Sunday, October 15, 2017

What Adulthood Looks Like in the Brain

A gene expression turning point in the mid-20's correlates with onset of schizophrenia, among other things.

Are brains magic? No. They may be magic-al in how they bring us the world in living color, but it is mechanism all the way down, as can be seen from the countless ailments that attack the brain and its functions, such as the dramatic degradation that happens in boxers and football players who have been through excessive trauma. All that amazing function relies on highly complex mechanisms, but we are only beginning to understand them.

One way to look at the brain is through its components, the proteins expressed from our genomes. Those proteins run everything, from the structural building program to the brain's metabolism and exquisitely tuned ion balances. Current technology in molecular biology allows researchers to tabulate the expression of all genes in any tissue, such as the brain or parts thereof. This is sort of like getting a quantitative parts list for all the vehicles active in one city at a particular time. It might tell you a little about the balance between mass transit and personal cars, and perhaps about brand preferences and wealth in the city, but it would be hard to conclude much about detailed activity patterns or traffic issues, much less the trajectories or motivations of the individual cars- why they are going where they are going.

So, while very high-tech and big-data, this kind of view is still crude. A recent paper deployed these methods to look at gene expression in the brain over time, in humans and mice, to find global patterns of change with age, and attempt to correlate them with diseases that are known to have striking age-related characteristics, like schizophrenia.

They duly found changes of gene expression over time, and tried to concentrate on genes that exhibit dramatic changes, reversing course over time, or plateauing at times that they call turning points. Below are a few genes that show a dramatic decline in mice, from youth to adolescence.

Expression of selected proteins in frontal cortex of mice, with age, showing turning points in early adulthood, which is about five months here in mice. These genes each have variants or other known associations with schizophrenia.

Perhaps the most interesting result was that, if they tabulate all the cases of turning points, most seem to occur at early adulthood. The graphs below show rates of genes with turning points at various age points. One can see that by about age 30 and certainly 40, (about age 7 months in mice), the brain is set in stone, gene-wise. There is little further change in gene expression.

Number of genes by age when their expression shifts direction, either up, down, or plateauing.

In contrast, age 15 to 30 is a very active time, with the most genes changing direction, and the largest changes of expression peaking about age 28. Given the many genes and complex patterns available, the authors reasoned that they could do some reverse engineering, predicting a sample's age from its expression pattern. And using only 100 genes, they show that they can reliably estimate the age of the source, within about 5 years. Secondly, they broke the gene sets down by the cell type where they are expressed, and found distinct patterns, like genes typical of endothelial cells attaining peaks of expression very early, before 10 years of age, as physical growth of the brain is maximal, while genes typical of pyramidal neurons, one of the most important and complex types of neurons, reach their inflection points much later, in the mid-twenties.

Types of genes and their rough times of expression shift, by age. Most key neuronal genes seem to settle into unchanging patterns in early adulthood. PSD is post-synaptic density, typical of synapses where learning takes place.

Particularly interesting to the authors are genes associated with post-synaptic density, part of the learning and plasticity system where connections between neurons are managed. These genes were especially enriched with turning points in early adulthood, and also feature a disproportionate number of genes implicated in schizophrenia, whose onset occurs around this time. The genes tended to be turned down at this time, in neurons. While these observations correlate with the age-specific nature of schizophrenia, they do not go much farther, unless it could be shown that the genetic variants that confer susceptibility are perhaps mal-regulated and more active than they are supposed to be, or some other mechanism that makes the connection between the defect (all of which so far which have very weak effects), and the outcome. For example, one such variation was found to increase expression of its gene, which is present and functional in the post-synaptic densities.

It is interesting to see the developmental program of our brains portrayed in this new way, but it is only a glimpse into issues that require far more detailed investigation.


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