I read somewhere that writers, or perhaps all artists, are haunted or hunted by unusually vivid memories of their early lives – as are the old, whose useful daily memories are decaying. Certainly I remember being obsessed as a child by a kind of ‘glittering’ quality about certain experiences, usually without deep importance in what I thought of as the narrative of my life – experiences excessively bright, strongly outlined, recognized so to speak as important, even when they were met for the first time. (Re-cognizedimplies memory, the existence of a former cognition.) It is not too much to say that these experiences were as tormenting as they were delightful, until I, the person who underwent them, formed the project of being a writer – because only the act of writing gave them a glimmer of the importance they had in life, and thus gave them a place, a form and an order which made sense of them. And which they seemed to ask for. Proust, at the beginning of À la Recherche du Temps Perdu, speaks of certain experiences which forced him to look at them – ‘a cloud, a triangle, a belltower, a flower, a pebble’ – and gave him, as a child, a sense of duty towards them, a feeling that they were a symbolic language which he ought to decipher.

The normal stimulus for the contraction of a skeletal muscle fibre in a living animal is an impulse in the motor nerve that innervates it. In the twitch muscles of vertebrates with which we are concerned in this chapter, this nerve impulse leads to a propagated action potential in the muscle fibre, which is then followed by a twitch contraction. The time relations of the action potential and twitch tension in a single muscle fibre are shown in fig. 20.1.

The sequence of these events is shown schematically in fig. 18.1. We have examined stages 1 to 4 of this sequence (the excitation processes) in earlier chapters of this book, and stage 6 (contraction) in chapters 19 and 20. Here we consider how excitation of the muscle fibre membrane initiates contraction of the myofibrils in the interior of the fibre. This constitutes stage 5 of fig. 18.1, the excitation–contraction coupling process. In terms of fig. 20.1, then, how does the action potential produce the contraction?

Excitation–contraction coupling

The importance of depolarization of the cell membrane

When muscle fibres are immersed in solutions containing a high concentration of potassium ions, they undergo a relatively prolonged contraction known as a contracture. Contractures can also be produced by various drugs, such as acetylcholine, veratridine and others. Kuffler (1946) showed that many of these substances produce depolarization of the cell membrane; furthermore, if the substance was applied locally the resulting contracture was limited to that part of the muscle fibre where depolarization occurred.

So far in our consideration of the mechanisms involved in synaptic transmission, we have been concerned very largely with postsynaptic structures and events. It is time to look at what happens in the presynaptic terminal and the synaptic cleft. How is the neurotransmitter released from the terminal when a nerve impulse arrives there? How is it synthesized and packaged for release? What happens to it after it has dissociated from the postsynaptic receptors? We begin by considering some classic experiments by Bernard Katz and his colleagues on the release of acetylcholine at the frog neuromuscular junction.

Transmitter release from synaptic vesicles

During the controversy in the 1930s as to whether synaptic transmission was essentially an electrical or a chemical process, those who held to the electrical hypothesis could not see how a chemical process could account for the speed of synaptic transmission. The advent of the intracellular microelectrode demonstrated, as we have seen in chapter 7, that the transmission process is dependent in most cases upon the release of a chemical substance, the neurotransmitter, from the presynaptic nerve terminal. It also showed that this release is a very rapid process: fast synaptic transmission really is fast, so that the action of the neurotransmitter begins within a millisecond or so of the nerve impulse reaching the presynaptic terminal. How is this rapid release of the neurotransmitter brought about?

The most striking anatomical feature of nerve cells is that part of the cell is produced into an enormously elongated cylindrical process, the axon. It is this part of the cell with which we shall be concerned in this chapter and the next. The essential function of the axon is the propagation of nerve impulses.

Action potentials in single axons

Let us consider a simple experiment on the giant fibres in the nerve cord of the earthworm. These fibres are anatomically not axons, because they are multicellular units divided by transverse septa in each segment, but physiologically each fibre acts as a single axon. There are three giant fibres, one median and two lateral, which run the length of the worm; the laterals are interconnected at intervals. The experimental arrangement for eliciting and recording impulses in the giant fibres is shown in fig. 4.1. The stimulator produces a square voltage pulse which is applied to the nerve cord at the stimulating electrodes. The recording electrodes pick up the electrical changes in the nerve cord and feed them into the amplifier. Here they are amplified about 1000 times, and then passed to the oscilloscope where they are displayed on the screen of the cathode ray tube. The output of the stimulator is also fed into the oscilloscope so that it is displayed on the second trace on the screen. The timing of the oscilloscope sweep is arranged so that both traces start at the moment that the pulse from the stimulator arrives.

All animals are sensitive to some extent to changes in their environment. Special parts of the body are responsive to some of these changes and feed information concerning them into the central nervous system. Information about the workings of the animal's own body, or about communication signals from other members of its species, may be acquired in a similar fashion. These specially sensitive structures are known as sense organs or sensory receptors. They are crucially important in the lives of animals.

Since there is a very great variety of different types of sense organ, the following pages must necessarily be no more than a selective introduction to their physiology. This chapter attempts to give a general outline of the properties of sensory receptors, the next four chapters survey some selected different types, with particular emphasis on their sensory cells and transduction processes. The books by Barlow & Mollon (1982), Dawson & Enoch (1984), Darian-Smith (1984b), Corey & Roper (1992) and Dusenbery (1992) are some of the many useful sources of further information.

The methods used for investigating receptors fall into two main categories. Firstly, there is the behavioural, or psychophysical, approach, where the receptor is investigated indirectly by observation of the response of the animal to a sensory stimulus. For example, suppose we are interested in the ability of an animal to discriminate colours. In the case of humans, the experiments are not too difficult, since we can ask the subject if two colours look different.

There has been a great flowering of our knowledge about the physiology of nerve, muscle and sensory cells in recent decades. This book aims to help the reader to learn about the subject by giving an account of some of the experimental evidence on which this knowledge is based. It is intended primarily for use by students taking courses in physiology, neuroscience, cell biology or biophysics, but it should also prove useful to those beginning research and to scientists of related disciplines.

This fourth edition reflects the continuing emphasis on molecular mechanisms that has been such a feature of the biological sciences in recent years. Exciting new developments have continued to flow from the use of the patch clamp technique for examining the currents flowing through single membrane channels, and from the application of recombinant DNA methods for determining the structures of proteins. Hence the book has been extensively revised to take account of these and other advances, and there is much new material throughout. I have also extended the range of the book to cover a wider range of sensory cells and to consider the cellular basis of learning, and I have restructured some of the chapters to maintain a sensible arrangement of the material.

Learning about science is a complicated business. Students are expected to know the phenomena that occur in the natural world and understand the concepts which we use to explain them.

In previous chapters we examined the physiology of sensory receptors responsive to mechanical, visual and chemical stimuli, and we saw that in some cases our knowledge of the transduction processes and related cellular mechanisms is quite extensive. In this chapter we look briefly at some further senses about whose mechanisms we have rather less information.

Thermoreceptors

Sensations of warm and cold are important to ourselves and other animals in rinding a suitable environment in which to live. Conditions are suboptimal if this is too cold or too hot, and extremes of temperature are fatal. The temperature of particular objects may be important, as in the detection of warm-blooded prey by snakes or fleas, or the control of the incubation mound by the mallee fowl.

Temperature-sensitive sensory nerve fibres with endings in mammalian skin are of two types, cold fibres and warm fibres, as is shown in fig. 17.1. Both groups have a low level of activity at the body heat level of 377deg;C. Cold fibres discharge increasingly as the skin temperature falls below this, reaching a maximum in the region of 27°C; sometimes they also discharge at very high temperatures, above 50°C. Warm fibres discharge increasingly at higher temperatures, with a maximum at about 46°C and a very rapid fall-off above this (Hensel & Zotterman, 1951; Hensel & Kenshallo, 1969; Pierau & Wurster, 1981).

These fibres also show marked responses to change in temperature. Cold fibres increase their discharge rate for a few seconds on rapid cooling and decrease it on rapid warming.

It is likely that all living organisms respond to some of the chemicals in their environment. Animals need to detect food sources at a distance, and to test the nature of those sources when they have reached them. Often they use chemical methods for communication between different individuals, and especially for sexual interactions.

The chemical senses are conventionally divided into smell, or olfaction, and taste, or gustation. For humans and other mammals the distinction seems fairly clear: we use our sense of smell to detect air-borne chemicals arising from a distant source, and we use our sense of taste to sample solid or liquid material in our mouths. For fish and other aquatic animals, where odorant substances are necessarily carried in water, the logic of distinguishing between olfaction and taste is less clear. Even in ourselves, the olfactory receptors are essential components of the sensations we receive from food or drink in the mouth, as anyone whose nasal passages are blocked during a cold will know.

In this chapter we concentrate on the transduction mechanisms in the receptors mediating taste and olfaction in mammals, and by way of contrast we also have a quick look at how insects do it.

Taste mechanisms in mammals

Soluble tastant molecules are detected by taste receptor cells on the tongue (see Roper, 1992; McLaughlin & Margolskee, 1994; Lindemann, 1996). The sensitive cells are grouped in taste buds (fig. 16.1).

The function of muscle cells is to contract: to shorten and develop tension. This means that the end-product of cellular activity can be measured with considerable precision, by mechanical measurement of the change in length or tension or both. Such activity must obviously involve the consumption of energy, some of which may appear as heat.

In this chapter and the next two we shall be concerned mainly with the properties of rapidly contracting vertebrate skeletal muscles, such as frog sartorius and the rabbit psoas. Skeletal muscles are activated by motoneurons, as we have seen in previous chapters. Their cells are elongate and multinuclear and the contractile material within them shows cross-striations; hence skeletal muscle is a form of striated muscle. Some of the special properties of other muscles are examined in chapter 21.

The normal stimulus for the contraction of a muscle fibre in a living animal is an impulse in the motor nerve by which it is innervated. The sequence of events following the nerve impulse is shown schematically in fig. 18.1. We have examined stages 1 to 4 of this sequence (the excitation processes) in previous chapters. This chapter is concerned with some of the overall consequences of contraction (stage 6); details of the cellular mechanisms involved in stages 5 and 6 are considered in the following chapters.

Anatomy

Skeletal muscle fibres (fig. 18.2) are multinucleate cells formed by the fusion of numbers of elongated uninucleate cells called myoblasts.

Darwin's legacy

Charles Darwin is most famous as a natural historian, but his work had a profound influence on our understanding of memory because of his conception of biological time. Darwin set biology in a much longer context of time than had previous religious versions of creation and biological history, and so he created a puzzle: what is the relation of natural time, measured in millions of years, to the human historical time-frame in which we measure, say, the growth of classes or the development of cities in decades and centuries? Historical time seems a mere blip on the evolutionary scale. As the psychologist William James noted, our personal experiences of time are even more inconsequential in the Darwinian scheme of things, since personal events usually span mere days and months.

Moreover, Darwin gave natural time a distinctive character: he depicted it as conflictual and competitive. The concept of the survival of the fittest came late in Darwin's thinking, and he was ambivalent about the idea. He did not, like Alfred, Lord Tennyson, imagine nature ‘red in tooth and claw’, but he did think that what we call today an ecosystem depended on the ever-changing strengths and weaknesses of the species it contained, and that extinction and species failure were part of this natural order. Time is a destroyer as well as a creator.

If an intracellular microelectrode is inserted into a nerve or muscle cell, it is found that the inside of the cell is electrically negative to the outside by some tens of millivolts. This potential difference is known as the resting potential. If we slowly advance a microelectrode so that it penetrates the cell, the change in potential occurs suddenly and completely when the electrode tip is in the region of the cell membrane; thus the cell membrane is the site of the resting potential. In this chapter we shall consider some of the properties of the cell membrane that are associated with the production of the resting potential.

Membrane structure

Plasma membranes are usually composed of roughly equal amounts of protein and lipid, plus a small proportion of carbohydrate. Human red cell membranes, for example, contain about 49% protein, 44% lipid and 7% carbohydrate. Intracellular membranes tend to have a higher proportion of protein, whereas the protein content of myelin (p. 49) is only about 23%.

Figure 3.1 shows the chemical structure of some membrane lipids. Phospholipid molecules are esters of glycerol with two long-chain fatty acids, the glycerol moiety being attached via a phosphate group to various small molecules. The fatty acid chains thus form non-polar tails attached to polar heads. The fatty acid chains are usually fourteen to twenty carbon atoms long, and some of them are unsaturated, with one or more double bonds in the chain.

In April 1991 ‘Cadbury World’ was opened by the then Prime Minister, John Major, in the multiracial city of Birmingham, England. ‘Cadbury World’ is a living museum, the museum of Cadbury, the celebrated Quaker family who established a world famous cocoa and chocolate business and made their name a household name. ‘Cadbury World’ replaced the factory tours and educational visits which Cadbury provided until 1970 on the Bournville site. After the factory was closed to visitors the firm received thousands of requests for information and finally decided to construct a purpose-built ‘experience’ – the chocolate experience – next to the factory. This chocolate theme park attracts half a million visitors a year. It combines an exhibition with a brief factory tour. It aims, in the words of the accompanying brochure, to ‘reflect the heritage of the UK's number one chocolate company‘.

It tells the story of Cadbury, the Quaker family firm which began in the 1830s as a small retail business in Bull Street, Birmingham, went through difficult times in the 1850s but by dint of the hard work of two Cadbury brothers was successful enough in the 1870s to warrant the purchase of extensive land in Bournville and build the ‘factory in the garden’, which became famous the world over. There the large modern factory was combined with a model village and community facilities to provide a whole way of life for Cadbury employees.

Synapses are junctional regions between neurons, or between a neuron and another cell, where information is passed rapidly from one cell to the other. Electrical activity in the first (presynaptic) cell produces a change in the electrical activity of the second (postsynaptic) cell. There are two general types of synaptic transmission, chemical and electrical. In chemical transmission, by far the commoner mechanism, the presynaptic cell releases a chemical transmitter substance which diffuses across the intercellular space between the two cells and then binds to receptor molecules on the surface of the postsynaptic cell. If the postsynaptic receptors are also ion channels, this produces rapid changes in the flow of ions across the cell membrane; such events imply fast synaptic transmission (fig. 7.1a), the subject of this chapter and the next. Sometimes the postsynaptic receptors are not themselves ion channels, but their activation produces further chemical changes before there are any changes in the electrical activity of the cell; events of this type occur in slow synaptic transmission (fig. 7.1b), examined in chapter 9. In electrical transmission (fig. 7.1c and chapter 12), current flows directly from the presynaptic cell into the postsynaptic cell so as to alter its membrane potential significantly.

The nature of synaptic transmission

With the realization, towards the end of the nineteenth century, that the nervous system was composed of individual cells, the neurons, the problem arose as to how excitation was transmitted across the gap between two of them.

In this book I propose a scientific naturalistic account of moral agency, offering answers to four central questions: (1) what counts as moral agency, both substantively and functionally? (2) how do we acquire our capacities as moral agents? (3) how do we put these capacities to work? and (4) what makes for justified true moral beliefs, proper moral motivations, and successful moral action? I argue that moral agency is a phenomenon of the natural world best understood with the help of sciences. Making use of recent theories and findings in evolutionary theory, developmental biology and psychology, and social cognitive theory in psychology, I set forth a model of moral agency as a complex four-level capacity consisting of (1) a base level of both evolutionarily based and operantly learned capacities; (2) a behavioral level consisting of cognitively acquired moral beliefs and desires that is the immediate source for moral behaviors; (3) a reflective level composed of moral beliefs and desires concerning the behavioral-level moral beliefs and desires and regulative of the latter; and (4) a self-referentially reflective level by means of which an agent conceives of herself as a moral agent.

In proposing my model, I pursue a goal common to many philosophers, the search for what Wilfrid Sellars (1963) aptly called the synoptic vision: the attempt to see things as a whole.

Abstract: The cellular basis of motor learning in the cerebellum has been attributed mostly to long-term depression (LTD) at excitatory parallel fiber (PF)-Purkinje cell (PC) synapses. LTD is induced when PFs are activated in conjunction with a climbing fiber (CF), the other excitatory input to PCs. Recently, by using whole-cell patch-clamp recording from PCs in cerebellar slices, a new form of synaptic plasticity was discovered. Stimulation of excitatory CFs induced a long-lasting (usually longer than 30 min) “rebound potentiation (RP)” of γ-amino-butyric acid A (GABAa)-receptor mediated inhibitory postsynaptic currents (IPSCs). As in LTD, induction of RP requires transient elevation of intracellular calcium concentration ([Ca2+]i) due to activation of voltage-gated Ca2+ channels. Activity of inhibitory synapses seems also to be necessary for RP to occur. RP is mainly due to up-regulation of postsynaptic GABAA receptor function, since PC response to bath-applied exogenous GABA is also potentiated with a time course similar to RP. The difference in the time scale between the Ca2+ transients (10–30 sec) and the durations of RP (>30 min) strongly suggests that some intracellular biochemical machinery is involved. Pharmacological evidence suggests that protein kinases are involved in RP of inhibitory synapses and LTD of excitatory PF synapses. Besides the well-described LTD, RP could be a cellular mechanism that plays an important role in motor learning.

Key words: Ca2+; cerebellum; GABAA receptor; inhibitory synapse; long-lasting potentiation; protein kinase; Purkinje cell.