Neuronal Plasticity as Evidenced by Reversal of Amblyopia

The
work of Li-Huei
Tsai on the partial restoration of memory was in the news a
few days ago.   Although the experiments were done on mice, it
was hoped that the results could indicate a reason to hope that humans
with dementia could be helped.



The study showed that an environment enriched with varied stimuli could
help organisms regain long-term memories.  

This
recovery of long-term memory was really the most
remarkable finding. It suggests that memories are not really erased in
such disorders as Alzheimer’s, but that they are rendered
inaccessible and can be recovered...



...The memories are still there, but they are rendered inaccessible by
neural degeneration...



...When the researchers studied the brains of the animals that had been
exposed to the extra stimuli, they found no evidence of increased
growth or formation of new neurons when compared to brains of mice that
had not experienced the enriched environment. However, they did find
anatomical and biochemical evidence for growth of connections among
neurons...

In a similar vein, a study recently published in Nature Neuroscience
indicates that environmental enrichment can lead to improvements in
vision under some circumstances.  



First, a little background...

rel="tag" href="http://en.wikipedia.org/wiki/Amblyopia">Amblyopia
is a condition that results when one eye (or both eyes) is (are) not
able to obtain a clear visual image during early development. It also
can happen when the two eyes are not aligned closely enough for the
brain to create a clear stereoscopic view ( href="http://en.wikipedia.org/wiki/Strabismus">strabismus). 
Amblyopia
affects about 2 to 3 percent of human children, often
persisting into adulthood if not treated.  



It appears that if the visual cortex does not get the correct inputs
during development, it never develops the capacity to form a good
mental representation of an image.



Originally, it was thought that treatment had to occur before about age
7.  A couple of years ago, it href="http://www.nei.nih.gov/news/pressreleases/041105.asp">was
shown that treatment up to age 17 could be beneficial.
 This demonstrated that the brain had greater plasticity than
previously believed.



Now, we have a study that shows a possible mechanism for this
plasticity in adulthood.

rev="review"
href="http://www.nature.com/neuro/journal/vaop/ncurrent/abs/nn1899.html">Environmental
enrichment in adulthood promotes amblyopia recovery through a reduction
of intracortical inhibition

Nature
Neuroscience

Published online: 29 April 2007; | doi:10.1038/nn1899

Alessandro Sale1, 3, José Fernando Maya Vetencourt1, 3,
Paolo Medini2, Maria Cristina Cenni2, Laura Baroncelli1, Roberto De
Pasquale1 & Lamberto Maffei1, 2



Loss
of visual acuity caused by abnormal visual experience during
development (amblyopia) is an untreatable pathology in adults. We
report that environmental enrichment in adult amblyopic rats restored
normal visual acuity and ocular dominance. These effects were due to
reduced GABAergic inhibition in the visual cortex, accompanied by
increased expression of BDNF and reduced density of
extracellular-matrix perineuronal nets, and were prevented by
enhancement of inhibition through benzodiazepine cortical infusion.

It had been shown earlier that maturation of intracortical inhibitory
circuits leads to the end of the visual cortical plasticity "window,"
meaning that once the inhibitory circuits are in place, it is difficult
if not impossible for the sensory pathways to change.



However, under conditions of enhanced sensory stimulation, some
recovery of vision is possible in rats.  Furthermore, it was
shown that a possible mechanism for this was a reduction in an
important inhibitory neurotransmitter:

In
vivo brain microdialysis showed that basal levels of GABA were
diminished by a factor of 3 in the binocular visual cortex (Oc1B)
contralateral to the formerly deprived eye of RS-EE rats.

Two
additional possible mechanisms were found:

The
reduction of cortical inhibition in RS-EE rats was paralleled by
variations of other molecular factors involved in cortical plasticity.
The expression of the neurotrophin title="Brain-derived neurotrophic factor">BDNF
was increased in the visual cortex contralateral to the formerly
deprived eye in RS-EE compared with RS-SC rats. Furthermore, the
typical organization of chondroitin sulfate proteoglycans in PNNs was
still present in RS-EE rats. PNN density, however, was lower compared
with RS-SC rats in the visual cortex contralateral to the long-term
deprived eye.

Of course, correlation is not causation, so researchers like to do a
little more to try to demonstrate that the microscopic changes they
found are responsible for the improved function.



To some extent, they did so.  This was done by administering
diazepam (Valium™) to some of the rats.  Diazepam
enhances the effect of GABA, such that the reduction of GABA in the
experimental condition would have less of an effect:

Finally,
to test whether the reduction of intracortical inhibition in
environmental enrichment was causally linked to the recovery of normal
visual functions, we chronically infused (via osmotic minipumps) a
different group of RS-EE animals with the benzodiazepine agonist
diazepam (2 mg ml–1) during the environmental enrichment
period. Cortical diazepam administration totally prevented the
environmental enrichment–induced recovery effect in both
visual acuity and the C/I VEP ratio.

This is of interest for two reasons.  One, it makes the
findings of the study more robust.  Two, it indicates a
possible mechanism for an observation in some psychiatric research.
 That is, there is href="http://www.semel.ucla.edu/adc/AnxietyCD/CBT%20Related%20Articles/CBT-Anxiety_disorders.pdf">some
evidence (PDF) that exposure therapy for phobias is less
effective in persons taking benzodiazepines (Valium-like drugs).