NewScientist has written an article about a new paper from Dr. Larry Feig's group at Tufts University School of Medicine. The paper expands on Feig's previous work(1, 2), which showed that exposure to an enriched environment increases long-term potentiation (LTP) -- a cellular process critical for learning and memory -- in the brains of both normal juvenile mice and mice with genetic LTP deficiencies. (The same effects were not seen in adults, indicating that a critical period exists for this effect.) The most recent study describes how the effects of an enriched environment can be passed on from mother to offspring in both wild-type and mutant mice. If a female mouse is exposed to an enriched environment while she is a juvenile, her offspring from later pregnancies show enhanced LTP and improved performance on memory-based tasks. This is true even though the offspring themselves are never exposed to any environmental enrichment, and the female is removed from the enriched environment before she becomes pregnant. The researchers posit that environmental enrichment leads to some form of heritable epigenetic modification in the mother mice that can be passed on to their offspring.
In the Feig group's previous papers, we learned that mutations in a family of genes called Ras-GRFs can disrupt LTP (as well as long-term depression, or LTD, the converse cellular mechanism to LTP) in the brains of mice. These genes code for proteins that regulate certain other proteins called kinases, which regulate a wide variety of cellular processes by controlling signaling via phosphorylation of different amino acid residues. These biochemical pathways and mechanisms can get extremely complicated and require vast diagrams to explain in full, but for the purposes of this discussion we can just say that Ras-GRF1 is involved with a protein called a p38 Map kinase, and Ras-GRF2 is involved with Erk Map kinase. Together, these proteins and many others help to regulate synaptic plasticity in the brain by helping to potentiate or depress the connections between neurons (that is, by creating LTP or LTD).
Dr. Feig and his colleagues conducted further studies to see whether environmental manipulations might affect the activity of the Ras-GRF pathway in normal and Ras-GRF knockout mice. It was known that environmental enrichment can play a major role in adult neurogenesis, as well as protection against or recovery from certain neurological diseases. You can read more about this in many, many articles, but one interesting paper on the topic comes from Dr. Li-Huei Tsai's lab(3). The Tsai paper describes how environmental enrichment can help mice recover learning and memory function even after massive neuronal loss similar to that seen in Alzheimer's disease. It also associates environmental enrichment with a process called histone acetylation, a form of genetic remodeling that has been implicated in heritable epigenetic modification.
When Dr. Feig exposed his mice to an enriched environment, defined in this study as "an enriched cage (45 x 30 x 25 cm) containing plastic play tubes, cardboard boxes, running wheel, various pet toys, and nesting material that were all changed or rearranged every other day to provide novel stimulation," he observed activation of a normally latent p38 Map kinase signaling cascade. You may remember p38 Map kinase -- it's one of the signaling pathways that works with Ras-GRF proteins to create LTP and LTD. Indeed, it turns out that activation of this signaling cascade, brought on by environmental enrichment, can compensate for the loss of Ras-GRF in knockout mice. Ras-GRF knockout mice that were exposed to an enriched environment have levels of LTP comparable to those of normal mice. Ras-GRF knockouts that received no environmental enrichment had significantly impaired LTP.
So far, fairly straightforward research. The scientists found a biochemical pathway associated with LTP. They observed that genetic manipulations to disrupt that pathway can disrupt LTP. They also observed that environmental manipulations activating a related pathway can restore normal LTP to mutant animals. Now it gets interesting, because they noted that the effects of environmental enrichment on LTP in both normal and mutant mice persist for several months. The group decided to see whether mice that reproduced during the two-month window after environmental enrichment would pass on any benefit to their offspring.
It turns out that they do. The mutant offspring of enriched mutant mice have normal LTP function. They also show enhanced memory formation ability compared to non-enriched mutants in a simple fear conditioning test. (The mice learn to fear a chamber where they have previously received a series of mild electrical shocks.) This effect is independent of paternal enrichment -- that is, it doesn't matter whether or not the fathers are exposed to an enriched environment; only the mother's experience matters. The effect is also independent of maternal care: mutant offspring of enriched mothers who were raised by non-enriched mutant foster mothers still exhibit improved LTP and fear conditioning.
The researchers then tested whether these effects could be passed on to a subsequent generaton -- the grandchildren of the original enriched mice. They found that it could not. The authors offered: "One possible explanation for the limited transmission of this [environmental enrichment] effect is that the phenotype ends at a younger age in the offspring of enriched mice than in their parents, such that it is no longer present and thus not transferable to offspring by the time the F1 generation are old enough to reproduce." Still, this study provides evidence that a mother mouse can somehow respond to changes in her environment in a way that not only alters her capacity for synaptic plasticity but improves the learning and memory function in her young. Why might this happen?
Dr. Feig and his colleagues make a great point in the discussion section of the article. They say: "The enriched environment used as an experimental paradigm in these studies may actually be more natural than a conventional laboratory environment that may border on sensory deprivation. Thus, the transgenerational inheritance of this new LTP-inducing signaling pathway may be a mechanism that has evolved to protect one's offspring from deleterious effects of sensory deprivation, which may be particularly potent in the young and exacerbated by the presence of mutations in signaling molecules like GRF proteins that contribute to synaptic plasticity." In other words, the "control" mice in studies on environmental enrichment might be the ones with abnormal brain function. Laboratory mice spend their entire lives in a shoebox-sized cage where they have nothing to play with and little space for exercise. It may be that the pathway activated by "enrichment" in Dr. Feig's experiments is active in normal, wild mice, and that the mice living in a control environment have lost their ability to induce LTP as effectively. Perhaps in the wild, mother mice with access to the outside world pass on this activated p38 Map kinase to their offspring in a transient manner to protect their brains while they are living in the relatively deprived environment of the nest. The age at which the heritable effect of environmental enrichment wears off is, coincidentally, the age at which baby mice are weaned and leave their nests.
There are many future avenues of research to be pursued based on this work. The next logical step would be to try to determine exactly what is happening in mother mice to allow them to pass on this effect to their offspring -- What physiological changes are occurring upon exposure to enrichment? What genes are being epigenetically modified, by what mechanisms, in response to this environmental stimulus? Since environmental enrichment likely affects many different things, it may be difficult to tease out the exact mechanism by which increased sensory or social stimulation activates a p38 Map kinase cascade, but it couldn't hurt to try. I'm also interested to learn more about why this enrichment-dependent effect on LTP only works in juvenile animals. Can this critical period for p38 Map kinase activation be extended or shifted by further experimental manipulation? Would a similar effect be seen in enriched versus deprived animals of other species, perhaps with a critical period that maps onto some important developmental stage across species?
Regardless of where Dr. Feig's group goes from here, their work has brought a hint of the Lamarckian to a month of celebrating Darwin. Epigenetics is a growing field, and I'm interested to learn more about the intersection between environmental factors, epigenetic modification, and neurological processes in healthy and dysfunctional brains.
J. A. Arai, S. Li, D. M. Hartley, L. A. Feig (2009). Transgenerational Rescue of a Genetic Defect in Long-Term Potentiation and Memory Formation by Juvenile Enrichment Journal of Neuroscience, 29 (5), 1496-1502 DOI: 10.1523/JNEUROSCI.5057-08.2009
1. Li S, Tian X, Hartley DM, Feig LA. The environment versus genetics in controlling the contribution of MAP kinases to synaptic plasticity. Curr Biol 16:2303–2313. (2006) doi: 10.1016/j.cub.2006.10.028
2. Li S, Tian X, Hartley DM, Feig LA. Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. J Neurosci 26:1721–1729. (2006) doi: 10.1523/JNEUROSCI.3990-05.2006
3. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature 447:178–182. (2007) doi: 10.1038/nature05772
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