Neural stem cells improve memory in an inducible mouse model of neuronal loss.

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
Journal of Neuroscience (Impact Factor: 6.75). 11/2007; 27(44):11925-33. DOI: 10.1523/JNEUROSCI.1627-07.2007
Source: PubMed

ABSTRACT Neuronal loss is a major pathological outcome of many common neurological disorders, including ischemia, traumatic brain injury, and Alzheimer disease. Stem cell-based approaches have received considerable attention as a potential means of treatment, although it remains to be determined whether stem cells can ameliorate memory dysfunction, a devastating component of these disorders. We generated a transgenic mouse model in which the tetracycline-off system is used to regulate expression of diphtheria toxin A chain. After induction, we find progressive neuronal loss primarily within the hippocampus, leading to specific impairments in memory. We find that neural stem cells transplanted into the brain after neuronal ablation survive, migrate, differentiate and, most significantly, improve memory. These results show that stem cells may have therapeutic value in diseases and conditions that result in memory loss.

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    ABSTRACT: Neuronal loss as a consequence of brain injury, stroke and neurodegenerative disorders causes functional impairments ranging from cognitive impairments to physical disabilities. Extensive rehabilitation and train-ing may lead to neuroprotection and promote functional recovery, although little is known about the molecu-lar and cellular mechanisms driving this event. To investigate the underlying mechanisms and levels of func-tional recovery elicited by repeated physical training or environmental enrichment, we generated an induc-ible mouse model of selective CA1 hippocampal neuronal loss. Following the CA1 neuronal injury, mice underwent one of the above mentioned conditions for 3 months. Exposure to either of these stimuli promoted functional cognitive recovery, which was associated with increased neurogenesis in the subgranular zone of dentate gyrus and enhanced synaptogenesis in the CA1 subfield. Notably, a significant correlation was found between the functional recovery and increased synaptogenesis among survived CA1 neurons. Collectively, these results support the utilization of cognitive and physical stimulation as approaches to promote recovery after neuronal loss and demonstrate the potential of this novel mouse model for the development of therapeu-tic strategies for various neurological disorders associated with focal neuronal loss.
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    ABSTRACT: Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease) and brain traumas (stroke, epilepsy, and traumatic brain injury). One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DT A mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DT A mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery. Citation: Myczek K, Yeung ST, Castello N, Baglietto-Vargas D, LaFerla FM (2014) Hippocampal Adaptive Response Following Extensive Neuronal Loss in an Inducible Transgenic Mouse Model. PLoS ONE 9(9): e106009. doi:10.1371/journal.pone.0106009 Copyright: ß 2014 Myczek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its supporting information files. Funding: This study was supported by grants from the National Institutes of Health (NIH): NIH/NIA AG027544-06, OD010420 (FML), and by The Larry Hillblom foundation #2013-A-016-FEL (DBV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interest exist.
    PLoS ONE 09/2014; 9(9). · 3.53 Impact Factor