Aging and running exercise affect adult hippocampal neurogenesis via different mechanisms

Abstract

Adult hippocampal neurogenesis continues throughout life and has been associated with the formation exhibition and clearance of certain types of memory The number of newborn neuron is determined by 1) the number of neural stem/progenitor cell (NSC) 2) proliferation of NSCs 3) neuron lineage specification and 4) survival of the newborn neurons The number of adult hippocampal neurogenesis declines during aging but can be increased by running exercise (Ex) However it remains unclear which of the determinants are affected by aging and Ex Here we characterized the four determinants in different ages (2 5 8 11 20 months) of mice that received one month of Ex training or remained sedentary (Sed) An intraperitoneal injection of bromodeoxyuridine (BrdU) was given two hours before sacrifice to label the newly proliferated cells The results showed that the numbers of newborn neuron double labeled by BrdU and DCX (a specific marker for immature neuron) were massively decreased (>95%) by the time the mice were 9-month-old while Ex increased the numbers of newborn neuron The numbers of nestin+ NSC were mildly reduced during aging and Ex delayed the decline of NSC numbers during aging The proliferation rates (numbers of BrdU+ cell/ numbers of nestin+ cell) were greatly decreased by the time the mice were 9-month-old and were not changed by Ex The rates of neuron lineage specification (numbers of BrdU+DCX+ cell/ numbers of BrdU+ cell) were decreased during aging but increased by Ex The survival rate (numbers of BrdU+ cell at four weeks after BrdU injection/ numbers of BrdU+ cell at two hours after BrdU injection) was not affected by age or Ex Aging greatly reduced newborn neuron maturation (numbers of DCX+ dendritic branch and length of DCX+ dendrite) while Ex potently enhanced newborn neuron maturation Knocking down the receptor of brain-derived neurotrophic factor (TrkB) reduced the numbers of both newborn cell and immature neuron In conclusion age-associated decline of hippocampal neurogenesis is mainly caused by reduction of NSC proliferation rate Ex increases adult hippocampal neurogenesis by sustaining the numbers of NSC and increasing the rates of neuron lineage specification Because Ex does not restore the massive decline of NSC proliferation rate the effect of Ex on adult hippocampal neurogenesis during aging is limited Rather Ex greatly enhances the maturation of newborn neurons TrkB is involved in adult hippocampal neurogenesis but its underlying mechanism requires further investigation

Date of Award	2014 Aug 16
Original language	English
Supervisor	Yu-Min Kuo (Supervisor)