Experience-Dependent Structural Plasticity of Adult-Born Neurons in the Aging Hippocampus

摘要

Synaptic modification in cortical structures underlies the acquisition of novel information that results in learning and memory formation. In the adult dentate gyrus, circuit remodeling is boosted by the generation of new granule cells (GCs) that contribute to specific aspects of memory encoding. These forms of plasticity decrease in the aging brain, where both the rate of adult neurogenesis and the speed of morphological maturation of newly-generated neurons decline. In the young-adult brain, a brief novel experience accelerates the integration of new neurons. The extent to which such degree of plasticity is preserved in the aging hippocampus remains unclear. In this work, we characterized the time course of functional integration of adult-born GCs in middle-aged mice. We performed whole-cell recordings in developing GCs from Ascl1CreERT2;CAGfloxStopTom mice and found a late onset of functional excitatory synaptogenesis, which occurred at 4 weeks (vs. 2 weeks in young-adult mice). Overall mature excitability and maximal glutamatergic connectivity were achieved at 10 weeks. In contrast, large mossy fiber boutons (MFBs) in CA3 displayed mature morphological features including filopodial extensions at 4 weeks, suggesting that efferent connectivity develops faster than afference. Notably, new GCs from aging mice exposed to enriched environment for 7 days showed an advanced degree of maturity at 3 weeks, revealed by the high frequency of excitatory postsynaptic responses, complex dendritic trees, and large size of MFBs with filopodial extensions. These findings demonstrate that adult-born neurons act as sensors that transduce behavioral stimuli into major network remodeling in the aging brain.