries); and f , percentage of time spent in the center with a novel object. Transitions in the light- dark box and percentage of center entries in the open-field and novel-object tests are not shown. Astressin-2B decreased anxiety-like behavior in the light- dark box, openfield, and novel-object tests in the stress condition but had little effect in the no-stress condition. In the light- dark box, 24 and 96 pmolofastressin-2Bdecreasedtheanxiogeniceffectofurocortin2inthestressconditionbuthadnoeffectinvehicle-treatedmice, whereasthe192pmoldosereducedanxietyinallstressedmice,decreasingthelatencytoenterthelightsideofthelight- darkbox ( a ) and increasing time spent in the light side ( b ). In the open field, 24 pmol of astressin-2B decreased the anxiogenic effect of urocortin 2 but had no effect in vehicle-treated mice in the stress condition ( d ). In the novel-object test, 24 and 96 pmol of the antagonist inhibited the anxiogenic effect of urocortin 2 but had no significant effect in vehicle-treated mice ( f ), whereas 192 pmol decreased anxiety in both groups. Data are presented as mean ± SEM. * p < 0.05; ** p < 0.01; *** p < 0.001.CC-BY-NC-SA · From the PDF
Image 7
CC-BY-NC-SA · From the PDF

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Metadata

Authors
Henry, B., Vale, W., & Markou, A.
Affiliations
  • Scripps Research Institute (US)
  • Salk Institute for Biological Studies (US)
Corresponding author
Markou, Athina
ORCID
Vale, Wylie
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2006-09-06
Volume
26
Issue
36
Pages
9142-9152
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1494-06.2006
PMC
PMC6674509
OpenAlex
W1996743601
Cited by
147
References
38
Citations by year
2026: 5 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 8 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 3 · 2012: 10
FWCI
5.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (U01 MH 69062, R01MH62527, U01MH069062, R01MH062527)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 26741, P01DK026741)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
corticotropin-releasing factor, CRF2 receptor, urocortin 2, antalarmin, lateral septum, anxiety, stress levels, restraint stress, CRF1 receptor, medial septum, dose dependence
MeSH terms
CRF Receptor, Type 1, Animals, Anxiety, Corticotropin-Releasing Hormone, Dose-Response Relationship, Drug, Injections, Intraventricular, Male, Mice, Inbred ICR, Stress, Psychological, Receptors, Corticotropin-Releasing Hormone, Mice, Knockout, Septum of Brain, Mice, Urocortins

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