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Cited by 196Neurogenesis and neuroplasticity mechanismsCircadian rhythm and melatoninSleep and Wakefulness Research

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Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters

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Gibson, Erin M., Wang, Connie, Tjho, Stephanie, Khattar, Neera, Kriegsfeld, Lance J.·2010·PLoS ONE
DOI 10.1371/journal.pone.0015267PMC PMC2995744
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Abstract

BACKGROUND: Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we investigated whether experimental 'jet lag' (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. CONCLUSIONS/SIGNIFICANCE: Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.

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Figure 1 Jet lag adversely impacts PCNA immunostaining and neurogenesis in the dentate gyrus. (A) The number of PCNA-labeled cells in the granule cell layer was affected by the hormonal condition of the animal (F2,20 = 4.014, P = 0.03), with ovariectomy and estradiol replacement significantly increasing the number of labeled cells as compared to intact hamsters (P = 0.04). Jet lag resulted in a significant decrease in the number of PCNA-labeled cells in both intact and OVX + E2 hamsters (P = 0.007 and P = 0.05, respectively by planned comparisons) while the number of PCNA-labeled cells in adrenalectomized animals was not affected by chronic temporal disruption (P = 0.80). (B) Neurogenesis was decreased by jet lag (F1,21 = 20.147, P<0.001), but there was no significant effect of hormone condition (F1,21 = 0.228, P = 0.80) and no interaction (F2,21 = 0.231, P = 0.80). Chronic jet lag resulted in a decrease in neurogenesis by >50% in intact, ADX, and OVX + E2 hamsters (P = 0.01, P = 0.007, and P = 0.05, respectively; * P<0.05, n = 4/5 animals/group). (C–F) Sections were processed for double-label BrdU (green) and NeuN (red), a marker for mature neurons, and quantified at 400×. (C) Photomicrograph of the dorsal and ventral blades of the dentate gyrus. Cells were considered double-labeled when BrdU (D) and NeuN (E) co-localized in the same focal plane (F; yellow).
Figure 1 Jet lag adversely impacts PCNA immunostaining and neurogenesis in the dentate gyrus. (A) The number of PCNA-labeled cells in the granule cell layer was affected by the hormonal condition of the animal (F2,20 = 4.014, P = 0.03), with ovariectomy and estradiol replacement significantly increasing the number of labeled cells as compared to intact hamsters (P = 0.04). Jet lag resulted in a significant decrease in the number of PCNA-labeled cells in both intact and OVX + E2 hamsters (P = 0.007 and P = 0.05, respectively by planned comparisons) while the number of PCNA-labeled cells in adrenalectomized animals was not affected by chronic temporal disruption (P = 0.80). (B) Neurogenesis was decreased by jet lag (F1,21 = 20.147, P<0.001), but there was no significant effect of hormone condition (F1,21 = 0.228, P = 0.80) and no interaction (F2,21 = 0.231, P = 0.80). Chronic jet lag resulted in a decrease in neurogenesis by >50% in intact, ADX, and OVX + E2 hamsters (P = 0.01, P = 0.007, and P = 0.05, respectively; * P<0.05, n = 4/5 animals/group). (C–F) Sections were processed for double-label BrdU (green) and NeuN (red), a marker for mature neurons, and quantified at 400×. (C) Photomicrograph of the dorsal and ventral blades of the dentate gyrus. Cells were considered double-labeled when BrdU (D) and NeuN (E) co-localized in the same focal plane (F; yellow).CC BY · PubMed Central
Figure 2 Gliogenesis is minimal in adult hippocampus. Hippocampal sections were immunostained for BrdU (green), GFAP (blue), and DAPI (red; color changed to red for purposes of visibility) to assess specificity of BrdU labeling and gliogenesis. (A) Representative photomicrograph (400×) of the dentate gyrus of the hippocampus expressing all three labels. Tissue was double-labeled immunofluorescently with antibodies against BrdU (B) and GFAP (C) to determine whether BrdU-labeled cells were glia (D). Approximately 2% of all BrdU-positive cells co-labeled with GFAP. In the triple-labeled image (D), three cells are labeled for BrdU, but do not co-express GFAP. Tissue was also labeled with fluorescent antibodies against BrdU (E) and DAPI (F) to ensure the specificity of BrdU labeling in mature neurons (G).
Figure 2 Gliogenesis is minimal in adult hippocampus. Hippocampal sections were immunostained for BrdU (green), GFAP (blue), and DAPI (red; color changed to red for purposes of visibility) to assess specificity of BrdU labeling and gliogenesis. (A) Representative photomicrograph (400×) of the dentate gyrus of the hippocampus expressing all three labels. Tissue was double-labeled immunofluorescently with antibodies against BrdU (B) and GFAP (C) to determine whether BrdU-labeled cells were glia (D). Approximately 2% of all BrdU-positive cells co-labeled with GFAP. In the triple-labeled image (D), three cells are labeled for BrdU, but do not co-express GFAP. Tissue was also labeled with fluorescent antibodies against BrdU (E) and DAPI (F) to ensure the specificity of BrdU labeling in mature neurons (G).CC BY · PubMed Central
Figure 3 Jet lag disrupts hippocampal-dependent learning and memory. Control (n = 10) and Jet Lag (n = 10) hamsters were introduced to the conditioned place preference (CPP) paradigm at the same time of day throughout the experiment to control for time of day effects on learning and memory [15]. (A) Control hamsters exhibited a significant bias for the black chamber during initial exposure to the apparatus (Pretest 1) (t18 = 4.193, P<0.001) whereas jet-lagged hamsters displayed no preference (t18 = 0.805, P = 0.43). (B) After training, control animals exhibited a significant preference for the chamber previously paired with the rewarding stimulus (Probe 1; t16 = 4.620, P<0.001), whereas animals undergoing jet lag during training did not learn the task and showed an equal preference for both chambers (t16 = 0.673, P = 0.51). Jet-lagged hamsters were then returned to a static LD cycle for 28 days in order to re-establish entrainment of biological rhythms with the LD cycle. (C) Several weeks after re-entrainment, control animals maintained a preference for the previously paired chamber (t18 = 2.2664, P = 0.02) whereas jet-lagged hamsters continued to show no preference (t18 = 1.113, P = 0.28). All animals were then trained with the wheel being placed in the chamber opposite to that used in the first behavioral test. (D) Even after recovering from chronic temporal disruption, jet-lagged animals did not learn the task (t14 = 1.532, P = 0.15), whereas control animals learned to prefer the new chamber (t12 = 2.692, P = 0.02). * P<0.05.
Figure 3 Jet lag disrupts hippocampal-dependent learning and memory. Control (n = 10) and Jet Lag (n = 10) hamsters were introduced to the conditioned place preference (CPP) paradigm at the same time of day throughout the experiment to control for time of day effects on learning and memory [15]. (A) Control hamsters exhibited a significant bias for the black chamber during initial exposure to the apparatus (Pretest 1) (t18 = 4.193, P<0.001) whereas jet-lagged hamsters displayed no preference (t18 = 0.805, P = 0.43). (B) After training, control animals exhibited a significant preference for the chamber previously paired with the rewarding stimulus (Probe 1; t16 = 4.620, P<0.001), whereas animals undergoing jet lag during training did not learn the task and showed an equal preference for both chambers (t16 = 0.673, P = 0.51). Jet-lagged hamsters were then returned to a static LD cycle for 28 days in order to re-establish entrainment of biological rhythms with the LD cycle. (C) Several weeks after re-entrainment, control animals maintained a preference for the previously paired chamber (t18 = 2.2664, P = 0.02) whereas jet-lagged hamsters continued to show no preference (t18 = 1.113, P = 0.28). All animals were then trained with the wheel being placed in the chamber opposite to that used in the first behavioral test. (D) Even after recovering from chronic temporal disruption, jet-lagged animals did not learn the task (t14 = 1.532, P = 0.15), whereas control animals learned to prefer the new chamber (t12 = 2.692, P = 0.02). * P<0.05.CC BY · PubMed Central
Figure 4 Jet lag transiently activates the HPA axis. (A) Jet-lagged animals (n = 7) exhibited increased concentrations of cortisol on days 8 and 15 (P<0.001 and P = 0.03) of the 25-day phase advance paradigm but not on the day following the first phase advance (P = 0.13) or the final day of the treatment (P = 0.11). The stress response in jet lag animals was attenuated throughout the course of the treatment with significantly lower concentration on day 25 compared to day 8 (P = 0.03). * Significantly greater than control animals (n = 7) at each time point, P<0.05. ** Significantly less than jet-lagged animals on Day 8 of sampling, P<0.05. (B–E) Jet-lagged animals ignore environmental light cues while maintaining rhythmic behavior. (B, D) Double-plotted actograms and (C, E) Fourier analysis of period length/rhythm amplitude of jet-lagged animals exposed to a chronic phase-advanced LD schedule. Records indicate that jet-lagged animals remain rhythmic (B, D), running with a period ∼24 hrs (C, E; P<0.01). Grey bars depict the dark phase of the LD cycle on these double-plotted activity records. Had animals been entrained to the LD cycle, activity would have been confined to these dark periods.
Figure 4 Jet lag transiently activates the HPA axis. (A) Jet-lagged animals (n = 7) exhibited increased concentrations of cortisol on days 8 and 15 (P<0.001 and P = 0.03) of the 25-day phase advance paradigm but not on the day following the first phase advance (P = 0.13) or the final day of the treatment (P = 0.11). The stress response in jet lag animals was attenuated throughout the course of the treatment with significantly lower concentration on day 25 compared to day 8 (P = 0.03). * Significantly greater than control animals (n = 7) at each time point, P<0.05. ** Significantly less than jet-lagged animals on Day 8 of sampling, P<0.05. (B–E) Jet-lagged animals ignore environmental light cues while maintaining rhythmic behavior. (B, D) Double-plotted actograms and (C, E) Fourier analysis of period length/rhythm amplitude of jet-lagged animals exposed to a chronic phase-advanced LD schedule. Records indicate that jet-lagged animals remain rhythmic (B, D), running with a period ∼24 hrs (C, E; P<0.01). Grey bars depict the dark phase of the LD cycle on these double-plotted activity records. Had animals been entrained to the LD cycle, activity would have been confined to these dark periods.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. M Orsini, 1961, The external vaginal phenomena characterizing the stages of the estrous cycle, pregnancy, pseudopregnancy, lactation and anestrous hamster, Mesocricetus auratus Waterhouse., Proceedings of Animal Care Panel, 14, 193

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Metadata

Authors
Gibson, E. M., Wang, C., Tjho, S., Khattar, N., & Kriegsfeld, L. J.
Affiliations
University of California, Berkeley (US)
Corresponding author
Kriegsfeld, Lance J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-12-01
Volume
5
Issue
12
Pages
e15267
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0015267
PMC
PMC2995744
OpenAlex
W2116127629
Cited by
196
References
83
Citations by year
2026: 2 · 2025: 6 · 2024: 8 · 2023: 17 · 2022: 12 · 2021: 12 · 2020: 17 · 2019: 10 · 2018: 18 · 2017: 16 · 2016: 10 · 2015: 17 · 2014: 20 · 2013: 15 · 2012: 10
FWCI
3.14
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)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • Northwestern University
  • National Institutes of Health (050470, HD 050470)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD050470, HD 050470)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Keywords
jet lag, circadian rhythm disruption, adult neurogenesis, hippocampal cell proliferation, learning and memory impairment, glucocorticoids, sex steroids, female hamsters, long-term cognitive deficits
MeSH terms
Animals, Brain, Cognition Disorders, Disease Models, Animal, Female, Glucocorticoids, Cricetinae, Hippocampus, Hypothalamo-Hypophyseal System, Memory, Neurons, Sleep, Jet Lag Syndrome, Cell Proliferation

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