Differential Effects of Extended Exercise and Memantine Treatment on Adult Neurogenesis in Male and Female Rats

Abstract

Adult neurogenesis has potential to ameliorate a number of disorders that negatively impact the hippocampus, including age-related cognitive decline, depression, and schizophrenia. A number of treatments enhance adult neurogenesis including exercise, NMDA receptor antagonism, antidepressant drugs and environmental enrichment. Despite the chronic nature of many disorders, most animal studies have only examined the efficacy of neurogenic treatments over short timescales (≤1 month). Also, studies of neurogenesis typically include only 1 sex, even though many disorders differentially impact males and females. We tested whether two known neurogenic treatments, running and the NMDA receptor antagonist, memantine, could cause sustained increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis, but effects were minimal after 1 month and completely absent after 5 months. Similarly, a single injection of memantine (sMEM) transiently increased neurogenesis before returning to baseline at 1 month. To determine whether neurogenesis could be increased over a 2-month timeframe, we next subjected rats to interval running (iRUN), multiple memantine injections (mMEM), or alternating blocks of iRUN and mMEM. Two months of iRUN increased DCX cells in females and iRUN followed by mMEM increased DCX cells in males, indicating that neurogenesis was increased in the later stages of the treatments. However, thymidine analogs revealed that neurogenesis was minimally increased during the initial stages of the treatments. These findings highlight temporal limitations and sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments.

Adult-born neurons inhibit developmentally-born neurons in the dentate gyrus

“…Indeed, combined RUN/MEM treatment increased immature DCX + cell density and reduced activity in both developmentally-born neurons and the broader granule cell population. The neurogenic efficacy of RUN/MEM treatment at 4 months extends our recent finding that 2 months of treatment also increases neurogenesis in male rats [33]. Thus, RUN/MEM is capable of promoting neurogenesis over extended intervals.…”

“…1C; T29=2.065, P=0.048). Whereas we have previously reported that alternating blocks of RUN/MEM increase neurogenesis (DCX + cells) at 2 months in male rats [33], these results indicate that RUN/MEM treatments can result in sustained increases in neurogenesis that are maintained even after 4 months of treatment.…”

“…Here we investigated functional relationships between DG neurons born in adulthood and the peak of DG development. Using RUN/MEM treatment to increase adult neurogenesis [33], and GFAP-TK rats to decrease adult neurogenesis [44], we tested the hypothesis that neurogenesis reduces activity in developmentally-born DG neurons. Indeed, combined RUN/MEM treatment increased immature DCX + cell density and reduced activity in both developmentally-born neurons and the broader granule cell population.…”

“…Neurogenesis was increased by subjecting rats to alternating blocks of intermittent running and memantine injections, as we have done previously [33]. Rats ran during the dark phase because they are more active at this time [34], and because this paradigm matches that of our previous work [33]. Briefly, running wheel cages consisted of a 23" x 18" x 15" plastic tub containing aspen chip bedding, ad libitum rat chow, water, and a 12" running wheel (Wodent Wheel, Exotic Nutrition).…”

“…Running distances were calculated as we have done previously, with individual distances tracked on weekdays during 4-hour blocks [33]. On weekends, when rats were pair housed with the running wheels, individual distances were estimated by assuming the relative distances 2 cage mates ran during the week held for the weekend as well.…”