FUNDAMENTALS OF HOW THE BRAIN WORKS

Elias D. KouvelasDepartment of Physiology

Faculty of MedicineUniversity of Patras

At the moment the biggest problem is this: We have a certain commonsense picture of ourselves as human beings which is very hard to square with our overall “scientific” conception of the physical world. We think of ourselves as conscious, free, mindful, rational agents in a world that science tells us consists entirely of mindless meaningless physical particles. Now, how can we square these two conceptions? How, for example, can it be the case that the world contains nothing but unconscious physical particles, and yet that it also contains consciousness? How can a mechanical universe contain intentionalistic human beings – that is, human beings that can represent the world to themselves? How, in short, can an essentially meaningless world contain meanings?

John Searle, Mind, Brain and Science , Harvard University Press, 1984.

In other words

HOW IS HUMAN MIND RELATED TO THE REST

OF THE UNIVERSE

Man ought to know that from nothing else but the brain come joys, delights laughter and sorrows, griefs, despondency, and lamentations. And by this, in an especial manner, we acquire wisdom and knowledge, and see and hear and know what are foul and what are fair, what are bad and what are good, what are sweet and what are unsavory …And by the same organ we become mad and delirious, and fears and terrors assail us… All these things we endure from the brain when it is not healthy …In these ways I am of the opinion that the brain exercises the greatest power in the man. Hippocrates. On the Sacred Disease (4th century B.C)

A drawing of human brain from the book of Vessalius “ De humanicorporis” (1543). The subject was probably a decapitated criminal.

The brain according to Descartes. Hollow nerves from the eyes project to the brain ventricles.

Pierre Paul Broca

The brain that convinced Broca of localization of function in the cerebrum

CELLULAR CONNECTIVITY THEORY

• Individual neurons are the signaling units of the brain; they are generally arranged in functional groups and connect to one another with the synaptic connections in a precise function.

• The different behaviors are mediated by different brain regions that are interconnected by discrete neural pathways.

LEVELS OF ANALYSIS

• Molecular level. Brain matter consists of a fantastic variety of molecules many of which are unique in the nervous system.

• Cellular level. This level of analysis focuses on how all those molecules work together to give the neuron its special properties.

• Systems level. Constellations of neurons form complex ciruits that perform a common function: vision or voluntary movements for example.

• Behavioral level. How do neural systems work together to produce integrated behavior?

• Cognitive level. The greatest challenge of neuroscience is understanding the neural mechanisms responsible for the higher levels of human mental activity.

•

An outside (above) and inside (below) view of cerebral hemispheres

Camillo Golgi (1843-1926)

Golgi Staining

Santiago Ramon y Cajal (1852-1834)

Cajal’s drawing

NERVE IMPULSES INVOLVE THE OPENING AND CLOSING OF ION CHANELS

Ion channels consist of membrane proteins that assemble to form a pore in the phospholipid bilayer of the cellular membrane. In this example the chanelprotein has 5 polypeptide subunits. Each subunit has a hydrophobic surface region (shaded) that readily associates with the phospholipid bilayer. Ion channels have 2 very important properties. The first property is ion selectivity. Potassium channels are selectively permeable to K+. Likewise sodium or calcium ions are almost exclusively permeable for Na+ or Ca+ and so on. The other important property of many channels is gating. Channels with this property can be opened and closed-gated- by changes of the local microenviroment of the membrane. Ions diffuse through the channels following there electrochemical gradient.

THE ABILITY OF A NEURON TO FIRE DEPENDS ON A SMALL DIFFERENCE IN ELECTRICAL CHARGE BETWEEN THE INSIDE AND THE OUTSIDE OF THE CELLDURING REST ( RESTING MEMRANE POTENTIAL).

A voltmeter measures the difference in electrical potential between the tip of a microelectrode inside the cell and a wire placed in the extracellular fluid. Typically the inside of the neuron is about -65 mV with respect to the outside. This potential (resting potential) is caused by the uneven distribution of electrical charge across the memrane.

HOW THIS UNEVEN DISTRIBUTION IS PRODUCED? A. During rest the cell membrane is permeable only to K+. Because the concentration of K+ is high in the intracellular fluid, the resting membrane potential is generated by the efflux of K+ down its concentration gradient. B. The continued efflux of K+ builds up an excess of positive charge on the outside of the cell and leaves behind on the inside an excess of negative charge. This buildup of charge generates an electrical field that impedes the further efflux of K+, so that eventually an equilibrium is reached, at which the electrical and chemical driving forces are equal and opposite.

THEREFORE

• The resting membrane potential equals to the equilibrium potential of K+ given by the equation of Nernst.

• Ek = RT/ZF ln [K+]o / [K+]Iwhere

EK = potassium equilibrium potentialR = gas constantT = absolute temperaturez = charge of the ionF = Faraday’s constant

[K+]o and [K+]I = K+ concentrations outside and inside the cell.

WHEN A NERVE IMPULSE BEGINS, A DRAMATIC REVERSAL AT ONE POINT OF THE CELL’S MEMBRANE OCCURS. THIS CHANGE IS CALLED ACTION POTENTIAL.

The action potential is a dramatic redistribution of electrical charge across the membrane. Depolarization of the cell during the action potential is caused by the influx of sodium ions across the membrane, and repolarization is caused by the efflux of potassium ions.

The sodium-potassium pump is an enzyme that breaks down ATP in the presence of internal Na+. The chemical energy released by this reaction drives the pump which exchanges internal Na+ for external potassium. The action of this pump ensures that K+ is concentrated inside the neuron and that Na+ is concentrated outside.

THE ACTION POTENTIAL PASSES ALONG THE MEMBRANE OF THE AXON AT SPEEDS UP TO SEVERAL HUNDRED MILES AN HOUR.

When action potential is initiated, the influx of positive charge depolarizes the segment of the membrane immediately ahead it until it reaches threshold and generates its own action potential. In this way , the action potential works its way down the axon until it reaches the axon terminal, thereby initiating synaptic tranmission.

An action potential initiated at one end of the axon propagates only in one. This is because the membrane just behind is refractory, due to the inactivation of the sodium channels.

The myelin sheath does not extend continuously. There breaks in the insulation, the nodes of Ranvier, where ions cross the membrane, to generate action potentials and therefore the action potentials travel the myelinatedaction from node to node. Thus, the myelin sheath allows current to spread faster and faster between nodes, speeding action potential conduction. This type of action potential propagation is called salvatory conduction.

Question: How nerve cells can vary their messages?

Reply: The code for the information carried by an axon is the frequency and pattern of action potentials since the strength of action potential is always the same.

CHEMICAL SYNAPTIC TRANSMISSION

Synaptic arrangements in synaptic arrangements in the CNS. (a) Axodendriticsynapse. (b)Axosomatic synapse. (c) Axoaxonic synapse.

The components of a chemical synapse. The presynaptic and postsynaptic membranes are separated by a synaptic cleft. The presynaptic side is usually an axon terminal. The terminal contains dozens of small membrane-enclosed spheres called synaptic vesicles. These vesicles store neurotransmitter, the chemical used to communicate with the postsynaptic neuron. The actual sites of neurotranmitterrelease are called active zones. Synaptic vesicles are clustered in the cytoplasm adjacent to the active zones. The protein thickly accumulated in and under the postsynaptic membrane is called the postsynaptic density. The postsynaptic density contains the neurotransmitter receptors, which convert the neurotransmitter signal into an intracellular signal in the postsynaptic cell (a change of the membrane potential or a chemical change), depending of the activated receptor.

Neurotransmitter release is triggered by the arrival of an action potential in the axon terminal. The depolarization of the terminal membrane causes voltage-gated calcium channels in the active zones to open and calcium will flood the cytoplasm of the axon terminal. The resulting elevation of [Ca++] in the axon terminal is the signal tht causes the neurotrasnmitter to be released. By a process called exocytosis. The membrane of the synaptic vesicle fuses the presynapticmembrane at the active zone, allowing the contents of the vesicle to spill out into the synaptic cleft. A quantal neurotransmitter release.

Neurotransmitters released into the synaptic cleft affect the postsynaptic neuron by binding to specific receptor proteins that are embedded in the postsynaptic density. The binding of neurotransmitter to the receptor is like inserting a key in alock; this causes a conformational changes in the protein, and the protein can then function differently. Although, there are well over 100 different neurotrasnmitter receptors, they can be classified into two types : neurotransmitter-gated channels and G-protein-coupled receptors.

TRANSMITTER-GATED ION CHANNELS

Receptors known as transmitter-gated ion channels are membrane-spanning proteins consisting of four or five subunits subunits that come together to form a pore between them. In the absence of neurotransmitter the pore is usually closed. When neurotransmitter binds to specific sites on the extracellular region of the channel, it induces a corformational change-just a slight twist – which within microseconds causes the pore to open. The functional consequence of this depends on which ions can pass through the pore.

If the open channels are permeable to Na+ the net effect will be to depolarize the postsynaptic cell. This action is said to be excitatory. A transient postsynaptic membrane depolarization caused by the presynaptic release of neurotrasnmitter is called excitatory post-synaptic potential (EPSP). Synaptic activation of Ach – gated and glutamate-gated ion channel causes EPSP.

If the transmitter-gated channels are permeable to Cl-, the net effect will be hyperpolarize the postsynaptic cell from the resting membrane potential. This effect is said to be inhibitory. A transient hyperpolarization of the postsynaptic membrane caused by the presynaptic release of neurotransmitter is called inhibitory postsynaptic potential (IPSP). Synaptic activation of glycine – gated or GABA-gated ion channels cause an IPSP

G-protein-coupled receptors can cause slower, longer-lasting, and much more diverse postsynaptic actions. This type of transmitter action involves three steps: 1. Neurotransmitter molecules bind to receptor proteins embedded in the postsynaptic membrane. 2. The receptors activate small proteins, called G-proteins, that are free to move along the intracellular face of the postsynaptic membrane. 3. The activated G proteins activate “effector” proteins. Effectorproteins can be G-protein-gated ion channels or enzymes that synthesize molecules called second messengers that diffuse in the cytosol.

NEUROTRANSMITTER RECOVERY AND DEGRADATION

Once the released neurotransmitter has interacted with the postsynaptic receptor it must be cleared from the synaptic cleft to allow another round of ofsynaptic transmission. There three ways this happens:

1. Simple diffusion of the transmitter molecules away from the synapse.

2. Reuptake into the presynaptic axon terminal.3. Enzymatic destruction in the synaptic cleft itself.

SYNAPTIC INTEGRATION

• Most CNS neurons receive thousands of synaptic inputs that activate different combinations of transmitter-gated ion channels and G-protein coupled receptors. The postsynaptic neuron integrates all these complex ionic and chemical signals and gives rise to a simple form of output: actions potentials. This transformation of many synaptic inputs to a single neuronal output constitutes a neural computation.

EPSP summation represents the simplest form of synaptic integration in the CNS. There are two types of summation: spatial and temporal. Spatial summation is the adding together of EPSPs generated simultaneously at many different synapses on a dendrite. Temporal summation is the adding together of EPSPs generated at the same synapse if they occur in rapid succession, within about 1-15 msec of one another.

EXPERIENCE IS A MAJOR DETERMINANT OF BRAIN ARCHITECTURE AND FUNCTION

Cortical representation of the 5th figure of the left hand of violin players (black arrow) is larger in comparison with the non-violin players (white arrow).

It has been said that beauty is in the eye of the beholder. As a hypothesis…this statement points clearly enough to the central problem of cognition…: the world of experience is produced by the man who experiences it…There certainly is a real world of trees and people and cars even books, and it has great deal to do with our experience of these objects. However, we have no direct immediate access to the world, nor to any of its properties…WHATEVER WE KNOW ABOUT REALITY HAS BEEN MEDIATED NOT ONLY BY THE ORGANS OF SENSE BUT BY COMPLEX SYSTEMS WHICH INTERPRET AND REINTEPRET SENSORY INFORMATION…The term “cognition” refers to all processes by which the sensory input is transformed, reduced, elaborated, stored, recovered and used.

Ulric Neisser

In analyzing the distinct attributes of images , the BRAIN INVENTS A VISUAL WORLD

Semir Zeki

Visual signals from the retina are transmitting onto the optic nerve ,optic chiasm, lateral geniculate nucleus and finally through the visual radiation to the primaryvisual cortex (area V1).

Area V1 is separated from the other areas of the visual cortex (V3, V4, V5) by the area V2.

Semir Zeki asked: Which areas of the visual cortex are stimulated when we see a painting of Mondrian or black and white moving images. PET scan analysis indicated that in the first case area V1 and V4 have been stimulated. Whereas in the second case areas V1 and V4.

Area V1 is devided in two regions. The blob and the interblob. As Margaret Livingston and David Hubel have shown the blob region contains cells sensitive to the different wave lengths whereas the interblob region contains cells sensitive to the form. Thus in V1 the different elements of the painting are analyzed according to the colourand the form (horizontal or vertical lines). The recostruction of the painting takes place in area V4. V2 plays also a role during the initial steps of reconstruction.

The ability of these cells to reconstruct the painting is based on the morphology of their receptive fields. There usually rectangular and they are activated by a specific color.

A MAJOR PART OF BRAIN FUNCTIONS ARE UNCONSCIOUS

Amygdala is situated in the pole of the temporal lobe just below the cortex in the medial side. Amygdala is a complex of nuclei, the basolateral (red) & corticomedial(dark) nuclei & the central nucleus. Afferents to the amygdala come from a large variety of sources including neocortex, hippocampal & cingulate gyri. Information from all sensory systems feeds into the amygdala, particularly in the basolateral nuclei.

Several experiments indicated that after training a sound tone becomes associated with fear. The presumed fear response is mediated by amygdala The emotional stimulus reaches the basolateral nuclei of the amygdala by the way of the auditory cortex and the signals are relayed to the central nucleus. Efferents from the central nucleus project to the hypothalamus, which can alter the state of the autonomic nervous system, and to periaqueductal gray matter in the brain stem, which can evoke behavioral reactions via the somatic motor system.

Thus, the central nucleus of amygdalacan induce fear and anxiety responses not only in the presence of a painful stimulus but after recall of the painful stimulus induced by an associated stimulus.Central nucleus also projects to cortical association areas, especially the orbitofrontalcortex and the cingulate gyrus and this pathway is important for the perception of the emotional experience.However, this experience has to be distinguished from what is happening inside the central nucleus. The memory that is established there, the cause of autonomic, motor and conscious reactions, does not reach the level of the explicit (declarative) memory, it is an unconscious, implicit (procedural ) memory.

I APPRECIATED YOUR ATTENTION