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Cited by 121Neurogenesis and neuroplasticity mechanismsMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

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Ablating Adult Neurogenesis in the Rat Has No Effect on Spatial Processing: Evidence from a Novel Pharmacogenetic Model

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Groves, James O., Leslie, Isla, Huang, Guo-Jen, McHugh, Stephen B., Taylor, Amy, Mott, Richard, Munafò, Marcus, Bannerman, David M., Flint, Jonathan·2013·PLoS Genetics
DOI 10.1371/journal.pgen.1003718PMC PMC3764151
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Abstract

The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis.

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Figure 1 Ganciclovir administration ablates neurogenesis in the dentate gyrus of the GFAP-TK rat. A, Schematic of the Tk-pA-FRTneorFRT genetic construct and position of insertion to replace the start codon of the rat Gfap gene within a Bacterial Artificial Chromosome (BAC). B, Number of doublecortin (DCX) positive (+) cells in the dentate gyrus of untreated 7-week old wild type (n = 5) and GFAP-TK (n = 5) rats. Data expressed as mean DCX+ cell counts (± s.e.m), generated from four 40 µm coronal sections taken from a ‘1 in 8’ series, starting at −2.5 mm from Bregma, along the dorsal/ventral extent of the hippocampus [73]. C, Number of DCX+ cells in the dentate gyrus of GFAP-TK rats dosed for 28 days with vehicle (saline, n = 2), or Ganciclovir (GCV) at 2 mg/kg/day (n = 2), 4 mg/kg/day (n = 2), 8 mg/kg/day (n = 2), or 10 mg/kg/day (n = 2). Data expressed as mean DCX+ cells as a percentage of vehicle control, generated from eight 40 µm coronal sections taken from a ‘1 in 12’ series from −2.5 mm from Bregma. D, Example of a DCX-stained dentate gyrus section from a wild type and GFAP-TK rat chronically treated with GCV (28 days, 10 mg/kg/day). Scale bar represents 200 µm.
Figure 1 Ganciclovir administration ablates neurogenesis in the dentate gyrus of the GFAP-TK rat. A, Schematic of the Tk-pA-FRTneorFRT genetic construct and position of insertion to replace the start codon of the rat Gfap gene within a Bacterial Artificial Chromosome (BAC). B, Number of doublecortin (DCX) positive (+) cells in the dentate gyrus of untreated 7-week old wild type (n = 5) and GFAP-TK (n = 5) rats. Data expressed as mean DCX+ cell counts (± s.e.m), generated from four 40 µm coronal sections taken from a ‘1 in 8’ series, starting at −2.5 mm from Bregma, along the dorsal/ventral extent of the hippocampus [73]. C, Number of DCX+ cells in the dentate gyrus of GFAP-TK rats dosed for 28 days with vehicle (saline, n = 2), or Ganciclovir (GCV) at 2 mg/kg/day (n = 2), 4 mg/kg/day (n = 2), 8 mg/kg/day (n = 2), or 10 mg/kg/day (n = 2). Data expressed as mean DCX+ cells as a percentage of vehicle control, generated from eight 40 µm coronal sections taken from a ‘1 in 12’ series from −2.5 mm from Bregma. D, Example of a DCX-stained dentate gyrus section from a wild type and GFAP-TK rat chronically treated with GCV (28 days, 10 mg/kg/day). Scale bar represents 200 µm.CC BY · PubMed Central
Figure 2 Thymidine kinase is expressed in the SVZ and DG, and co-localizes with GFAP positive cells. Thymidine kinase (TK) positive cells are detected in the subventricular zone (SVZ) and dentate gyrus (DG) of GFAP-TK rats, but not in wild type controls. Panels A and B show controls and panels D and E show GFAP-TK rats, Panel C shows double labeling of TK (red) and glial fibrillary acidic protein (GFAP, green) in the DG of a GFAP-TK rat. Higher magnification of a segment of panel C shows that TK positive (red) cells co-localize with GFAP staining. Scale bar represents 200 µm for panels A, B, D & E.
Figure 2 Thymidine kinase is expressed in the SVZ and DG, and co-localizes with GFAP positive cells. Thymidine kinase (TK) positive cells are detected in the subventricular zone (SVZ) and dentate gyrus (DG) of GFAP-TK rats, but not in wild type controls. Panels A and B show controls and panels D and E show GFAP-TK rats, Panel C shows double labeling of TK (red) and glial fibrillary acidic protein (GFAP, green) in the DG of a GFAP-TK rat. Higher magnification of a segment of panel C shows that TK positive (red) cells co-localize with GFAP staining. Scale bar represents 200 µm for panels A, B, D & E.CC BY · PubMed Central
Figure 3 Ablating adult neurogenesis decreases anxiety. A Time to begin eating a novel food in a novel environment, expressed as the mean latency (± s.e.m). B Time to begin eating as a survival plot (black line = wild type, n = 18, Red line = GFAP-TK, n = 22). C Time to emerge from a black alley and enter a white alley expressed as the mean latency (± s.e.m). D Time to emerge from a black alley survival plot (black line = wild type, n = 18, Red line = GFAP-TK, n = 22). Grey vertical line at right side of survival plots represents the termination of the experiment. *p<0.05, **p<0.01 significantly different from GCV-treated wild type controls. E Time to begin eating a novel food and F Time to emerge from a black alley in untreated WT (n = 26) and GFAP-TK (n = 18) rats.
Figure 3 Ablating adult neurogenesis decreases anxiety. A Time to begin eating a novel food in a novel environment, expressed as the mean latency (± s.e.m). B Time to begin eating as a survival plot (black line = wild type, n = 18, Red line = GFAP-TK, n = 22). C Time to emerge from a black alley and enter a white alley expressed as the mean latency (± s.e.m). D Time to emerge from a black alley survival plot (black line = wild type, n = 18, Red line = GFAP-TK, n = 22). Grey vertical line at right side of survival plots represents the termination of the experiment. *p<0.05, **p<0.01 significantly different from GCV-treated wild type controls. E Time to begin eating a novel food and F Time to emerge from a black alley in untreated WT (n = 26) and GFAP-TK (n = 18) rats.CC BY · PubMed Central
Figure 4 Ablating adult neurogenesis does not affect fear conditioning. A Freezing behavior of GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats during 60 s preceding a tone previously paired with a shock (Pre Tone) and during the first 20 s of tone presentation (Tone). Data represent % time spent freezing during each time period (± sem). B Freezing behavior of GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats in a context previously associated with shock presentation. Data represent % time freezing during 4 minutes (60 s time bins; ± sem). *p<0.05 tone significantly different from pre-tone. Wild type data are represented by an open circle connected by an interrupted line, GFAP-TK data are represented by filled squares and a solid line.
Figure 4 Ablating adult neurogenesis does not affect fear conditioning. A Freezing behavior of GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats during 60 s preceding a tone previously paired with a shock (Pre Tone) and during the first 20 s of tone presentation (Tone). Data represent % time spent freezing during each time period (± sem). B Freezing behavior of GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats in a context previously associated with shock presentation. Data represent % time freezing during 4 minutes (60 s time bins; ± sem). *p<0.05 tone significantly different from pre-tone. Wild type data are represented by an open circle connected by an interrupted line, GFAP-TK data are represented by filled squares and a solid line.CC BY · PubMed Central
Figure 5 Ablating adult neurogenesis does not affect spatial reference memory in the water maze. A Time spent swimming to reach a submerged platform by GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats during the acquisition and reversal phase of a spatial reference memory water maze task. Each data point represents the mean score (±sem) per session (1 session consists of 4×90 second trials). R1/R2 represents a reversal phase, where the platform was moved to the opposite quadrant of the pool. B Percentage time spent swimming in each quadrant by GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats during the probe trial. L = adjacent left quadrant, T = target quadrant, R = adjacent right quadrant, O = opposite quadrant. Interrupted horizontal line represents a value of chance. Data represent mean % time (±sem) during a 60 s trial. *p<0.05 significantly different from time spent in other quadrants. Wild type data are represented by an open circle connected by an interrupted line, GFAP-TK data are represented by filled squares and a solid line.
Figure 5 Ablating adult neurogenesis does not affect spatial reference memory in the water maze. A Time spent swimming to reach a submerged platform by GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats during the acquisition and reversal phase of a spatial reference memory water maze task. Each data point represents the mean score (±sem) per session (1 session consists of 4×90 second trials). R1/R2 represents a reversal phase, where the platform was moved to the opposite quadrant of the pool. B Percentage time spent swimming in each quadrant by GCV-treated wild type (n = 7) and GFAP-TK (n = 10) rats during the probe trial. L = adjacent left quadrant, T = target quadrant, R = adjacent right quadrant, O = opposite quadrant. Interrupted horizontal line represents a value of chance. Data represent mean % time (±sem) during a 60 s trial. *p<0.05 significantly different from time spent in other quadrants. Wild type data are represented by an open circle connected by an interrupted line, GFAP-TK data are represented by filled squares and a solid line.CC BY · PubMed Central
Figure 6 Ablating adult neurogenesis does not affect spatial working memory in the radial maze. A Arm configuration for radial maze task. B Mean number (± sem) of correct arm entries made during a maximum of 6 entries per trial, by GCV-treated wild type (n = 13) and GFAP-TK (n = 13) rats. C Number of arm entries made before all 6 arms had been visited in a trial, by GCV-treated wild type (n = 13) and GFAP-TK (n = 11) rats. The mean score (± sem) is shown for four sessions (4 trials per session). D Rats made 3 initial arm choices, followed by a 1, 20 or 60 minute delay, followed by 3 final arm choices. Data show the number of errors made during the final 3 arm choices, by GCV-treated WT (n = 13) and GFAP-TK (n = 11) rats. Each data point represents the mean score (± sem) for 3 trials for each rat. E Number of errors made per trial into the single arm, pair of arms and arm trio, by GCV-treated wild type (n = 13) and GFAP-TK (n = 11) rats. Data are adjusted according to the number of arms in each group (e.g. total number of arm entries into the trio was divided by 3). Each data point represents the mean score (± sem) per trial. F Arm configuration for the binary choice delayed non-matching to place radial maze task. G The percentage of trials (± sem) in which the novel arm was correctly chosen, by GCV-treated wild type (n = 11) and GFAP-TK (n = 9) rats in the delayed non-matching to place task. Wild type data are represented by an open circle connected by an interrupted line, GFAP-TK data are represented by filled squares and a solid line. The interrupted horizontal line represents chance levels of performance.
Figure 6 Ablating adult neurogenesis does not affect spatial working memory in the radial maze. A Arm configuration for radial maze task. B Mean number (± sem) of correct arm entries made during a maximum of 6 entries per trial, by GCV-treated wild type (n = 13) and GFAP-TK (n = 13) rats. C Number of arm entries made before all 6 arms had been visited in a trial, by GCV-treated wild type (n = 13) and GFAP-TK (n = 11) rats. The mean score (± sem) is shown for four sessions (4 trials per session). D Rats made 3 initial arm choices, followed by a 1, 20 or 60 minute delay, followed by 3 final arm choices. Data show the number of errors made during the final 3 arm choices, by GCV-treated WT (n = 13) and GFAP-TK (n = 11) rats. Each data point represents the mean score (± sem) for 3 trials for each rat. E Number of errors made per trial into the single arm, pair of arms and arm trio, by GCV-treated wild type (n = 13) and GFAP-TK (n = 11) rats. Data are adjusted according to the number of arms in each group (e.g. total number of arm entries into the trio was divided by 3). Each data point represents the mean score (± sem) per trial. F Arm configuration for the binary choice delayed non-matching to place radial maze task. G The percentage of trials (± sem) in which the novel arm was correctly chosen, by GCV-treated wild type (n = 11) and GFAP-TK (n = 9) rats in the delayed non-matching to place task. Wild type data are represented by an open circle connected by an interrupted line, GFAP-TK data are represented by filled squares and a solid line. The interrupted horizontal line represents chance levels of performance.CC BY · PubMed Central
Figure 7 Meta-analysis of adult neurogenesis literature. Forest plot showing the results of studies examining the relationship between adult neurogenesis and three tests of learning and memory (contextual and cued fear conditioning, the probe trial of the Morris water maze (MWM)), and two tests of anxiety (total activity in the open-field arena (OF) and time spent in the open-arms of an elevated plus maze (EPM)). The figure shows the standardized mean difference for each study, the associated 95% confidence intervals and the pooled estimate, all based on a random-effects (RE) model and Hedge's estimator. Multiple entries for one publication arise when authors report analyses using different ablation methods (irradiation vs genetic for example) or variation in experimental protocols. On the right of each panel is the reference number for each publication, followed by a number that identifies the data set we extracted from the literature. This number refers to an entry in the supplemental table containing details of each data set and relevant covariates [8], [11], [12], [13], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [32], [36], [37], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [74], [75], [76], [77].
Figure 7 Meta-analysis of adult neurogenesis literature. Forest plot showing the results of studies examining the relationship between adult neurogenesis and three tests of learning and memory (contextual and cued fear conditioning, the probe trial of the Morris water maze (MWM)), and two tests of anxiety (total activity in the open-field arena (OF) and time spent in the open-arms of an elevated plus maze (EPM)). The figure shows the standardized mean difference for each study, the associated 95% confidence intervals and the pooled estimate, all based on a random-effects (RE) model and Hedge's estimator. Multiple entries for one publication arise when authors report analyses using different ablation methods (irradiation vs genetic for example) or variation in experimental protocols. On the right of each panel is the reference number for each publication, followed by a number that identifies the data set we extracted from the literature. This number refers to an entry in the supplemental table containing details of each data set and relevant covariates [8], [11], [12], [13], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [32], [36], [37], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [74], [75], [76], [77].CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Paxinos G, Watson C (2007) The Rat brain in sterotaxic coordinates. : Sydney: Academic Press.
  2. JO Groves, 2013, Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model, Plos Genetics
  3. I Imayoshi, 2008, Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain, Nat Neurosci, 11, 1153, 10.1038/nn.2185 · DOI · Paper page

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Metadata

Authors
Groves, J. O., Leslie, I., Huang, G.-J., McHugh, S. B., Taylor, A., Mott, R., Munafò, M., Bannerman, D. M., & Flint, J.
Affiliations
  • Centre for Human Genetics (GB)
  • Chang Gung University (TW)
  • University of Oxford (GB)
  • University of Bristol (GB)
Corresponding author
Bannerman, David M.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2013-09-05
Volume
9
Issue
9
Pages
e1003718
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1003718
PMC
PMC3764151
OpenAlex
W2089949016
Cited by
121
References
77
Citations by year
2026: 3 · 2025: 6 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 7 · 2017: 18 · 2016: 18 · 2015: 22 · 2014: 10 · 2013: 2
FWCI
1.86
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Explore Bristol Research (submittedVersion)
Funders
Wellcome Trust (089269, 083573, 084655, 087736, 089269/Z/09/Z, 090532, 083573/Z/07/Z, 090532/Z/09/Z, 090532/Z/09/, 083573/Z/07)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
adult neurogenesis, hippocampus, spatial pattern separation, spatial learning, spatial memory, fear conditioning, contextual fear, ganciclovir, anxiety
MeSH terms
Animals, Anxiety, Conditioning, Psychological, Fear, Glial Fibrillary Acidic Protein, Hippocampus, Memory, Neurons, Pharmacogenetics, Thymidine Kinase, Maze Learning, Rats, Neurogenesis, Cognitive Dysfunction

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