Yu, R. Q. | Search bioRxiv

bioRxiv2018

Differential effects of extended exercise and memantine treatment on adult neurogenesis in male and female rats

The creation of new neurons in adulthood has potential for treating a number of disorders that are characterized by neurodegeneration or impaired plasticity. Animal models of reduced neurogenesis, and studies of the volume and structural integrity of the hippocampus in humans, suggest a possible therapeutic role for adult neurogenesis in age-related cognitive decline, depression, and schizophrenia. Research over the past 20 years has identified a number of approaches for enhancing adult neurogenesis, such as exercise, NMDA receptor antagonists, antidepressant drugs and environmental enrichment. However, despite the chronic nature of many disorders that impact the human hippocampus, most animal studies have only examined the efficacy of neurogenic treatments over relatively short timescales ([~]1 month or less). Additionally, investigations into the regulation of neurogenesis typically include only 1 sex, even though many disorders that affect the hippocampus differentially impact males and females. Here, we therefore tested whether two known pro-neurogenic treatments, running and the NMDA receptor antagonist, memantine, could lead to long-term increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis in both sexes, but effects were minimal after 1 month (both sexes) and completely absent after 5 months (males). Similarly, a single injection of memantine (sMEM) only transiently increased adult neurogenesis in both males and females. To determine whether extended increases in neurogenesis were possible with 2 months of RUN and MEM treatments, we subjected rats to interval running (iRUN), weekly memantine injections (mMEM), or combined treatments (iRUN-mMEM, mMEM-iRUN). We found that 2 months of iRUN increased DCX+ cell density in females but iRUN-mMEM treatment increased DCX+ cell density in males. However, analyses with thymidine analogs revealed that neurogenesis was minimally increased during the initial phases of the 2 month treatments. Collectively, our findings identify sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments that target the hippocampus.

neuroscience↗

bioRxiv2016

Early survival and delayed death of developmentally-born dentate gyrus neurons

The storage and persistence of memories depends on plasticity in the hippocampus. Adult neurogenesis produces new neurons that mature through critical periods for plasticity and cellular survival, which determine their contributions to learning and memory. However, most granule neurons are generated prior to adulthood; the maturational timecourse of these neurons is poorly understood compared to adult-born neurons, but is essential to identify how the dentate gyrus, as a whole, contributes to behavior. To characterize neurons born in the early postnatal period, we labeled dentate gyrus neurons born on postnatal day 6 (P6) with BrdU and quantified maturation and survival across early (1 hour to 8 weeks old) and late (2-6 months old) cell ages. We find that the dynamics of developmentally-born neuron survival is essentially the opposite of neurons born in adulthood: P6-born neurons did not go through a period of cell death during their immature stages (from 1-8 weeks). In contrast, 17% of P6-born neurons died after reaching maturity, between 2-6 months of age. Delayed death was evident from the loss of BrdU+ cells as well as pyknotic BrdU+caspase3+ neurons within the superficial granule cell layer. Patterns of DCX, NeuN and activity-dependent Fos expression indicate that developmentally-born neurons mature over several weeks and a sharp peak in zif268 expression at 2 weeks suggests that developmentally-born neurons mature faster than adult-born neurons (which peak at 3 weeks). Collectively, our findings are relevant for understanding how developmentally-born dentate gyrus neurons contribute to memory and disorders throughout the lifespan. High levels of early survival and zif268 expression may promote learning, while also rendering neurons sensitive to insults at defined stages. Late neuronal death in young adulthood may result in the loss of hundreds of thousands of dentate gyrus neurons, which could impact memory persistence and contribute to hippocampal/dentate gyrus atrophy in disorders such as depression.

neuroscience↗