Thursday, April 17, 2014
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Clearing A Path Through the Brain

MADRID – Our brains are like a dense forest – a complex, seemingly impenetrable terrain of interacting neurons that mediates cognition and behavior. The great challenge is to uncover its mysteries, that is, to find out how the neurons are structured and mutually connected. How close are we to that goal?

In general, the exchange of information between the billions of neurons that make up the neuronal forest takes place through two types of highly specialized structures: chemical synapses (the majority) and so-called gap junctions (a substrate of one class of electrical synapse). Chemical synaptic transmission involves the release of specific molecules, neurotransmitters, which diffuse through the intercellular space and interact with specific receptors located on an adjacent neuron. In the electrical transmission mediated by gap junctions, the plasma membranes of adjacent neurons are separated by a gap of about two nanometers (two-billionths of a meter), but contain small channels (the gap junctions) that connect the cytoplasm of the adjoining neurons, permitting the diffusion of small molecules and the flow of electric current.

The major problem when analyzing the brain is the extreme complexity of its synaptic connections. A very dense network of processes occupies the space between the cell bodies of the neurons, neuroglia (cells that support and protect neurons), and blood vessels. This space (the neuropil) represents 90-98% of the volume of the human cerebral cortex, with an estimated one billion synapses per cubic millimeter of neuropil.

As if that didn’t make the brain mappers’ job difficult enough, a wide variety of synaptic relationships has been observed. And a neurotransmitter may diffuse and act not only on other synaptic contacts, but also on extrasynaptic receptors. Likewise, not all electrical transmission is mediated by gap junctions, and these forms involve different specialized structures. In addition, electrical interactions take place between closely apposed neuronal elements without obvious membrane specializations.

Furthermore, it has been proposed that glial cells are involved in information processing through their bi-directional signaling with neurons. And we now know that the activity of neuronal circuits is strongly influenced by neuromodulators (such as dopamine, serotonin, and acetylcholine), which are secreted by a small group of neurons and diffuse through large regions of the nervous system. Neurohormones, released by neurosecretory cells, also have an effect on many brain regions via the circulatory system.

Nonetheless, we are beginning to find our way through the forest. The brain’s wiring – its “synaptome” – is the anatomical substrate for a variety of functions that require information to be communicated rapidly from one point to another. The neuronal circuits involved in reflexes are a typical example – relatively simple, fast, automatic actions that occur at a subconscious level. Other, much more complex functions related to the synaptome include information processing in large but discrete circuits in the sensory and motor systems and in the brain regions associated with language, calculation, writing, and reasoning.

The modulatory systems, however, act on multiple neuronal circuits and brain areas. This diffuse action is related to the overall moods and states of the brain (for example, attentiveness, sleep, and anxiety).

Rapid and automatic serial reconstruction of large tissue volumes, enabled by the recent development of automated electron microscopy techniques, is the method of choice in defining the synaptome. Nevertheless, even using this technology, full reconstruction of whole brains is possible only for relatively simple nervous systems. Indeed, even for a small mammal like the mouse, it is impossible to reconstruct the brain completely at the ultrastructural level, because the magnification needed to visualize synapses yields relatively small images.

For example, it has been estimated that if we were to use sections of about 35 square micrometers (millionths of a meter) at a thickness of 20 nanometers, we would need more than 1.4 billion sections to reconstruct fully just one cubic millimeter of tissue. So, while complete reconstructions of a small region of the mammalian brain are feasible, structures like the cerebral cortex – with a surface area of 0.22 square meters and a thickness of between 1.5-4.5 millimeters – cannot be fully reconstructed.

Nonetheless, despite the technical difficulties, it should be possible to make spectacular advances in unraveling brain organization, even in humans, by adopting appropriate strategies with the tools now available. For example, although the synaptic density within a given area and layer may vary, this variability remains within a relatively narrow window, so the statistical distribution of the variation can be modeled. That means that we do not need to reconstruct the entire layer within a given area to determine the absolute number and types of synapses; instead, the range of variability can be determined by multiple sampling of relatively small regions within that area.

By combining these detailed structural data with the incomplete light and electron microscopy wiring diagrams, it could be possible to generate a realistic statistical model, rather than attempting to reconstruct the brain in its entirety. Computational models of neuronal networks based on real circuits already have become useful tools to study aspects of the functional organization of the brain.

Thus, although a true synaptome of the mammalian brain is a chimerical quest, it is possible that in the near future we will be able to construct a “silicon cortex,” a computerized machine based on a realistic model of the complete anatomical, physiological, and molecular design of the cortical circuit. If we succeed, we will finally be able to see the forest – without having to look for every tree.

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  1. CommentedEdward Ponderer

    There is a particularly fascinating thought that we are on the verge -- through globalization, Internet, and wireless communication -- of a "brain squared" Humanity. That is, where individual human brains become as the neurons of a vast, world-wide Humanity brain.

    The only difference I see to this natural organization is the fact that neurons -- so-to-speak -- are concerned with the welfare and functioning of all other neurons, while humans are principally concerned with themselves. In an age of ever-growing interconnection, this ever-growing self-swelling of ego, especially in oligarchical groups -- cartels, political parties, terrorist organizations, and so forth, is a brain swelling with tumors.

    So the question seems not academic -- can we become mutually responsible and transform into the Humanity brain that could have powers of homeostatic solutions to internal human and external natural problems beyond our wildest hopes? Or will we travel the entropy path of Murphy's law into complete brain death?

    The crises and its two roads lay before us. A very interesting video in this regards will be found at

  2. CommentedZsolt Hermann

    This more and more precise, incisive research is very exciting as we descend into micro and nano-meter details of our brain structure...
    But at the end of the day what we are dissecting, analyzing is still only the hardware, and even the best hardware does not work, makes no sense without knowing the software running it.
    The situation is very similar to how we behave with the global crisis, although the whole picture starts to merge into one large interdependent picture, we still keep analyzing, "solving" individual problems, details without relating all the problems to each other.
    There is a saying "the final goal is within the initial thought", without aiming for a very specific, final purpose our research, all our adventures, recognition are pointless, aimless since the multitude of beautiful details, sparks do not complement each other comprising a final mosaic.
    Humanity has matured enough, is developed enough to start recognizing an overall purpose for our existence, the reason for us learning, knowing, developing.
    And this purpose is not even that difficult to find since it is all around us, the whole of our reality, life depends on it.
    This purpose is to maintain balance, to maintain homeostasis against, above any disturbances, problems, rejections.
    Our whole biological body, all our cells, tissues, as any other living or even still part of the Universe exist and makes efforts for the same reason.
    The complexity of the human brain also developed for only this purpose, to help human beings to keep this natural balance, homeostasis against any disturbances, most of it which comes from the developed human ego pulling us into multiple other directions causing crisis and destruction.
    Thus we are at crossroads, we have to decide if we use this brilliant, unique hardware for the right purpose, if we continue to allow the disturbance, our inherent egoistic human "mutation" to drive us to destruction?
    Humans are the only species that are capable of critical self-analysis and self-change.
    But such change is only possible by the recognition that we have to change.
    And this recognition is only possible if we identify and accept our final purpose.
    If we start with the right purpose all the details will fall into place, start to make perfect sense.