Ganciclovir administration ablates neurogenesis in the dentate gyrus of the GFAP-TK rat.

<p><b>A</b>, Schematic of the <i>Tk</i>-pA-FRTneo^rFRT genetic construct and position of insertion to replace the start codon of the rat <i>Gfap</i> gene within a Bacterial Artificial Chromosome (BAC). <b>B</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 <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Paxinos1" target="_blank">[73]</a>. <b>C</b>, 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. <b>D</b>, 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.</p

Thymidine kinase is expressed in the SVZ and DG, and co-localizes with GFAP positive cells.

<p>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.</p

Meta-analysis of adult neurogenesis literature.

<p>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 <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Revest1" target="_blank">[8]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Shors1" target="_blank">[11]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Santarelli1" target="_blank">[12]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Saxe1" target="_blank">[13]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Snyder2" target="_blank">[17]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Dupret1" target="_blank">[18]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Deng1" target="_blank">[19]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Zhang1" target="_blank">[20]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Jessberger1" target="_blank">[21]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-HernandezRabaza1" target="_blank">[22]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Meshi1" target="_blank">[23]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Winocur1" target="_blank">[24]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Ko1" target="_blank">[25]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Wojtowicz1" target="_blank">[26]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Kitamura1" target="_blank">[32]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Tronel1" target="_blank">[36]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Scobie1" target="_blank">[37]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Jaholkowski1" target="_blank">[49]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Garthe1" target="_blank">[50]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Rola1" target="_blank">[51]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Zhao1" target="_blank">[52]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Shimazu1" target="_blank">[53]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Bergami1" target="_blank">[54]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Ageta1" target="_blank">[55]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Pollak1" target="_blank">[56]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-WarnerSchmidt1" target="_blank">[57]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Denny1" target="_blank">[58]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Drew1" target="_blank">[59]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-David1" target="_blank">[60]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Goodman1" target="_blank">[61]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Fuss2" target="_blank">[62]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Clark1" target="_blank">[74]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Groves1" target="_blank">[75]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Imayoshi2" target="_blank">[76]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003718#pgen.1003718-Raber1" target="_blank">[77]</a>.</p

Ablating adult neurogenesis does not affect fear conditioning.

<p><b>A</b> 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>B</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.</p

Ablating adult neurogenesis does not affect spatial working memory in the radial maze.

<p><b>A</b> Arm configuration for radial maze task. <b>B</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. <b>C</b> 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). <b>D</b> 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. <b>E</b> 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. <b>F</b> Arm configuration for the binary choice delayed non-matching to place radial maze task. <b>G</b> 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.</p