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Cited by 110Neurogenesis and neuroplasticity mechanismsMemory and Neural MechanismsStress Responses and Cortisol

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Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice

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Fuss, Johannes, Ben Abdallah, Nada M. B., Hensley, Frank W., Weber, Klaus-Josef, Hellweg, Rainer, Gass, Peter·2010·PLoS ONE
DOI 10.1371/journal.pone.0012769PMC PMC2940841
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Abstract

Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.

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Figure 1 Experimental scheme and effects of focal hippocampal irradiation on cell proliferation and neurogenesis. (A) Radiation decreased cell proliferation significantly. This decrease persisted even after voluntary wheel running. (B) Running induced a significant increase in DCX positive cells in sham-treated runners, while both irradiated groups had significantly less DCX-cells within the dentate gyrus. (C) In contrast, running had no impact on the number of Ki-67-positive cells in sham-treated mice. *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.
Figure 1 Experimental scheme and effects of focal hippocampal irradiation on cell proliferation and neurogenesis. (A) Radiation decreased cell proliferation significantly. This decrease persisted even after voluntary wheel running. (B) Running induced a significant increase in DCX positive cells in sham-treated runners, while both irradiated groups had significantly less DCX-cells within the dentate gyrus. (C) In contrast, running had no impact on the number of Ki-67-positive cells in sham-treated mice. *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.CC BY · PubMed Central
Figure 2 Histological stainings used in this study. Pictures illustrating the staining for neurogenesis (A = Doublecortin), cell proliferation (B = Ki67), and c-Fos activity in a running (C) and sedentary mouse (D). Black arrows point at representative cells for the counting procedure.
Figure 2 Histological stainings used in this study. Pictures illustrating the staining for neurogenesis (A = Doublecortin), cell proliferation (B = Ki67), and c-Fos activity in a running (C) and sedentary mouse (D). Black arrows point at representative cells for the counting procedure.CC BY · PubMed Central
Figure 3 Hippocampal irradiation is not affecting the circadian rhythmicity of running. All runners were highly active during the dark phase of the light-dark-rhythm as noted by their running activity. Additionally, no running differences were observed between sham-treated (black line) and irradiated (red line) runners. The graph illustrates the running pattern of the last day of running (day 20) displaying averaged values in 30 min segments. Bars represent standard errors.
Figure 3 Hippocampal irradiation is not affecting the circadian rhythmicity of running. All runners were highly active during the dark phase of the light-dark-rhythm as noted by their running activity. Additionally, no running differences were observed between sham-treated (black line) and irradiated (red line) runners. The graph illustrates the running pattern of the last day of running (day 20) displaying averaged values in 30 min segments. Bars represent standard errors.CC BY · PubMed Central
Figure 4 Voluntary running produces an anxious phenotype in sham-treated, but not in irradiated mice. (A) Sham-treated runners had significantly less approaches to the center of the open field and moved a lower total distance. Sham-treated runners spent significantly less time in the center of the open field and exhibited delayed habituation. (B) Latencies to venture out on the open arm of the O-maze were higher in sham-treated runners compared to sham-treated sedentary controls and to irradiated runners. Consistently, the total time spent on the open, unprotected arms was shorter in sham-treated runners compared to sham-treated sedentary controls, while both irradiated groups performed comparably. *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.
Figure 4 Voluntary running produces an anxious phenotype in sham-treated, but not in irradiated mice. (A) Sham-treated runners had significantly less approaches to the center of the open field and moved a lower total distance. Sham-treated runners spent significantly less time in the center of the open field and exhibited delayed habituation. (B) Latencies to venture out on the open arm of the O-maze were higher in sham-treated runners compared to sham-treated sedentary controls and to irradiated runners. Consistently, the total time spent on the open, unprotected arms was shorter in sham-treated runners compared to sham-treated sedentary controls, while both irradiated groups performed comparably. *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.CC BY · PubMed Central
Figure 5 Both running and irradiation increase anxiety in the dark-light box. Sham-treated runners exhibited an anxious phenotype when compared to sham-treated sedentary controls. Furthermore, irradiated mice were significantly more anxious than sham-treated sedentary controls in all parameters investigated. Nevertheless, irradiated runners exhibited less anxiety than sham-treated runners (time spent in lit p<0.05; endexploration time p<0.05). *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.
Figure 5 Both running and irradiation increase anxiety in the dark-light box. Sham-treated runners exhibited an anxious phenotype when compared to sham-treated sedentary controls. Furthermore, irradiated mice were significantly more anxious than sham-treated sedentary controls in all parameters investigated. Nevertheless, irradiated runners exhibited less anxiety than sham-treated runners (time spent in lit p<0.05; endexploration time p<0.05). *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.CC BY · PubMed Central
Figure 6 When exposed to an anxiogenic situation, sham-treated runners have a different c-Fos expression in the hippocampus. (A) In control mice not exposed to the cat odor open field, c-Fos activation was remarkably higher in the dentate gyrus and CA1 region of regularly running mice, irrespective of irradiation. (B) After exposure to cat odor, runners had reduced numbers of c-Fos positive cells in CA3. This effect of running was completely abolished by previous irradiation in CA1. *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.
Figure 6 When exposed to an anxiogenic situation, sham-treated runners have a different c-Fos expression in the hippocampus. (A) In control mice not exposed to the cat odor open field, c-Fos activation was remarkably higher in the dentate gyrus and CA1 region of regularly running mice, irrespective of irradiation. (B) After exposure to cat odor, runners had reduced numbers of c-Fos positive cells in CA3. This effect of running was completely abolished by previous irradiation in CA1. *, °, # indicate significant post-hoc differences between sham-treated sedentary and runners, sham-treated runners and irradiated runners, sham-treated sedentary and irradiated mice, respectively; columns represent means + standard error.CC BY · PubMed Central
Figure 7 Hippocampal BDNF increases in runners irrespective of irradiation. Four weeks of voluntary running increased hippocampal brain-derived neurotrophic factor (BDNF) levels significantly. Though irradiation affected neurogenesis dramatically, it had no impact on the concentration of BDNF. Columns represent means + standard error.
Figure 7 Hippocampal BDNF increases in runners irrespective of irradiation. Four weeks of voluntary running increased hippocampal brain-derived neurotrophic factor (BDNF) levels significantly. Though irradiation affected neurogenesis dramatically, it had no impact on the concentration of BDNF. Columns represent means + standard error.CC BY · PubMed Central
Figure 8 Locomotor home cage activity is not altered by voluntary running. After 21 days of running, both running and sedentary mice exhibited comparable home cage activity. Thus running mice do not display hypo-locomotion under familiar conditions, ruling out a confounding factor for anxiety testing. Columns represent means + standard error.
Figure 8 Locomotor home cage activity is not altered by voluntary running. After 21 days of running, both running and sedentary mice exhibited comparable home cage activity. Thus running mice do not display hypo-locomotion under familiar conditions, ruling out a confounding factor for anxiety testing. Columns represent means + standard error.CC BY · PubMed Central

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Metadata

Authors
Fuss, J., Ben Abdallah, N. M. B., Hensley, F. W., Weber, K.-J., Hellweg, R., & Gass, P.
Affiliations
  • Heidelberg University (DE)
  • Charité – Universitätsmedizin Berlin (DE)
Corresponding author
Fuss, Johannes
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-09-16
Volume
5
Issue
9
Pages
e12769
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0012769
PMC
PMC2940841
OpenAlex
W2046295151
Cited by
110
References
50
Citations by year
2025: 3 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 9 · 2014: 15 · 2013: 26 · 2012: 13
FWCI
4.66
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Deutsche Forschungsgemeinschaft (HE 1392/3-1, SFB 636)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
hippocampal neurogenesis, anxiety, voluntary wheel running, focal irradiation, physical activity, c-fos, brain-derived neurotrophic factor, anxiety-like behavior, elevated plus maze, open field, sedentary behavior
MeSH terms
Animals, Anxiety, Hippocampus, Mice, Inbred C57BL, Phenotype, Radiotherapy, Running, X-Rays, Brain-Derived Neurotrophic Factor, Cell Proliferation, Mice, Neurogenesis

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