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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (3) : 168-181
Adult neurogenesis and pattern separation in rodents: A critical evaluation of data, tasks and interpretation
Martha Hvoslef-Eide1,2,3,Charlotte A. Oomen4,5,6,*()
1. Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom
2. Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3 EB, United Kingdom
3. Current addess Department of Biosciences, University of Oslo, 0370 Oslo, Norway
4. Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute, Geert Grooteplein 21, 6500 HB, Nijmegen, The Netherlands
5. Current address Centre for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
6. Current address Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
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The ability to discriminate and store similar inputs as distinct representations in memory is thought to rely on a process called pattern separation in the dentate gyrus of the hippocampus. Recent computational and empirical findings support a role for adult-born granule neurons in spatial pattern separation. We reviewed rodent studies that have manipulated both hippocampal adult neurogenesis and assessed pattern separation. The majority of studies report a supporting role of adult born neurons in pattern separation as measured at the behavioral level. However, closer evaluation of the published findings reveals variation in both pattern separation tasks and in the interpretation of behavioral performance that, taken together, suggests that the role of hippocampal adult neurogenesis in pattern separation may be less established than is currently assumed. Assessment of pattern separation at the network level through the use of immediate early gene expression, optogenetic, pharmacogenetic and/or in vivo electrophysiology studies could be instrumental in further confirming a role of adult born neurons in pattern separation further. Finally, hippocampal adult neurogenesis and pattern separation are not an exclusive pair, as evidence for hippocampal adult neurogenesis contributing to the temporal separation of events in memory, forgetting and cognitive flexibility has also been found. We conclude that whereas current empirical evidence for the involvement of hippocampal adult neurogenesis in pattern separation seems supportive, there is a need for careful interpretation of behavioral findings and an integration of the various proposed functions of adult born neurons.

Keywords adult neurogenesis      memory      pattern separation      dentate gyrus      behavioral paradigms     
Corresponding Author(s): Charlotte A. Oomen   
Just Accepted Date: 01 June 2016   Online First Date: 23 June 2016    Issue Date: 05 July 2016
 Cite this article:   
Martha Hvoslef-Eide,Charlotte A. Oomen. Adult neurogenesis and pattern separation in rodents: A critical evaluation of data, tasks and interpretation[J]. Front. Biol., 2016, 11(3): 168-181.
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Martha Hvoslef-Eide
Charlotte A. Oomen
Effect on task(s) Dissimilar condition? Support role of NG in PS? Change in NG/experimental manipulation Species/Sex/Age Reference
1 Impaired novel object in place recognition memory No Yes Decreased NG after early malnutrition Rat/m/- Perez-Garcia et al., 2016
2 No effect on location discrimination learning (touchscreen) Yes No Increased NG after electroconvulsive seazures Rat/m/8+ weeks Svensson et al., 2016
3 Improved performance on the DNMTP radial arm maze Yes Yes Innate higher levels of NG correlate positively with task performance in male spatial strategy users. Rat/m and f/10+ weeks Yagi et al., 2016
4 Improved performance on contextual fear discrimination (in 3 month old mice) No Yes Increased NG after fingolimod treatment Mice/m/ 3,7,12 months Efstathopoulos et al., 2015
5 No effect on contextual fear discrimination No No Decreased NG in a Dorfin homozygous knockout mouse Mice/-/- Park et al., 2015
6 No effect on trial-unique nonmatching to location (touchscreen) Yes No Increased neurogenesis after electroconvulsive seazures Rat/m/8+weeks Svensson et al., 2015
7 Improved contextual fear discrimination No Yes Increased NG after postnatal sevoflurane treatment Rat/m/5–8 weeks Chen et al., 2015
8 Impaired learning in a high-interference condition of submerged T-maze paradigm Yes, low interference Yes Decreased NG after chemotherapy drug treatment Rat/f/5 months Winocur et al., 2015
9 Improved contextual fear discrimination after running in aged animals No Yes Decreased NG in aging, increased neurogenesis after voluntary exercise Mice/m/2,17 months Wu et al., 2015
10 Improved novel object recognition of similar, but not distinct objects Yes Yes Increased NG after voluntary exercise Mice/f/8+ weeks Bolz et al., 2015
11 Impaired contextual fear discrimination No Yes Decreased survival and changed dendritic complexity after PS1 knockdown of adult-born neurons Mice/m/8 months Bonds et al., 2015
12 Improved spontaneous location recognition memory Yes Yes Increased NG after systemic ghrelin administration Rats/m/8+ weeks Kent et al., 2015
13 Impaired performance on a spatial metric task and temporal object association task No Yes Decreased NG in DNMT-1 knockout mice Mice/m/1–3 months Kesner et al., 2014
14 Impaired performance on similar and dissimilar trials in the location discrimination task during reversal only. Yes No Decreased NG in GFAP-TK mice Mice/m/8+ weeks Swan et al., 2014
15 Impaired object-in-place memory No Yes Decreased NG due to inflammatory factors (and normalization through ibuprofen treatment) Mice/f/8+ weeks Llorens-Martin et al., 2014
16 Impaired spontaneous location recognition memory Yes Yes Decreased NG through viral delivery of Wnt Rats/m/8+ weeks Bekinschtein et al.,2014
17 Impaired contextual fear discrimination (use of randomized and non-randomized version) No Yes Decreased NG (dorsal versus ventral) through X-ray irradiation Mice/m/7+ weeks Wu and Hen, 2014
18 Impaired contextual fear discrimination and subsequent normalization No Yes Decreased NG (Btg1 mice) and normalization using voluntary exercise Mice/-/8+ weeks Farioli-Vecchioli et al., 2014
19 Impaired DNMTP in the radial arm maze at both small and large separations Yes Yes Decreased NG in Ezh2knockout mice Mice/m/- Zhang et al., 2014
20 More perseverance in the Morris water maze, less precise search patterns. No Yes Decreased NG in Cyclin-D2 knockout mice Mice/f/8+ weeks Garthe et al., 2014
21 Impaired contextual fear discrimination (reported in separate study: Jin et al., 2013) No Yes Decreased NG in Ras/Grf1 knockout mice Mice/-/- Darcy et al., 2014 (Jin et al., 2013)
22 No effect on contextual fear discrimination No No Increased NG in Pet knockout mice (serotonin depletion) Mice/m/8–10 weeks Diaz et al., 2013
23 No effect on DNMTP in the radial arm maze at small or large separations Yes No Decreased NG in GFAP-TK rats Rats/m/8 weeks Groves et al., 2013
24 Impaired performance on small separation in touchscreen location discrimination Yes Yes Decreased NG in TNiK knockout mice Mice/m/8+ weeks Coba et al., 2012
25 Impaired and improved novel object in place memory Yes Yes Decreased NG in SREB2 transgenic mice/ Increased NG in SREB2 knockout mice Mice/m/4–6 months Chen et al., 2012
26 Impaired cognitive flexibility No Yes Decreased NG in GFAP-TK mice and after X-ray irradiation Mice/m/10+ weeks Burghardt et al., 2012
27 Impaired contextual fear discrimination Yes, in a separate experiment Yes Deletion of NR2B of the NMDAR in adult born neurons only; Mice/m/14–16 weeks Kheirbek et al., 2012
28 Impaired contextual fear discrimination after NG ablation (main finding: improved performance upon inhibited neurotransmission of adult cells) Yes, in a separate experiment Yes Inhibited neurotransmission of adult granule cells in combination with decreased NG after X-ray irradiation. Mice/m/14+ weeks Nakashiba et al., 2012
29 Impaired performance on a high interference odor discrimination paradigm No Yes Decreased NG after X-ray irradiation Rats/m/3+ months Luu et al., 2012
30 Impaired DNMTP in the radial arm maze at both small and large separations Yes Yes Decreased NG in ERK5 inducable knockout (adult born neurons only) Mice/m/12 weeks Pan et al., 2012
31 Improved contextual fear discrimination in males, no effect in females No No Ablation of postnatal NG in DNMT1 knockout mice Mice/m and f/ 3–5 months Cushman et al., 2012
32 Impaired contextual fear conditioning Yes Yes Ablation of NG using HSV-tk under the nestin promotor and by means of systemic temozolomide treatment Mice/m/10 weeks Niibori et al., 2012
33 Impaired performance on an adapted version of the Barnes’ maze No Yes NF-kB knockout results in a (pathological) increase in NG Mice/m/- Imielski et al., 2012
34 Improved performance in a submerged radial arm maze (and a lack thereof in knockout animals) Yes Yes Increased NG in control animals after enrichment; and a lack thereof in mice with conditional knock-out of CREB binding protein Mice/f/2–5 months(?) Lopez-Atalaya et al., 2011
35 Improved (and impaired) contextual fear discrimination (normal absence of fear memory in novel context) No Yes Increase (and decrease) in NG through genetic manipulation and X-ray irradiation. Mice/m and f/14–18 weeks Sahay et al., 2011
36 Impaired contextual fear discrimination No Yes Decreased NG in Nestin rtTA/Tet mice Mice/m/8 weeks Tronel et al., 2010
37 Improved location discrimination learning (touchscreen) Yes Yes Increased NG after running Mice/m/3 and 22 months Creer et al., 2010
38 Improved location discrimination learning and improved DNMTP in the radial arm maze (on similar conditions only) Yes Yes Decreased NG after X-ray irradiation and viral delivery of Wnt knockdown Mice/f/8+ weeks Clelland et al., 2009
Tab.1  Empirical animal studies of neurogenesis and pattern separation
Fig.1  Pattern separation task examples. (A) Contextual fear discrimination in which animals are trained to discriminate context A (paired with a foot shock) from a safe context (B) Delayed non-matching to location in the radial arm maze. Trial example (top): during the sample phase animals collect a reward from one arm (sample arm) and after a delay, are required to choose between the sample arm (incorrect, unbaited) and a novel arm (correct, baited) during the choice phase. Below, three different choice phase configurations are shown, taxing similarity between the sample arm and novel arm by presenting them at different separations (2, 3 or 4). Note; arms and locations should vary between trials. S= start arm. (C) The spontaneous location recognition paradigm for pattern separation. Animals explore three identical copies (A1, A2, A3) of objects during a sample phase (left) and after a delay, memory is assessed using preference for the object placed in a novel location (A5) compared to the familiar location (A4) in the choice phase (right). Two trial types are used in randomized order, implementing a small or large distance between objects A2 and A3 thereby varying pattern separation load. (Figures drawn based on task descriptions in Tronel et al., 2012; Clelland et al., 2009 and Bekinschtein et al., 2013.)
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