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Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable?

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Abstract

Adult-generated neurons in the dentate gyrus of the hippocampus have been the focus of many studies concerned with learning and memory (L&M). It has been shown that procedures like environmental enrichment (EE) or voluntary physical exercise (Vex) can increase neurogenesis (NG) and also enhance L&M. It is tempting to conclude that improvements in L&M are due to the increased NG; that is, a causal relationship exists between enhancement of NG and enhancement of L&M. However, it remains unclear whether the L&M enhancement observed after these treatments is causally dependent on the increase in newborn neurons in the dentate gyrus. It remains a possibility that some unspecified change – a “third variable” – brought about by EE and/or Vex could be a causal determinant of both NG and L&M. We suggest that this third variable could be neurotrophic and/or plasticity-related factors such as BDNF. Indeed, both EE and Vex can induce expression of such proteins, and BDNF in particular has long been linked with L&M. In addition, we argue that a very likely source of variation in previous experiments was the load on “pattern separation”, a process that keeps similar memories distinct, and in which NG has been shown to be critically involved. To attempt to bring these ideas together, we present preliminary evidence that BDNF is also required for pattern separation, which strengthens the case for BDNF as a candidate third variable. Other ways in which BDNF might be involved are also discussed.

Highlights

► Environmental enrichment is associated with increased learning and memory. ► Voluntary exercise is associated with increased learning and memory. ► Environmental enrichment and voluntary exercise increase neurogenesis and BDNF. ► Both neurogenesis and BDNF are required for pattern separation. ► BDNF might be a third variable responsible for learning and memory enhancement.

Section snippets

Effects of environmental enrichment and physical exercise on neurogenesis and learning and memory

The adult brain produces new neurons in substantial numbers, a phenomenon that has been firmly established since its initial discovery [1], [2]. Of particular interest to researchers interested in the neurobiology of L&M are the newborn granule neurons in the hippocampus. These cells functionally integrate into the hippocampal dentate gyrus (DG) network [3], and receive synaptic input from the entorhinal cortex and form functional terminals onto CA3 cells [4], [5]. In addition, adult-born

Correlation, causation, and the problem of the third variable

As discussed previously, there is much evidence to demonstrate that both EE and Vex can increase NG in the adult hippocampus. However, whether the beneficial effects of EE and Vex on L&M are caused directly by NG, remains unclear. One obvious problem is that correlation does not imply causation. One alternative interpretation of the finding that NG correlates with EE or Vex is that, rather than increases in NG being causally related to improvements in L&M, there may be a “third variable” caused

Brain-derived neurotrophic factor (BDNF) as a possible third variable

Several lines of evidence provide a link between BDNF and L&M. First, BDNF has been found to play an important role in the late phase of long-term potentiation (LTP), the best known cellular plasticity phenomenon in the brain [36], [37], [38], which is thought to be one of the plastic phenomena that underlie L&M [39], [40]. For example, Pang and others have shown that BDNF is necessary for the late phase of LTP (L-LTP) in the CA1 region of the hippocampus [41]. Second, BDNF mRNA and protein

Concluding remarks

To summarise, we have suggested that in experiments investigating the link between EE, Vex, NG and L&M, there could exist a third variable, brought about by EE and/or Vex, acting as a causal determinant of both NG and L&M, and that this third variable could be a neurotrophic and/or plasticity-related factor such as BDNF. Of course this suggestion could be wrong; further appropriate experiments testing EE/Vex with NG knock-down and L&M (ideally examining pattern separation) may well generate

Acknowledgments

The authors would like to thank Dr. Henriette van Praag for helpful discussion of the manuscript. This work was funded by a grant from the BBSRC (TJB, LMS and PB). CAO is supported by a grant from Janssen Pharmaceuticals.

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