The fast synaptic responses that we looked at in the previous chapter are mediated by ion channels that open when they bind to the neurotransmitter active at the synapse. Thus transmission at the vertebrate neuromuscular junction or electric organ is mediated by acetylcholine-gated channels, excitatory transmission at spinal motoneurons is mediated by glutamate-gated channels, and inhibitory transmission there is mediated by glycine-gated or GABA-gated channels. These channels are also receptors since they are each specifically activated by their own particular neurotransmitter.

Structure of the nicotinic acetylcholine receptor

There are two main types of acetylcholine receptor. The type we have met previously, which mediates fast synaptic transmission at vertebrate neuromuscular junctions and electric organs, is known as the nicotinic acetylcholine receptor, or nAChR for short. The second type, known as the muscarinic acetylcholine receptor, is involved in some slow synaptic transmission processes and contains no ion channel. Nicotinic receptors are activated by nicotine and blocked by curare, whereas muscarinic receptors are activated by muscarine and blocked by atropine. We will look at muscarinic receptors in chapter 9.

The richest known source of nAChRs is the electric organ of the electric ray Torpedo, 1 kg of which contains over 100 mg of the receptor protein. Lower concentrations are present in the electric organ of Electrophorus, the electric eel, and in vertebrate muscle fibres. Acetylcholine receptors have been isolated from all these sources, but the Torpedo electric organ remains the biochemists' favourite.

The Hodgkin–Huxley analysis of nervous conduction, which we examined in the chapter 5, showed that the sodium and potassium conductances of the axon membrane are switched on and off (or ‘gated’) by changes in membrane potential. Hence the channels through which the sodium and potassium ions flow are themselves gated by changes in membrane potential. In this chapter we examine some of the properties of these voltage-gated channels.

Voltage-gated sodium channels

Voltage clamp studies of the Hodgkin–Huxley type can provide information about the overall actions of large numbers of channels, but they cannot tell us how the individual channels behave. Two methods have been developed for this: fluctuation analysis and the patch clamp technique. Fluctuation analysis was developed first, but the patch clamp method allows more direct observation if the individual channel currents are large enough.

Patch clamping

The patch clamp technique has the very great advantage that the current flow through individual ion channels can be measured. An outline of the method is given in chapter 2. For voltage-gated channels, the stimulus for channel opening is a clamped depolarization applied to the patch of membrane containing the channel.

The first single-channel records of sodium channel currents were obtained by Sigworth & Neher (1980) by patch clamping myoballs, which are spherical cells prepared by tissue culture of embryonic rat muscle in the presence of colchicine. They used pipettes containing tetraethylammonium (TEA) to block any potassium channels present and α-bungarotoxin to block acetylcholine channels (p. 114).

Although she came to see me as an analytical patient five times a week, Miss A. found it very difficult to remember anything from one session to the next. Shortly after we had met and started working together, she had told me that she needed me to remember why she had gone into a shoe shop. It was not like going into a grocer's and forgetting the sugar – anyone could do that; she did not even know why she was in the shoe shop. She added, somewhat embarrassed by what she had said, that she did not need me to know it too well, that would be absolutely awful.

Mr B., on the other hand, had an excellent memory and prided himself on recalling what I had said more accurately than I did. But one day when I mentioned something it turned out he had forgotten, he snapped at me, ‘How can you expect me to remember that when I can't even remember my own mother from one day to the next?’ Mr B.'s widowed mother needed his daily attention. Mr B. had a particular memory of childhood that was probably what we call a ‘screen’ memory – a mixture of experience and highly relevant fantasy, like a dream image. In this mnemic image he was standing shaking out a tarpaulin sheet together with his father, a DIY enthusiast: he could see the garden, himself, his hands on the tarpaulin, the tarpaulin held at both ends shaking, and then the image stopped.

The brain's operation depends on networks of nerve cells, called neurons, connected with each other by synapses. Scientists can now mimic some of the brain's behaviours with computer-based models of neural networks. One major domain of behaviour to which this approach has been applied is the question of how the brain acquires and maintains new information; that is, what we would call learning and memory. Neural networks employ various learning algorithms, which are recipes for how to change the network to store new information, and this chapter surveys learning algorithms that have been explored over the last decade. A few representative examples are presented here to illustrate the basic types of learning algorithms; the interested reader is encouraged to consult recent books listed in the section on Further reading, which present these algorithms in greater detail and provide a more complete survey.

It is important to keep in mind that the models of neural networks that are simulated in computers are far simpler than the highly complex and often messy neural systems that nature has devised. Although much simpler, neural network models capture some of the most basic features of the brain and may share some general properties that will allow us to understand better the operation of the more complex system. Neural network models are built from simple processing units that work together in parallel, each concerned with only a small piece of information.

In this chapter we examine some aspects of the sensory receptor cells in our most complex sense organ, the eye. The optical apparatus of the eye focuses an image of the visual field on the retina. The retina contains, in humans, about 100 million photoreceptor cells, which are connected in a rather complicated fashion to about a million fibres in the optic nerve. When light falls upon the photoreceptor cells they are excited, and their excitation eventually leads to the production of action potentials in the optic nerve fibres.

The light sensitivity of the eye is caused primarily by the existence in the receptor cells of a visual pigment, whose function is to absorb light and, in so doing, to change in some way so as to start the chain of events leading to excitation of the optic nerve fibres. As a reflection of this photochemical change in the pigment, we find that the pigment molecules are bleached by illumination, and have to be regenerated before they regain their photosensitivity.

The range of sensitivity of the eye is enormous: the intensity of the brightest light which we can see is about 1010 times that of the dimmest. There are a number of mechanisms which enable this wide range to be perceived, which constitute the phenomena of visual adaptation. Dark adaptation is the increase in sensitivity which occurs when we pass from brightly lit to dim surroundings, and light adaptation is the reverse of this.

In chapters 18 to 20 we have been very largely concerned with the properties of vertebrate twitch skeletal muscle, exemplified by the sartorius of the frog. But it must be realized that the frog sartorius represents only one of a considerable variety of types of muscle, and a rather specialized one at that.

Muscles vary greatly in the time characteristics of their contractions. Some have much higher velocities of shortening than others; the muscles of the hare contract faster than do those of the tortoise. Muscles involved in sound production often contract more rapidly than do the locomotor muscles. Even similar muscles from similar animals have higher contraction speeds in small animals than in large animals; compare the wing-beat frequencies of a sparrow and a pelican (Hill, 1950b). These differences are correlated with differences in the ATPase activities of the myosin extracted from the various muscles (Bárány, 1967), and these in turn with differences in the amino acid sequences of the myosin and other myofibrillar molecules (Schiaffino & Reggiani, 1996).

The way the contractile machinery is organized is not uniform, although all muscles work via actin–myosin interactions involving the splitting of ATP. Striated muscles from different animal phyla may have different arrangements of the thick and thin filaments. Not all muscles are striated. The arrangement of myosin molecules in the thick filaments varies. Some muscles contain extra proteins such as paramyosin in their filaments.

Microscopic examination reveals one of the most characteristic features of vertebrate skeletal muscles: they are striated. Suitable optical techniques or staining methods show that bands of light and dark material alternate along the length of the myofibrils, and that these bands are aligned across the breadth of the fibre.

Detailed descriptions of these striation patterns, and sometimes observations on how they altered with changes in fibre length, were made by a number of nineteenthcentury microscopists. But, as Andrew Huxley (1980) has pointed out, this knowledge was disregarded and further structural studies were largely neglected in the first half of the twentieth century. The advances in understanding of muscle during this time arose largely from biochemical and physiological studies, and the nature of the striation pattern seemed to have no relevance to these approaches.

All this changed with the advent of the sliding filament theory in 1954. Quite suddenly muscle fine structure made sense in terms of function. The search for structural detail as the means of interpreting physiological and biochemical observations began afresh, with new and increasingly sophisticated methods. As a result we now have some exciting glimpses of the molecular activity that underlies muscular contraction. But let us first put the sliding filament theory in its context by taking a look at the biochemical and structural background from which it emerged.

The myofibril in 1953

The contractile machinery of striated muscle cells consists of a small number of different proteins which are aggregated together in filaments.

Although all of us experience memory failures at some time or another, these slips of memory do not cause severe disruptions to our daily lives. Most of us can still function adequately at work, engage in conversation, and remember the gist of the programme we saw on television last night, while accepting as normal the forgetting of certain details. After all, nobody remembers everything. For some people, however, their memory failure is of such a proportion that the effects can be devastating.

Imagine waking up and not being able to remember what you did yesterday. Imagine living in a time vacuum where there is no past to anchor the present and no future to anticipate. Such is the fate of many people suffering from organic amnesia. Although amnesia means literally ‘an absence of memory’, in practice people with organic amnesia do not have a total loss of memory. They remember who they are, they remember how to talk, and how to read, and they usually remember how to do things they learned before the onset of their memory loss, such as how to swim, ride a bike or play the piano. Unfortunately, they have great difficulty in learning new skills or information, experience problems when trying to remember ongoing events, and usually have a memory gap for the few days, weeks, months or even years before becoming ill.

In contrast, people with functional amnesia following, say, an emotional trauma, sometimes seem to lose memory for personal identity.

The biological importance of memory

It is not brains that make memories; it is people, who use their brains to do so. And animals, non-human animals, also make memories, and can learn and change their behaviour as a result of experience. Even some animals without much in the way of brains at all, just rather basic nervous systems, can do it. What this points to is the tremendous importance that the capacity to learn and remember has for the survival of animals. Plants do not need nervous systems, because all they have to do is to stand around with their arms – or branches – spread wide so that their leaves can catch the sun and photosynthesize. But animals which live on plants, and even more so animals which live on other animals, have to use their wits to find and capture their prey, and to avoid being eaten in their turn at least long enough to be able to reproduce. Such ways of making a living in the world demand the development of sensitive sense organs, and the capacity to register and interpret the data provided by those sense organs, to compare it with past experience and, even more, with the outcomes of that past experience. And this is what learning and memory are all about. It is not the only route to evolutionary success. After all, bacteria do pretty well without either brains or nervous systems, or even much by way of memory – though there have been some disputed claims that they can learn from experience.

The preceding two chapters have examined the mechanisms of fast synaptic transmission, which involves the opening of ion channels by the direct action of the neurotransmitter. In this chapter we consider the slower responses produced by indirect mechanisms, where the neurotransmitter receptor does not contain its own intrinsic channel. Activation of the receptor, we shall see, sets in train a series of changes in one or more other proteins, leading eventually to the opening or closing of a particular set of ion channels. Let us look first of all at the electrical phenomena that need to be explained.

Slow synaptic potentials

In the sympathetic nervous system of vertebrates there is a chain of ganglia lying near to the spinal cord. These contain the cell bodies of the postganglionic fibres which terminate on smooth muscle or gland cells. The preganglionic fibres arise in the spinal cord and form synapses with the cell bodies of the postganglionic fibres in the ganglia.

Bullfrog sympathetic ganglia contain B cells and C cells, the B cells being the larger. Each is innervated by preganglionic fibres which form numerous synaptic boutons on the neuronal soma. They show a variety of different types of synaptic activity (Kuffler, 1980; Adams et al.9 1986), as is shown in fig. 9.1.

A single stimulus applied to the preganglionic fibres produces a fast EPSP in both B and C cells, and this may be large enough to produce an action potential in the postganglionic fibres (fig. 9.1a).

Excitable cells can be studied by the great variety of techniques that are available for the study of living cells in general. These include light and electron microscopy, X-ray diffraction measurements, experiments involving radioactive tracers, cell fractionation techniques, cell imaging techniques, biochemical methods, and so on. The techniques which are particular to the study of excitable cells are those involving the measurement of rapid electrical events. So in order to understand the subject, we need to have some idea of how these measurements are made. Here we look briefly at some of the more general methods used. Duncan (1990) gives more detail on a variety of electrical measurement techniques.

Recording electrodes

If we wish to record the potential difference between two points, it is necessary to position electrodes at those points and connect them to a suitable instrument for measuring voltage. It is desirable that these electrodes should not be affected by the passage of small currents through them, i.e. that they should be non-polarizable. For many purposes fine silver wires are quite adequate. Slightly better electrodes are made from platinum wire or from silver wire that has been coated electrolytically with silver chloride. For very accurate measurements of steady potentials, calomel half-cells (mercury/mercuric chloride electrodes) may have to be used.

If the site we wish to record from is very small in size (such as occurs in extracellular recording from cells in the central nervous system), the electrode must have a very fine tip, and be insulated except at the end.

We have seen in chapter 7 that the controversy as to whether synaptic transmission was electrical or chemical in nature seemed to have been resolved by the advent of intracellular recording in the early 1950s. It was a great surprise, therefore, when intracellular recordings at the end of that decade provided clear evidence that some synapses do operate by the direct flow of current from one cell to another (see Bennett, 1985). Such synapses are described as electrotonic or electrically transmitting.

Synapses operating by electrotonic transmission

An excitatory electrotonic synapse is one in which the postsynaptic cell is directly excited by the electrotonic currents accompanying an action potential in the presynaptic axon. Electron microscopy of electrotonic synapses shows regions where the intercellular space between the two cells is much narrower than usual. These regions are known as gap junctions. As we shall see later, they contain channels which provide direct connections between the pre- and postsynaptic cells, so that current can flow readily from one cell to the other.

In order for electrotonic transmission to be effective, the electrical and geometrical characteristics of the junction must be arranged in a certain way. Figure 12.1 represents a junction between two cells, each of which is electrically excitable. The local circuit currents produced by inward movement of sodium ions in the presynaptic cell at A will be completed by currents flowing out of the synaptic cleft at B and out of the postsynaptic cell at C.