Algorithm-based classification of search strategies.

<p>(A) Determination of variables used in the classification process. The pool was divided into distinct zones to calculate the amount of time spent in the respective areas (left). Average distance of all datapoints of a given swim path to its centroid and to the present or previous goal position was used during the classification process (middle). Search patterns based on a directional preference for the goal position were identified using a triangular shaped corridor expanding from the starting point with its bisecting line towards the platform (right). (B) Each strategy was identified by one or two parameters representing their respective abstract key properties. (C) Because some search patterns were defined less specific than others exclusion of strategies had to be achieved in a particular order. Search patterns not recognized were classified by hand.</p

LTP in C57BL/6 mice with suppressed adult neurogenesis.

<p>(A) In TMZ mice treatment prevented LTP in the dentate gyrus of hippocampal slices perfused with ACSF, but LTP was induced in control mice (ANOVA F(1,198) = 252.8, p<0.05). Previous studies showed that new, adult generated granule cells facilitate the weak LTP observed, while LTP induction in mature neurons is blocked by GABAergic inhibition under physiologic conditions (16, 17). (B) Using GABA_A antagonist biculline a strong LTP was observed in both treated mice and controls. (C) Significant differences between TMZ mice and controls appeared only for ACSF-LTP. (D) A cumulative histogram for both ACSF (right) and bicuculline (left) perfused hippocampal slices. Dashed lines represent TMZ mice, solid lines controls. (E) LTP in hippocampal region CA1 was not affected by TMZ.</p

At the time point of behavioral testing no potentially confounding side effects were found.

<p>(A and B) As expected, hematology only revealed a significant leucopenia immediately after four cycles of TMZ (t-test: t(4) = 3.59, p<0.05). The number of leukocytes fully recovered after four weeks of resting. No differences were found for erythrocytes, hemoglobin and platelets. (C and D) Locomotor abilities and exploratory behavior appeared to be unimpaired after TMZ treatment. (E and F) Expression of Iba-1 was used to identify activated microglia in the dentate gyrus of C57BL/6 mice. No elevated numbers of Iba-1⁺ cells were found for any of the TMZ doses used in the dosage finding experiment indicating the absence of inflammatory processes. The right micrograph represents microglia in mice treated with 50 mg/kg TMZ.</p

Effective suppression of adult hippocampal neurogenesis in C57BL/6 mice using temozolomide (TMZ).

<p>(A) Suppression of proliferation in the dentate gyrus was dosage dependent. After monocyclic treatment (one daily injection on three consecutive days) using 25 mg/kg TMZ total numbers of proliferating cells were reduced by more than 80%. Because doubling the dose did not result in significant lower numbers of BrdU⁺ cells, we used 25 mg/kg as the standard dose for all other experiments in this study. Proliferation was detected by incorporation of BrdU following a single injection using 50 mg/kg i.p. BrdU four days after end of TMZ treatment. (B) One treatment cycle consisted of single daily injections on three consecutive days followed by a resting period of four days. After four cycles of TMZ treatment proliferation was reduced by more than 90% (t(9) = 2.94, p<0.001). A single injection of BrdU was given four days after end of TMZ treatment. (C and D) BrdU⁺ cells in the dentate gyrus of mice after multicyclic treatment using either saline or TMZ (25 mg/kg), respectively.</p

Qualitative analysis of spatial learning in mice with suppressed adult hippocampal neurogenesis.

<p>(A) Examples of search strategies recognized by the classification algorithm used. (B) Both groups showed a clear progression towards increasingly hippocampus-dependent strategies. The top row represents the basic experimental protocol including the hidden platform position and the four starting positions used (arrows). Contribution of respective strategies to group performance in learning the MWM task was analyzed by classifying all trials using a parameter-based algorithm (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005464#pone-0005464-g005" target="_blank">Figure 5</a>). Strategies are color coded. See text for statistical comparisons. (C) Compared to controls in treated animals respective strategies contributed differentially to group performance. Differences are shown as percent of contribution relative to controls. The color code used is the same as in (B). The black line shows the mean difference between groups in latency to reach the hidden platform. (D) Principle of convolution analysis according to Brody et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005464#pone.0005464-Brody1" target="_blank">[14]</a>. (E and F) Comparison of measured mean path lengths with predictions derived from convolution analysis using a constant-frequency model and a constant-quality model. An efficient progression towards directed or place-specific navigation strategies was found to be the general underlying learning scheme in both groups.</p

Spatial learning in C57BL/6 mice with suppressed adult neurogenesis.

<p>(A) Both groups successfully learned to navigate to the hidden goal, but TMZ treated mice needed longer to locate the hidden platform. While the TMZ group reached comparable latency times at the end of the first acquisition phase, mice with suppressed adult neurogenesis performed worse both transiently before and consistently after reversal. (B) For controls, the occupancy plot shows the rapid development of a place-specific preference for the platform position both before and after reversal. (C) In TMZ treated mice learning a correct place-specific response for the first goal position was significantly delayed but still effective. After platform reversal mice with suppressed adult neurogenesis showed a profoundly perseverating preference for the previous platform position. (D–G) Probe trials indicated successful spatial learning of the first goal for both groups. After reversal treated animals failed to develop a preference for the new goal quadrant.</p

Topographic firing patterns in the EC.

<p>Top left panel: Formation of a grid governing the firing of a particular EC cell. A single vertex is placed at the specified grid origin (solid circle) which we choose for this example to be at the centre of the environment, then surrounded by six further vertices at the specified grid spacing (grey-filled circles). These vertices in turn are surround by twelve further vertices (white-filled circles) which begins to cover the spatial environment with a grid of equilateral triangles. Bottom left panel: Completed grid covering the entire spatial environment. In our simulations, the grid is extended to 1 m beyond the boundary wall to minimise edge effects. Middle panels: Two example grids in environment . Firing rates range from zero Hertz (white) to twelve Hertz (black). The dashed lines indicate the “centre line” of each grid which passes through the grid origin. The grids have different origins as well as vertex spacings and field sizes, but similar orientations. Right panels: The same two grids after entry to environment . The grids have undergone a coherent rotation of grid orientation and independent random shifts in grid origin. The dashed lines show the new grid centre lines in environment superimposed on the (unrotated) centre line from the previous environment , shown as a dotted line.</p

Development of spatial dependence of activity in the dentate gyrus layer of our network upon entry into a novel environment.

<p>We show four cells (from top to bottom) at four different time points (, , and days, from left to right). Left column: After day in the new environment each DG cell us activated by a large area of the spatial environment. Middle left column: After days a degree of refinement has occurred and the place fields have become more restricted. Middle right column: After days further refinement leads to activation patterns that resemble place cells in the DG. Right column: After days the final response of the cells are very similar to experimentally observed place cells with one main place field and occasionally some scattered areas of secondary activation. The network uses an additive neurogenesis with plasticity algorithm, but results are qualitatively the same for any of the four variations of neurogenesis we explored in the <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1001063#s3" target="_blank">results</a> section.</p

Performance of a network using a combination of neurogenesis and random turnover across environments.

<p>Left panel: The more sophisticated algorithm successfully achieves a recoding accuracy of for all twelve environments but once again suffers from an increased retrieval error. Right panel: Adding plasticity improves network performance considerably resulting in a network that can deal with all twelve environments while producing a retrieval error that is consistently lower than either conventional plasticity or neuronal turnover algorithms operating alone.</p

Evolution of the recoding and retrieval errors over environments for the fixed, reinitialising and plastic networks.

<p>Left panel: The recoding error (lower solid line) and retrieval error after adaptation to the final environment (dashed line) of the reinitialising network are a measure of how well a completely specialised network deals with the same kind of statistics. This is the best possible average recoding performance, and correspondingly the worst possible retrieval performance we can expect for a network with DG units. The recoding error of the fixed network (upper solid line) is a measure of how well a completely generic network deals with the statistics of the spatially driven input we have used. We expect that any adaptation strategy would produce at least this level of recoding accuracy. Right panel: Evolution of the recoding error (solid line) and the retrieval error (dashed line) as a function of environment number for a network that uses a neural gas-like plasticity algorithm with a recoding error threshold of . In all subsequent plots we conform to the convention of plotting recoding errors with a solid line and retrieval errors with a dashed line. The errors lie in the range to which we also adopt as our standard vertical scale. Conventional plasticity successfully reduces the recoding error in each environment to the target value but only at the expense of increasing the retrieval error for previously stored memory patterns.</p