Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis

We here show that living in a stimulus‐rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss‐of‐function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals’ behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro‐neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end‐point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

[1]  Gerd Kempermann,et al.  The neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for? , 2008, Trends in Neurosciences.

[2]  Mareike Kritzler,et al.  Emergence of Individuality in Genetically Identical Mice , 2013, Science.

[3]  Fred H. Gage,et al.  A role for adult TLX-positive neural stem cells in learning and behaviour , 2008, Nature.

[4]  F. Mora,et al.  Environmental enrichment increases the in vivo extracellular concentration of dopamine in the nucleus accumbens: a microdialysis study , 2010, Journal of Neural Transmission.

[5]  L. Putte,et al.  Antigen-Induced Arthritis: Inflammation and Antigen Handling , 1981 .

[6]  L. Kaczmarek,et al.  Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits , 2014, Genes, brain, and behavior.

[7]  K. Fabel,et al.  Differential 24 h responsiveness of Prox1–expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid–induced seizures , 2008, Neuroscience.

[8]  Janet Wiles,et al.  Potential role for adult neurogenesis in the encoding of time in new memories , 2006, Nature Neuroscience.

[9]  Laurenz Wiskott,et al.  A functional hypothesis for adult hippocampal neurogenesis: Avoidance of catastrophic interference in the dentate gyrus , 2006, Hippocampus.

[10]  V. Holthoff,et al.  Effects of Physical Activity Training in Patients with Alzheimer’s Dementia: Results of a Pilot RCT Study , 2015, PloS one.

[11]  Laurenz Wiskott,et al.  The Role of Additive Neurogenesis and Synaptic Plasticity in a Hippocampal Memory Model with Grid-Cell Like Input , 2011, PLoS Comput. Biol..

[12]  T. Shors,et al.  Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain , 2012, The European journal of neuroscience.

[13]  Larry R Squire,et al.  Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. , 2009, Learning & memory.

[14]  G. Kempermann,et al.  Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli , 2003, The Journal of comparative neurology.

[15]  M. Drew,et al.  Characterization of the role of adult neurogenesis in touch‐screen discrimination learning , 2014, Hippocampus.

[16]  L. Saksida,et al.  A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation , 2009, Science.

[17]  P. Frankland,et al.  Suppression of adult neurogenesis impairs population coding of similar contexts in hippocampal CA3 region , 2012, Nature Communications.

[18]  F. Gage,et al.  Experience-Specific Functional Modification of the Dentate Gyrus through Adult Neurogenesis: A Critical Period during an Immature Stage , 2007, The Journal of Neuroscience.

[19]  Jason S. Snyder,et al.  Inhibition of neurogenesis interferes with hippocampus‐dependent memory function , 2006, Hippocampus.

[20]  F. Mora,et al.  Effects of an enriched environment on the release of dopamine in the prefrontal cortex produced by stress and on working memory during aging in the awake rat , 2008, Behavioural Brain Research.

[21]  Johan Wagemans,et al.  Sex differences in human virtual water maze performance: Novel measures reveal the relative contribution of directional responding and spatial knowledge , 2010, Behavioural Brain Research.

[22]  D. Storm,et al.  Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 Mitogen-Activated Protein Kinase Specifically in Adult Neurogenic Regions Impairs Contextual Fear Extinction and Remote Fear Memory , 2012, The Journal of Neuroscience.

[23]  G. Kempermann,et al.  Adult-Generated Hippocampal Neurons Allow the Flexible Use of Spatially Precise Learning Strategies , 2009, PloS one.

[24]  F. Gage,et al.  New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? , 2010, Nature Reviews Neuroscience.

[25]  R. J. McDonald,et al.  A role for adult neurogenesis in spatial long-term memory , 2005, Neuroscience.

[26]  J. Rhodes,et al.  Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice , 2012, Neuroscience.

[27]  J. Arthur,et al.  MSK1 regulates environmental enrichment-induced hippocampal plasticity and cognitive enhancement. , 2012, Learning & memory.

[28]  P. Frankland,et al.  Age‐dependent effects of hippocampal neurogenesis suppression on spatial learning , 2013, Hippocampus.

[29]  G. Kempermann New neurons for 'survival of the fittest' , 2012, Nature Reviews Neuroscience.

[30]  W. Abraham,et al.  Enriched environment exposure regulates excitability, synaptic transmission, and LTP in the dentate gyrus of freely moving rats , 2006, Hippocampus.

[31]  D. Dupret,et al.  Spatial Relational Memory Requires Hippocampal Adult Neurogenesis , 2008, PloS one.

[32]  Gerd Kempermann,et al.  Additive Effects of Physical Exercise and Environmental Enrichment on Adult Hippocampal Neurogenesis in Mice , 2009, Front. Neurogenesis.

[33]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[34]  Blake A. Richards,et al.  Hippocampal Neurogenesis Regulates Forgetting During Adulthood and Infancy , 2014 .

[35]  A. Redish Beyond the Cognitive Map: From Place Cells to Episodic Memory , 1999 .

[36]  Janet Wiles,et al.  Computational Influence of Adult Neurogenesis on Memory Encoding , 2009, Neuron.

[37]  Afra H. Wang,et al.  Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus , 2007, Nature Neuroscience.

[38]  David P. Wolfer,et al.  Does cAMP Response Element-Binding Protein Have a Pivotal Role in Hippocampal Synaptic Plasticity and Hippocampus-Dependent Memory? , 2003, The Journal of Neuroscience.

[39]  P. Strata,et al.  Learning-related feedforward inhibitory connectivity growth required for memory precision , 2011, Nature.

[40]  G. Kempermann,et al.  An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis , 2013, Front. Neurosci..

[41]  Y. Shaham,et al.  Running is the neurogenic and neurotrophic stimulus in environmental enrichment. , 2011, Learning & memory.

[42]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.

[43]  A. Fenton,et al.  Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation , 2011, Nature.

[44]  R. Palmiter,et al.  Genetic Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis and Extends Hippocampus-Dependent Long-Term Memory , 2014, The Journal of Neuroscience.