Running throughout Middle-Age Keeps Old Adult-Born Neurons Wired.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.

Vivar C ，Peterson B ，Pinto A ，Janke E ，van Praag H ... -  《eNeuro》

Running rewires the neuronal network of adult-born dentate granule cells.

Exercise improves cognition in humans and animals. Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain area important for learning and memory. It is unclear how running modifies the circuitry of new dentate gyrus neurons to support their role in memory function. Here we combine retroviral labeling with rabies virus mediated trans-synaptic retrograde tracing to define and quantify new neuron afferent inputs in young adult male C57Bl/6 mice, housed with or without a running wheel for one month. Exercise resulted in a shift in new neuron networks that may promote sparse encoding and pattern separation. Neurogenesis increased in the dorsal, but not the ventral, dentate gyrus by three-fold, whereas afferent traced cell labeling doubled in number. Regional analysis indicated that running differentially affected specific inputs. Within the hippocampus the ratio of innervation from inhibitory interneurons and glutamatergic mossy cells to new neurons was reduced. Distal traced cells were located in sub-cortical and cortical regions, including perirhinal, entorhinal and sensory cortices. Innervation from entorhinal cortex (EC) was augmented, in proportion to the running-induced enhancement of adult neurogenesis. Within EC afferent input and short-term synaptic plasticity from lateral entorhinal cortex, considered to convey contextual information to the hippocampus was increased. Furthermore, running upregulated innervation from regions important for spatial memory and theta rhythm generation, including caudo-medial entorhinal cortex and subcortical medial septum, supra- and medial mammillary nuclei. Altogether, running may facilitate contextual, spatial and temporal information encoding by increasing adult hippocampal neurogenesis and by reorganization of new neuron circuitry.

Vivar C ，Peterson BD ，van Praag H 《-》

A combination of running and memantine increases neurogenesis and reduces activation of developmentally-born dentate granule neurons in rats.

During hippocampal-dependent memory formation, sensory signals from the neocortex converge in the dentate gyrus. It is generally believed that the dentate gyrus decorrelates inputs in order to minimize interference between codes for similar experiences, often referred to as pattern separation. The proportion of dentate neurons that are activated by experience is therefore likely to impact how memories are stored and separated. Emerging evidence from mouse models suggests that adult-born neurons can both increase and decrease activity levels in the dentate gyrus. However, the conditions that determine the direction of this modulation, and whether it occurs in other species, remains unclear. Furthermore, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, newborn neurons may not modulate all cells equally. We aimed to investigate whether adult neurogenesis in rats regulates activity in dentate gyrus neurons that are born at the peak of early postnatal development. Adult neurogenesis was increased by subjecting rats to an alternating running and memantine treatment schedule, and it was decreased with a transgenic GFAP-TK rat model. Activity was measured by Fos expression in BrdU+ cells after rats explored a novel environment. Running+memantine treatment increased adult neurogenesis by only 17%, but completely blocked experience-dependent Fos expression. In contrast, GFAP-TK rats had a 68% reduction in adult neurogenesis but normal experience-dependent Fos expression. The inconsistent relationship between neurogenesis and Fos expression suggests that neurogenesis does not regulate DG activity during exploration of a novel environment. Nonetheless, running and memantine may benefit disorders where there is elevated activity in the dentate gyrus, such as anxiety and age-related memory impairments.

Cahill SP ，Martinovic A ，Cole JD ，Seib DR ，Snyder JS ... -  《-》

Adult neurogenesis modifies excitability of the dentate gyrus.

Ikrar T ，Guo N ，He K ，Besnard A ，Levinson S ，Hill A ，Lee HK ，Hen R ，Xu X ，Sahay A ... -  《-》

Stereological Investigation of the Effects of Treadmill Running Exercise on the Hippocampal Neurons in Middle-Aged APP/PS1 Transgenic Mice.

Chao F ，Jiang L ，Zhang Y ，Zhou C ，Zhang L ，Tang J ，Liang X ，Qi Y ，Zhu Y ，Ma J ，Tang Y ... -  《-》