View Full Version : Choose one or the other. . .


Amtram
08-31-13, 08:21 PM
In advance of publication, I read an article about this piece of research in a place I can't link to directly because you need a subscription. . .but here's a link to the unedited paper. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic)

And this is a portion of the article, just to give you an idea of what you're looking at:

Somewhere on the campus of Stanford University, among the stately oaks and tile-roofed temples of scientific inquiry, live Carla Shatz’s super-mice. They learn complex physical tasks more quickly than their ordinary cousins. If one eye is deprived of sight, they rapidly rewire their brains to compensate, then beat normal one-eyed mice on tests of visual acuity. They recover more readily from some brain injuries, too. What sets these rodents apart is their superior ability to form new neural connections, or strengthen existing ones, in response to experience.

Shatz is proud of her prodigies. But when I ask for permission to visit them, the pioneering neurobiologist turns me down. “They’re in a germ-free facility,” she says apologetically, glancing away from a video in which a tiny champion powers through a water maze. Only their handlers are allowed into the lab where the animals are kept, Shatz explains, and even they must shower and don sterile garments before entering. That’s because the mice have incomplete immune systems. They’ve been bred to lack proteins — members of a family called MHCI (which stands for major histocompatibility complex class I) — crucial to fighting pathogens. The same mutation that gives them their supremely adaptive brains has left them with extraordinarily vulnerable bodies.

So by fiddling around with mitochondrial RNA, the researchers gave the mice incredibly plastic brains - but this was done by weakening the protection of the blood-brain barrier to the point that it would take very little to kill the mice, because any pathogen could enter the brain.

Somewhere in the middle, there may be a way to improve the plasticity of the brain without destroying disease resistance. Right now, it's either/or for these mice.

Stevuke79
08-31-13, 10:12 PM
That's pretty cool.

Amtram
09-01-13, 12:01 AM
This is one of those cases in which they were studying one thing and something else astonishing came up. They were really looking at brain chemistry and needed to deplete the immune proteins in the brain to see it - the incredible plasticity was not the goal of the research.

It's not an easy read. I'm going to have to go through it a few more times to see if I can get a handle on it. (Anyone who has more professional knowledge is MORE than welcome to help out. . .)

Some of what was in the paper reminded me of the electrical patterns of savants, in which thoughts that normally pass through the inhibitory mechanism of the parietal lobes before becoming speech or behavior get routed around it. The paper mentions changes in the parietal lobes in a couple of spots, and how this might have some potential in autism research, but I need to mentally take it apart and put it together again to see if they're saying something like that or I'm just making assumptions.

SB_UK
09-01-13, 02:38 AM
The presence of MHCI in neurons also suggests new ways to understand and ultimately to treat neurological and psychiatric disorders including those with known autoimmune components such as Multiple Sclerosis (Bhat and Steinman, this issue). It is also known that exogenous cytokines such as TNF alpha can alter MHCI cell surface expression on neurons ... ...
What is interesting is that the last 2 or so scientific studies that I've referenced provide proven intervention against MS and jnflammation.

Personally - MHC/TCR and IgX are the last loci I'd ever fiddle with.

Amtram
09-01-13, 12:44 PM
It looks like they were initially studying the effect on vision, based on prior research. And yes, given the vital role MHCI plays in immunity (and the evidence of the fragility of the immune system in these mice as a good illustration) it's not something to release to the public as a potential "cure" or even "treatment" for anything. But the fact that this unexpected outcome holds potential for a better understanding of neuroplasticity is good. From the paper:

Our identification of MHCI in our unbiased screen implied an unexpected and novel role for MHC Class I in nervous system development and function. Yet, there had been much controversy over whether or not neurons express MHCI (mRNA or protein). Until relatively recently, it had been thought that, with the exception of damage or viral infection in vivo and/or cytokine stimulation in vitro, neurons did not express MHCI (Lampson, 1995 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R30); Joly et al, 1991 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R26); Neumann et al, 1997 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R38); Rall et al, 1995 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R43); Oliveria et al, 2004 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R39)). These findings have contributed in part to the idea that the brain is “immune-privileged”. Others had argued that neurons express MHCI only when they are electrically silenced (Neumann et al, 1997 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R38); Rall et al, 1995 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R43))- that is, under pathological conditions. However, it is important to note that in those experiments, fetal hippocampal neurons were dissociated, cultured in vitro and then stimulated to express MHCI with cytokines followed by TTX. In our experiments, we found that MHCI genes are dynamically regulated in neurons in the healthy, unmanipulated brain during development; expression also remains high in specific regions of adult brain (Corriveau et al, 1998 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R14); Huh et al, 2000 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R23)). Following blockade of action potentials, there was a clear decrease in mRNAs encoding MHCI in the LGN (Corriveau et al, 1998 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R14), Goddard et al, 2007 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R18)), which is why we had initially picked up this gene in our unbiased screen. Further, MHCI mRNA can be down-regulated in LGN neurons not only by blocking spontaneous retinal waves early in development, but also simply by occluding normal vision in one eye during early postnatal life. Conversely, following kainate-induced seizures, MHCI mRNA is increased in adult hippocampal neurons (Corriveau et al, 1998 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773547/?report=classic#R14)). Together, these findings clearly demonstrated that neurons in the healthy brain not only normally express MHCI mRNA, but that expression can be regulated by neural activity and is correlated with times and places of known synaptic plasticity. Thus, MHCIs are excellent candidates for linking neural activity to structural changes at synapses, and imply an unexpected and novel role for MHC Class I in nervous system development and function.

Even though they were attempting to manipulate the mRNA in order to study an isolated aspect of neurological development, they ended up with a broad-ranging effect. I expect that they will examine these mice much further to see what else has happened with their brains so they can attempt to duplicate positive results while minimizing negative ones.

Carla Shatz is a well-respected neuroscientist, and is an author or co-author on 125 published papers. Most of her work has been focused on ocular neurology and plasticity. This isn't the first time she's worked on the effect of immune mechanisms on neurodevelopment, though. I think there will be a lot of related research on this in the next few decades.