In order to appreciate vast complexity it is necessary to zoom in. It does not do to try and grasp the entirety of the rain forest, to stand at its edge and to simply muse on the knowledge that there are nearly two million unique species that reside in its depths.
No, the truly breathtaking aspects of the Amazon come from kneeling down and watching a butterfly with transparent wings alight on a leaf, or gazing into the dirt and seeing a line of army ants laying siege to a wasp nest.
The human brain is comparable in terms of the sheer intricacy of its inner workings. And like the rain forest, no matter how many times one hears the phrase “the brain is very complicated”, it is impossible to grasp how complicated, and how incredible it really is without delving into neurology. It’s like the congenitally blind thinking they understand the beauty of Starry Night or the new Star Wars movie (fingers crossed) simply from hearsay.
Billions of neurons make trillions of connections, as shown in this diffusion MRI
A recent study performed by researchers at the University of Utah, Colombia University, and the University of California looked at a single protein, thought to be linked to learning disabilities.
The brain is divided into subsections that specialize in particular roles. One of the portions responsible for learning and memory, the hippocampus, is located underneath the large upper portion of the brain known as the cerebral cortex.
The hippocampus is part of the limbic system, known to play a large role in emotions and memory formation
It is one of the first components to be damaged during the onset of Alzheimer’s, and trauma to this centre is associated with amnesia. Thus, it is a prime target for learning disability research.
The shape of the hippocampus is commonly compared to that of a ram’s horn, which contributes to the nomenclature of some of its subdivisions (CA stands for cornu ammonis, or ram’s horn).
The subdivisions of the hippocampus
Neurons, or nerve cells from the entorhinal cortex (EC, not pictured but positioned around where the subiculum label is in the above diagram), receive information from many different parts of the brain.
The EC acts as a harbor- ‘cargo’ comes in from all around the brain, including sections responsible for sensory processing, metabolism, and motor control. This ‘cargo’ is then unloaded, processed, and transmitted down the highway that is the hippocampus.
The signals are sent from the EC to the dentate gyrus (DG). From there, they are transmitted to CA3, then to CA1.
Of course, the circuit is a little more convoluted than that. The EC also interacts with CA3 lightly, and a different portion of the EC interacts with CA1. In fact, the circuits are even more complex than in this diagram; there are other connections not present, and others still that we do not yet understand
Some of the signals may trigger the recollection of old memories, while others the formation of new ones.
In fact the both of these processes are not clearly understood, due to the millions of neurons involved. They are processes which are ever so slightly elucidated by the efforts of the aforementioned researchers, who used a mouse model.
Dentate gyrus (DG) neurons not only connect to CA3 neurons. They also connect to an intermediary composed of what the researchers refer to as GABAergic neurons (nerve cells that use GABA as a neurotransmitter). These GABAergic neurons in turn also connect to the CA3 neurons, but with one difference; they inhibit, rather than activate the CA3 neurons.
Thus, the dentate gyrus (DG) regulates both the activation and the inhibition of CA3. This is known as feed-forward inhibition (in contrast to feedback inhibition)
DG neurons activate both CA3 and GABAergic neurons. However, the GAGAergic neurons inhibit the CA3 neurons. The result is intimate control of the CA3 complex by the DG
The researchers found a protein present in DG neurons and GABAergic neurons, but not in CA3 neurons. The gene coding for this protein, when deleted, resulted in impaired synapse formation between the DG and GABAergic neurons, but had no effect on the DG-CA3 synapses.
The result of the protein, known as kirrel3, being removed was the unnaturally excessive activity of CA3 neurons.
Removing the GABAergic neurons from the equation results in overactive CA3
Since the GABAergic neurons were not being activated as much as they should, they failed to rein in the activity of CA3 neurons.
This is analogous to one traffic light at an intersection being permanently stuck at green. It sounds great for that one lane of traffic, but for the perpendicular lane it is horrific. Furthermore, traffic on the perpendicular lane being backed up to that degree has far reaching consequences, which may disrupt traffic throughout the whole city and ultimately even in the apparently ‘blessed’ lane.
Kirrel3 mutation has been linked to various intellectual disabilities, including autism and Jacobsen’s syndrome. In addition to shedding light on brain function, this research could lead to treatments for developmental disorders.
And yet, one last finding brings us back to our original position- that the brain will continue to elude attempts to understand it.
When the mice with kirrel3 deficiencies were given behavioural tests, they only had mild difficulty with them. Puzzled, the researchers looked at the DG-GABAergic-CA3 circuit more closely, and found that the DG-CA3 connection shrunk by the time the mice were two months of age. The shrinking allowed CA3 activity to decrease back to relatively normal levels.
Returning to the traffic analogy, it is as if a police officer came in and started manually directing traffic. Somehow, the brain was able to detect the dysfunctional circuit and compensate for it.
How it does that is yet to be discovered.
We only have detailed study concerning about 1% of the species in the Amazon rain forest, and it looks like we have done a similar amount of cataloging, proportionally, for the brain.
Sources:
Martin EA, Muralidhar S, et al. (2015). The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus. eLife 2015;4:e09395
Diffusion MRI retrieved from https://nihdirectorsblog.files.wordpress.com/2015/10/white-matter-fibers-hcp-dataset-red-corpus-callosum.jpg
Image of hippocampus location retrieved from http://www.memorylossonline.com/glossary/images/hippocampus.jpg
Image of hippocampus subdivisions retrieved from https://en.wikipedia.org/wiki/File:Hippocampus_(brain).jpg
Image of hippocampus circuit retrieved from https://en.wikipedia.org/wiki/File:CajalHippocampus_(modified).png
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