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

Highlights

• Adult neurogenesis is increased in the dorsal dentate gyrus by running.

• Running enhances short-term plasticity and input from lateral entorhinal cortex.

• Running recruits input from the caudal–medial entorhinal cortex.

• Input from the supra- and medial mammillary nuclei increases 13-fold by running.

• Synaptic transmission onto new neurons is unchanged, mature neurons are inhibited.

Abstract

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.

Introduction

Human and animal research indicates that exercise benefits brain function throughout the lifespan. In adult humans, spatial memory, working memory, and processing speed are improved by exercise (Voss et al., 2013), and in children academic achievement is enhanced (Donnelly et al., 2009). Furthermore, both epidemiological and intervention studies in aging subjects indicate that exercise may delay or prevent the onset of Alzheimer's disease (Larson et al., 2006, Lautenschlager et al., 2008). Research shows that the hippocampus, a brain area important for spatial navigation and memory formation (Buzsáki and Moser, 2013), is substantially modulated by physical activity (Voss et al., 2013). In humans, exercise increases hippocampal volume and vascularization (Erickson et al., 2011, Pereira et al., 2007, Maass et al., 2015). In rodents, multiple running-induced changes have been observed in the hippocampus (Vivar et al., 2013). Specifically, hippocampal neurotransmitter, neurotrophin levels, neuronal spine density, synaptic plasticity, angiogenesis and adult neurogenesis are increased with running (Voss et al., 2013, Sleiman and Chao, 2015, Patten et al., 2015).

In the hippocampus, the dentate gyrus subfield is considered to be particularly important for pattern separation, the processing of similar incoming information into distinct events and experiences (Marr, 1971, Treves et al., 2008, Yassa and Stark, 2011). New dentate granule cell neurons (Altman and Das, 1965, Eriksson et al., 1998) that become functionally integrated into the hippocampal circuitry (van Praag et al., 2002, Vivar et al., 2012) are considered to contribute to fine discrimination processes (Sahay et al., 2011a). Deficient adult neurogenesis impairs the ability to distinguish between closely related stimuli (Clelland et al., 2009, Guo et al., 2011, Tronel et al., 2012), whereas running-induced and transgenic elevation of neurogenesis enhance the ability to differentiate between similar stimuli (Creer et al., 2010, Sahay et al., 2011b, Bolz et al., 2015). However, whether such cognitive improvements can be attributed solely to a local increase in neurons is unclear. Lesion of perirhinal–lateral entorhinal cortex (PRH–LEC), a major input to new neurons, reduces performance on a high interference task in a touchscreen (Vivar et al., 2012). In addition, discrimination deficits result from silencing of synaptic transmission of adult-born neurons onto area CA3 (Nakashiba et al., 2012). Furthermore, new neuron ablation impairs area CA3 contextual encoding processes (Niibori et al., 2012). Thus, running-induced enhancement of mnemonic tasks may result from modifications in new neuron networks in conjunction with elevated levels of neurogenesis.

To begin to address this issue we analyzed the effects of voluntary wheel running on the afferent circuitry of new neurons. The majority of projecting cells were located in the entorhinal cortex. Running increased entorhinal input to new neurons, in proportion to the enhanced neurogenesis. In particular, lateral entorhinal cortex innervation and paired-pulse facilitation of lateral perforant pathway synapses onto new neurons was enhanced by running, which may support pattern separation in the dentate gyrus. Furthermore, running upregulated caudo-medial entorhinal cortex inputs, considered to convey temporal and spatial information to the hippocampus. Concurrently, subcortical monosynaptic input from medial mammillary nucleus and supramammillary nucleus, while few in cell number, showed a striking elevation (~ 13-fold). Innervation from medial septum was enhanced proportionate to the elevated neurogenesis. Our research shows that running recruits input to new hippocampal neurons from distal brain areas relevant to contextual and spatial–temporal information processing, and the genesis of the hippocampal theta rhythm. Overall, effects of running on the brain go beyond increased hippocampal neurogenesis, to modifications of cortical and subcortical brain regions that comprise the circuitry of new neurons.