BRAIN - The miracle to learning



"What is a brain? How does it develop? Why am I here?"

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Where does the brain develop  from?  How does the information contained within the fertilized egg, in combination with internal and external environmental factors, manage to generate an organism of such stunning complexity?   On the other hand, the understanding of development reveals something about the processes that underlie recovery from injury (biological and psychological) as well as regeneration of body and spirit.   Current opinion holds that factors operating during development could help the repair of damaged nerves.   Another reason for being interested in development of brain and nervous system  is that we have been negatively conditioned and view development from a restricted perspective.  While the development of  the entire organism and the magic derived from it, its multiplicity of different cell types which reflects the pattern of greater Cosmos, its patterns and organization of structures has not been addressed  in a way to help us be filled with the wonder and awe that they exude.  In this way we have been ripped off the great opportunity to evoke inside us feelings, thoughts and attitudes  conductive to the great miracle of  Mind and Life, whose wonderful apparatus we all bear in our heads.


No doubt that our lives are filled with problems or rather say challenges, adversities and occurances that go beyond our comprehension.  But while our attention is solely focused upon them, the great beauty of life is unfolding itself quietly in our midst, filled with wisdom, solutions and grace, which goes amiss. 


But lets see how we ended up being what we are.  The scale of the problem facing the human zygote is vast.  There it is so tiny, looks so vulnerable, so beautiful about the size of a full stop on this page, and yet when the baby is born 270 days later it weighs bout 3 kg and is 50 cm in length.  The zygote consists of one cell, yet at birth the brain alone contains about 10 (11) than is, neurons.  Not only is there this vast and rapid increase in the number of cells, but there is also the problem of organizing and delegating the constantly growing population of cells into organs and tissues and coordinating their function as a whole. 


Here is the story of a fertilized egg, about four weeks after fertilization when the human brain is starting to develop in the embryo.


When the embryo is about the size of a pea, a groove that runs along the dorsal surface of the embryo closes over and becomes a tube.  The tube consists of the cells, named stem cells, which will become neurons and glia and it is from this tube that the brain, spinal cord and other parts of the nervous system are formed.  The tube swells at one end and this will become the forebrain, and there are two smaller swelling behind it, which  are the rudiments of the midbrain and hindbrain.  At these swelling the hollow core of the tube becomes the ventricles.  Within the walls of the tube surrounding the ventricles, stem cells divide to produce neuron and glial cells, which move to form the characteristic structure of the brain.  Neurons clump together to form distinct structures, and axons begin to link them together.  At five or six weeks the tube has to bend to accommodate its own growth within the skull.  Two bends occur in very specific places and thereby locate the brain in its characteristic position with respect to the spinal cord.   From now on there is a rapid appearance of recognizable structures.  By the end of the third fetal month, cerebral and cerebellar hemispheres are obvious and the thalamus, hypothalamus and other nuclei within the brain can all be distinguished.   In the following month the cerebral hemispheres swell and extend.  By the fifth month the characteristic wrinkles of the cerebral hemispheres begin to appear.  Most of the sulci and gyri are apparent by the eighth month of development, although frontal and temporal lobes are still small by comparison with the adult and the total surface area of the cortex is much below its eventual size. 


The full adult complement of neurons in the human brain is present shortly after birth, after which no more are produced.  The gross structure of the nervous system has been established. However the micro-anatomy of the brain, namely the synapses, never stop to increase and fine tune the neuronal connections.  Thus increasing the quality and quantity of excitement through nervous communication. But glial cells continue to increase in number until adolescence, when the mature adult brain structure is achieved.  It is the increase in glial cells and the growth of axons and dendrites that leads the 350 gr newborn brain to become the 1400 gr adult brain.  The gross anatomy of the nervous system, which, once established, is relatively stable, and the micro-anatomy of the nervous system, for example, synapses, where changes can and do occur throughout life is an important distinction  which can lead us to the principle of plasticity.


Plasticity is the property exhibited by the growing nervous system.  Changes occur throughout life and there is competition between axons for survival factor, with the loss of inappropriate synapses.   In the adult there are changes in the neuromuscular junction and changes at the synapses which commensurate with learning.  Thus microanatomy remains plastic till the end of life.  Changes accounting for learning cannot occur until synapses have been formed.   Synaptogenesis occurs at different rates and at different times in different parts of the brain.


The birth and growth of neurons


How the nervous system grows out of this single “full stop” of zygote?  How cells come to be neurons?  How neurons move through the embryo and stop at some appropriate position within the embryo?  How axons establish appropriate connections with other neurons and with muscles and glands?  This is the story of expansion and growth and deals with synapse formation.


There are six main phases in the development of the nervous system.  These phases are consecutive generally speaking but often overlap in time.  For example many neurons grow producing an axon, while they are migrating. The six phases are:


·        The proliferation phase, during which cell division occurs, and the number of cells increase enormously.   Metaphorically speaking they follow the command of  Multiply, expand and conquer”!  (Πληθυσμιακή έκρηξη, αυξάνου και πληθύνου….)


·        The phase of differentiation, during which cells form the characteristic features of neurons. Now  the metaphor is the command “Find your mission”!

  φάση της διαφοροποίησης και της αναζήτησης προσωπικής αποστολής)



·        The phase of migration, during which neurons move from their place of origin to their final position.  Here it is like following the silent command of “find your rightful place”!  

(Η φάση της αποδημίας – αναζήτησε την θέση που σου ταιριάζει)


·        The growth phase, during which neurons grow axons, like extending their “hands” to touch a target and form a functional network.  In this new environment they have to grow and reach out!  (Η φάση της ανάπτυξης και της καρποφορίας -  ανοίγω τα φτερά μου)


·        The phase during which the axons establish synaptic connections with targets (like sense organs, muscles or other neurons) and themselves become targets for other neurons.  The analogy of this state can be likened with the formation of society.  “Network, and be part of the network”!  (η φάση των διασυνδέσεων, των σχέσεων συνεργασίας και καλής γειτονίας)


·        The modification phase, during which the connections formed during growth phase are modified, with some being removed (involving death of up to 50% of the neurons originally generated) and some others are strengthened.  This modification, filtering or fine tuning, depends  critically on the establishment of functional connections!   Here the hint is “Be useful or leave”!  Pity but true: those who do not adapt neither do they exert their functional influence to the society of neurons are eliminated.  (η φάση της εκλεπτυσμένης διαμόρφωσης,  γίνου χρήσιμος στο σύνολο ή ξεκουμπίσου)


What are the factors that control these phases?  Why a neuron differentiate to become a specialized cell, for example a Purkinje cell rather than a granule cell in the cerebellum?  Why does it become a rod rather than a cone?  What inner command do they follow and they group together  to form a heart  and not a liver?   And those which chose the  mission of a liver why didn’t they chose to function as a heart?  What guides a growing axon so that it connects to one particular target rather than another?  Do sensory neurons find an appropriate target or are neurons non-specific until they meet a target, becoming sensory if they meet for example a Paccinian corpuscle and motor if they meet a muscle?  These are the kinds of questions to which we seek answers, not always succeeding to get them.  But if the answers go sometimes amiss, the wonder and awe finds its way to our hearts and minds.


Proliferation Phase


The very first division of the fertilized egg is particularly important as it defines the midline of the embryo.  It will be the “route” of spinal cord and the extension of brain.  The resulting two cells each divide again, making four cells.  These cells continue to divide, eventually making a hollow ball of cells.  At about 10 hours the cells then go through a complex series of movements.  The potential human being is dancing its way to existence.   The ball of cells effectively turns in on itself through a region called the Blastopore, to produce a structure consisting of three cell layers.  Each of these cell layers develops into a particular class of cell.  The outermost layer of cells, the ectoderm (εξώδερμα), forms the skin and nervous system, the middle layer or mesoderm (μεσόδερμα) forms the muscles of the body and skeletal structures and the innermost layer  endoderm (ενδόδερμα), forms the internal organs and the gut.    In this stage there is already a clear difference in the way different classes of cells grow and mature.  In other words, differentiation has begun.


Differentiation Phase


Now we have the beginning of nervous system from the cells of ectoderm.  Not the mesoderm, or the endoderm.  Why is that so?   Why the endoderm cells become neurons, or glial cells?  Why not muscle cells?  The answer seems to come from the differentiation.  Essentially, ectodermal cells are already differentiated to the extent that not all developmental paths are open to them, some paths, for example those leading to muscle cells, are closed.   Identity has already taken place in their midst. 


Migration Phase


The neurons and glia of the peripheral nervous system do not originate from the neural tube, but arise from  special cells that collect on either side of the dorsal part of the neural tube called neural crest cells.  These neural crest cells migrate away from the neural tube.  Their migration pattern is closely related to the pattern of the somites, they only migrate through the rostral half of each somite.  After a neuron is born and has migrated to its final position in the nervous system, how it develops depends both on its ancestry and also on its local environment, that is, on intercellular messages.  Both the  ancestry and the local environment are able to affect which parts of a cell’s DNA are translated into proteins, and hence, how the cell differentiates.  The projection of the axon, both in the central and in the  peripheral nervous system, is affected by the location of the cell body. 


Axon growth Phase


One of the first signs that a cell will become a neuron is the extension of a process, the future axon, from one point on the cell body.  This usually happens when the cell reaches its final location in the brain, but can also occur as cells are migrating.   Ramon y Cajal was one of the first neuroanatomists who realized that the cell guidance involves dynamic interaction between the growth cone and the environment through which it is growing.   Some axons appear to extend and then attach to whatever they are growing through, whereas others are retracted. The cytoplasm in the central region then flows into the ‘web’ between the filopodia.  This moves the growth cone forwards as the filopodia extend further.   The growing cell both pulls force from the filopodia (they contain contractile filaments) and attract pushing force from the flow of material into the growth cone.   The  factors that influence the direction of growth give the guidance cues.  But what are these cues and how are axons guided?   How do they know “where to grow”?   Surely they do not grow haphazardly.  Rather its path is very precisely controlled.  Its growth has been likened to that of a climber: the climber’s progress up a rock face is aided by finding good holds.


Their “holds” are the immunohistochemistry.  That is  specific substances which open “this” way and not “that” way for a specific cell.  Laminin is one of them, another called glycoprotein. (γλυκοπρωτεϊνη).  Other substances guide at a distance.  Chemotactic for instance helps cells to find their way by “touching” them.  It is like finding your way into a dark room.  You extend your arms and by what you touch you decide where to go.   Chemotropic guidance on the other hand helps a cell find its way by smell, they don’t have to touch, by distance they do get their cue.   Cells have all the help they want, and each “helping hand” satisfies their multiple needs!


Synaptic Connections Phase


Now cells are into position to establish contacts or in other words “shake hands” with their colleagues in the same job.   But before they could exclame “here we are, lets do business now  they have to undergo  a strict clearing.  Some 50% of them will be eliminated.  Why there should be such a loss, and the ways in which neurons are selected to survive we can only guess.  But with sheer determination they decide with whom they are going to make a life and whom will be excluded and aborted. 


Lets follow the steps of a muscle cell.  A neuron axon contacts a muscle cell and they communicate.  We know this on account of the size and frequency of postsynaptic potentials.  Two hours of connection passes and the postsynaptic membrane thickens, showing in this way that the relationship has been consolidated.   The consolidation happens by acetylcholine receptors which concentrate beneath the contact point as it is detected by the observers  (for the validity of their observation) and by antibodies that recognize the receptor molecule.  A little later vesicles begin to cluster in the presynaptic terminal and the postsynaptic membrane begins to take the form of a complex structure of the neuromuscular junction.   This completes the consolidation of the relationship.  From then on they are “colleagues” and information  in the form of chemical messages will flow freely between them.  Will the relationship be a long lasting one?  It will depend on the maintainance of  mutuality and the quality of the communication between them!


The modification Phase


From now on their communication will be refined, and there is strong interaction between neurons occurring as a result of their synaptic connections and activity, which influence their survival and growth.  Connections of course between neurons can change, they are particularly flexible .   Demonstration  of this flexibility reflects the importance of neuronal interaction in shaping connections in the nervous system.  Different neuronal connections exhibit very different timetables of development and extents of flexibility.   Another demonstration of flexibility is the response to injury and the changes that occur during learning and it is a fundamental property of nervous systems that they can adapt to changing circumstances. 


These phases include the development of the “full-stop” size zygote to the embryo.  This wonderful network of neurons set  the apparatus  through which God, or Mother Nature of the Vast Potential of Universe can find expression and communication.  How can we feel alone and impoverished after that?


Athens, August 10th, 2000

Vicky Chrisikou



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