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

Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2012; 32(19):6444-55. DOI: 10.1523/JNEUROSCI.6076-11.2012
Source: PubMed


Although there is evidence suggesting that adult neurogenesis may contribute to hippocampus-dependent memory, signaling mechanisms responsible for adult hippocampal neurogenesis are not well characterized. Here we report that ERK5 mitogen-activated protein kinase is specifically expressed in the neurogenic regions of the adult mouse brain. The inducible and conditional knock-out (icKO) of erk5 specifically in neural progenitors of the adult mouse brain attenuated adult hippocampal neurogenesis. It also caused deficits in several forms of hippocampus-dependent memory, including contextual fear conditioning generated by a weak footshock. The ERK5 icKO mice were also deficient in contextual fear extinction and reversal of Morris water maze spatial learning and memory, suggesting that adult neurogenesis plays an important role in hippocampus-dependent learning flexibility. Furthermore, our data suggest a critical role for ERK5-mediated adult neurogenesis in pattern separation, a form of dentate gyrus-dependent spatial learning and memory. Moreover, ERK5 icKO mice have no memory 21 d after training in the passive avoidance test, suggesting a pivotal role for adult hippocampal neurogenesis in the expression of remote memory. Together, our results implicate ERK5 as a novel signaling molecule regulating adult neurogenesis and provide strong evidence that adult neurogenesis is critical for several forms of hippocampus-dependent memory formation, including fear extinction, and for the expression of remote memory.

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Available from: Chay Kuo, Mar 22, 2014
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    • "not low , interference ( Sahay et al . , 2011b ; Kheirbek et al . , 2012 ; Nakashiba et al . , 2012 ; Niibori et al . , 2012 ; Tronel et al . , 2012 ) . Studies using a delayed non - match to place paradigm and touch screen based object spacing detection assays have obtained similar results in some , but not all studies ( Clelland et al . , 2009 ; Pan et al . , 2012 ; Groves et al . , 2013 ; Swan et al . , 2014 ; Zhang et al . , 2014 ) . However , the neural mechanisms by which adult hippocampal neurogenesis modulates interference in these tasks are poorly understood ( Yassa and Stark , 2011 ; Piatti et al . , 2013 ; Lepousez et al . , 2015 ; Wadiche and Overstreet - Wadiche , 2015 ) . Theoretical "
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    ABSTRACT: The dentate gyrus (DG) of mammals harbors neural stem cells that generate new dentate granule cells (DGCs) throughout life. Behavioral studies using the contextual fear discrimination paradigm have found that selectively augmenting or blocking adult hippocampal neurogenesis enhances or impairs discrimination under conditions of high, but not low, interference suggestive of a role in pattern separation. Although contextual discrimination engages population-based coding mechanisms underlying pattern separation such as global remapping in the DG and CA3, how adult hippocampal neurogenesis modulates pattern separation in the DG is poorly understood. Here, we propose a role for adult-born DGCs in re-activation coupled modulation of sparseness through feedback inhibition to govern global remapping in the DG.
    Frontiers in Systems Neuroscience 09/2015; 9(120):1-7. DOI:10.3389/fnsys.2015.00120
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    • "Combined with the fact that CD44 is expressed by neural stem cells [6] [14] and that neural stem cells undergoing neurogenesis are implicated in hippocampal learning and memory [15], our data raise the possibility that CD44 may influence adult hippocampal neurogenesis. Some components of contextual fear conditioning involve hippocampal neurogenesis [21] and spatial memory in the Morris water maze is also sensitive to alterations in adult neurogenesis [22]. Given the contributions of CD44 and hyaluronan to regulating cell proliferation and differentiation , it will be interesting to test how their disruption influences cells within neural stem cell niches. "
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    ABSTRACT: CD44 is a transmembrane receptor for the glycosaminoglycan hyaluronan, a component of the extracellular matrix. CD44 is expressed by neural stem/progenitor cells, astrocytes, and some neurons but its function in the central nervous system is unknown. To determine the role of CD44 in brain function, we behaviorally analyzed CD44-null (KO) and wild-type (WT) mice. KO mice showed increased activity levels in the light-dark test and a trend towards increased activity in the open field. In addition, KO mice showed impaired hippocampus-dependent spatial memory retention in the probe trial following the first hidden-platform training day in the Morris water maze: WT mice showed spatial memory retention and spent more time in the target quadrant than any other quadrant, while KO mice did not. Although there were no genotype differences in swim speeds during the water maze training sessions with the visible or hidden platform, sensorimotor impairments were seen in other behavioral tests. In the inclined screen and balance beam tests, KO mice moved less than WT mice. In the wire hang test, KO mice also fell off of the wire faster than WT mice. In contrast, there was no genotype difference when emotional learning and memory were assessed in the passive avoidance test. These data support an important role for CD44 in locomotor and sensorimotor functions, and in spatial memory retention.
    Behavioural Brain Research 09/2014; 275. DOI:10.1016/j.bbr.2014.09.010 · 3.03 Impact Factor
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    • "The open field assay was performed as described[25] "
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    ABSTRACT: ERK5 MAP kinase is highly expressed in the developing nervous system but absent in most regions of the adult brain. It has been implicated in regulating the development of the main olfactory bulb and in odor discrimination. However, whether it plays an essential role in pheromone-based behavior has not been established. Here we report that conditional deletion of the Mapk7 gene which encodes ERK5 in mice in neural stem cells impairs several pheromone-mediated behaviors including aggression and mating in male mice. These deficits were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety, or by depression. Using mouse urine as a natural pheromone-containing solution, we provide evidence that the behavior impairment was associated with defects in the detection of closely related pheromones as well as with changes in their innate preference for pheromones related to sexual and reproductive activities. We conclude that expression of ERK5 during development is critical for pheromone response and associated animal behavior in adult mice.
    PLoS ONE 10/2013; 8(10):e76901. DOI:10.1371/journal.pone.0076901 · 3.23 Impact Factor
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