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 1- Structure, development and localization. 
 2- Components and cellular organization.
 3- Neuronal netwoks. Hippocampus and memory.
 4- Dendritic spines. Brain plasticity.
 5- References and links.
                            
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STRUCTURE, DEVELOPMENT AND LOCALIZATION

                The cerebral cortex of mammals is represented by a sheet of gray matter from 2 to 4 mm in thickness covering the cerebral hemispheres. In the human brain is a tightly folded formation with characteristic grooves and convolutions resulting in a geometry capable to pack as many neurons in the smallest possible volume. This sheet of gray matter, that extended would not occupy more than the area of a newspaper, is an extremely complex structure in which the various sensory organs are represented in areas known as primary sensory areas (somatic, visual, auditory, gustatory and olfactory).            
                 

                                          FIG. 1
            

          The cerebral cortex is divided into two basic types: isocortex or neocortex and allocortex. The first one is the part where a stratification in six superimposed layers or sheets can always be recognized (Fig. 1), while allocortex, represented by archicortex (hippocampus and fascia dentata) and palecortex (olfactory cortex itself ), exhibit a single structure composed of three layers. Both cortical types are separated by a number of secondary areas that have been the subject of great interest in the study of brain evolution.

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        FIG. 1 Nissl stained coronal section through the brain of the monkey (Macaca
mulatta).
Section taken from BrainMaps: An interactive multiresolution Brain Atlas; http://brainmaps.org [retrieved on July 25, 2015]. Red asterisk marks the hippocampal formation immediately above the e
ntorhinal cortex, two important structures implicated in memory processes.

 
 
                 In addition to the primary sensory areas, the cerebral cortex has other motor and association areas, in which, including various subcortical regions and nuclei, the different systems of neural connections are elaborated in complex learning patterns and behavior. The organization of the cerebral cortex which, from our human perspective, reaches its maximum complexity in man, is the result of a slow evolutionary process that began 150-200 million years ago in the alleged reptile-mammal transition.         

                 In man the neocortex occupies more than 90% of the total extent of the cerebral cortex but the paleocortex or olfactory cortex was the dominant structure in those early animals during the Upper Triassic. These primitive subjects, with the appearance of shrews and mice, probably escaped extinction after the episode of the asteroid impact at Chicxulub, in the Yucatan rainforest, about 65 million years ago that wiped out the dinosaurs (if indeed there was such an event). Survivors developed certain adaptations for a nocturnal habitat, allowing them to increase the sense of smell and giving them an evolutionary advantage eventually evolving into the current species. Some fossil mammals or "mammal-like" species from as long ago as some 220 million years, where creatures in which virtually all cerebral cortex was paleocortex [1]          
 
  
                                                                          
           Some studies speculate that the neocortex developed in the middle of an "olfactory" primitive cortex (paleocortex), spreading like an oil slick up to occupy 98% of the cortex in the human brain. It seems, therefore, no exaggeration to say that we are here thanks to those early "proto-mammals" which survived during the Middle Triassic. These were animals with nocturnal habitat, small body, short-legged, long, pointed snout, which developed a sense of smell so extraordinarily effective allowing them to survive until all lead to an evolutionary branch that, for over 200 million years, went on to become the full panoply of mammals that inhabit the Earth today, including humans. However, despite the differences in size and shape of the mammalian brain, from the sense of smell to vision, each sensory modality has its own cortical territory, which maintains a constant location in all mammals, as, for example, the visual cortical areas (Fig. 2).             

________________________

  F IG. 2 Location of the visual cortex (red) and various secondary visual areas (blue and green) in the right hemisphere, in a representative range of mammals. Mouse and cat, dorsal view of the cerebral hemispheres; Monkey, rear view showing the occipital pole; Man, medial aspect of the right cerebral hemisphere, the different visual areas occupy almost the entire occipital lobe, maintaining a relatively constant position along the mammalian scale. The size of the brains are not proportional.  (Taken from [2]). 

                                                                      FIG. 2

     COMPONENTS AND CELLULAR ORGANIZATION


The legend of the chess game.

          Once upon a time, in the northwest of India, a powerful Brahmin named Rai Bhalit, despite his immense wealth, was bored to death. Not having anything else to do, tired of contemplating one's belly button or counting the stars of heaven, one day he ordered a very wise sage, called Sissa, to invent a game that could entertain him for the rest of his days. Sissa invented the game of chess and showed it to his lord who was so delighted with the game. Wishing to thank the wise creation, the Brahmin offered him anything he wished for. Sissa did not think of anything else than to ask his master that, putting a grain of rice on the first square of the chessboard and doubling in each square the number of the previous one, will surrender the resulting amount after covering the 64 squares of the chessboard : 1,2,4,8,16,32,64. . .and so one.

         The Brahmin, which most probably did not knew how much were 2 + 2, commanded to bring a couple of bags of rice to be placed next to the chessboard, while a servant performed the operation to covering the squares on the board, as requested by Sissa. Even remotely he would not suspect that it was impossible to satisfy the desire of the wise; in the last box he would have to put more than 9 x 1018 grains of rice, as the total amount in the 64 squares surpass 18 x 1018  grains: the Brahmin would need 1.500 years of intensive rice cultivation worldwide to meet its debt . It is not known how the story ends; a feature is that outraged the Brahmin, sent to kill the wise, while others say that Sissa married the beautiful daughter of the Brahmin and inherited his kingdom. Since then, Sissa played chess with his wife every night but never won a single game.
                  In the human cerebral cortex there are 2,3 x 1010 neurons [3]. If their axons were tied one after the other, they would form an endless thread surrounding more than four times the Earth by the Ecuator. Women have fewer number of neurons, estimated at 16% (related to body size variability) and over the life another 10% is lost. In our history of the game of chess, if instead of one grain of rice we put one neuron in the first box, we should get to box 35 or 36 (a little more than half the board) to find a number similar to the number of neurons in our neocortical mantle. We are separated from our Australopithecine ancestors by only one or two squares. It seems that genus homo "crossed the Rubicon" in the square number 34. Then, what is the difference between the neocortex in the human brain and neocortex in all other creeping creatures? As our own studies  have shown, the difference lies in essentially in the number, morphology and packing density of certain cells known as short-axon or intrinsic neurons  [4] .

                    Assuming that each neuron can receive from 20.000 to 50.000 synaptic contacts (there are estimates as much as 100.000 or even more) it was considered that the number of inter-neuronal contacts (synapses) in the brain may range in the value 1014. In any case, the magnitude of these figures has dazzled more than one and it is not uncommon to find someone wanting to communicate that the processing power of the human brain is 500 petabytes (one petabyte is the number 1 followed by 15 zeros). As a curiosity it may be noted that a humble worm may have just over 300 neurons (the 9th or 10th boxes of our chessboard); small mammals such as mice, 4 millions neurons (box 23), while large mammals such as whales and elephants, for obvious reasons of body size, more than 3,7 x 1010 (36th or 37th box), almost twice the number contained in the human brain. What would the size of the human brain if it reaches some of the latest squares on the board?
              
                   
Recent data suggest that duplication of neocortical develpmental genes created novel functions at a time corresponding to the transition from Australopithecus to Homo habilis begining neocortical expansion some 2-3 million years ago [5]. One gene, named ARHGAP11B, might be responsible for the emergence of human intelligence and memory capacities by increasing the number of neurons and thus the brain size. This gene is found in modern humans, in Homo neanderthalensis and in the denisovan hominins, but not in chimpanzees, which is supposed to separate from ourselves about 6-7 million years ago. This gene activates the growth and proliferation of progenitor cells in the embryonic brain germinal matrix, increasing dramatically the number of neurons in the cerebral cortex. When this gene is inserted into mouse embryos it is capable of causing some "gyrificación" (development of convolutions and small folds of the cerebral cortex in a normally smooth brain) to accommodate more neurons  [6]. It has not been evaluated whether this super-mouse is smarter than their peers.

                  _______________________________               

               
The brain does not work as if it were a binary machine, nor it operates on the basis of contacts on and off or through algorithms if-then-elese type. We do not have a hard disk spinning inside the skull; each nerve cell can connect with a large number of other neurons forming an extensive network where "almost everything connect with almost everything". One synaptic excitation on the end of a dendrite may not awake the activity of a single neuron, but a number of simultaneous active synapses can exceed the threshold and trigger the recipient cells to fire. It is what is known as spatial summation of fundamental importance in the integrative action of the central nervous system. Synaptic contacts have a mechanism for enhancing or facilitate subsequent firing when a synapse has been repeatedly excited in what has been known as the Hebbian theory of learning and memory  [7] . This theory had already been anticipated by Ramón y Cajal  [8] when he spoke of the benefits of some kind of brain gymnastics: "Thanks to an intelligent culture, pyramidal cells can multiply their branches, further sink its roots and produce each day the finest flowers and fruits". We know that neurons do not work in isolation but are connected to form neural networks. Due to the enormous variety of neurons, many of which are peculiar to a particular species, it is impossible to build a brain assembling structural units as placing bricks to erect a building. Then, one may ask: is there anything beyond the assembly of neuronal populations to build a thinking brain?          
                       In general, each nerve cell or neuron has a single fiber (or axon) conducting the nerve impulse to other neurons and a number of branches (dendrites) that act as receptors of nerve impulses from other neurons. Of the six layers in which the neocortex is divided, each neuron has its own individuality given by the specificity of their different connections. In the basic scheme of organization of the sensory areas, the fibers ascending from the underlying white matter (cortical afferent fibers) branch into the middle layers III and IV (Fig. 3).         

                     The individual cortical layers are related to the components of the other layers; this is the philosophy on which the concepts of modular operation of the cortex, were developed. From the early 1960s the understanding of the cerebral cortex has been dominated by the concept of columnar organization. The elementary unit is the cortical column which can be viewed as a cylinder of cortical tissue heavily connected vertically from the surfece of the cortex to the white matter having a central axis formed by the cortical afferent fibers (see Fig. 4). It is important to consider that these units are also interconnected in the tangential plane and therefore are not isolated entities. The cortical column in man may contain up to 105 neurons. This modularity extends to the entire cortical mantle, being one of the best known the ocular dominance columns of the visual cortex [9].         
_______________________
   
FIG. 3
Basic circuit formation in the mouse sensory cortex. Ascending afferent fibers (F) branch in the middle cortical layers connecting with the vertically oriented apical dendrite of the pyramidal cell (a) and the intrinsic cell dendrites (b). The axon of the latter (in red) branches in the upper layers of the cortex. Based on slides stained by the Golgi  method
. Taken from [10]. 

                                                    FIG. 3
                                                       FIG.  4
                
        FIG. 4 Visual cortex of the monkey (
Macaca mulatta). Representation of a cortical column based on slides stained by the Golgi method. Various types of pyramidal cells (a, b), stellate cells in sublayer IVa (c, d), cells with recurrent axons in sublayer IVc (e, f, g) and in layer and V (h, i). In red, cortical afferent fibers (F) ascending from white matter branch in sublayers IVa and IVc. Slightly modified from [12]
              In the cerebral cortex neurons communicate via specialized junctions called synapses (derived from the Greek word meaning link) where certain chemicals called neurotransmitters are released. There are excitatory and inhibitory synapses according to the action on other neurons. Synaptic contacts are fundamental to understanding brain fuction, thus the organization, signaling and plasticity of synapses underlie activity- and experience-dependent changes relevant to learning and memory.        

                Neurons of the cerebral cortex were classified into two main types: long axon cells (cell projecting over long distances, pyramid or type I cells) and short axon cells (with axonal ramifications restricted in the vicinity of the cell, intrinsic or type II cells) [11]. In neocortex, the most important type of neuron which exists only in mammals, is undoubtedly the pyramidal cell, whereas the intrinsic cells, which have been described more than one hundred varieties, are the seasoning; a necessary and indispensable seasoning, of course.
  
          T
he body of pyramidal cells stretches into a long apical dendrite ascending perpendicularly to the surface, where it finishes in an elegant plume, so it is able to receive contacts in all layers it traverses. Pyramidal cells own a group of basal dendrites extending radially from the cell body and one axon projecting over long distances that descends to penetrate the underlying white matter.


             We know a wide spectrum of intrinsic cell varieties that can be characterized not only by their morphology, but also by the length and type of axonal and dendritic branching they possess. There are neuronal cell varieties that, from a morphological point of view and probably also functionally, are different for each subject; there are cell varieties that are not found in other species so the description of a single structural pattern is not applicable unless resorting to extreme simplification and generalization, of course devoid of any descriptive and functional value.

_________________________
 
FIG. 5. Visual cortex in the brain of the mouse (Mus musculus) showing various cell types in layers II and III. Notice intrinsic cell "a" with ascending axon and one pyramidal cell "b" in layer V. The axon of cell "a" (in red) emits numerous collateral branches in layers IV and V, ending in a plexus of terminals fibers in the layer I. Preparation stained by the method of Golgi. Taken from
[13]

                                         FIG.  6
             
 FIG. 6. Varieties of cells in the visual cortex of the cat (Felis catus) showing one chandelier cell (a) whose axon, after forming a large plexus with branches in contact with the initial segments of the axons of pyramidal cells (not stained) continues with a descending projection branch . Stellate cells (b, c, d) with vertical and horizontal axonal branches and one aracneiforme cell  (e). Afferent fiber (F) form terminal side branches distributed in layer IV. Based on slides stained by the Golgi method Taken from
[14].            




_____________________________________



FIG. 7.
"Double bouquet"
cells with axons of different length and morphology in the cerebral cortex of the monkey (Macaca mulatta). The two cells located on the left are from the primary visual area, or area 17; the two cells to the right correspond to the secondary visual area, or area 18, showing axonal branches extendeding to virtually all cortical layers. Based on slides stained by the Golgi method. Taken from [15].

             




                                         FIG.  5
                                          FIG.  7

                                                   

NEURONAL NETWORKS. HIPPOCAMPUS AND MEMORY
    

                 The neural activity does not depend on the individual characteristics of each cell but to the contacts they establish with other cells of the same neuronal circuit. The synaptic connections that appear in neural network models are intended to illustrate a remarkable and important property: they can transmit different impulses through the same pattern of cell connections, which greatly increases the functionality of neural circuits [16].
               
                  During learning, the flow of information would result in the activation of some of these neural networks of limited duration (short term memory) that can become permanent when synapses were repeatedly activated. Under these circumstances, synapses become more efficient and is under this synaptic efficacy when other influences tend later to go through these same neural structures (long term memory or LTP) [17]. This can originate a fixation, a memory trace that can be stored and be evoked during the lifetime, even remaining in cases of  coma or deep anesthesia. It is a phenomenon in which that brain structure known as the hippocampus plays a key role intervening in complex processes of consolidation, memory storage and retrieval and spatial positioning.          
FIG. 8. Photomicrograph of a preparation stained by the Golgi method in the visual cortex of the monkey (Macaca mulatta). Variety of spiny stellate cell with recurving axon "on hook", typical of primates, with axon dividing into two ascending branches (arrow) reaching the surface layers of the cortex.


                              
                              
                                             












FIG. 9.
Photomicrograph of a preparation stained by the Golgi method in the somatosensory cortex of the hedgehog (Erinaceus europaeus) showing a variety of pyramidal cell whose axon arises from the apical dendrite (arrow).







        
                                                                    FIG. 10.

           FIG. 10.  Highly schematic neural network. The two diagrams, top and bottom, are exactly the same, representing the arbitrary connections of 20  neurons. It is assumed to need, at least two synapses to excite each neuron. With this premise, an input entering for A and B (upper diagram), can only follow through the red neuronal chain leading to exit by C5; if the impulse enters by C and D (lower diagram), the output can only be through B5. Based on the schemes proposed by Eccles [16].
            However, consolidation or fixation mechanisms are not immediate; there are known cases of patients having suffered severe trauma with loss of consciousness, in which the  hippocampus had no time to register (consolidate) what happened so they will not remember anything when they wake of his accident.


         A
typical example of the importance of hippocampal structures in memory processes is that of a patient, known by the initials HM, submitted in 1956, at the age of 27, to an operation in which it was resected bilaterally much of the hippocampus and some adjacent brain structures. The operation was intended to cure a refractory epilepsy suffering from ten years as a result of trauma [18].

             After the operation he stopped having seizures but
presented a severe amnesia for recent memories that made him to live like in a permanent present. He retained all his previous memories but could not remember what had made just a few seconds before so, and, for more than forty years, he was resolving the same crossword puzzle every day without remembering that he had done hundreds of times and reading the same magazine again and again. The HM case, perhaps the most famous in the history of neurology, has led to an extensive bibliography. He died at the age of 82 and his brain, which has been extensively studied, represents a material leaving a priceless legacy for the study of the processes of storing and retrieving memories and brain function.




               We now can imagine the neocortical mantle as a neuronal network similar to the one depicted in Fig. 10, but containing thousands or millions of neurons heavily interconnected. We may also consider that each node in this network is one cortical column, as depicted before (see Fig. 4), with 105 neuronal components. Even more, in these networks, a particular neuron or group thereof can be integrated in a number of differente functional circuits much like the same pixel is able to function in varieties of figures in a TV display screen. With this in mind, we realize that the countless number of possible different circuits, with hundreds or thousands units flashing as infinite galaxies lost in the immensity of the Brain Universe, each with its unique architecture, each with its own special remembrance, each with its own particular individuality, amounts such a figure number that shakes hands with infinity.

             The hippocampus is a part of the brain hidden deep in the temporal lobe. Apparently has a much simpler and ordered stratification than the layers of the neocortex, as it can be seen by looking at the image that underlies the title of this essay. It is an structure involved in episodic and spatial memory and has a key role in the formation and consolidation of new memories. His injury causes severe disorders of anterograde (formation of new memories) and retrograde amnesia (recall of events and previous experience). It is known that it is involved in transferring memories to other brain regions for permanent file.

                    The hippocampus actually is like a catch in which all the evils have fallen for which a clear explanation has not been found. It has been implicated in many diseases and mental disorders, sleep and behavior of different nature, aging processes, epilepsy, stress, Alzheimer's disease and other brain pathologies. There are even studies that claim to have shown that taxi drivers have a larger hippocampus due to the enormous street names they have to retain.
                    
                     In the hippocampus there are place-modulated cells there are specific neurons that form a positioning system or "cognitive map" (familiar cerebral GPS), which allows to know and remember the situation and the path taken to reach a particular place. Hippocampal relations with the neighboring entorhinal cortex, containing grid cells, have clarified how these sets of cells can run higher cognitive functions. The modularly organized network of place and grid cells may underlie the unique ability of the hippocampus to store large amounts of information but their interactions with representations in other cortical areas remain to be determined.This positioning system, affected by injury in both hippocampus and entorhinal cortex in Alzheimer's disease, explains why these patients lose their ability to recognize the environment, forget their way back and suffer severe memory loss. The authors of these studies have been awarded the Nobel Prize in Physiology or Medicine 2014 [19].

     

                                                                         

     DENDRITIC SPINES.  BRAIN PLASTICITY.

          The dendrites of nerve cells possess structures called "dendritic spines" which, as its name suggests, resemble the thorns that grow along the stems (dendrites) of the roses, but in much larger numbers. Dendritic spines are structures that greatly increase the contact surface of neurons. Its shape is that of a thin protrusion or pedicle one to three microns (1 micron = 0.001 mm) in length, finishing in a small spherical head of varying size and shape similar to a fungus (Fig. 11). Dendritic branches of a single neuron can contain hundreds or thousands of spines that receive the excitatory synaptic connections of other neurons. Dendritic spines were first discovered by Cajal in 1891.               

         We now know that over 80% of neural connections in the cerebral cortex are conducted through contacts on dendritic spines. They are a dynamically, very active structures and their maintenance and plasticity, allegedly involved in memory and learning, makes them to appear, move or vary in shape and size in a few seconds [20].

               
In layer V of the visual cortex reside pyramidal cells whose apical dendrites ascend vertically to the surface of the neocortex. They are densely provided with numerous dendritic spines as they traverse through the area where the ramifications of afferent fibers are distributed (layer IV, see Fig. 3) and where they receive numerous direct contacts.
                 

          It has recently been discovered that SRGAP2 gene involved in the development of the cerebral cortex during evolution [21], is able to promote growth and increase the number and density of dendritic spines extending its maturity period with the logical consequence of greater synaptic function in learning and memory processes  [22].


                                                 FIG. 11.
  
FIG. 11. Electron microscope image showing a dendritic spine (Es) connected by a thin pedicle to a dendrite (D) cut transversely in the visual cortex of the mouse (Mus musculus). Contacting the spine there is an axon terminal (T) loaded with synaptic vesicles making synaptic contacts (contacts thickened) on the spine. Dendritic spines are specifically recognized by the presence of flattened diverticula (the apparatus of the spine) frequently in continuity with the microtubules of the dendrite itself (small arrowhead in B). A, B and C is the sequence of three successive sections. The scale in A represents 0,5 micron.  



                FIG. 12.
    
Fig. 12. Photomicrographs of segments 50 microns in length of apical dendrites of pyramidal cells in layer IV in the visual cortex of the mouse (Mus musculus). A, normal mouse one month old with abundant dendritic spines; B, mouse kept in total darkness since birth for 24 days showing almost a total absence of dendritic spines. Golgi method.

               By using modern techniques (two-photon microscopy, gene transfer, calcium imaging) it has been known that dendritic spines are very sophisticated structures that have provided fundamental basis for understanding the structural plasticity of the brain [23]. Possibly, in the time to read these lines some dendritic spines of neurons in our brain have been shaken, slightly changing shape or size and their activity has been reinforced. Perhaps, they have also grown a few, sprouting like mushrooms after the autumn rain and, if one remembers what you have read, it is because dendritic spines and their connections have been stabilized and strengthened.  

                  
 Classical visual deprivation experiments showed that mice kept in complete darkness since birth had a decreased number of dendritic spines in the appical shafts of pyramidal cells of the visual cortex (Fig. 12). This decrease was highly significant in the first month of life of the animal after they open their eyes (usually around day 13-14 in mice) demonstrating that visual stimulation is necessary in order to develop proper visual connections. It was the first demonstration of anatomical plasticity of brain connections [24]        
                 
                 
In comparison, mice kept in darkness from birth for long periods of time, also showed a decrease in the number of spines but the variation was not as pronounced as in juvenile periods. According to the data obtained it showed that, although there is a tendency to recover the number of spines after returning to normal environment, there was a population of neurons in which the number of spines never reach normal levels (see Fig. 13 frequency histogram, group 20 + 4 + darkness, arrow).
           
                  
The presence of a permanent damage is likely to indicate the existence of a "critical period" in which some neurons and/or their connections could recover before becoming permanently damaged[25].This idea of a critical period arose after several studies demonstrated that shortly after birth the organization of the visual cortex may be modified by activity dependent plasticity [26].      
Fig. 13. Frequency histograms of dendritic spines per segment of 100 micra in the visual cortex of mice (Mus musculus) in age groups of normal (red), raised in complete darkness (black) and darkness + light (blue). Comparing the number of spines per segment in animals kept in darkness and controls before they open their eyes, there is no appreciable difference (A). When mice open the eyes an explosive increase in the number of dendritic spines occur; in just 10 or 12 days the number of spines is doubled (B); the average being around 90-100 dendritic spines per segment, away from the mean value found in dark-grown (average values between 60 and 70).
    
    
     One interesting thing about this study is that mice kept in darkness from birth for 20 days and returned to normal conditions for 4 days (B, blue histogram) clearly shows two populations of pyramidal neurons: one group reaches values close to the normal (right side of the blue histogram), while another group maintains a very low number of spines (arrowed oval). It probably corresponds to a group of damaged pyramidal cells affected beyond the alleged critical period.  Taken from [25].






                                                                     FIG. 13.
                 Just like a summary. Three are the memory stages we can recognize: Registration, Storage and Recovery. Actually, the place where memory or memories are stored is unknown. Most probably, memory, once encoded, lies in the region of the cortex in which the information was perceived and processed. The memories are preserved for life, and, according to some authors, the total amount of events occuring during a life span, are recorded in our brain; what sometimes fail is the way to access them. It might be possible that the process takes place in large parts of the cerebral cortex being stored as temporo-spatial engrams encoded in our neuronal networks we have described becoming "triggered" by some mechanism not yet known . It is quite possible that our memories are evoked by certain "keys" that can be represented by a word, a sound, an image or even a smell. Perhaps a spring fragrance, a sound, an image or whatever calls our attention brings us a flood of memories launching all neuronal circuitry hidden in the depths of our brain. These neural activities must be based on a lasting change that occurs in the fine structure of the nervous system during consolidation and recall. In this essay we have just outlined some small aspects of the operation of that special machine: our brain, and how much it costs to show their secrets. Hopefully one day we will clearly reveal their true structure and function and to correct and adjust their mistakes. I hope so.


REFERENCES    

Clic the reference number to return to the reading point. 


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(2) Valverde,F. (2004) Estructura y organización de la corteza visual primaria. Mente y cerebro, Nr. 6. Pp. 10-19.
(3) Pakenberg,B. and Gundersen,H.J. (1997) Neocortical neuron number in humans: effects of sex and age. Journal of  Comparative Neurology, 384:312-320.
(4) Valverde,F. (2002) Estructura de la corteza cerebral. Organización intrínseca y análisis comparativo del neocortex. Revisiones en Neurociencia.
Revista de Neurología, 34:758-750.
(5) Dennis,M.Y. and cols. (2012) Evolution of human-specific neural
SRGAP2 genes by incomplete segmental duplication. Cell, 149:912-922.
(6) Florio,M. and cols. (2015) Human-specific gene ARHGAP11B promotes basal progenitor amplification  and neocortex expansion. Science Express, February 26, pp. 1-9.
(7) Hebb,D.O (1949) The Organization of Behavior: A neurophysiological theory. New York, Wiley.
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Ramón y Cajal,S. (1894) La fine structure des centres nerveux. The Croonian Lecture. Proceedings of the Royal Society, London, 55:444-468.
(9) Hubel,D.H. and Wiesel,T.N. (1962) Receptive fields, binocular interaction and functional architecture in the cat's visual cortex. Journal of Physiology, 160:106-154.
(10) Valverde,F. (1970) The Golgi method. A tool for comparative structural analyses. In: Contempporary Research Methods. Ed. by W.J.H.Nauta and S.O.E.Ebbesson. Berlin, Heidelberg, New York, Pp. 12-31.
(11) Cajal,S.R. (1891) Sur la structure de l'ecorce cérébrale de quelques mammifères. La Cellule, Vol. VII.
(12) Valverde,F. (1971) Short axon neuronal subsystems in the visual cortex of the monkey. International Journal of Neuroscience, 1:181-197.
(13) Valverde,F. (1976) Aspects of cortical organization related to the geometry of neurons with intra-cortical axons. Journal od Neurocytology, 5:509-529.
(14) Fairén,A. and Valverde,F. (1979) Specific thalamo-cortical afferents and their presumptive targets in the visual cortex. A Golgi study. In: Development and Chemical Specificity of Neurons. Progress in Brain Research, Vol. 51, Elseviert, Amasterdam, Pp. 419-438.
(15) Valverde,F. (1985) The organizing principles of the primary visual cortex in the monkey. In: Cerebral Cortex, Vol. 3. Ed. by A.Peters and E.G.Jones, New York, Plenum Press, Pp. 207-257.
(16) Eccles,J. (1970) Facing Reality: Philosophical Adventures by a Brain Scientist. Berlin, Springer.
(17) Bliss,T. and Lømo,T. (1973) Long-lasting potentiation of synaptic transmission in the dentate area
of the anaesthetized rabbit following stimulation of the perforant path. Journal of Physiology, 232:331-35.

(18) Scoville,W.B. and Milner,B. (1957) Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery and Psychiatry, 20:11-21.
(19) Moser,E.I., Kropff,E. and  Moser,M.-B. (2008) Place cells, grid cells and the brain's spatial representation system. Annual Review of Neurosciences, 31:69-89.
(20) Alvarez,V and Sabatini,B. (2007) Anatomical and physiological plasticity of dendritic spines. Annual Review of Neuroscience, 30:79-97. 
(21) Dennis,M.Y. and cols. (2012)  Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell, 149:912-922.
(22) Charrier,C. and cols. (2012)  Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell, 149:923-935.
(23)
Sala,C. and Segal,M. (2014) Dendritic spines: The locus of structural and functional plasticity. Physiol.Rev. 94:141-188.
(24) Valverde,F. (1967) Apical dendritic spines of the visual cortex and light deprivation in the mouse. Experimental Brain Research, 3:337-352-
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(26) Hubel,D.H. and Wiesel,T.N. (1970) The period of susceptibility to the physiological effects of unilateral eye closure in kittens.  Journal of Physiology (London). 206:419-436.


Some interesting links:

- The Cajal Institute. One hundred years.
- Welcome to the Cajal Institute.





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