This volume arose from an International Congress held in Bordeaux during 1986 and organised jointly by the Comparative Endocrinology Group of the Society for Experimental Biology, Laboratoire de Neurobiologie, Universite de Bordeaux I and Centre National de la Recherche Scientifique (CNRS).

The chapters which follow have been prepared by the invited seminar series speakers attending that meeting, and are designed as broad overviews of their particular specialities.

For the original meeting in Bordeaux we particularly extend warm and grateful thanks to our friend and colleague Professor Adrien Giradie and his collaborators in the Neurobiology Laboratory, Bordeaux, without whom the symposium could not have taken place, and this volume would not have been produced.

The symposium also benefited from the support of the following organisations: Society for Experimental Biology, UK; Centre National de la Recherche Scientifique, France; Direction de la Cooperation et des Relations Internationales du Minitere de l'Education Nationale, France; Universite de Bordeaux 1; Beckman; Bioblock Scientific; Bordeaux Chimie-Cofralab; Etablissements Laurent; Imperial Chemical Industries pic. (Plant Protection, Jealot's Hill, UK); Laboratory Data Control; Mairie de Bordeaux; Mairie de Gradignan; Office du Tourisme de Bordeaux; Peninsula Laboratories Europe; Pfizer Research Ltd.; Poly-Labo; Rohm Haas Chemical Co; Shell Research Ltd.; Sofranie-Mettler; Wild Leitz France.

Introduction

Study of model-systems has played a major role in the developments which have taken place in neurobiology during the past decades. Studies of opisthobranch and pulmonate molluscs have made important contributions in this area. These animals make excellent models, because they possess a relatively small central nervous system (CNS), which contains a limited number of large (polyploid, e.g. Boer et al., 1977) and readily accessible neurons. Two species have been studied in particular; the opisthobranch Aplysia californica (e.g. Strumwasser et al. 1980) and the pulmonate freshwater snail Lymnaea stagnalis (e.g. Joosse & Geraerts 1983; Roubos 1984).

Immunocytochemistry has become an important tool in neurobiology. In our laboratory the CNS of L. stagnalis has been investigated extensively using immunocytochemical methods (Boer et al., 1979, 1980, 1984a,b, 1986; Schot & Boer 1982; Schot et al 1981, 1983, 1984, see also Chapter 13, this volume). Recently monoclonal antibodies were raised to homogenates of whole CNS from L. stagnalis (Boer & Van Minnen 1985). These investigations, in conjunction with functional and electrophysiological studies can illustrate the central position of the peptidergic neuron in neurotransmission and in neuro-endocrine control processes (Joosse 1986).

Neural and hormonal communication

Animals possess two major systems for the regulation and coordination of body functions: the nervous system and the endocrine system. In the classic view these systems differ in a number of aspects. The chemical messengers of the nervous system (neurotransmitters) are small molecules (acetylcholine, biogenic amines, amino acids), which are released at sites of direct contact (synapse) between neurons and their targets.

Introduction: identifiable insect skeletal mononeurones and why they are important

Insect skeletal muscle is innervated by monopolar motoneurones in the segmental ganglia of the CNS which send motor axons to specific muscle targets. The specificity of muscle innervation allows us to identify motoneurones uniquely by their target muscles. Motoneurones innervating particular muscles have a characteristic position and morphology in the central nervous system, and these characteristics can also be used to identify them. An example is provided by the slow coxal depressor or Ds motoneurone of the cockroach Periplaneta americana. This neurone, as its name suggests, innvervates coxal depressor muscles and it has an invariant position and morphology. It is one of perhaps 5 motoneurones involved in the innervation of the coxal depressors. In addition to being identifiable, skeletal motoneurones innervating particular muscles in insects are few in number (in contrast to vertebrate muscle innervation for example). Thus the large extensor muscle of the locust tibia, the extensor tibialis muscle, is innervated by only 4 motor cells, each of which has been identified (see below). The identifiability of insect motorneurones and their small number have combined to make insect neuromuscular systems important model preparations.

The simplicity of insect neuromuscular systems has obvious advantages for the study of muscle physiology in these organisms. Insect motor neurones differ from the classical vertebrate model by using multiple transmitters. This feature has allowed us to study fundamental aspects of synaptic physiology, pharmacology and neuronal function which perhaps could not be studied as conveniently in other organisms.

It has proved difficult through the study of human amnesics to elucidate several matters critical to understanding the disorder. First, human cases are not usually appropriate for identifying the critical lesions that cause the core memory problems because their lesions often extend into brain regions where damage causes unrelated deficits. Second and relatedly, it is hard to determine from human amnesics the extent to which their memory deficits result from damage to neurons that release specific transmitters, such as acetylcholine or noradrenalin. Third, despite developments with electrophysiological recording techniques and the emergence of the PET scan, study of human amnesics and healthy people is not an effective means of exploring the anatomical connections and physiology of the brain regions lesioned in amnesics in order to gain a clearer idea of precisely what functions are disrupted in patients. These three issues have been more effectively examined through physiological studies with animals and pharmacological studies with animals and humans. The next section discusses animal models of the amnesic state. The third section briefly reviews what light pharmacological studies have thrown on amnesia, and the last section considers animal work involving lesions, electrophysiological recordings, and manipulations of long-term potentiation (LTP). As indicated in chapter 1, LTP is an increase in neural responsiveness, particularly striking in hippocampal neurons, that occurs when brief bursts of high-frequency stimulation are given to the inputs of the relevant neurons. It may persist for weeks and is believed by many to be based on a memory-like change. LTP is of interest here because it has been used to examine the functions of the structures whose damage is believed to be critical in amnesia.

People may do badly at different kinds of memory tasks, and they may do so for different reasons. It is the purpose of memory assessment to ascertain the ways in which a subject's memory is poor and the causes of this poor performance. Clinicians need such assessments to help them see how patients will cope in everyday life, what their prognoses are, whether there are any therapies to which they are likely to respond, and whether there is any response to treatment. Theoreticians are most concerned with identifying the range of memory disorders and their specific causes. Both groups need valid, reliable tests of particular kinds of memory for which normative data exist so that the severity of the deficits can be determined. But whereas clinicians need tests that tap everyday memory performance, which exist in several equivalent forms, theoreticians need standardized tests with normative data so that results from different laboratories can be compared. Furthermore, as theoreticians seek to identify new kinds of memory disorder, they need to develop their own special-purpose tests to compare the performance of a patient on these tests with that of a group of matched control subjects. The theoretical aim is to identify elementary memory deficits that cannot be subdivided into further simpler disorders and to see what, if any, kinds of brain damage cause them.

The problem that the theoretician faces is that most memory disorders are messy, are poorly understood, and involve several kinds of elementary memory breakdown that arise for many reasons.

In this book, five possible groups of elementary organic memory disorders have been discussed. It is still controversial whether the disorders considered are truly elementary or whether at least some of them are composed of two or more independent disorders that could be separately compromised by more selective lesions. For example, the organic amnesia caused by medial temporal lobe lesions may differ from that caused by diencephalic lesions, and lesions of the hippo-campal and amygdalar circuits may disrupt recognition for somewhat different reasons. This kind of issue is hard to resolve, partly because lesions in humans are adventitious and tend not to honour boundaries between functionally distinct brain regions, so that it is often difficult to distinguish between cognitive deficits that are essential to a memory deficit and those that are incidental to it.

Despite the problems, five groups of organic memory deficits can be identified. The first group of memory deficits is caused by lesions to PTO association neocortex. This neocortical region includes parts of the parietal, temporal, and occipital lobes and is not specialized for obvious motor or sensory functions. Instead, as its neurons lie several relays away from the sensory input, it is probably concerned with the later stages of analysis and interpretation of sensory information. Lesions to it can cause breakdowns that comprise several kinds of fairly selective short-term memory deficits specific to certain types of information. These disorders, which are discussed in chapter 3, probably arise for a number of reasons, although it still needs to be shown convincingly that they are ever caused by isolated disruption of short-term storage, rather than of specific encoding and retrieval processes.

Section One: The aims of this book

What were you doing immediately before you picked up this book? This question should cause you little difficulty, but there are people who would find it very hard to answer. For these people, known as organic amnesics, life must be experienced as if they were continually waking from a dream. Brain damage has made them very poor at remembering recently experienced events and at learning new information. It also makes them poor at remembering things that were learnt up to many years prior to the brain trauma. Despite such memory impairments, organic amnesics may have normal or superior intelligence. Not all memory deficits caused by brain damage are like organic amnesia, however. Other patients with lesions different from those responsible for organic amnesia show a very rapid loss of spoken information whilst possessing good longer term remembering of most things. For example, such a person might be unable to repeat back more than two spoken digits even with no delay but be able to give the gist of a newspaper article recounted by someone else on the previous day (something well beyond the powers of an organic amnesic). This kind of short-term memory failure is associated with the language disorder known as conduction aphasia and is clearly distinct from the memory deficits seen in organic amnesia, although both are caused by brain damage.

There is a rare disorder that is apparently caused by certain lesions of the parietal neocortex of the left hemisphere, in which patients are unable to point on verbal command, to parts of their own bodies as well as to body parts of their examiner or of a picture of the human body. This disorder, known as autotopagnosia, is often accompanied by other cognitive deficits, such as a general difficulty in naming things, known as an anomia, or a difficulty understanding any words that refer to concrete as opposed to abstract concepts. If autotopagnosia is accompanied by these kinds of problem, then it is possible to argue that it is caused by a general difficulty with word names or an inability to understand the meaning of concrete words. There are cases, however, in which patients can name body parts on their own bodies when these parts are pointed to by the examiner, although they cannot point to their own body parts on command or point to their own body part that corresponds to a numbered part on a picture of a body. These autotopagnosias cannot be caused by verbal deficits, but some patients with this pattern of disorder also have difficulty pointing, on verbal command, to parts of inanimate objects. As such patients are also unable to relate a well-known story in logical sequence, it has been argued that autotopagnosia is caused by a general inability to analyse a whole into its component parts.

Research on short-term memory disorders, disorders of well-established memory, frontal memory disorders, and organic amnesia is still in a very open stage of development. Hypotheses about the functional deficits underlying these deficits as well as the lesions that cause them may well undergo a sea change in the face of new discoveries over the next few years. All the interpretations advanced in previous chapters are tentative suggestions that seem plausible in the light of available evidence. Currently, it is unwise to become strongly attached to hypotheses about the bases of organic memory disorders, but quite a bit has been learnt about their main features. The same cannot be said about disorders of the kinds of implicit memory that are probably preserved in organic amnesics. Nor can it be said about the memory disorders that form an often variable part of certain complex psychiatric and neurological disturbances, such as schizophrenia and Parkinson's disease. This chapter considers first the small amount of research that has been directed at exploring whether brain damage can cause selective impairments of priming, skill acquisition and retention, and conditioning (all kinds of implicit memory in which the evidence of remembering is indirect rather than direct). The evidence concerning the memory deficits associated with the complex psychiatric and neurological syndromes is then briefly reviewed in order to ascertain whether the memory deficits reported in these conditions can be interpreted as compounds of the elementary memory disorders, discussed earlier in the book.

Organic amnesia is a fairly common disorder, but most often the amnesia is intermixed with other cognitive symptoms because the brain damage that is responsible for it extends into regions unconnected with the amnesia, such as the association neocortex. Pure cases of amnesia show four major characteristics, two positive and two negative. First, intelligence, as assessed by standard tests, such as the WAIS, is preserved. Although the fine print of this claim is still disputed by some, patients with exceedingly poor memory have been described with IQs of 140. Subtle and selective cognitive deficits cannot be excluded yet, but there is no real evidence for them. Second, short-term memory, as assessed by digit span and the recency effect, is preserved. Third, there is poor acquisition and retention of new episodic and semantic information (anterograde amnesia). And fourth, there is poor memory for information that was acquired pre-traumatically (retrograde amnesia). As will be discussed in more detail later in this chapter, not all kinds of memory are disturbed in amnesics. It has been claimed that amnesics show preserved learning and memory for certain motor, perceptual, and cognitive skills, for conditioning, and for what was referred to in chapter 1 as priming (i.e., changed or more efficient processing of stimuli that results from having recently perceived them).

The evidence, reviewed in chapter 4, strongly suggests that PTO association neocortex stores many aspects of well-established semantic memory, and probably also the semantic components of episodic memory. In this chapter, the role in complex memory of the frontal association neocortex is considered. Although many issues remain unresolved and much research needs to be done, the role in memory of the frontal cortex is perhaps best approached by comparing it with the role in memory of PTO association cortex and of the structures damaged in organic amnesics. First, both PTO and frontal association cortex receive inputs of sensory information that has already undergone some processing, and the frontal region projects to areas that more directly control motor output. If they have broadly similar roles in memory, then one would expect the frontal cortex to be involved in storing certain kinds of well-established information. One possibility is that it may store action plans and ‘scripts’ that indicate what should be done in different kinds of situations, such as meeting friends or going to a restaurant. Strong evidence for a frontal cortex role in these kinds of storage does not yet exist. The second comparison is with the structures involved in organic amnesia. Warrington and Weiskrantz (1982) have argued that organic amnesia is caused by lesions that disconnect the frontal cortex from PTO association cortex. It is not the links across the neocortex that are severed, however, but those that connect frontal and PTO cortex via the limbic system and diencephalic structures. The effect of this disconnection is that amnesics cannot either store or retrieve all those kinds of information that require elaborative processing and planning during encoding.

Normal people forget some information in a few seconds but remember other things for years. It is widely believed that the information that is forgotten in seconds has been held in a limited-capacity short-term store and has not been transferred to a more stable, large-capacity long-term store. Of course, forgetting is a continuous process, and normal people forget things after seconds, minutes, hours, days, weeks, months, and years, but researchers do not propose that there are hundreds of stores to cover all these delays. Indeed, most workers believe that one kind of memory store is sufficient to explain all forgetting that occurs with delays of more than a few seconds. So why is belief in a separate kind of short-term store from which information is lost in seconds so widespread? As discussed in chapter 1, there are now psychologists, such as Wickelgren (1974), who argue that all the phenomena of rapid forgetting can be explained in terms of the properties of a single storage system. The evidence, based on studies of normal people, that immediate memory is affected differently from longer term memory by such variables as type of encoding and learning time can just as easily be interpreted in terms of a single storage hypothesis as it can in terms of the existence of separate short- and long-term stores. The short-term-storage hypothesis probably derives its appeal from two factors. First, rapid forgetting is something of which we are all very aware and distinguish from stable, long-term memory, which gives plausibility to the feeling that there is a discontinuity between rapid and slower kinds of forgetting.