Elsevier

Neuroscience

Volume 171, Issue 3, 15 December 2010, Pages 769-778
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Young hippocampal neurons are critical for recent and remote spatial memory in adult mice

https://doi.org/10.1016/j.neuroscience.2010.09.047Get rights and content

Abstract

New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functions.

Research Highlights

ā–¶Reduced hippocampal neurogenesis impairs recent and remote memory in the spatial water maze whereas performances in the cued Morris water maze task remain intact. ā–¶Memory in the object location task is altered when hippocampal neurogenesis is reduced. ā–¶Non-spatial recognition memory is insensitive to hippocampal neurogenesis reduction. ā–¶Newborn hippocampal neurons aged between 1 and 2 weeks are required for hippocampal-dependent forms of memory.

Section snippets

Animals and housing conditions

Adult male C57BL/6 mice (9 week-old, Charles River Laboratories, OrlƩans, France) were housed in fours in a temperature-controlled animal facility with a 12 h light/dark cycle and had access to food and water ad libitum. All experiments were performed in strict accordance with the recommendations of the European Union and the French National Committee (86/609/EEC).

BrdU injections and MAM treatment

We first identified a dose for MAM administration in mice that reduced neurogenesis in the hippocampus, without affecting general

Hippocampal neurogenesis is reduced by MAM treatment during behavioral tests

Mice were sacrificed after completion of the behavioral tests (day 22), when BrdU-labeled (BrdU+) cells were 10 to 11 days old (Fig. 1A). Quantification of double-labeled BrdU+/NeuN+ cells revealed that the dentate gyrus of MAM-treated mice contained a significantly lower number of new neurons (368.1Ā±86.4) compared to control mice (896.6Ā±107.6) (F(1,15)=14.192; P<0.01; Fig. 1B, C). Thus, the subchronic treatment with MAM reduced by 59% the population of hippocampal neurons younger than 14 days

Discussion

In the present study we report that a reduced number of young hippocampal neurons leads to memory impairment depending both on the type of task (spatial vs. non-spatial) and on the task's dependence on the hippocampus (dependent vs. independent). Our findings demonstrate that spatial hippocampal-dependent types of memory are vulnerable to a partial reduction of adult neurogenesis.

To reduce neurogenesis in the hippocampus, we used the cytostatic agent MAM which reversibly stops progenitor cells

Conclusion

Altogether, our findings support the idea that newborn hippocampal neurons aged between 1 and 14 days are required for hippocampal-dependent forms of memory. These data are in agreement with our recent report that new neurons contribute to remote spatial memory retrieval (Trouche et al., 2009) and further point out that they are critically involved in recent spatial memory. Although adult-generated granular neurons represent only a small population of cells within the adult dentate gyrus,

Acknowledgments

We warmly thank HĆ©lĆØne Halley for her technical help and Bernard FrancĆØs for his advice. This work was supported by grants from the Agence Nationale pour la Recherche (ANR-06-NEURO-027) and the EU Frameworkprogram 6 (Integrated project PROMEMORIA 512012) to C.R., by the CNRS and Toulouse University.

References (53)

  • G. Stupien et al.

    Involvement of the hippocampal CA3-region in acquisition and in memory consolidation of spatial but not in object information in mice

    Neurobiol Learn Mem

    (2003)
  • V.I. Weisz et al.

    A putative role for neurogenesis in neuro-computational terms: inferences from a hippocampal model

    Cognition

    (2009)
  • C. Zhao et al.

    Mechanisms and functional implications of adult neurogenesis

    Cell

    (2008)
  • E. Bruel-Jungerman et al.

    New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment

    Eur J Neurosci

    (2005)
  • C.D. Clelland et al.

    A functional role for adult hippocampal neurogenesis in spatial pattern separation

    Science

    (2009)
  • J.C. Dodart et al.

    Scopolamine-induced deficits in a two-trial object recognition task in mice

    Neuroreport

    (1997)
  • D. Dupret et al.

    Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus

    Eur J Neurosci

    (2005)
  • D. Dupret et al.

    Spatial relational memory requires hippocampal adult neurogenesis

    PLoS One

    (2008)
  • A. Ennaceur et al.

    Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix

    Exp Brain Res

    (1997)
  • M.S. Esposito et al.

    Neuronal differentiation in the adult hippocampus recapitulates embryonic development

    J Neurosci

    (2005)
  • S. Farioli-Vecchioli et al.

    The timing of differentiation of adult hippocampal neurons is crucial for spatial memory

    PLoS Biol

    (2008)
  • A. Garthe et al.

    Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies

    PLoS One

    (2009)
  • S. Gaskin et al.

    Retrograde and anterograde object recognition in rats with hippocampal lesions

    Hippocampus

    (2003)
  • S. Ge et al.

    GABA regulates synaptic integration of newly generated neurons in the adult brain

    Nature

    (2006)
  • E. Gould et al.

    Learning enhances adult neurogenesis in the hippocampal formation

    Nat Neurosci

    (1999)
  • S. Jessberger et al.

    Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats

    Learn Mem

    (2009)
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    These authors contributed equally to this work.

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