Neural Networks (Interconnections)
Until the nineteenth century, we really had no idea what neurons looked like. Early workers were only able to stain the neurons’ cell bodies: until the axons and dendrites could be seen, neurons looked not so very different from liver or muscle cells. This changed in 1862, when a cell staining method was developed (largely by accident) that enabled the structure of a single neuron to be seen clearly through a microscope. Camillo Golgi’s staining method was a bit hit and miss: sometimes no cells at all might be stained; at other times all the cells in a particular section of brain might be so densely stained that the whole section looked black and individual cells could not be distinguished at all. But sometimes just a few cells would be darkly stained, and their morphology could then be established. It soon became clear that there are many different kinds of neurons. The great brain anatomists like Ramón y Cajal ([1892] 1968) and Lorente de Nó (1934) used these kinds of techniques to examine, describe and draw the structures of the brain at a level of detail that would previously have been inconceivable. Nowadays you can inject a dye directly into a cell, so that it alone is filled; you can then visualize the neuron in its entirety. Where such studies are combined with functional studies recording the activity of that cell and the other neurons most intimately connected with it, the relationship between form and function can be established with great rigour. We also discover where each neuron’s incoming connections originate, and where their own outputs go, by injecting anatomical tracers. These are substances that are absorbed by cell bodies, or by axon terminals, and then transported through the cell. This, coupled with electrophysiological studies in which we stimulate activity in one area and determine its effects in others, enables us to identify how neurons interconnect and interact. Neuronal interaction is what the brain is all about.
[Santiago Ramón y Cajal (1852–1934) was born in the Spanish village of Petilla. His father, at that time the village surgeon but subsequently the Professor of Dissection at the University of Zaragoza, found him a difficult teenager, and apprenticed him first to a shoemaker and later to a barber. The young Ramón y Cajal himself wished to become an artist, but eventually went to medical school, graduating in 1873. He entered academic life in 1875, but his great life’s work began when, in 1887, he was shown brain sections stained by Camillo Golgi’s silver method. Ramón y Cajal was captivated. Thereafter he studied and drew the nervous system in great detail. His observations led him to propose that the nervous system is made up of vast numbers of separate nerve cells: the ‘neuron doctrine’. He shared the Nobel Prize with Golgi in 1906.]
Electrical Activity
Neurons are integrators. They can have a vast number of different inputs, but what they produce is a single output signal, which they transmit to their own targets. How is this done? The key lies in the electrical potentials they generate. There is a small voltage difference between the inside and the outside of the neuron. The inputs are tiny amounts of chemical neurotransmitters. The target cell has specialized receptor sites, which respond to particular neurotransmitters by subtly changing the cell’s electrical potential for a short time. If enough signals come in together, then the total change can become big enough for the target cell to ‘fire’ – or to transmit an output signal along its axon to modify the activity in its own target cells. So our first task is to find out how neurons produce electric potentials. Then we can see how these potentials change in response to inputs. Once we understand that, we can look at the way this same electrical potential system produces a fast and reliable output from the cell.
Resting Potential
The outside of a neuron is made of a highly specialized membrane.Within the neuron, much of the chemical machinery is made up of large, negatively charged protein molecules, which are too big to leak out through the membrane. Outside the membrane, in the gaps between neurons, lies the extra-cellular space, which contains fluid with electrically charged ions dissolved in it.
What does this mean? Well, common salt, for example, also called sodium chloride, is a compound of two elements – sodium and chlorine (giving a chemical formula of NaCl). When it is dissolved in water, it dissociates into a positively charged sodium ion (Na) and a negatively charged chloride on (Cl−). Potassium chloride also dissociates into its ionic constituents – potassium (K) and Cl−.
Mobile, positive ions are electrically attracted to the negatively charged proteins held within the neurons, but although the neuronal membrane lets potassium ions through, it is relatively impermeable to sodium ions. So potassium ions are pulled into the cell and held there by the electrical charge on the intracellular proteins. As potassium levels within the cell rise above those outside it, this inward flow of charged ions reduces, because there is now a concentration gradient tending to pull potassium out of the neuron. Equilibrium is reached (with the inside of the neuron more negative than the outside) when the opposing pulls of the concentration gradient and of the electrical gradient balance each other. There is also an active pumping of ions across the neuronal
membrane: for example, some sodium leaks into the neuron and is actively pumped out. These processes give neurons their characteristic electrical charge – the resting potential. Some ions have their own channels that let them pass through the cell membrane. These can be opened or closed, selectively altering membrane permeability Some pumps move ions inwards and others move them outwards. Neurotransmitters use these different ion channels to manipulate the cell’s membrane potential – a complicated balancing act. These activities consume a lot of energy. Your brain is only
2.5 per cent of your body weight, but uses some 20 per cent of your resting energy. This increases when the nervous system is actively processing signals. When a region increases its energy consumption, its blood supply needs to increase as well. This can be detected by functional neuro-imaging systems to help us identify which parts of the brain are activated during particular kinds
of mental processing.
Action Potential
When a neuron is activated by its input, the potential across the cell membrane changes. This is because when a neurotransmitter binds to its receptor, it can open channels that let particular ions
go through the membrane. Say we open a sodium channel. Positive Naions will flow through the membrane into the cell for two reasonsThe resting potential keeps the inside of the cell negatively
charged, so positive ions are attracted in.nThere is an attracting concentration gradient for sodium,
because there are many more Naions outside the cell than inside it. The resulting influx of positive ions makes the inside of the cell less negative, reducing the resting potential. This is called depolarizing the cell. If the cell is depolarized from its resting potential of around minus 70 millivolts
to its threshold potential of about minus 55 millivolts, an abrupt change is seen. This is called an action potential . It has been studied with great precision by controlling the membrane potential directly using electrical stimulation. The potential across the cell membrane suddenly flips radically from the normal state, in which the inside is negative relative to the outside, to a transient state in which, for a millisecond or so, the inside becomes positive relative to the outside. The normal direction of polarization is rapidly restored once the stimulation stops. In fact, the neuron becomes hyperpolarized for a few milliseconds, which means that its inside becomes even more negatively charged than usual. During this time – the refractory period – the hyperpolarized neuron is less readily able to respond to further input. So a single, relatively small, stimulation pulse can produce a radical change in the neuron’s electrical state. How does this happen? The crucial mechanism lies in the way that the different ion channels are controlled. While some are controlled by neurotransmitter receptors, others respond to the electrical potential across the cell membrane. When the cell has been depolarized all the way to the threshold potential, additional sodium channels suddenly open. More sodium ions pour into the cell through these channels, because there is still both a concentration gradient and an electrical gradient to attract them. This drives the depolarization further downwards, leading to further opening of sodium channels. So depolarization proceeds very rapidly. If we are to restore the original resting potential, ready for the next action potential, we have to reverse this current flow as quickly as possible. This is achieved by an outflow of positively charged potassium ions from the cell, combined with a process that deactivates sodium flow. Although the full picture is much more complicated than this, and involves many more different
ions and channel types, an understanding of the sodium and potassium currents conveys its essence.
Once an action potential has been generated, it will rapidly travel along the cell’s axon, changing membrane permeability as it goes. This active, self-regenerating method of spreading makes the classical action potential a very effective and reliable way to transmit information. If the neurons’ signals were conducted passively, in the way that heat is conducted along a wire, the signals would get weaker and weaker the further they had to go. If you use a long enough poker you can safely stir the red hot embers of a fire without your hand getting burnt. The hotter the fire, the longer the poker you need to use. But if heat were propagated actively, like an action potential, you would have to wear asbestos gloves, however long the poker. The action potential is the same size whether the depolarizing stimulus is only just strong enough to reach threshold or depolarizes well beyond threshold. This all-or-nothing property often leads people to liken action potentials to the digital signals in a computer. But this vastly underestimates the complexity of the nervous system and the potential subtlety of its responses. As we shall see, the propagation of the action potential may be all or nothing, but its effect can be very subtly graded.
Until the nineteenth century, we really had no idea what neurons looked like. Early workers were only able to stain the neurons’ cell bodies: until the axons and dendrites could be seen, neurons looked not so very different from liver or muscle cells. This changed in 1862, when a cell staining method was developed (largely by accident) that enabled the structure of a single neuron to be seen clearly through a microscope. Camillo Golgi’s staining method was a bit hit and miss: sometimes no cells at all might be stained; at other times all the cells in a particular section of brain might be so densely stained that the whole section looked black and individual cells could not be distinguished at all. But sometimes just a few cells would be darkly stained, and their morphology could then be established. It soon became clear that there are many different kinds of neurons. The great brain anatomists like Ramón y Cajal ([1892] 1968) and Lorente de Nó (1934) used these kinds of techniques to examine, describe and draw the structures of the brain at a level of detail that would previously have been inconceivable. Nowadays you can inject a dye directly into a cell, so that it alone is filled; you can then visualize the neuron in its entirety. Where such studies are combined with functional studies recording the activity of that cell and the other neurons most intimately connected with it, the relationship between form and function can be established with great rigour. We also discover where each neuron’s incoming connections originate, and where their own outputs go, by injecting anatomical tracers. These are substances that are absorbed by cell bodies, or by axon terminals, and then transported through the cell. This, coupled with electrophysiological studies in which we stimulate activity in one area and determine its effects in others, enables us to identify how neurons interconnect and interact. Neuronal interaction is what the brain is all about.
[Santiago Ramón y Cajal (1852–1934) was born in the Spanish village of Petilla. His father, at that time the village surgeon but subsequently the Professor of Dissection at the University of Zaragoza, found him a difficult teenager, and apprenticed him first to a shoemaker and later to a barber. The young Ramón y Cajal himself wished to become an artist, but eventually went to medical school, graduating in 1873. He entered academic life in 1875, but his great life’s work began when, in 1887, he was shown brain sections stained by Camillo Golgi’s silver method. Ramón y Cajal was captivated. Thereafter he studied and drew the nervous system in great detail. His observations led him to propose that the nervous system is made up of vast numbers of separate nerve cells: the ‘neuron doctrine’. He shared the Nobel Prize with Golgi in 1906.]
Electrical Activity
Neurons are integrators. They can have a vast number of different inputs, but what they produce is a single output signal, which they transmit to their own targets. How is this done? The key lies in the electrical potentials they generate. There is a small voltage difference between the inside and the outside of the neuron. The inputs are tiny amounts of chemical neurotransmitters. The target cell has specialized receptor sites, which respond to particular neurotransmitters by subtly changing the cell’s electrical potential for a short time. If enough signals come in together, then the total change can become big enough for the target cell to ‘fire’ – or to transmit an output signal along its axon to modify the activity in its own target cells. So our first task is to find out how neurons produce electric potentials. Then we can see how these potentials change in response to inputs. Once we understand that, we can look at the way this same electrical potential system produces a fast and reliable output from the cell.
Resting Potential
The outside of a neuron is made of a highly specialized membrane.Within the neuron, much of the chemical machinery is made up of large, negatively charged protein molecules, which are too big to leak out through the membrane. Outside the membrane, in the gaps between neurons, lies the extra-cellular space, which contains fluid with electrically charged ions dissolved in it.
What does this mean? Well, common salt, for example, also called sodium chloride, is a compound of two elements – sodium and chlorine (giving a chemical formula of NaCl). When it is dissolved in water, it dissociates into a positively charged sodium ion (Na) and a negatively charged chloride on (Cl−). Potassium chloride also dissociates into its ionic constituents – potassium (K) and Cl−.
Mobile, positive ions are electrically attracted to the negatively charged proteins held within the neurons, but although the neuronal membrane lets potassium ions through, it is relatively impermeable to sodium ions. So potassium ions are pulled into the cell and held there by the electrical charge on the intracellular proteins. As potassium levels within the cell rise above those outside it, this inward flow of charged ions reduces, because there is now a concentration gradient tending to pull potassium out of the neuron. Equilibrium is reached (with the inside of the neuron more negative than the outside) when the opposing pulls of the concentration gradient and of the electrical gradient balance each other. There is also an active pumping of ions across the neuronal
membrane: for example, some sodium leaks into the neuron and is actively pumped out. These processes give neurons their characteristic electrical charge – the resting potential. Some ions have their own channels that let them pass through the cell membrane. These can be opened or closed, selectively altering membrane permeability Some pumps move ions inwards and others move them outwards. Neurotransmitters use these different ion channels to manipulate the cell’s membrane potential – a complicated balancing act. These activities consume a lot of energy. Your brain is only
2.5 per cent of your body weight, but uses some 20 per cent of your resting energy. This increases when the nervous system is actively processing signals. When a region increases its energy consumption, its blood supply needs to increase as well. This can be detected by functional neuro-imaging systems to help us identify which parts of the brain are activated during particular kinds
of mental processing.
Action Potential
When a neuron is activated by its input, the potential across the cell membrane changes. This is because when a neurotransmitter binds to its receptor, it can open channels that let particular ions
go through the membrane. Say we open a sodium channel. Positive Naions will flow through the membrane into the cell for two reasonsThe resting potential keeps the inside of the cell negatively
charged, so positive ions are attracted in.nThere is an attracting concentration gradient for sodium,
because there are many more Naions outside the cell than inside it. The resulting influx of positive ions makes the inside of the cell less negative, reducing the resting potential. This is called depolarizing the cell. If the cell is depolarized from its resting potential of around minus 70 millivolts
to its threshold potential of about minus 55 millivolts, an abrupt change is seen. This is called an action potential . It has been studied with great precision by controlling the membrane potential directly using electrical stimulation. The potential across the cell membrane suddenly flips radically from the normal state, in which the inside is negative relative to the outside, to a transient state in which, for a millisecond or so, the inside becomes positive relative to the outside. The normal direction of polarization is rapidly restored once the stimulation stops. In fact, the neuron becomes hyperpolarized for a few milliseconds, which means that its inside becomes even more negatively charged than usual. During this time – the refractory period – the hyperpolarized neuron is less readily able to respond to further input. So a single, relatively small, stimulation pulse can produce a radical change in the neuron’s electrical state. How does this happen? The crucial mechanism lies in the way that the different ion channels are controlled. While some are controlled by neurotransmitter receptors, others respond to the electrical potential across the cell membrane. When the cell has been depolarized all the way to the threshold potential, additional sodium channels suddenly open. More sodium ions pour into the cell through these channels, because there is still both a concentration gradient and an electrical gradient to attract them. This drives the depolarization further downwards, leading to further opening of sodium channels. So depolarization proceeds very rapidly. If we are to restore the original resting potential, ready for the next action potential, we have to reverse this current flow as quickly as possible. This is achieved by an outflow of positively charged potassium ions from the cell, combined with a process that deactivates sodium flow. Although the full picture is much more complicated than this, and involves many more different
ions and channel types, an understanding of the sodium and potassium currents conveys its essence.
Once an action potential has been generated, it will rapidly travel along the cell’s axon, changing membrane permeability as it goes. This active, self-regenerating method of spreading makes the classical action potential a very effective and reliable way to transmit information. If the neurons’ signals were conducted passively, in the way that heat is conducted along a wire, the signals would get weaker and weaker the further they had to go. If you use a long enough poker you can safely stir the red hot embers of a fire without your hand getting burnt. The hotter the fire, the longer the poker you need to use. But if heat were propagated actively, like an action potential, you would have to wear asbestos gloves, however long the poker. The action potential is the same size whether the depolarizing stimulus is only just strong enough to reach threshold or depolarizes well beyond threshold. This all-or-nothing property often leads people to liken action potentials to the digital signals in a computer. But this vastly underestimates the complexity of the nervous system and the potential subtlety of its responses. As we shall see, the propagation of the action potential may be all or nothing, but its effect can be very subtly graded.
[Lord Adrian (1889–1977) was a physiologist who initiated single neuron recording methods. He was the Nobel Prize winner in 1932, shared with Sir Charles Sherrington. Adrian pioneered the use of then state-of-the-art electronics to amplify the signals he recorded and display them on an oscilloscope. This was a crucial technological advance that allowed him to monitor activity in single nerve fibres. One of his key findings was that intensity of sensation was related to the frequency of the all-or-nothing action potentials of constant size – so-called ‘frequency coding’, as opposed to ‘intensity coding’. Adrian also studied the sensory homunculus in different species. He reported that in humans and monkeys both the face and the hand have large areas of the sensory cortex devoted to them, whereas in pigs, the greater part of sensory cortex dealing with touch is allocated to the snout. So the richness of sensory representation can be related to the typical needs and activities of the species concerned. Subsequently, Adrian moved from work on the peripheral nervous system to study the electrical activity of the brain itself, opening up new fields of investigation in the study of
epilepsy and other types of brain injury]
epilepsy and other types of brain injury]
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