Neurogenesis: state of the field and implications for education

By Lisa M. Saksida, Reader in Cognitive Neuroscience, University of Cambridge. 

Nearly everything that we do has an impact on our brains. Changes in our behaviour and in our environment can lead to structural and functional alterations in our brains. These changes can happen at a number of different levels, from molecular and cellular changes that happen as a result of learning, up to the reorganization of entire cortical areas as a result of injury. This process is sometimes called experience-dependent plasticity, and it occurs at all ages, although the degree of plasticity is relatively high in childhood and decreases over the course of our lifetime. Neuroplasticity is what allows us to learn, to remember, to adapt and to modify our actions on the basis of experience.

One specific aspect of neuroplasticity that has received much attention over the past two decades is adult neurogenesis – the notion that new neurons can be produced in an adult brain. Until the mid-1960s it was firmly believed that neurogenesis in mammals ends in the period just after birth. Technological developments in the 1990s led to an ongoing period of intensive research in this area, and it is now well-established that every day thousands of new neurons are produced in the adult mammalian brain (Cameron and McKay, 2001; Spalding et al., 2013). Many of these new neurons are produced within a region of the brain called the hippocampus, which has long been established as being critical for learning and memory processes.

Although the process of neurogenesis has been well-studied, it is only very recently that the specific functional or behavioural consequences of neurogenesis have been considered. Increased neurogenesis generally correlates with better memory, as might be expected when the part of the brain associated with learning and memory is increased in volume. But what is the specific role of these new neurons in learning and memory?

There are several theories, but the largest body of evidence so far (although it is still very preliminary) supports the idea that new neurons in the hippocampus are important for a memory process known as “pattern separation” (Clelland et al., 2009) . In contrast to our usual notion of memory as the ability to retain information over time, pattern separation at the behavioural level refers to the ability to keep memories distinct and resistant to confusion. Imagine you are asked to remember where you parked your car this morning, yesterday morning and the day before. This task is difficult not because you need to remember something that happened a long time ago– it is easy to remember much of what happened three days ago – but because the similar memories of parking your car in the same car park over three consecutive mornings are so easily mixed up.

One very interesting aspect of neurogenesis is that it is highly responsive to environmental influences, some of which are described below. A number of simple factors have been shown to enhance neurogenesis. Less research has been done on the specific knock-on effects of increased neurogenesis on cognition, but some promising initial studies have been performed.

Exercise

Aerobic exercise causes a large increase in the number of cells that are produced. Wheel-running in rodents can lead to a 3 – 4 fold increase in the production and survival of new neurons in the hippocampus (van Praag, 2008). This increase can be maintained throughout life in rodents, and consistent running from youth to middle age can prevent the age-related decline in neurogenesis that is normally observed(Kronenberg et al., 2006). Exercise also has well-established beneficial effects on cognition, and the degree of neurogenesis can be correlated with the degree of cognitive improvement. Recently it was shown that increased neurogenesis caused by exercise resulted in improved pattern separation abilities in mice. In contrast, older mice whose neurogenesis did not increase with exercise did not show this improvement (Creer et al., 2010). Importantly, however, many factors other than neurogenesis are affected by exercise (e.g., networks of blood vessels and changes in the strength of connections between neurons) so it is difficult to pinpoint neurogenesis as the only, or even the most important factor. But it is safe to say that the beneficial effects of exercise are likely to be mediated at least in part by neurogenesis.

Diet

Mild caloric restriction reduces age-related cognitive decline and also increases neurogenesis, but the mechanisms underlying this finding are unclear. Some evidence suggests the involvement of a hunger-stimulating hormone that regulates appetite and body weight: ghrelin. Ghrelin levels increase before meals and decrease after them. Administering ghrelin directly to the brain can improve learning and memory(Diano et al., 2006; Atcha et al., 2009), and also increases hippocampal neurogenesis(Moon et al., 2009). A recent study has shown that, like exercise, increases in neurogenesis induced by ghrelin are accompanied by improvements in pattern separation. Some researchers have suggested that the optimal time for learning may be when the stomach is empty, since ghrelin levels are higher at these times.

Mental Training

Even if lots of new neurons are generated, they won’t have much of an effect if they don’t survive and become integrated into existing brain circuits important for learning and memory. In fact, about half of newly-generated neurons undergo programmed cell death within a couple of weeks after their birth. However, these new cells can be kept alive via cognitive training. When animals learn difficult tasks that require a sustained effort over many days, most new cells in the hippocampus stay alive for several months and become integrated into learning and memory circuits. Interestingly, less intensive training procedures do not keep the cells alive, and training only works when successful learning occurs; if you prevent learning pharmacologically during training the cells do not survive.   Since this type of cognitive training enhances neuronal survival, researchers have suggested that combining it with a physical training regime that increases the number of new neurons may be an optimal strategy for cognitive enhancement (Curlik and Shors, 2013).

Environmental enrichment

Complex or novel environmental conditions can provide high sensory, cognitive and motor stimulation and increase both hippocampal neurogenesis and the integration of newly born cells into functional circuits (Paylor et al., 1992; van Praag et al., 1999). At the behavioural level, enrichment enhances learning and memory, reduces memory decline in aged animals and decreases anxiety.

What are the limiting factors of applying this area of neuroscience to education?

The main limiting factor is that we do not at present have the tools required to study neurogenesis in humans. All of the data so far have been generated in animal models. In fact, until last year there was no clear evidence of neurogenesis in humans at all. Several researchers have argued that the degree of neurogenesis has likely decreased during primate evolution and, even if some human neurogenesis does occur, it is likely to be insufficient to affect brain function (Rakic, 1985; Kempermann, 2012).

However a recent post-mortem study which assessed hippocampal neurogenesis in humans by carbon dating the age of different neurons suggested that neurons are generated throughout human adulthood at a rate similar to mice (Spalding et al., 2013). Thus, the studies that have been done so far on mice are likely to be relevant to humans and neurogenesis in humans may indeed be sufficient to affect brain function.

A second limiting factor is that we are only starting to explore the functional and behavioural outcomes of increased neurogenesis. We need a much better idea of specifically how neurogenesis influences cognitive function if we want to influence educational strategies effectively. Knowing that exercise increases neurogenesis is interesting, but doesn’t help us much; we already know that exercise is good for cognitive function. Knowing that neurogenesis contributes to a specific function such as pattern separation, on the other hand, may give us something to think about. Perhaps certain types of material rely more on pattern separation for successful learning – for example, material in which the challenge is to learn a number of similar things—and so would benefit more from increased neurogenesis. Perhaps individual students have difficulties with pattern separation due, for example, to early life stress or depression, both of which are factors that affect neurogenesis negatively. It would in principle be possible to quantify such difficulties, and remedial training programmes to enhance neurogenesis might benefit such students. If ghrelin does indeed enhance neurogenesis and pattern separation ability, then tasks requiring high degrees of pattern separation might be better placed before lunch.

However it needs to be emphasised that the above is all speculation, and much more research needs to be done before implementing such programmes would make any sense. Such interventions may increase neurogenesis and enhance memory, but they will have other effects, and some may not be positive. Indeed the very act of increasing neurogenesis itself may have some negative effects; for example, some researchers have suggested that neurogenesis in the very young is responsible for infantile amnesia (the inability of adults to remember events during the first few years of life) (Josselyn and Frankland, 2012).Any form of cognitive enhancement needs to be approached with caution. More is not always better.

 

Atcha Z, Chen W-S, Ong AB, Wong F-K, Neo A, Browne ER, Witherington J, Pemberton DJ (2009) Cognitive enhancing effects of ghrelin receptor agonists. Psychopharmacology 206:415–427.

Cameron HA, McKay RD (2001) Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435:406–417.

Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325:210–213.

Creer DJ, Romberg C, Saksida LM, Van Praag H, Bussey TJ (2010) Running enhances spatial pattern separation in mice. Proceedings of the National Academy of Sciences 107:2367–2372.

Curlik DM 2nd, Shors TJ (2013) Training your brain: Do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus? Neuropharmacology 64:506–514.

Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neuroscience 9:381–388.

Josselyn SA, Frankland PW (2012) Infantile amnesia: a neurogenic hypothesis. Learn Mem 19:423–433.

Kempermann G (2012) New neurons for “survival of the fittest.” Nat Rev Neurosci 13:727–736.

Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G (2006) Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiology of Aging 27:1505–1513.

Moon M, Kim S, Hwang L, Park S (2009) Ghrelin regulates hippocampal neurogenesis in adult mice. Endocrine Journal 56:525–531.

Paylor R, Morrison SK, Rudy JW, Waltrip LT, Wehner JM (1992) Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats. Behav Brain Res 52:49–59.

Rakic P (1985) Limits of neurogenesis in primates. Science 227:1054–1056.

Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J (2013) Dynamics of Hippocampal Neurogenesis in Adult Humans. Cell 153:1219–1227 Available at: http://www.sciencedirect.com/science/article/pii/S0092867413005333.

van Praag H (2008) Neurogenesis and exercise: past and future directions. Neuromolecular Med 10:128–140.

van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running Enhances Neurogenesis, Learning, and Long-Term Potentiation in Mice. Proc Natl Acad Sci USA 96:13427–13431.