CONNECTOMES US The hottest topic in neuroscience today revolves around brain wiring. In 2009 the NIH started a new project called The Human Connectome Project. This ambitious endeavor is attempting to map the basic wiring of the entire brain. This work could lead to new insight into schizophrenia, autism multiple sclerosis, etc. Researchers believe that cognition emerges from the interplay of electrical impulses along brain circuitry, but we lack insight into how brain connections underlie brain functions. The brain contains over 100 billion neurons (as many as stars in the Milky Way) and ten times more glial cells, forming trillions of connections,
Transcript
CONNECTOMES US
The hottest topic in neuroscience today revolves around brain wiring. In 2009 the NIH started a new project called The Human Connectome Project. This ambitious endeavor is attempting to map the basic wiring of the entire brain. This work could lead to new insight into schizophrenia, autism multiple sclerosis, etc.
Researchers believe that cognition emerges from the interplay of electrical impulses along brain circuitry, but we lack insight into how brain connections underlie brain functions.
The brain contains over 100 billion neurons (as many as stars in the Milky Way) and ten times more glial cells, forming trillions of connections, since one neuron may connect to as many as 1200 other neurons. Moreover these connections are dynamic and change almost on a daily basis in relation to the environment or stressors. Some of the neurons have very long axons, reaching to various other areas of the brain, but most of these trajectories are uncharted.
This is how it all started: the Human Genome Project identified multiple genes that predispose individuals to schizophrenia. Some of
the genes, replicated in multiple studies, include: DISC-1, dysbindin, neuregulin, and BDNF.
The surprising discovery was that these genes do not code for neurotransmitters or receptors, as it would be expected, but for the proteins of the neuronal cytoskeleton.
The neuronal cytoskeleton has to do with brain wiring, synapse formation, dendritic cone growth and shape of the neurons – the word neuroplasticity was coined to describe all the above.
Who could imagine that the neuronal cytoskeleton was that important? But it seems to account for the difference between a schizophrenic and a normal brain. This is how the idea of connectom was borne.
Here is a quick reminder of the main elements of the neuronal cytoskeleton.
THE SKELETON IN THE CLOSET
The cytoskeleton plays a key role in maintaining the shape of both neurons and glial cells. The shape is essential for neuronal physiology including neurotransmission and synapse formation. Formation of new dendrites is also a function of the cytoskeletal reorganization.
Aside from maintaining the cell shape and borders, neuronal cytoskeleton, consisting of hollow tubules, also transports proteins and cell organelles from the center of the cell to the axon and denrites.
The cytoskeleton of the neuron is comprised of three elements:
Neuronal microtubules consist of alpha and beta tubulin. These molecules are arranged in a circular form, creating hollow tubules used for transporting proteins and organelles along the axon and the dendrites.
Several studies revealed that beta tubulin was decreased in the anterior cingulate cortex(ACC) of patients with schizophrenia.
Intermediate filaments are ropelike fibers of 8-12 nm in diameter. They make the bulk of axonal volume and represent a substantial fraction of the total protein synthesis in the brain.
They are thought to provide mechanical strength to the cytoskeleton of both neurons and glia.
Microfilaments such as actin, spectrin and ankyrin are found both in both neurons and glia. They are particularly concentrated in presynaptic terminals, dendritic spines and growth cones. Because of their proximity to the cell membrane they are thought to stabilize the trans-membrane proteins.
Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that in turn lose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain.
In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairments of neurotransmission occurs.
In Alzheimer’s disease, the neurofibrillary tangles are paired helical filaments consisting of microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuronal
structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of the formation of paired helical filaments – neurofibrillary tangles (NFT).
In Parkinson’s disease and Lewy body dementia, the Lewy bodies are made of abnormal tubulin.
In schizophrenia neuronal shape, loss of dendrites and spines as well as irregular distribution of neuronal elongations occur in specific brain areas leading to abnormal connections, thus abnormal connectomes.
A recent study reported on 1/24/12 (Medwire) suggests "that patients with schizophrenia have regional alterations in the expression of an isoform of the cytoskeleton protein β-tubulin." Investigators "studied 110 postmortem brain tissue samples from the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC), the hippocampus (HC), and the superior temporal gyrus (STG) of elderly patients with schizophrenia and 103 from similarly aged mentally healthy individuals" and used Western blot analysis to find "that ACC tissue samples from schizophrenia patients showed a significant decrease in βI expression compared with those from controls" while "DLPFC tissue samples from schizophrenia patients showed a significant increase in βI expression compared with those from controls." To learn more about the Human Connectome Project go to http://www.humanconnectomeproject.org/
