Molecular roots of plasticity

A Harvard Medical School press release (via Science Blog) describes a study by Majdan and Shatz in the current Nature Neuroscience:

A new study focusing on the molecular roots of plasticity has found that visual stimulus turns up the expression of some genes and turns down the expression of others, somewhat like a conductor cueing the members of an orchestra. The study also found that during different stages of life in rodents, distinct sets of genes spring into action in response to visual input. These gene sets may work in concert to allow synapses and neural circuits to respond to visual activity and shape the brain, reports the May issue of Nature Neuroscience.
The investigators' identification of many distinct sets of activity-dependent genes follows a shift in neuroscience research toward a more holistic view of the role of genes in neural development and plasticity.
"What we found opens science up to a more global look at genes, from studying one gene at a time to looking at families of genes acting together," said first author Marta Majdan, Harvard Medical School research fellow in neurobiology. These findings suggest that genetic therapies for neurodegenerative diseases, some of which are largely limited to treatment focused on a single gene, will require more extensive knowledge of molecular pathways and gene interactions to be successful.

Why is this interesting? We have known for a long time that there is a critical period of development of visual cortex. If mammals are light deprived during this time period, their cortex will not develop properly. In other words, an environmental stimulus in a critical window is necessary for the "wiring" of neural circuits related to visual perception.

This study examined gene expression in mouse cortex during those time periods to find out which genes are activated at the critical times:

There are critical periods in development when sensory experience directs the maturation of synapses and circuits within neocortex. We report that the critical period in mouse visual cortex has a specific molecular logic of gene regulation. Four days of visual deprivation regulated one set of genes during the critical period, and different sets before or after. Dark rearing perturbed the regulation of these age-specific gene sets. In addition, a 'common gene set', comprised of target genes belonging to a mitogen-activated protein (MAP) kinase signaling pathway, was regulated by vision at all ages but was impervious to prior history of sensory experience. Together, our results demonstrate that vision has dual effects on gene regulation in visual cortex and that sensory experience is needed for the sequential acquisition of age-specific, but not common, gene sets. Thus, a dynamic interplay between experience and gene expression drives activity-dependent circuit maturation (Majdan and Shatz 2006:650).

This has a couple of implications. One is that a deactivation of one or more of the genes that are activated during the developmental window may have the same effect as depriving the individual of the environmental stimulus. So some variation in the development of visual perception might be attributable to variation in this system of genes.

Another is that it takes the coordination of several developmentally relevant genes to introduce this window of plasticity. There may be underlying commonalities -- perhaps these sets of genes that differ in timing may be regulated by a few genes that determine timing. That may imply that changes in life history that impact the timing of environmental cues -- such as changes in gestation lengths, for instance -- may incur a lot of pushback on the part of gene sets that respond to timing. Or it may mean that there are a few underlying genes related to life history timing that can pull effects along with them easily.

And of course, it makes a model for the development of other brain processes where there may be developmental windows, such as language.

The next paper in the issue, by Daniela Tropea and colleagues, is also related to plasticity of the visual cortex and gene regulation. Here's the abstract:

Two key models for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD). Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin expression, implicating parvalbumin-expressing interneurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates molecular pathways related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. Expression of a binding protein of insulin-like growth factor-1 (IGF1) is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo.

So fiddling with the genes does generate changes to plasticity responses after environmental alterations. And Harvard does have a better PR department than MIT...

References:

Majdan M, Shatz CJ. 2006. Effects of visual experience on activity-dependent gene regulation in cortex. Nature Neurosci 9:650-659. DOI link

Tropea D, Kreiman G, Lyckman A, Mukherjee S, Yu H, Horng S, Sur M. 2006. Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nature Neurosci 9:660-668. DOI link