One
of the greatest challenges in neuroscience is to identify the map of
synaptic connections between neurons. Called the “connectome,” it is the
holy grail that will explain how information flows in the brain. In a
landmark paper, published the week of 17th of September in the Proceedings of the National Academy of Sciences, the
EPFL’s Blue Brain Project (BBP) has identified key principles that
determine synapse-scale connectivity by virtually reconstructing a
cortical microcircuit and comparing it to a mammalian sample. These
principles now make it possible to predict the locations of synapses in
the neocortex.
“This
is a major breakthrough, because it would otherwise take decades, if
not centuries, to map the location of each synapse in the brain and it
also makes it so much easier now to build accurate models,” says Henry
Markram, head of the BBP.
A
longstanding neuroscientific mystery has been whether all the neurons
grow independently and just take what they get as their branches bump
into each other, or are the branches of each neuron specifically guided
by chemical signals to find all its target. To solve the mystery,
researchers looked in a virtual reconstruction of a cortical
microcircuit to see where the branches bumped into each other. To their
great surprise, they found that the locations on the model matched that
of synapses found in the equivalent real-brain circuit with an accuracy
ranging from 75 to 95%.
This
means that neurons grow as independently of each other as physically
possible and mostly form synapses at the locations where they randomly
bump into each other. A few exceptions were also discovered pointing out
special cases where signals are used by neurons to change the
statistical connectivity. By taking these exceptions into account, the
Blue Brain team can now make a near perfect prediction of the locations
of all the synapses formed inside the circuit.
Virtual reconstruction
The
goal of the BBP is to integrate knowledge from all the specialised
branches of neuroscience, to derive from it the fundamental principles
that govern brain structure and function, and ultimately, to reconstruct
the brains of different species—including the human brain—in silico.
The current paper provides yet another proof-of-concept for the
approach, by demonstrating for the first time that the distribution of
synapses or neuronal connections in the mammalian cortex can, to a large
extent, be predicted.
To
achieve these results, a team from the Blue Brain Project set about
virtually reconstructing a cortical microcircuit based on unparalleled
data about the geometrical and electrical properties of neurons—data
from over nearly 20 years of painstaking experimentation on slices of
living brain tissue. Each neuron in the circuit was reconstructed into a
3D model on a powerful Blue Gene supercomputer. About 10,000 of virtual
neurons were packed into a 3D space in random positions according to
the density and ratio of morphological types found in corresponding
living tissue. The researchers then compared the model back to an
equivalent brain circuit from a real mammalian brain.
A major step toward accurate models of the brain
This
discovery also explains why the brain can withstand damage and
indicates that the positions of synapses in all brains of the same
species are more similar than different. “Positioning synapses in this
way is very robust,” says computational neuroscientist and first author
Sean Hill, “We could vary density, position, orientation, and none of
that changed the distribution of positions of the synapses.”
They
went on to discover that the synapses positions are only robust as long
as the morphology of each neuron is slightly different from each other,
explaining another mystery in the brain—why neurons are not all
identical in shape. “It’s the diversity in the morphology of neurons
that makes brain circuits of a particular species basically the same and
highly robust,” says Hill.
Overall
this work represents a major acceleration in the ability to construct
detailed models of the nervous system. The results provide important
insights into the basic principles that govern the wiring of the nervous
system, throwing light on how robust cortical circuits are constructed
from highly diverse populations of neurons—an essential step towards
understanding how the brain functions. They also underscore the value of
the BBP’s constructivist approach. “Although systematically integrating
data across a wide range of scales is slow and painstaking, it allows
us to derive fundamental principles of brain structure and hence
function,” explains Hill.
Source: EPFL
