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 trainning may lead to neuroprotection and promote functional recovery, although little is known about the molecular and cellular mechanisms driving this event. To investigate the underlying mechanisms and levels of functional recovery elicited by repeated physical training or environmental enrichment, we generated an inducible 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 therapeutic strategies for various neurological disorders associated with focal neuronal loss.
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