Running is the neurogenic and neurotrophic stimulus in environmental enrichment

Abstract

Environmental enrichment (EE) increases dentate gyrus (DG) neurogenesis and brain-derived neurotrophic factor (BDNF) levels. However, running is considered an element of EE. To dissociate effects of physical activity and enrichment on hippocampal neurogenesis and BDNF levels, young female C57Bl/6 mice were housed under control, running, enrichment, or enrichment plus running conditions, and injected with bromodeoxyuridine. Cell genesis was assessed after 12 d and differentiation was analyzed 1 mo later. In addition, locomotor activity in the open field and hippocampal mature BDNF peptide levels were measured. Open-field adaptation was improved in all groups, compared to controls, but more so with running. New cell proliferation, survival, neuron number, and neurotrophin levels were enhanced only when running was accessible. We conclude that exercise is the critical factor mediating increased BDNF levels and adult hippocampal neurogenesis.[Supplemental material is available for this article.]Exposure to environmental enrichment (EE) has positive effects on brain function, including increased numbers of dendritic branches and spines, enlargement of synapses, and improved cognition (Bennett et al. 1964;Rosenzweig and Bennett 1996). More recently, it was discovered that EE enhances the survival of newly born neurons in the dentate gyrus (DG) of the hippocampus (Kempermann et al. 1997) and increases brain-derived neurotrophic factor (BDNF) levels (Falkenberg et al. 1992;Rossi et al. 2006;Sun et al. 2010). EE has many aspects, including increased opportunity for learning, socialization, and physical activity. Among these, exercise was found to enhance neurogenesis (van Praag et al. 1999). Subsequently, physical activity and enrichment have been regarded as equivalent neurogenic stimuli, albeit with different underlying mechanisms. Exercise is considered to mainly enhance cell proliferation, whereas enrichment is deemed to increase new cell survival (Olson et al. 2006;Kempermann et al. 2010). However, in many studies the enriched environment includes physical activity (Kempermann et al. 1997(Kempermann et al. , 1998van Praag et al. 1999;Rossi et al. 2006;Schloesser et al. 2010;Sun et al. 2010), making it difficult to assess the unique contributions of EE and exercise to adult neurogenesis, neurotrophin levels, and behavior.The current study aims to directly differentiate between the effects of enriched environment only (EEO), physical activity (RUN), and the combination of enrichment and running (EER). Here we show that running is the critical factor in stimulating adult hippocampal neurogenesis and enhancing mature BDNF peptide levels. Moreover, enrichment in the absence of running does not increase adult hippocampal neurogenesis or BDNF levels in the hippocampus. Open-field adaptation was improved in all groups as compared to controls, but more so in the groups that included running. These findings suggest that enrichment and exercise are distinct functional interventions.Forty female C57B1/6 mice (5 wk old) were div...

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…APP SWE /PS-1 E9 mice which were housed under environmental enrichment conditions from two months of age to 8.5 months old surprisingly displayed an exacerbated amyloid pathology compared to their counterparts housed under standard conditions (Jankowsky et al, 2003). This finding could be explained however by the low ratio of running wheels to mice in the cage, which is in line with more recent work from the van Praag laboratory highlighting the importance of the running wheel in the enriched environment (Kobilo et al, 2011). Subsequent studies reported an amelioration in amyloid pathology in APP SWE /PS-1 E9 mice and improvements in cognitive function in the APP SWE mice housed in an enriched environment (Arendash et al, 2004;Lazarov et al, 2005) Building upon these data, studies have also investigated the use of exercise exclusively in mouse models of AD and have made some interesting observations.…”

“…While there is still much focus on the signalling mechanisms by which exercise effects are mediated, upregulation of the neurotrophin brain-derived neurotrophic factor (BDNF) has been consistently reported following exercise interventions. Increased expression of hippocampal BDNF and its receptor TrkB has been observed following voluntary wheel running (Gibbons et al, 2014;Kobilo et al, 2011;Marlatt et al, 2012) and forced treadmill exercise Griffin et al, 2009;Wu et al, 1985). At a behavioural level, improvements in spatial learning and memory, associative learning and recognition memory have all been observed in animals following exercise training.…”

“…Many research groups have independently reproduced these results and indeed have built upon this work further. Studies have demonstrated that voluntary wheel running (both in mice and rats) increases cell proliferation, neuronal differentiation and cell survival in the DG (Bruel-Jungerman et al, 2009;Garrett et al, 2012;Gibbons et al, 2014;Kobilo et al, 2011). Interestingly, it has been demonstrated that even a relatively short exercise exposure can be pro-neurogenic.…”

“…Housing of laboratory rodents in enriched environments compared to standard laboratory housing increases hippocampal neurogenesis and also improves cognitive performance (Kempermann et al, 1997). It is worthwhile to note that when van Praag and colleagues studied the various components of the enriched environment, they determined the access to exercise in the enriched environment to be the key neurogenic stimulus (Kobilo et al, 2011). Finally, exercise has potent pro-neurogenic and pro-cognitive effects (van Praag et al, 1999a,b) as will be discussed below.…”

The effects of environmental enrichment on biochemical and metric parameters of aged rats

“…In a relevant study, Kobilo et al (2011) investigated the effects of physical activity in EE and concluded that this environment can promote some benefits to the organism such as the increase of brain derived neurotrophic factor (BDNF).…”