History of Behavioral Neuroscience

History of Behavioral Neuroscience G F Koob, The Scripps Research Institute, La Jolla, CA, USA M Le Moal, Neurocentre Magendie, INSERM, U862, Universite´ Victor Segalen – Bordeaux 2, Bordeaux, France R F Thompson, University of Southern California, Los Angeles, CA, USA S M Zola, Yerkes National Primate Research Center, Atlanta, GA, USA ª 2010 Elsevier Ltd. All rights reserved.

Glossary Cognition – The process of knowing, perceiving, etc. (Webster). Emotion – Strong feeling (Webster). Brain – The central nervous system, where all the processes listed below take place. Learning – The acquiring of knowledge or skill (Webster). Memory – The power or act of remembering (Webster). Mind – Memory, the seat of consciousness in which thinking, feeling, etc., take place (Webster). Motivation – That which causes one to act (Webster).

Behavioral neuroscience is literally the study of the neural bases of behavior, which forms a major discipline within the field of neuroscience and also within the field of psychology. By the same token, behavioral neuroscience has two historical roots, one in psychology – physiological psychology – and one in the brain sciences. The great questions of philosophy – the mind–body problem and the nature of knowledge – were also the questions that drove early developments in physiological psychology. Wilhelm Wundt, who founded experimental psychology, entitled his major work Foundations of Physiological Psychology (1874; see 1908). William James, the other major figure in the development of modern psychology, devoted a third of his influential text Principles of Psychology (1890) to the brain and nervous system. Both Wundt and James studied medicine and philosophy, and both considered themselves physiologists. Their goal was not to reduce psychology to physiology but rather to apply the scientific methods of physiology to the study of the mind. The other driving force in early behavioral neuroscience was the study of the brain and nervous system. The major topics in modern behavioral neuroscience are the neural bases of learning and memory, motivation and emotion, and cognition. A number of other areas began in behavioral neuroscience and have spun off to become fields in their own right. Thus, ‘sensation and perception’ have become separate fields (e.g., vision, audition, olfaction, etc.). We first sketch very briefly the recent philosophical and physiological roots.

The Mind The history of such issues as the mind–body problem and epistemology is properly the domain of philosophy. Our focus in this brief section is on the history of the scientific study of the mind, which really began in the nineteenth century.

Psychophysics Perhaps the first experimental attacks on the nature of the mind were the observations of Weber as generalized by Fechner. Ernst Weber, a physiologist, was attempting in 1834 to determine whether the nerves that respond to the state of the muscles also contribute to judgments about weights. As the reader knows, he found that the ‘‘just noticeable difference’’ (jnd) in weight that could be reliably detected by the observer was not some absolute amount but rather a constant ratio of the weight being lifted. The same applied to the pitch of tones and the length of lines. Gustav Fechner realized that Weber had discovered a way of measuring the properties of the mind. Indeed, in his Psychophysics (1860; see 1966) he felt he had solved the problem of mind and body. He generalized Weber’s observations to state that as the psychological measurement in jnd’s increased arithmetically, the intensity of the physical stimulus increased geometrically – the relationship is logarithmic. Fechner, trained as a physicist, developed the classical psychophysical methods and the concepts of the absolute and differential thresholds. The methods Fechner developed were of great help to the early experimental psychologists like Wundt and his student Tichner in their attempts to measure the attributes of sensation. Tichner identified the elements of conscious experience as quality, intensity, extensity, protensity (duration), and attensity (clearness) (see Tichner, 1898). But for all their attempts at scientific observation, the basic approach of Wundt and Tichner was introspection, and other observers (e.g., Ku¨lpe at Bonn) had different introspections. Edwin Boring studied with Tichner and was for many years chair of the Department of Psychology at

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History of Behavioral Neuroscience

Harvard. He attempted to recast Tichner’s views in more modern terms by emphasizing that the dimensions related to discrimination of physical stimuli. His student S.S. Stevens showed that trained observers could reliably form judgments of sounds in terms of pitch, loudness, ‘volume,’ and ‘density.’ Stevens, at Harvard, later introduced an important new method of psychophysics termed direct ‘magnitude estimation.’ The subject simply assigned a number to a stimulus, a higher one to a more intense stimulus, and a lower number to a less intense stimulus. Somewhat surprisingly, this method gave very reliable results. Using this method, Stevens found that the proper relationship between stimulus intensity and sensation is not logarithmic, as Fechner had argued, but rather a power function: the sensation (i.e., sensory magnitude) equaled the stimulus intensity raised to some power, the exponent ranging from below to above one. This formulation proved very useful in both psychophysical and physiological studies of sensory processes. The key point of all this work on psychophysics is of course that it is not necessary to be concerned at all about subjective experience or introspection. The observer simply pushes a button, or states a word or number, to describe his/her judgment of the stimulus. The more the observer practices, the more reliable the judgments become and the more different observers generate the same results. Psychophysics had become purely behavioral. Signal Detection The modern era of psychophysics can perhaps be dated to a seminal paper by John Swets in 1961: ‘‘Is there a sensory threshold?’’ His answer was ‘no.’ He and David Green developed the theory and methodology of signal detection. There is always noise present with signals. When one attempts to detect a signal in noise, the criteria used will determine the outcome. This approach has proved immensely useful in fields ranging from the telephone to psychophysical studies in animals to detection of structural failures in aircraft wings to detection of breast cancer. But where is the mind in decision theory? It has disappeared. The initial hope that psychophysics could measure the mind has been reduced to considerations of observer bias. A similar conclusion led to the downfall of introspection.

The Brain In the nineteenth century, debate focused on how mental activities (or cognitive processes) are organized in the brain. An early idea, which became known as the localizationist view, proposed that specific mental functions were carried out by specific parts of the brain. An alternative idea, which became known as the equipotential view, held

that large parts of the brain were equally involved in all mental activity and that there was no specificity of function within a particular brain. The ‘Thinking Machine’ to Phrenology Our concepts of mind, soul, body, and brain relationships come from a long history, and for the Western world, from a long battle between church dogma and progress of science. During the Renaissance, physicians began to explore the body. They dissected the brain and described it similarly to the other organs, emphasizing an intestinelike, random appearance of the convolutions. A landmark conceptual advance was Rene´ Descartes, who conceived of the ‘thinking machine’ (la machine pensante) about a hypothetical machine in the brain. In his treatise De Homine (1632–33) he wrote: I would like you to consider that all the functions I have allocated to this machine all depend by nature from the arrangement of the organs – – no more no less as the movements of a clock do, or an automaton moved by its counterweights and its cogwheels – . . . so that we do not have to conceive in the inner world of the body a soul or any other principle of movement or of life . . . other than of its blood and its spirits moved by the heat of the fire that burns permanently in the blood and that is not of a different nature of what exists in the inanimate matters’’. And also ‘‘ . . . I suppose that our body is nothing else than a statue or a machine made of organic substances . . . ’’ To move this thinking machine, and to be in accordance with the church, Descartes argued that the soul was necessary, but he put it in the pineal gland, a convenient organ in the middle of the brain and on its surface . . . and close to the ventricles. At that time, the ventricles were where the ‘functional regions’ for all of the faculties were organized, and the part of that brain was considered the common site for the sensations, reason, and memory. The sensations were created in the first ‘cell’ of the ventricles; they were transformed in the second cell (reasoning); and what remained was placed in the third cell (memory). For the Catholic Church to integrate and incorporate the soul was too much, and Descartes had to escape to Amsterdam to save his life. A very important transition was the work of Nicolas Stenon (1638–86), one of the greatest and most famous anatomists of his time. He stated in a meeting in Paris as part of a strong critique of the pineal gland hypothesis, ‘‘There are only two ways to succeed in the knowledge of the machine in the brain: either the Master who conceived it deliver to us His secret for this ingenious device, or we dismantle piece by piece all its springs and examine them separately, exactly as we do for the other machines, and then, in a second time we will consider what these pieces can do as they work together’’. From that point, an enormous effort began to understand and

History of Behavioral Neuroscience

describe the different pieces of the brain and attribute functions to those pieces. Thus, by the eighteenth century, the search for the role and function of the small machines in the brain were already underway, supported by materialist and monist (as opposed to dualist) points of view. Perhaps the most influential idea about localization of brain function derived from Franz Joseph Gall during the early part of the nineteenth century. Gall’s insight was that, despite its similarity in appearance, brain tissue was not equipotential but instead was actually made up of many discrete areas that had different and separate functions. Eventually, Gall was able to characterize 27 different regions, or organs, of the brain in a scheme that he called organology. (Later, the term ‘phrenology’ came to be associated with Gall’s work.) However, this term was coined by Gall’s colleague, Spurzheim, with whom he had a falling out, and Gall himself never used the term. Gall’s ideas about the localization of cognitive functions began to tear at the religious and social fabric of the nineteenth century. In particular, his notion that various mental faculties were represented in different places in the brain was seen by various governmental and religious authorities as being in conflict with moral and religious views of the unity of the soul and mind. (In some ways this is reminiscent of current attacks on evolution by fundamentalist religious groups.) Gall’s theory had a limited factual basis. The way in which Gall had determined the locus and extent of each of the 27 organs was questionable, to say the least. Another scientific issue raised by critics during the nineteenth century was the fact that Gall never specified the precise extent or the anatomical borders of any of the organs. This lack of rigor, it was argued, made it impossible to correlate a specific faculty with the size of an organ or cranial capacity. Related criticisms involved Gall’s seeming failure to acknowledge that there were variations in the thickness of the skull (i.e., variations from one individual specimen to another and from one locus to another within the same skull). In a sense, Gall seemed to be vindicated in 1861 with the publication of Broca’s discovery of the anterior speech area, now termed Broca’s area, in his study of the patient Monsieur Leborgne. (This patient subsequently was referred to by the name ‘Tan,’ the only utterance Broca ever heard Monsieur Leborgne make; Broca 1861.) Broca’s finding from his patient Tan has been regarded by some historians as the most important clinical discovery in the history of cortical localization. Moreover, within the decade, what some historians regard as the most important laboratory discovery pertaining to cortical localization was reported (i.e., Gustav Fritsch and Eduard Hitzig discovered the cortical motor area in the dog). This proved that cortical localization was not restricted to a single function. The discoveries of the

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speech area by Broca and the motor area by Fritsch and Hitzig were seen as support for Gall’s ideas and reestablished him as the father of localization. Evolution of Phrenology Thus, phrenology continued into the nineteenth century from the early arguments that: (1) the mental functional organs definitively migrate from the ventricle to the gray substance, the ‘‘cerebral lobes’’ and (2) ‘‘attention, memory, imagination . . . are not primary faculties of mind BUT solely forms of activities of any intellectual faculty.’’ Phrenology has been at the origin of a ‘vertical’ and a modular organization of the brain, one with the definitive implementation of the mind into matter. Paul Broca inherited directly from these hypotheses. A second phrenological revolution came with Wernike when he claimed that aphasia resulted from (dis)connections between modules and then evolved the modern hypothesis of function resulting from connections and fibers. Phrenology further matured into the pursuit of function during the twentieth century. Spearman (1937) argued that ‘‘the basic idea of the scientific enterprise consists in reducing the countless actual activities to a small number of underlying separable principles named faculties or capacities.’’ Herbert Simon argued in his parable of the two watch makers, Hora and Tempus, ‘‘The time required for the evolution of a complex form from simple elements depends critically on the number and potential intermediate stable forms.’’ David Marr (1976) stated, ‘‘A large computation should be split as a connection of small subparts that are as clearly independent of one another as the overall task allows . . . if not, a small change in one place will have consequences in many other places.’’ Following the pioneering study by Fritsch and Hitzig (1870) on the localization and organization of the motor area of the cerebral cortex, localization of function quickly won the day, at least for sensory and motor systems. In the last three decades of the nineteenth century, the general locations of the visual and auditory areas of the cortex were identified. The field of physiology, in particular neurophysiology, for example, in the work of Sir Charles Sherrington, together with clinical neurology and neuroanatomy, were exciting new fields at the beginning of the twentieth century. At this time, the only experimental tools for studying brain organization and functions were ablation and electrical stimulation. Neuroanatomy was in its descriptive phase; thanks in part to the Golgi method, the monumental work of Ramon y Cajal was completed over a period of several decades beginning near the end of the nineteenth century. Neurochemistry was in its descriptive phase, characterizing chemical substances in the brain.

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Finally, the birth of neuropsychopharmacology, involving the discovery of the first antipsychotic and then of the biogenic amines in Sweden (1963–1964), has stimulated much research in the realm of ‘brain and behavior,’ leading to a sort of parallel ‘chemical phrenology.’ While it is now clear that the highly distributed monoamine systems have more specific actions related to the regions of the brain they innervate, residual roles for serotonin in depression, dopamine in incentive salience, and norepinephrine in arousal still carry significant weight today. Neurophysiology The first recording of a nerve action potential with a cathode ray tube was done by Gasser and Erlanger in 1922, but the method was not much used until the 1930s. The human EEG was rediscovered in 1929 by H. Berger, and the method applied to animal research and human clinical neurology, particularly epilepsy, in the 1930s, for example, by Alexander Forbes, Hallowell Davis, and Donald Lindsley. The pioneering studies of Adrian in England (1940) and of Wade Marshall, Clinton Woolsey, and Philip Bard (1941) at Johns Hopkins were the first to record electrically evoked potentials from the somatic sensory cortex in response to tactile stimulation. Woolsey and his associates developed the detailed methodology for evoked potential mapping of the cerebral cortex. In an extraordinary series of studies, Woolsey and his colleagues determined the localization and organization of the somatic sensory areas, the visual areas, and the auditory areas of the cerebral cortex in a comparative series of mammals. They initially defined two projection areas (I and II) for each sensory field (i.e., two complete functional maps of the receptor surface were found for each sensory region of the cerebral cortex; e.g., two complete representations of the skin surface in the somatic–sensory cortex). In the 1940s and 1950s, the evoked-potential method was used to analyze the organization of sensory systems at all levels, from the first-order neurons to the cerebral cortex. The principle that emerged was strikingly clear and simple: in every sensory system, the nervous system maintained receptotopic maps or projections at all levels from receptors (skin surface, retina, and basilar membrane) to cerebral cortex. The receptor maps in the brain were not point-to-point; rather they reflected the functional organization of each system (fingers, lips, and tongue areas were much enlarged in primate somatic cortex; half the primary visual cortex represented the fovea, and so on). The Microelectrode The evoked potential method was very well suited to analysis of the overall organization of sensory systems in

the brain. However, it could reveal nothing about what the individual neurons were doing. This had to await development of the microelectrode (a very small electrode that records the activity of a single cell). Indeed, the microelectrode has been the key to analysis of the finegrained organization and ‘feature detector’ properties (most neurons respond only to certain aspects or features of a stimulus) of sensory neurons. The first intracellular glass pipette microelectrode was actually invented by G. Ling and R.W. Gerard in 1949 – they developed it to record intracellularly from frog muscle. Metal electrodes were generally found to be preferable for extracellular single-unit recording (i.e., recording the spike discharges of a single neuron where the tip of the microelectrode is outside the cell but close enough to record its activity clearly). Metal microelectrodes were improved in the early 1950s. R.W. Davies at Hopkins developed the platinum–iridium glass coated microelectrode, and D. Hubel and T. Wiesel at Harvard developed the tungsten microelectrode. The search for putative stimulus coding properties of neurons was on. The pioneering studies were those of V. Mountcastle and associates at Hopkins on the organization of the somatic–sensory system, those of Hubel and Wiesel (1959) at Harvard on the visual system, and J.E. Rose, J.E. Hind, C.N. Woolsey, and associates at Wisconsin on the auditory system. Thanks to the microelectrode and the careful and painstaking studies of a number of investigators, we now know that each sensory ‘area’ of the cerebral cortex consists of a number of subfields, separate areas coding different aspects of the stimulus. There are now more than 30 functionally distinct areas within the visual cortex of monkey and human (Zola-Morgan, 1995). This is localization of function with a vengeance! It was not until many years later that imaging methods were developed to study the organization and functions of the normal human brain (see below). Heroic studies had been done on human brain functioning much earlier in neurosurgical procedures (heroic both for the surgeon and the patient; e.g., Penfield and Rasmusson, 1950). However, these patients typically suffered from severe epilepsy. The development of positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and other modern techniques is largely responsible for the current explosion of information in cognitive neuroscience (see below).

Learning and Memory Karl Lashley is the most important figure in the development of physiological psychology and the biology of memory in America. He obtained his PhD at Johns Hopkins University. At Hopkins, he studied with John

History of Behavioral Neuroscience

Watson and was heavily influenced by Watson’s developing notions of behaviorism. While there he also worked with Sheherd Franz at a government hospital in Washington – they published a paper together in 1917 on the effects of cortical lesions on learning and retention in the rat. Lashley then held teaching and research positions at the University of Minnesota (1917–26), the University of Chicago (1929–35), and then at Harvard from 1935 until his death in 1958. During the Harvard years, he spent much of his time at the Yerkes Primate Laboratory in Orange Park, Florida. Lashley devoted many years to an analysis of brain mechanisms of learning, using the lesion-behavior method, which he developed and elaborated from the work with Franz. During this period, Lashley’s theoretical view of learning was heavily influenced by two congruent ideas: localization of function in neurology and behaviorism in psychology. Lashley describes the origins of his interest in brain substrates of memory and Watson’s developing views of behaviorism in the following letter written to Ernest Hilgard in 1935:

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In 1914, I think, Watson called attention of his seminar to the French edition of Bechterev, and that winter the seminar was devoted to translation and discussion of the book. In the spring I served as a sort of unpaid assistant and we constructed apparatus and planned experiments together. We simply attempted to repeat Bechterev’s experiments. We worked with withdrawal reflexes, knee jerk, pupil. Watson took the initiative in all this, but he was also trying to photograph the vocal cord, so I did much of the actual experimental work. I devised drainage tubes for the parotid and submaxiallary ducts and planned the salivary work which I published. As we worked with the method, I think our enthusiasm for it was somewhat dampened. Watson tried to establish conditioned auditory reflexes in the rat and failed. Our whole program was then disrupted by the move to the lab in Meyer’s clinic. There were no adequate animal quarters there. Watson started work with the infants as the next best material available. I tagged along for awhile, but disliked the babies and found me a rat lab in another building. We accumulated a considerable amount of experimental material on the conditioned reflex which has never been published. Watson saw it as a basis for a systematic psychology and was not greatly concerned with the nature of the reaction itself. I got interested in the physiology of the reaction and the attempt to trace conditioned reflex paths through the nervous system started my program of cerebral work. (Letter of May 14, 1935, K.S. Lashley to E.R. Hilgard, reproduced with the kind permission of E.R. Hilgard).

as the behaviorist views it.’’ He was elected President of the American Psychological Association in 1914. As we noted earlier, localization of function in the cerebrum was the dominant view of brain organization at the beginning of the twentieth Century. In Watson’s behaviorism, the learning of a particular response was held to be the formation of a particular set of connections, a series set. Consequently, Lashley argued, it should be possible to localize the place in the cerebral cortex where that learned change in brain organization was stored – the engram. (It was believed at the time that learning occurred in the cerebral cortex.) Thus, behaviorism and localization of function were beautifully consistent; they supported the then notion of an elaborate and complex switchboard where specific and localized changes occurred when specific habits were learned. Lashley set about systematically to find these learning locations – the engrams – in a series of studies culminating in his 1929 monograph Brain Mechanisms of Intelligence. In this study, he used mazes differing in difficulty and made lesions of varying sizes in all different regions of the cerebral cortex of the rat. The results of this study profoundly altered Lashley’s view of brain organization and had an extraordinary impact on the young field of physiological psychology. The locus of the lesions is unimportant; the size is critically important, particularly for the more difficult mazes. These findings led to Lashley’s two theoretical notions of equipotentiality and mass action (i.e., all areas of the cerebral cortex are equally important, at least in maze learning; what is critical is the amount removed). Lashley’s interpretations stirred vigorous debate in the field. Walter Hunter, an important figure in physiological–experimental psychology at Brown University who developed the delayed response task in 1913, argued that in fact the rat was using a variety of sensory cues – as more of the sensory regions of cortex were destroyed, fewer and fewer cues became available. Lashley and his associates countered by showing that removing the eyes has much less effect on maze learning than removing the visual area of the cortex. Others argued that Lashley removed more than the visual cortex. Out of this came the long series of lesion-behavior studies analyzing behavioral ‘functions’ of the cerebral cortex. Beginning in the 1940s, several laboratories, including Lashley’s and those of Harry Harlow at the University of Wisconsin and Karl Pribram at Yale, took up the search for the more complex functions of association cortex using monkeys and humans. Lashley’s pessimistic conclusions in his 1929 monograph subsequently put a real but temporary damper on the field concerned with brain substrates of memory:

It was in the previous year, 1913, that Watson published his initial salvo in an article entitled, ‘‘Psychology

This series of experiments has yielded a good bit of information about what and where the memory trace is

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History of Behavioral Neuroscience not. It has discovered nothing directly of the real nature of the memory trace. I sometimes feel, in the reviewing the evidence of the localization of the memory trace, that the necessary conclusion is that learning is just not possible. It is difficult to conceive of a mechanism that can satisfy the conditions set for it. Nevertheless, in spite of such evidence against it, learning sometimes does occur. (Lashley, 1950, pp. 477–478).

Milner and H.M. Perhaps the most important single discovery in this field is Brenda Milner’s studies with patient H.M. who, following bilateral temporal lobectomy (removing the hippocampus and other structures), lived forever in the present (see below). Work on higher brain functions in monkeys and humans is one of the key roots of modern cognitive neuroscience, to be discussed below. Since the discovery of H.M., the hippocampus has been of particular interest in biological psychology. Another facet of hippocampal study in the context of the biological psychology of memory is long-term potentiation (LTP), discovered by Bliss and Lomo (1973). Brief tetanic stimulation of monosynaptic inputs to the hippocampus causes a profound increase in synaptic excitability that can persist for hours or days. Many view it as a leading candidate for a mechanism of memory storage, although direct evidence is still lacking. Yet another impetus to the study of the hippocampus is the remarkable discovery of ‘place cells’ by John O’Keefe (see O’Keefe, 1979). When recording from single neurons in the hippocampus of the behaving rat, a given neuron may respond only when the animal is in a particular place in the environment (e.g., in a box or maze), reliably and repeatedly. There is great interest now in the possibility that LTP may be the mechanism that forms place cells. A number of laboratories are making use of genetically altered mice to test this possibility. Riesen and Hebb Lashley’s influence is felt strongly through the many eminent contemporary physiological psychologists who worked or had contact with him. We select two examples here: Austin Riesen and Donald O. Hebb. The basic problem of the development of perception fascinated Lashley and his students. How is it that we come to perceive the world as we do? Do we learn from experience, or is it told to us by the brain? Riesen did the pioneering studies of raising monkeys for periods of time in the dark and then testing their visual perception. They were clearly deficient. This important work served as one of the stimuli for Donald Hebb to develop a new theory of brain

organization and function, The Organization of Behavior, published in 1949. This book had an immediate and profound impact on the field. Hebb effectively challenged many traditional notions of brain organization and attempted to pull together several discordant themes – mass action and equipotentiality, the effects of dark rearing on perception, the preorganization of sensory cortex, the lack of serious intellectual effects of removal of an entire hemisphere of the brain in a human child – into a coherent theory. Important influences of Gestalt notions can be seen in Hebb’s theory. He is a connectionist but in a modern sense – connections must underlie brain organization, but there is no need for them to be in series. One concept in Hebb’s book has come to loom large (too large perhaps) in modern cognitive-computational neuroscience: The Hebb synapse: When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased (Hebb, 1949, p. 62).

Pavlov and Classical Conditioning But there were other major traditions developing. Perhaps the most important of these was the influence of Pavlov. His writings were not readily available to Western scientists, particularly Americans, until the publication of the English translation of his monumental work Conditioned Reflexes in 1927. It is probably fair to say this is the most important single book ever published in the field of behavioral neuroscience. Pavlov developed a vast and coherent body of empirical results characterizing the phenomena of conditioned responses, which he termed ‘‘psychic reflexes.’’ He argued that the mind could be fully understood by analysis of the higher order learned reflexes and their brain substrates. As an example of his influence, Clark Hull, in his Principles of Behavior (1943) wrote as though he were a student of Pavlov. W. Horsley Gantt, an American physician, worked with Pavlov for several years and then established a Pavlovian laboratory at Johns Hopkins. He trained several young psychologists (e.g. Roger Loucks and Wulf Brogden) who became very influential in the field. Perhaps the most important modern behavioral analyses of Pavlovian conditioning are the works of Robert Rescorla and Allan Wagner (e.g., Rescorla and Wagner, 1972). Although Pavlov worked with salivary secretion, most studies of classical conditioning in the West tended to utilize skeletal muscle response, a la Bechterev. Particularly productive have been Pavlovian conditioning of discrete skeletal reflexes (e.g., the eyeblink response)

History of Behavioral Neuroscience

characterized behaviorally by Isadore Gormezano and Allan Wagner and analyzed neuronally by Richard Thompson and his many students, showing localization of the basic memory trace to the cerebellum, specifically the cerebellar interpositus nucleus (Thompson, 1986; Christian and Thompson, 2003). Masao Ito and associates in Tokyo had discovered the phenomena of long-term depression (LTD) in the cerebellar cortex (see Ito, 1984). Repeated conjunctive stimulation of the two major inputs to the cerebellum, mossy-parallel fibers and climbing fibers, yields a long-lasting decrease in the excitability of parallel fibers – Purkinje neuron synapses. Ito developed considerable evidence that this cerebellar process underlies plasticity of the vestibular–ocular reflex. Thompson and associates developed evidence, particularly using genetically altered mice, that cerebellar cortical LTD is a key cortical mechanism modulating classical conditioning of eyeblink and other discrete responses. Fear Conditioning and Consolidation Fear conditioning was characterized behaviorally by Neal Miller and analyzed neuronally by several groups, particularly Michael Davis (1992), Joseph LeDoux (2000), and Michael Fanselow (1994) and their many students. They showed that at least for classical conditioning of fear, the essential structure is the amygdala, which may contain the basic memory trace for this form of learning. The process of LTP may serve to code the amygdalar fear memory. Duncan’s discovery of the effects of electroconvulsive shock on retention of simple habits in the rat, in 1949, began the modern field of memory consolidation. Hebb and Gerard were quick to point out the implication of two memory processes, one transient and fragile and the other more permanent and impervious. McGaugh and his associates have done the classic work on the psychobiology of memory consolidation (McGaugh, 1989). McGaugh and his colleagues introduced posttraining treatment and demonstrated memory facilitation with drugs and showed that these effects were not due to effects on performance or to possible reinforcement effects of the drugs (and similarly for impairment due to electroconvulsive shock (ECS) impairment). The amygdala is critical for instrumental learning of fear. James McGaugh and his associates demonstrated that for both passive and active avoidance learning (animals must either not respond, or respond quickly, to avoid shock), amygdala lesions made immediately after training abolished the learned fear. Surprisingly, if these same lesions were made a week after training, learned fear was not abolished, consistent with a process of consolidation (see McGaugh, 2000). The apparent difference in the role of the amygdala in classical and instrumental learning of fear remains a puzzle to this day.

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Chemical approaches to learning and memory are recent. The possibility that protein molecules and RNA might serve to code memory was suggested some years ago by such pioneers as Gerard and Halstead. The RNA hypothesis was taken up by Hyden and associates in Sweden and by several groups in America. An unfortunate by-product of this approach was the ‘transfer of memory’ by RNA. These experiments, done by investigators who shall remain nameless, in the end could not be replicated. At the same time, several very productive lines of investigation of neurochemical and neuroanatomical substrates of learning were developing. In 1953, Krech and Rosenzweig began a collaborative study of relationships between brain chemistry and behavior. Krech did classic early work in animal learning (under his earlier name, Kreshevsky) and was a colleague and collaborator with Tolman. Soon after they began their joint work in 1953, they were joined by E.L. Bennett and later by M.C. Diamond. Their initial studies concerned brain levels of acetylcholinesterase in relation to the hypothesized behavior and included analysis of strain differences (see Krechel et al., 1960). They discovered the striking differences in the brains of rats raised in ‘rich’ versus ‘poor’ environments. William Greenough (1984), at the University of Illinois, replicated and extended this work to demonstrate dramatic morphological changes in the structures of synapses and neurons as a result of experience. Where does the field now stand relative to the key issue of the localization of function, in this case of memory traces, the neuronal substrates for memory? It is now clear that memory traces for more elementary forms of learning and memory do have specific loci in the brain. The memory traces for classical conditioning of eyeblink and other discrete responses are stored in localized regions of the cerebellum. The traces for fear conditioning appear to be stored in localized regions of the amygdala. But for more complex forms of learning, the answer is still out. Certain brain structures (e.g., hippocampus) are critical for initial learning of declarative memories (e.g., experiential and semantic memories; see below) but the memory traces are not stored permanently there, but rather hypothesized to be stored in the cerebral cortex. Hebb’s notion of distributed sets of traces, each with some specificity, but overlapping among the neurons of the cerebral cortex, continues to have appeal. This is high on the agenda for the next generation of behavioral neuroscientists to solve. Model Systems The use of model biological systems has been an important tradition in the study of neural mechanisms of elementary forms of behavioral plasticity and learning.

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History of Behavioral Neuroscience

This approach has been particularly successful in the analysis of habituation – itself a very simple form or model of learning (see article on habituation). Sherrington did important work on flexion reflex ‘fatigue’ in the spinal animal at the turn of the century. In 1936, Prosser and Hunter completed a pioneering study comparing habituation of startle response in intact rat and habituation of hindlimb flexion reflex in spinal rat. They established, for habituation, the basic approach of Sherrington, namely that spinal reflexes can serve as models of neural–behavioral processes in intact animals. Sharpless and Jasper (1956) established habituation as an important process in electroencephalographic (EEG) activity. Modern Russian influences have been important in this field – the key studies of Evgeny Sokolov (1963), first on habituation of the orienting response in humans and more recently on mechanisms of habituation of responses in the simplified nervous system of the snail. The defining properties of habituation were clearly established by Thompson and Spencer in 1966, and the analysis of mechanisms began. Several laboratories using different preparations – aplysia withdrawal reflex (e.g., Kandel and his many associates; see Kandel, 1976), vertebrate spinal reflexes (e.g., Thompson, Spencer, and Farel), crayfish tail flip escape (e.g., Krasne and Kennedy; see Krasne, 1969) – all arrived at the same underlying synaptic mechanism for short-term, within-session habituation, a decrease in the probability of transmitter release from presynaptic terminals in the habituating pathway. Habituation, at least short-term habituation, is thus a very satisfying field. Agreement ranges from defining behavioral properties to synaptic mechanisms. However, the mechanisms underlying long-term, betweensession habituation are not yet known (Ezzeddine and Glanzman, 2003).

History of Motivation and Emotion Emotion can be defined as ‘‘a psychic and physical reaction (as anger or fear) subjectively experienced as strong feeling and physiologically involving changes that prepare the body for immediate vigorous action’’ (Webster’s Ninth New Collegiate Dictionary, 1984). Although the introspective emphasis on the ‘feeling’ aspect of emotions played a prominent role in the development of many theories of emotion, much progress in the neurobiology of emotion has been made with the experimental analysis of behavioral phenomena objectively defined. Indeed, Darwin argued as early as 1872 that both observable expressions of emotions as well as underlying brain processes (direct action of the excited nervous system on the body are not unique to humans) (Darwin, 1872). Key emotional expressions were considered innate, instinctive

recognition of expression but subject to the evolutionary process: That the chief expressive actions, exhibited by man and by the lower animals, are now innate or inherited – that is, have not been learnt by the individual – is admitted by every one. So little has learning or imitation to do with several of them that they are from the earliest days and throughout life quite beyond our control; for instance, the relaxation of the arteries of the skin in blushing, and the increased action of the heart in anger (Darwin, 1872, chapter 14).

Emotions: The Search for Biological Bases Historically, for emotional behavior, the measurement of bodily changes associated with emotional behavior focused on a peripheral response mechanism largely related to the autonomic and endocrine system. Peripheral measures of emotion ranged from galvanic skin responses to heart rate to salivary secretion to levels of autonomic hormones. Consistent with a key role of peripheral physiological variables was the famous William James theory of emotion in which he argued, ‘‘Bodily changes follow directly the perception of the exciting fact, and that our feeling of the same changes as they occur in is the emotion’’ (James, 1884, p. 189–190). Nevertheless the brain was pulled into serious consideration as a key mediator of emotion by parallel advances in conceptual framework, neuroanatomy, and actual experimental studies, some of which were initiated early in the history of behavioral neuroscience. In the latter half of the nineteenth century, Ferrier (1875) showed that orbitofrontal ablations in monkeys had no major effect on an organism’s sensory abilities but produced a definite change in the disposition of the animal. Broca (1878) described the ‘‘grand lobe limbique’’ (limbic indicates that this lobe surrounds the brain stem) which included the olfactory tubercle, prepyriform cortex, diagonal band of Broca, septal region, hippocampus, and cingulate as a common circuit in all mammals. Brown and Shafer (1888) showed that certain brain areas, such as the temporal lobe, were involved in emotion in which lesions of the temporal lobe in rhesus monkeys again had little effect on sensory abilities but produced a loss of ‘intelligence.’ The demonstration of decorticate ‘sham rage’ in the 1920s led to the hypothesis that emotional expression involved specific subcortical structures. Lesion studies led the way, followed later by stimulation studies by Hess, Ranson, and Masserman, all of which pointed to subcortical structures, such as the hypothalamus, soon to be labeled ‘limbic’ structures in the neural circuitry of the expression of emotional responses.

History of Behavioral Neuroscience

Early on, Cannon argued against the James-Lange theory, largely on the basis of the observation that animals continued to express emotional behavior in the absence of information from the periphery. Later, he hypothesized that emotional experience and emotional behavior were a release from cortical inhibition of neural impulses originating in the thalamus (Cannon, 1927, p. 120). Bard removed the neocortex of cats, leaving the rhinencephalon intact, which produced placidity that could be changed to ferocity by removal of the amygdaloid complex (Bard, 1951). Bard’s extensive work made modifying Cannon’s theory possible so that it could better define the neurocircuitry of emotional behavior. A key influential study in 1937 by Kluver and Bucy found dramatic emotional changes with extensive temporal lobe lesions in rhesus monkeys, in which normally intractable animals became tame and friendly, were compulsively mouthing anything, and were markedly hypersexual. Concurrently, the elaboration of the now famous Papez circuit was proposed in 1937 as a circuit for emotion and evolved into the terminology and conceptual framework of the limbic system which remains today. The Papez circuit, discovered by injecting rabies virus into the cat hippocampus and monitoring its progression, included the hippocampus, mammillary bodies, anterior thalamus, cingulate gyrus, and parahippocampal gyrus. It was one of the first organized attempts to delineate cortical mechanisms involved in emotion. Thus, the limbic system came to represent not only Broca’s 1878 grand lobe limbique, but also most allocortical regions of the brain from the Papez circuit, and from the conceptualizations of MacLean (1949) the amygdala and the hypothalamus for emotional expression. Brain circuitry explorations of emotion via interventions (lesions) evolved into more modern approaches, such as neuropharmacological challenges and probes and imaging of the human brain. Recent Perspectives of the Biological Bases of Emotion Key conceptual advances that laid the foundation for the modern neuroscience of emotion was the suggestion by Schachter and Singer (1962) that cognitive factors may be major determinants of emotional states. More specifically, they showed that cognition arising from the immediate emotional experience, as interpreted by past experience, provides the framework for labeling one’s feelings, and thus cognition determines whether a state of physiological arousal will be labeled as a given emotion. Schachter in fact predicted the direction of research on emotion: We will be forced to deal with concepts about perception, about cognition, about learning, and about the social situation. We will be forced to examine a subject’s perception of his bodily state and his interpretation of it in

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terms of his immediate situation and his past experience (Schachter, 1975, p. 561).

A strong argument for a biological basis for emotion also came from the pioneering studies of Ekman and Friesen (1986), in which a universality of six emotions was proposed based on extensive cross-cultural work on facial expression: happiness, surprise, fear, sadness, anger, and disgust combined with contempt. Ekman hypothesized distinctive patterns of central nervous system activity. A watershed translational approach far ahead of the field was the pioneering work of Jaak Panksepp identifying similar emotional states in rodents, including distress, anger, social bonding, play, and laughter (Panksepp, 1998). Others, such as Russell (2003), have eschewed a specific categorization of emotion and argued that any emotionally charged event is a state experienced as simply feeling good or bad, energized or enervated – in other words, a free-floating mood or core affect that is subject to interpretation by the perception of affective quality. In this context, the modern somatic marker hypothesis of Damasio (1996) in a sense validates some aspects of the original James-Lange theory in which decision-making is a process that is influenced by marker signals that arise in bioregulatory processes, including those that express themselves in emotions and feelings.

Brain Imaging and Emotion Modern brain imaging studies have not only confirmed earlier work from lesion studies but are extending the circuitry to domains of emotion previously inaccessible in animal studies. Morris et al. (1996) showed that the amygdala in humans responds differentially in subjects shown facial expressions of fear and happiness, with the neuronal response in the left amygdala significantly greater to fearful versus happy faces. Damasio (2002) in a series of studies has argued that the term ‘emotion’ should be defined as specific and consistent collections of physiological responses triggered by certain brain regions when the organism is presented with a certain situation. The substrates for the representation of emotions include homeostatic circuitry in the brainstem, hypothalamus, basal forebrain, amygdala, ventromedial prefrontal cortex, and cingulate cortex. By contrast, Damasio defined ‘feelings’ as the mental states that arise from the neural representation of the collection of responses that constitute an emotion, and as such should be reserved for the private, mental experience of an emotion. Key structures involved in feelings, he argued, include the brainstem, hypothalamus, thalamus, cingulate, somatosensory cortices of the insula, and somatosensory I and II, and to monitor cognitive processing, the prefrontal cortex is engaged. This approach has led to arguments in which specific brain systems,

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History of Behavioral Neuroscience

including the posteromedial cortices (precuneus, posterior cingulated cortex, and retrosplenial region) and anterior insula, are recruited in addition to the basic homeostatic circuitry for specific types of emotions, such as social emotions (e.g., admiration and compassion): Overall, the finding that homeostatic regulatory mechanisms are engaged in the experience of admiration and compassion supports the hypothesis that social emotions use some of the same basic devices involved in primary emotions (Moll et al., 2005) and the salience system (Seeley et al., 2007) (Immordino-Yang et al., 2009, p. 8024).

Behavioral Analysis of Emotion: Bridge to Motivation The role of emotion in motivation also profited from conceptual and experimental advances. The behavioral analysis of motivational and emotional interactions championed by Brady (1978) led to a response-inferred foundation for a unifying operational framework relating motivational and emotional function that fueled the dramatic advances forming the experimental analysis of behavior: Even the ‘hedonic’ characteristics of motivational functions can be accommodated within the empirical framework of this conceptual analysis by appealing to the experimentally based distinctions between ‘positive’ and ‘negative’ reinforcement operations. The evident byproducts (e.g., ‘euphoria’) of ‘appetitive’ consequating relations which increase the likelihood of behavior, on the one hand, and the ‘dysphoric’ accompaniments of ‘aversive’ consequences which weaken behavior (or strengthen escape and avoidance performances), would seem to provide a fruitful point of departure for the experimental analysis of this eudaemonic dimension (Brady and Emurian, 1978, p. 83).

Here, the basic building blocks are the contingencies relating ‘occasions’ and their ‘consequences’ (three-term contingency of Skinner: occasion, behavior, and consequences), and thus a motivational function would be any operation that would affect the potency of the ‘consequences’ (e.g., food deprivation potentiates the consequence or increases the likelihood of consummatory behaviors). Under this formulation, the analysis of emotional function focuses on procedures that affect the efficacy of occasioning events or enhance the discriminability of occasioning events in the occasion component of the contingency (e.g., startle effects may disrupt the occasioning situation and decrease the likelihood of a consummatory behavior). Such emotional functions emphasize the prominent role of inner events (e.g., feelings), and as such, terms related to hedonic function can be accommodated in terms of positive reinforcement, negative reinforcement, and punishment. Thus, the hedonic dimension of Brady’s

‘‘behavioral universe’’ refers primarily to the affective valence of the bridge between emotion and motivation. Indeed, emotions are often linked to motivation but not necessary for motivation. History of Motivation Consistent with this view, an early motivational theory involving a key emotional component was the Miller (1948) and Mowrer (1950) two-process fear theory in which fear consisted of ‘‘an innate (internal) response to certain stimuli, such as pain, and the fear response innately produces the fear stimulus, just as electric shock produces pain’’; or, in other words, the conditioned stimulus serves as a danger signal and elicits a state which has been described as fear. For example, a conditioned stimulus that produces fear then elicits a fear-reducing response, and the fear emotion is an explicit part of the motivation needed for conditioned response learning. Finally, Olds and Milner (1954) discovered that electrical stimulation of the medial forebrain bundle was highly rewarding to animals, providing a key experimental bridge of the neurobiology of emotion with the neurobiology of motivation. Early on theorists such as J. Anthony Deutsch argued that brain stimulation reward activated two pathways: a pathway conveying reinforcement and a pathway conveying excitation (motivation), another early link between emotion (hedonic function) and motivation (Deutsch, 1960). Motivation, similar to emotion, is a concept that has many definitions. An early definition reflected the mixed dualism of later theories. Motivation was defined as ‘‘an inner psychological process or function, a driving force to be found chiefly within the organism itself and a plan, purpose or ideal with the definite implication of an ideational element,’’ that may not be consciously and overtly recognized (Perrin, 1923). Hebb argued that motivation is ‘‘stimulation that arouses activity of a particular kind’’ (Hebb, 1949), and Richter argued that ‘‘spontaneous activity arises from certain underlying physiological origins and such ‘internal’ drives are reflected in the amount of general activity’’ (Richter, 1927). Bindra defined motivation as a ‘‘rough label for the relatively persisting states that make an animal initiate and maintain actions leading to particular outcomes or goals’’ (Bindra, 1976). A more behavioristic view is that motivation is ‘‘the property of energizing behavior that is proportional to the amount and quality of the reinforcer’’ (Kling and Riggs, 1971). Finally, a more neurobehavioral view is that motivation is a ‘‘set of neural processes that promote actions in relation to a particular class of environmental objects’’ (Bindra, 1976). These definitions trace the history of motivation and point to certain common characteristics of our concept of motivation. It is a state that varies with arousal and guides

History of Behavioral Neuroscience

behavior in relationship to changes in the environment. The environment can be external (incentives) or internal (central motive states or drives), and such motivation or motivational states are not constants and vary over time. Influential Theories of Motivation An early and influential theory of motivation by Hull (1943), termed the ‘drive-reduction theory,’ was predicated on the hypothesis of homeostatic mechanisms of motivation in which behavior could be regarded as an outward expression of the organism’s pursuit of biological health. Here, all motivation was theorized to derive from biological imbalances or needs. A need in this formulation, such as hunger (here, the need is for more energy), was a biological requirement of the organism. Motivation, according to Hull, then aimed at making up for or erasing a deficiency or lack of something in the organism. The word ‘drive’ was used to describe the state of behavioral arousal resulting from a biological need and was the energy that powered behavior. The animal searched for food to reduce the hunger drive. Hull theorized that the animal would repeat any behavior that reduced a drive, whenever such a need arose again. Drive-reduction theory was not supported by most research because it became clear that many of its tenets were unsupported. In particular, much motivated behavior could be generated without any biological drives being manifest. However, the theory did engage reactions that moved the field forward. A key component of the development of incentive motivation theory was the major assault on drive-reduction, largely led by Bolles in the period around 1972 (Bolles, 1975) and followed by the work of Bindra (1974) and Toates (1981). Bolles argued that many issues remained unexplained by drive reduction theory, but a major issue was that individuals were motivated by incentive expectancies or learned expectancies of reward (stimulus–stimulus [S–S] associations or what in Pavlovian associations are conditioned and unconditioned stimuli [CS and US]). Bindra argued that the CS for a reward came to elicit the same motivational state as the reward itself, thus causing the individual to perceive the CS as reward, not just the expectancy of reward. Toates (1981) further refined the model by arguing that physiological states (drive states) could enhance the incentive value of the reward. Others, including Konorski, Young, Solomon, Rescorla and Dickinson, contributed significantly to the development of modern incentive– motivation theory which guides the neurobiology of motivation, and the reader is referred to their scholarly works. Subsequent theories of motivation have linked motivation with hedonic, affective, or emotional states and have postulated changes in motivation over time and experience. The incentive–sensitization (or incentive salience) theory of Robinson and Berridge (1993) divides, but in a sense extends, the power of incentives and moves them to

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a neuroadaptive trajectory. Here, incentives have been split into two components – ‘wanting’ and ‘liking’ – based on the hypothesis that different brain mechanisms mediate these separate components in which ‘liking,’ mediated by opioid systems in the nucleus accumbens and ventral pallidum, is defined as hedonic impact or the brain response to sensory reward or pleasure without motivational power. In contrast, ‘wanting,’ mediated by the mesolimbic dopamine system, is hypothesized to be the incentive salience or the motivational incentive value of the same reward. The extrapolation of behavioral sensitization (increases in the locomotor response to psychostimulant drugs with repeated administration) to increases in incentive salience in the incentive–sensitization model has early roots in the facilitation of conditioned reinforcement and drug-seeking behavior described by Hill and Robbins. Here, drug-seeking behavior is controlled by a succession of drug-associated discriminative stimuli, which can also function as conditioned reinforcers when presented as a consequence of instrumental responses. In addiction, many have argued that by means of associative learning, the enhanced incentive salience state becomes oriented specifically toward drug-related stimuli, leading to escalating compulsion for seeking and taking drugs. Originally, Mogenson (1980) proposed that the process of motivation to action involved ventral striatal–ventral pallidal–thalamic circuits, and others emphasized the role of the mesolimbic dopamine system innervating the nucleus accumbens in incentive salience. Everitt and Robbins (2005) extended a key motivational role for dorsal striatal–pallidal–thalamic circuits in the plasticity of motivational processing. The recruitment of the dorsal striatal circuitry is hypothesized to mediate habits and compulsivity associated with aspects of drug addiction and other motivational pathology. The underlying activation of neural structures involved in maintaining the incentive–salience state persists, making addicts vulnerable in the long term to relapse. Thus, the incentive salience component of incentive sensitization theory has significant heuristic value as a common element of drug addiction in that it narrows the focus to drug-seeking at the expense of natural rewards, and drugs are hypothesized to usurp systems in the brain put in place to direct animals to stimuli with salience for preservation of the species. The clinical observation that individuals with substance use disorders have an unusual focus on drugseeking to the exclusion of natural rewards fits the incentive salience view. Emotion and Motivation in Opponent Process An alternate, potentially complementary, motivational theory also incorporating a strong emotional component is opponent process theory. Solomon and Corbit (1974)

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History of Behavioral Neuroscience

argued that hedonic, affective, or emotional states, once initiated, are automatically modulated by the central nervous system with mechanisms that reduce the intensity of hedonic feelings and provide an additional motivational state for directing behavior. Solomon hypothesized that there is affective or hedonic habituation (or tolerance) and affective or hedonic withdrawal (abstinence). More specifically, a-processes, which could be either positive or negative hedonic responses, were proposed to occur shortly after presentation of a stimulus, correlate closely with the stimulus intensity, quality, and duration of the reinforcer, and show tolerance. In contrast, the b-processes appear after the a-process has terminated, are sluggish in onset, slow to build up to an asymptote, slow to decay, and get larger with repeated exposure. As such, the affective dynamics of the opponent process produces new motivation (i.e., new opportunities for reinforcing and energizing behavior). From a neurobehavioral perspective, the initial acute effect of an emotional stimulus or drug in brain motivational systems is hypothesized to be opposed or counteracted by homeostatic changes in brain systems. Certain systems in the brain were hypothesized to suppress or reduce all departures from hedonic neutrality. This affect control system was conceptualized as a single negative feedback or an opponent loop that opposes the stimulus-aroused affective state. For example, in the context of drug dependence, Solomon argued that the first few self-administrations of an opiate drug produce a pattern of motivational changes in which the onset of the drug effect produces a euphoria that is the a-process which is followed by a decline in intensity. After the acute drug effect wears off, the b-process state emerges as an aversive craving state. Thus, in opponent process theory, drug tolerance and dependence are inextricably linked, and affective states, pleasant or aversive, were hypothesized to be automatically opposed by centrally mediated mechanisms that reduce the intensity of these affective states: We have been taught to think of aversion and trauma as the only affective sources of physiological stress. The opponent-process model implies that often repeated pleasures are just as fertile a source of physiological stress (Solomon, 1980, p. 709).

During this period, Cabanac (1971) hypothesized a process by which a given stimulus can induce a pleasant or unpleasant sensation depending on the subject’s internal state. This state was termed ‘alliesthesia’ and was applied to both temperature regulation and appetite. Here, for example, pleasant responses to sweet solutions occur with low gastric load, but aversive responses to sweet solutions occur with high gastric load. The existence of alliesthesia implies the presence of internal

signals modifying the conscious sensations aroused from peripheral receptors and supports the hypothesis that both peripheral and central processes contribute to motivation. More recently, opponent process theory has been expanded by Koob and Le Moal (2001, 2008) into the domains of the neurocircuitry and neurobiology of drug addiction from a neurobiological perspective. Both within-system (mesolimbic dopamine dysfunction) and between-system (recruitment of corticotropin-releasing factor) neuroadaptations are hypothesized to mediate the opponent process. An allostatic model of the brain motivational systems was proposed that explains some of the persistent changes in motivation that are associated with vulnerability to relapse in addiction, and this model may generalize to other psychopathologies associated with dysregulated motivational systems. In this framework, during the development of drug addiction, counteradaptive processes such as opponent-process which are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. The allostatic state is hypothesized to be a chronic deviation of reward set point that is fueled not only by dysregulation of reward circuits per se but by recruitment of antireward systems (e.g., brain and hormonal stress responses). Conclusion Thus, emotion can be defined as passions or sensibilities of both physiological responses and mental states, and motivation can be defined as a persistent state leading to organized activity. Both are intervening variables, are intimately related, and have neural representations in modern neuroscience. Emotional responses have long been associated with classic ‘limbic’ system circuitry, and modern imaging studies involve a cognitive component, can dissociate emotional expression from feelings and empathy, and identify an important role for the physiological responses in how feelings are interpreted as originally outlined in the James-Lange theory of emotion. Motivation has long been hypothesized to involve an emotional intervening variable, whether it be fear or incentive states, and neural substrates have been identified that have key roles in the incentive, hedonic, and aversive aspects of motivation – notably the circuitry involving the nucleus accumbens and amygdala which recruit dorsal striatal circuits and stress circuits respectively – as motivation becomes pathological such as observed in impulsive and compulsive disorders. Emotional and motivational circuits also color key elements of brain cognitive function that have important roles in the decision-making processes that guide all behavior.

History of Behavioral Neuroscience

Cognition The term ‘cognitive neuroscience’ is very recent, dating perhaps from the 1980s. The Journal of Cognitive Neuroscience was first published in 1989. Indeed, Posner and Shulman’s comprehensive chapter on the history of cognitive science (1979) does not even mention cognitive neuroscience (human imaging techniques were not yet much in use then). Here we note briefly the biological roots of cognitive neuroscience (see Gazzaniga, 1995). Karl Lashley was again a key figure. One of the most important aspects of cognitive neuroscience dates from the early days at the Orange Park laboratory, where young scientists like Chow and Pribram began studies of the roles of the association areas of the monkey cerebral cortex in learning, memory, and cognition.

H.M. and Primate Models The period of the 1950s was an especially rich time of discovery regarding how cognitive functions were organized in the brain. Pribram, Mortimer Mishkin, and Hal Rosvold at the National Institute of Mental Health, using lesion studies in monkeys, discovered that the temporal lobe was critical for aspects of visual perception and memory. Work with neurologic patients also played a critical role in uncovering the neural substrates of cognition. As noted earlier, one particular discovery became a landmark in the history of memory research. ‘‘In 1954 Scoville described a grave loss of recent memory which he had observed as a sequel to bilateral medial temporal resection in one psychotic patient and one patient with intractable seizures. In both cases . . . removals extended posteriorly along the medial surface of the temporal lobes . . . and probably destroyed the anterior two-thirds of the hippocampus and hippocampal gyrus bilaterally, as well as the uncus and amygdala. The unexpected and persistent memory deficit which resulted seemed to us to merit further investigation’’ (Scoville and Milner, 1957). That passage comes from the first paragraph of Scoville and Milner’s 1957 report, ‘‘Loss of recent memory after bilateral hippocampal lesions.’’ This publication became a landmark in the history of memory research for two reasons. First, the severe memory impairment (or amnesia) could be linked directly to the brain tissue that had been removed, suggesting that the medial aspect of the temporal lobe was an important region for a particular aspect of cognition (i.e., memory function). Second, comprehensive testing of one of the patients (H.M.) indicated that memory impairment could occur on a background of otherwise normal cognition. This observation showed that memory is an isolatable function, separable from perception and other cognitive and intellectual functions.

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More specifically, H.M. could not remember his own experiences and could not learn new factual information after his surgery. This aspect of memory is termed ‘declarative’ memory because normal individuals, when asked, can state or declare the memories, and they can consciously retrieve and express them. But there are other types of memory, often grouped under the heading ‘procedural’ or nondeclarative (see below) on which H.M. performs like normal people. These include motor skills, Pavlovian conditioning of eyeblink and other aspects of basic associative learning, and even complex ‘cognitive’ puzzles like the tower of Hanoi, forms of memory that can be performed without conscious awareness of the memories, only the procedural performance of them. H.M., whom we now know as Henry Molaison, died of respiratory failure at the age of 82 on December 2, 2008. He lived for many years at an extended care facility in Windsor Locks, Connecticut, where he served as the subject in hundreds of memory experiments. Those who worked with him described him as a very generous man, soft spoken, polite, and with a good sense of humor. The extraordinary depth of his declarative memory deficit was described to one of the authors (R.F.T.) by a colleague, Karl Pribram, a very senior neurosurgeon/neuroscientist when the two were colleagues at Stanford. He interviewed H.M. a few months after the surgery. They talked for a while, and Karl was impressed at how very bright and normal H.M. seemed (he had an aboveaverage IQ). Then Karl had to leave the room for a phone call. When he returned a few minutes later, H.M. said, ‘‘Who are you? I have never seen you before.’’ H.M. once said that everything seemed clear at the moment, but he worried about what had just happened. He felt as though he were just awakening from a dream and could not remember. He provided his brain to science, and it will be prepared in serial sections (2600 of them) by Jacopo Annese and colleagues at the University of California, San Diego. Mr. Molaison has contributed more to our understanding of human memory than any other human, and we will always be profoundly grateful to him. The findings from patient H.M. (Scoville and Milner, 1957) early on identified a region of the brain important for human declarative memory (i.e., the medial portion of the temporal lobe). The damage was originally reported to have included the amygdala, the periamygdaloid cortex (referred to as the uncus in Scoville and Milner, 1957), the hippocampal region (referred to as the hippocampus), and the perirhinal, entorhinal, and parahippocampal cortices (referred to as the hippocampal gyrus). Subsequent, magnetic resonance imaging of patient H.M. suggested that his medial temporal lobe damage did not extend as far posteriorly as originally believed and that damage to the parahippocampal cortex was minimal (the lesion appeared to extend caudally from the temporal pole approximately 5 cm, instead of 8 cm, as originally reported; Corkin et al., 1997).

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History of Behavioral Neuroscience

While these observations identified the medial temporal lobe as important for memory, the medial temporal lobe is a large region including many different structures. To determine which structures are important required that studies be undertaken in which the effects of damage to medial temporal lobe structures could be evaluated systematically. Accordingly, soon after the findings from H.M. were reported, efforts were made to develop an animal model of medial temporal lobe amnesia. During the next 20 years, however, findings from experimental animals with intended hippocampal lesions or larger lesions of the medial temporal lobe were inconsistent and difficult to interpret. In 1978, Mishkin introduced a method for testing memory in monkeys that captured an important feature of tests sensitive to human memory impairment (Mishkin, 1978). This method allowed for the testing of memory for single events at some delay after the event occurred. The task itself is known as the trialunique delayed nonmatching to sample task, and it measures object recognition memory. In Mishkin’s study, three monkeys sustained large medial temporal lobe lesions that were intended to reproduce the damage in patient H.M. The operated monkeys and three unoperated monkeys were given the delayed nonmatching to sample task in order to assess their ability to remember, after delays ranging from 8 s to 2 min, which one of two objects they had recently seen. The monkeys with medial temporal lobe lesions were severely impaired on the nonmatching task, consistent with the severe impairment observed in patient H.M. on delay tasks. Thus, lesions that included the hippocampal region and amygdala, as well as adjacent perirhinal, entorhinal, and parahippocampal cortices, caused severe memory impairment. This work, together with work carried out in the succeeding few years, established a model of human amnesia in nonhuman primates (Mishkin et al., 1982; Squire and Zola-Morgan, 1983). Although other tasks have been useful for measuring memory in monkeys (object discrimination learning, the visual paired-comparison task, see below), much of the information about the effects of damage to medial temporal lobe structures has come, until recently, from the delayed nonmatching to sample task. Once the animal model was established, systematic and cumulative work eventually identified the structures in the medial temporal lobe that are important for declarative memory. The important structures are the hippocampal region and the adjacent perirhinal, entorhinal, and parahippocampal cortices (for early reviews describing the medial temporal lobe memory system, see Zola-Morgan and Squire, 1993; Mishkin and Murray, 1994; for recent reviews, see Squire et al., 2007, Eichenbaum and Lipton, 2008, Suzuki, 2009).

More Than One Kind of Memory The medial temporal lobe is necessary for establishing a kind of memory that is termed long-term declarative or explicit memory. Declarative memory refers to the capacity for conscious recollection of facts and events (Squire, 1992). It is specialized for rapid, even one-trial learning, and for forming conjunctions between arbitrarily different stimuli. It is typically assessed in humans by tests of recall, recognition, or cued recall, and it is typically assessed in monkeys by tests of recognition (e.g., the delayed nonmatching to sample task). The medial temporal lobe memory system appears to perform a critical function beginning at the time of learning in order that representations can be established in long-term memory in an enduring and usable form (see also Eichenbaum et al., 1994). Another important discovery that paralleled in time the work on the medial temporal lobe system involved the understanding that there is more than one kind of memory. Specifically, work with amnesic patients and with experimental animals who sustained lesions to specific brain regions showed that other kinds of abilities (including skills, habit learning, simple forms of conditioning, and the phenomenon of priming, which are collectively referred to as nondeclarative or procedural memory) lie outside the province of the medial temporal lobe memory system. Nondeclarative forms of memory are intact in amnesic patients and intact in monkeys with medial temporal lobe lesions. For example, as noted above, classical delay conditioning of skeletal musculature was found to depend on the cerebellum (Thompson and Krupa, 1994), conditioning of emotional responses depends on the amygdala (LeDoux, 2000; Davis, 1992), and habit learning (win–stay, lose–shift responding) depends on the neostriatum (Salmon and Butters, 1995; Packard et al., 1989). Nondeclarative memory thus refers to a variety of ways in which experience can lead to altered dispositions, preferences, and judgments without providing any conscious memory content. Further work with monkeys has demonstrated that the severity of memory impairment depends on the locus and extent of damage within the medial temporal lobe memory system. Damage limited to the hippocampal region causes significant memory impairment, but damage to the adjacent cortex increases the severity of memory impairment. It is important to note that the discovery that larger medial temporal lobe lesions produce more severe amnesia than smaller lesions is compatible with the idea that structures within the medial temporal lobe might make qualitatively different contributions to memory function. This is because anatomical projections carrying information from different parts of the neocortex enter the medial temporal lobe memory system at different points (Suzuki and Amaral, 1994, Squire et al., 2007). This might be

History of Behavioral Neuroscience

viewed as a modern reformulation of Lashley’s principle of ‘‘mass action.’’ Another important brain area for memory is the diencephalon, However, the critical regions in the diencephalon that when damaged produce amnesia have not at the time of this writing (mid-2009) been identified with certainty. The important structures appear to include the mediodorsal thalamic nucleus, the anterior nucleus, the internal medullary lamina, the mammillothalamic tract, and the mammillary nuclei. Because diencephalic amnesia resembles medial temporal lobe amnesia in many ways, these two regions together probably form an anatomically linked, functional system (Squire and Zola, 1997; Gold and Squire, 2006). These findings in monkeys are fully consistent with the findings from human amnesia. Damage limited to the hippocampal region is associated with moderately severe amnesia and more extensive damage that includes the hippocampal region as well as adjacent cortical regions is associated with more severe memory impairment (Zola-Morgan et al., 1986). The same principle, that more extensive damage produces more severe impairment, has also been established for the hippocampus proper in the case of the rat (Moser et al., 1993). The dorsal hippocampus of the rat is essential for spatial learning in the water maze, and progressively larger lesions of this region produce a correspondingly larger impairment. Thus, in all three species, it has turned out that the brain is organized such that memory is a distinct and separate cognitive function, which can be studied in isolation from perception and other intellectual abilities. Information is still accumulating about how memory is organized, what structures and connections are involved, and what functions they support. The disciplines of both psychology and neuroscience continue to contribute to this enterprise. Roger Sperry was another key player in the origins of cognitive neuroscience. After receiving his PhD in zoology, he joined Lashley for a year at Harvard and moved with Lashley to the Yerkes Laboratory at Orange Park, where he stayed for several years. Sperry did his pioneering studies on the selective growth of brain connections during this time (see Sperry, 1951). Lashley was fascinated by the mind-brain issue – the brain substrates of consciousness (although he never wrote much about it) – and often discussed this problem with his younger colleagues at Orange Park (Sperry, personal communication). Sperry and his associates at the California Institute of Technology tackled the issue with a series of commissurotomy patients – the human ‘splitbrain’ studies. This work proved to be extraordinary, perhaps the most important advance in the study of consciousness since the word itself was developed many thousands of years ago (Sperry, 1968). Brenda Milner studied for her PhD at McGill under Hebb’s supervision. Hebb arranged for her to work with Wilder Penfield’s neurosurgical patients at the Montreal

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Neurological Institute. Her work on temporal lobe removal in humans, including H.M., really began the modern study of the memorial functions of the hippocampus (see above). She also collaborated on studies with Roger Sperry and Karl Pribram. Another very important influence in modern cognitive neuroscience comes from the Soviet scientist Alexander Luria, who died in 1977. Luria approached detection and evaluation of damage to higher regions of the human brain both as a clinician with extraordinary expertise in neurology and as a scientist interested in higher functions of the nervous system (e.g., his book Language and Cognition, 1981). EEG and Evoked Potentials Yet another origin of cognitive neuroscience is recording the activity of the human brain, initially using EEG. Donald Lindsley was a pioneer in this work. After his PhD, he took a 3-year postdoctoral stage at Harvard Medical School (1933–35). The neurophysiologist Alexander Forbes was at Harvard doing pioneering studies on brain evoked potentials and EEG in animals. The first human EEG recording laboratory was set up at Harvard, and Lindsley and other pioneering figures (e.g., Hallowell Davis) did the first EEG recording in America (Lindsley, 1936). More recently, the method of averaging evoked potentials recorded from the human scalp made it possible to detect brain signals relevant to behavioral phenomena that could not be detected with individual trial recording. Donald Lindsley was a pioneer in this field as well, doing early studies on evoked potential correlates of attention. Brain Imaging But the techniques that have revolutionized the study of normal human brain organization and functions are of course the methods of imaging. The first such method was X-ray computed tomography, developed in the early 1970s. The major innovation beyond simple X-rays was complex mathematical and computer techniques to reconstruct the images. Somewhat later, PET was developed. It is actually based on a long used method in animal neuroanatomy – autoradiography. In this technique, a radioactive substance that binds to a particular type of molecule or brain region is infused, and brain sections are prepared and exposed to X-ray film. For humans, PET involves injecting radioactive substances, for example radiolabeled oxygen (15O) in water. Increased neuronal activity in particular regions of the brain causes a rapid increase in blood flow to the regions, determined years earlier in work by Seymour Kety and others. Consequently, the radioactive water in the blood becomes more concentrated in active brain areas, detectable by radioactivity detectors.

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The most widely used method at present is magnetic resonance imaging (MRI). This is based on the fact that changes in blood flow cause changes in the blood magnetic properties, which can be detected as changes in a strong imposed magnetic field. This method was first used in 1990 (Ogawa et al., 1990). The current procedure is termed fMRI, involving very fast acquisition of images. A landmark publication in human brain imaging is the elegant book by two pioneers in the field, Michael Posner and Marcus Raichle, Images of Mind, 1994. The fMRI procedures have several advantages, such as the fact that they are noninvasive – no radioactive substance is injected – and this technique provides better spatial resolution than does PET imaging. Functional magnetic resonance imaging exploits variations in magnetic susceptibility that arises from molecular binding of oxygen to hemoglobin, which can be used to detect blood flow changes associated with neuronal activity (blood oxygen level reduction, BOLD). At the present time, these neuronal activity-related signals can be derived from areas of the brain with a spatial resolution of 1-2 mm. Moreover, the temporal resolution of this functional imaging technique is compatible with the time course needed to carry out most perceptual and cognitive operations. An important and promising strategy for the use of fMRI is its use in conjunction with other kinds of neurobiological techniques, including neurophysiology and anatomical and behavioral analyses. Thus, fMRI provides an extraordinary new window through which one can probe the neural machinery of cognition (Schacter et al., 1998; Albright, 2000; Persson et al., 2006).

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Boring EG (1942) Sensation and Perception in the History of Experimental Psychology. New York: Appleton-Century. Boring EG (1950) A History of Experimental Psychology, 2nd edn. New York: Appleton-Century-Crofts. Brady JV (1978) Emotional behavior. In: Porter R (ed.) Neurophysiology III: International Review of Physiology, vol. 17, pp. 1529–1552. Baltimore, MD: University Park Press. Brady JV and Emurian HH (1978) Behavioral analysis of motivational and emotional interactions in a programmed environment. In: Dienstbier RA (ed.) Human Emotion: Nebraska Symposium on Motivation, vol. 26, pp. 81–122. Lincoln, NE: University of Nebraska Press. Broca P (1861) Remarks on the seat of the faculty of articulate speech, followed by the report of a case of aphemia (loss of speech), Wasterlain C and Rottenberg DA (trans.). Bulletins de la Socie´te´ Anatomique de Paris 6: 332–333; 343–357 (from French). Broca P (1878) Le grand lobe limbique et la scissure limbique dans les series des mammaliferes. Review d’Anthropologie 2: 385–498. Brown S and Schafer EA (1888) An investigation into the functions of the occipital and temporal lobes of the monkey’s brain. Philosophical Transactions of the Royal Society of London B 179: 303–327. Cabanac M (1971) The physiological role of pleasure. Science 173: 1103–1107. Cannon WB (1927) The James–Lange theory of emotions: A critical examination and an alternative theory. American Journal of Psychology 39: 106–124. Corkin S, Amaral DG, Gonzalez RG, Johnson KA, and Hyman BT (1997) H.M.’s medial temporal lobe lesion: Findings from magnetic resonance imaging. Journal of Neuroscience 17: 3964–3980. Damasio AR (2002) A second chance for emotion. In: Lane RD, Nadel L, and Ahern G (eds.) Cognitive Neuroscience of Emotion, pp. 12–23. New York: Oxford University Press. Darwin C (1872) The Expression of the Emotions in Man and Animals. London: J. Murray. Davis M (1992) The role of the amygdala in fear and anxiety. Annual Review of Neuroscience 15: 353–376. Delay J and Deniker P (1955) Neuroleptic effects of chlorpromazine in therapeutics of neuropsychiatry. Journal of Clinical and Experimental Psychopathology 16: 104–112. Descartes R (1686) Tractatus de Homine et de Formatione Foetus. Amsterdam: The Huntington Library. Deutsch JA (1960) The Structural Basis of Behavior. Chicago: University of Chicago Press. Duncan CP (1949) The retroactive effect of electroshock on learning. Journal of Comparative and Physiological Psychology 42: 34–44. Eichenbaum H and Lipton PA (2008) Towards a functional organization of the medial temporal lobe memory system: Role of the parahippocampal and medial entorhinal cortical areas. Hippocampus 18(120): 1314–1324. Eichenbaum H, Otto T, and Cohen NJ (1994) Two functional components of the hippocampal memory system. Behavioral Brain Science 17: 449–518. Ekman P and Friesen WV (1988) Who knows what about contempt: A reply to Izard and Haynes. Motivation and Emotion 12: 17–22. Everitt BJ and Robbins TW (2005) Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nature Neuroscience 8: 1481–1489; erratum: 9(7): 979. Fanselow MS (1994) Neural organization of the defensive behavior system responsible for fear. Psychonomic Bulletin Review 1: 429–438. Fechner GT (1966) Elements of Psychophysics, Boring EG and Howes DH (eds.) and Adler HE (trans.), vol. 1. New York: Holt, Rinehart and Winston. Ferrier D (1875) The Croonian lecture: Experiments on the brain of monkeys. Philosophical Transactions of the Royal Society of London 165: 433–488. Finger S (1994) Origins of Neuroscience: A History of Explorations into Brain Function, pp. 32–62. New York: Oxford University Press. Fritsch G and Hitzig E (1870) Uber die elektrische Erregbarkeit des Grosshirns. Archiv fu¨r Anatomie, Physiologie, und Wissenchaftliche Medizin 37: 200–332. Gasser HS and Erlanger J (1922) A study of the action current of nerves with the cathode ray oscillograph. American Journal of Physiology 62: 496–524.

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