Placing Hippocampal Single-Unit Studies in a Historical Context

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1 HIPPOCAMPUS 9: (1999) Placing Hippocampal Single-Unit Studies in a Historical Context Phillip J. Best* and Aaron M. White Department of Psychology and Center for Neuroscience, Miami University, Oxford, Ohio ABSTRACT: A profound increase in the study of the role of the hippocampus in behavior and cognitive processing resulted from the startling discovery by O Keefe and Dostrovsky in 1971 that hippocampal neurons fire selectively in different regions or place fields of an environment. That discovery spawned a comprehensive theory of hippocampal function that was elucidated in the publication, The Hippocampus as a Cognitive Map by O Keefe and Nadel in According to the theory, the hippocampus serves as the neural substrate for maps of allocentric space. The goal of this paper is to revisit the historical background for the development of the cognitive map theory and to examine the context in which the theory and the phenomenon of place field activity began to gain acceptance by the scientific community. While subsequent research has led some to question if the theory can adequately account for all consequences of hippocampal lesions and all the correlates of hippocampal cellular activity, it is clear the theory has stood the test of time and has been successful in generating an enormous amount of fruitful research. Hippocampus 1999;9: Wiley-Liss, Inc. KEY WORDS: place cells; place fields; cognitive map; navigation In the 20 years since the publication of The Hippocampus as a Cognitive Map (O Keefe and Nadel, 1978), the cognitive mapping theory has become one of the preeminent theories of hippocampal function in cognitive processing. The theory proposes that the hippocampus serves as the neural substrate for maps of allocentric space. Such maps free organisms from the confines of stimulus-response (S-R) interactions with the environment, and allow them to anticipate the existence of important stimuli from a distance. For instance, internal representations of the environment, or cognitive maps, allow organisms to avoid locations in the world where predators have been encountered, and to approach distant locations known to contain food, water, or mates. Since the publication of the theory, all new theories regarding hippocampal function in animals have been stated, by necessity, in juxtaposition to the cognitive mapping theory. Further, most studies investigating the effects of hippocampal lesions on behavior, or examining the behavioral correlates of hippocampal single-unit activity, are designed to test some facet of the cognitive mapping theory. Even when lesion and recording studies are not designed to directly address the cognitive mapping theory, the results are typically interpreted in light of it. The seed for O Keefe and Nadel s theory was actually planted during the first half of this century with the work of E.C. Tolman. In the 1930s, when the central theme of American behavioral psychology was that all forms of knowing and understanding in rats and humans are merely the result of Grant sponsor: NSF; Grant number: IBN *Correspondence to: Phillip J. Best, D epartment of Psychology, Benton H all, Miami U niversity, O xford, O H bestpj@muohio.edu Accepted for publication 3 May 1999 complex S-R or S-S conditioning, Tolman and his students espoused views that were much more in line with those of the Gestaltists than the Behaviorists. Tolman s observations of rats performing maze tasks led him to conclude that animals do not simply learn to complete such tasks on the basis of S-R relationships. He believed that rats learn to complete such tasks by creating and using maps of the environment. In his own words, In the course of learning, something like a field map of the environment gets established in the rat s brain (Tolman, 1948). Such maps represent the environment as a configuration of elements, a gestalt, that allows the subject to navigate flexibly, approaching the food reward along the shortest route possible from any given location. A study performed by Tolman et al. (1946) represents a prime example of such flexible navigation. Rats were trained on an elevated maze to traverse a particular circuitous route to obtain a food reward. During a probe trial, the alley previously used to approach the reward location was blocked, and subjects were forced to enter one of 18 new alleys radiating out from the maze. A large proportion of the subjects chose the novel alley that led directly towards the reward location. Tolman believed that such choice behavior was only possible with the use of a spatial map, and that the behavior was driven by the expectation that the novel alley would serve as the shortest route to the location containing food. Because maps of the environment afforded the expectation of reward in a particular location, Tolman (1948) considered the maps to be cognitive. The debate between supporters of Tolman and the S-R theorists, including Hull and his students, continued through the 1940s and well into the 1950s. Contemporary cognitive scientists hold a somewhat sardonic view of this debate, Place learning organisms, guided by cognitive maps in their heads, successfully negotiated obstacle courses at Berkeley, while their response learning counterparts, propelled by habits and drives, performed similar feats at Yale (Tulving and Madigan, 1970). To many, the controversy regarding the existence of cognitive maps was finally put to rest in 1957 with the publication of a paper by Restle (1957), a student of Hull s, entitled A resolution of the place-vs WILEY-LISS, INC.

2 HIPPOCAMPAL PLACE CELL RESEARCH 347 response question. Restle argued that even in Tolman s experiments, the rat s behavior could be accounted for by S-R learning to extramaze cues. Thus, there was no need to assume that the rat s behavior was guided by an internal representation of the environment. While the idea of cognitive maps was dismissed by the mainstream, some investigators continued to attribute the persistence of position habits and the observation of apparently spatial hypotheses as strong evidence for the existence of an internal representation of space or a cognitive map. Most notable among the spatial mapping holdouts was D.O. Hebb (1961), who has had a profound influence on many aspects of modern neuroscience, through his theories, and also through his influence on his students at McGill (including O Keefe and Nadel). Much of the early evidence provided by O Keefe and Nadel in support of their theory came from a reexamination of the lesion literature, and most of the subsequent experiments testing the theory examined the effects of hippocampal lesions. However, the primary impetus for the theory was a finding reported by O Keefe and Dostrovsky in The authors reported that the firing rates of a number of hippocampal neurons appeared to be closely linked to an animal s location in the environment. Given the link between the location of the animal and the activity of the cell, the authors referred to such neurons as place-cells. Without this remarkable discovery, it is unlikely that the cognitive map theory would have been developed. Of course, the discovery of place-cells could not have occurred until the appropriate recording techniques had been developed. Before discussing the early place-cell work, we will first turn to a discussion of the historical development of techniques used to record from freely behaving animals. It had been a goal of neuroscientists to record activity in brains of freely behaving animals since Adrian and Zotterman (1926) first recorded the activity of peripheral sensory nerves. The development of the glass pipette microelectrode by Ling and Gerard (1949) made it possible to impale individual neurons and, thus, detect changes in the transmembrane potentials. However, the technique did not permit holding cells in the brains of breathing, let alone behaving, animals. The development of the etched metal electrode for extracellular recording by Hubel (1957) and Jasper et al. (1960) made it possible to record single cell activity in conscious mammals, and permitted significant advances in the study of sensory processing (Hubel and Weisel, 1959; Mountcastle, 1961), motor function (Evarts, 1966; Fetz, 1969), and sleep (Huttonlocher, 1961). However, etched electrodes have some limitations. It is difficult to hold cells for extended periods of time, especially in freely behaving animals. A major breakthrough was made by Felix Strumwasser (1958), who developed a method of implanting microwires into the brain of squirrels to study neuronal activity during hibernation. Rather than the electrode tip being etched to a fine point, the wire was merely cut tangential to its axis, and the cross-section of the blunt electrode tip served as the recording surface. An advantage of the microwire electrode was that it appeared to hold cells for long periods of time even when the animal engaged in vigorous activity. Originally, the wires were cemented to the skull in an anesthetized animal, and the recording was done after the animal recovered from the anesthesia. Unfortunately, the yield could be quite low, or the isolation quite poor, because, during recovery from anesthesia, the electrode might shift with respect to the brain. If an experienced surgeon implanted eight to ten electrodes in an animal, then, following recovery, one would find viable unit activity with acceptable signal-to-noise ratio on two or three electrodes. The activity from each electrode was passed through discriminatory circuits to insure that only waveforms with specific characteristics were counted as the activity from one neuron. James Olds was the first to develop a comprehensive research program using these techniques (Olds, 1965). Shortly thereafter, a number of laboratories began employing similar recording techniques to address a variety of questions concerning the relationship of brain cell activity to various behaviors. While recording hippocampal single unit activity in freely behaving rats, O Keefe and Dostrovsky (1971) stumbled across place field activity. Their initial manuscript describing place-cells was hardly the shot heard round the world. In fact, it provided hardly a blip on the oscilloscope traces of those who had been studying the relationship of hippocampal cellular activity to behavior. It was a brief report in Brain Research, which provided very little information about the activity of a few vaguely described cells that appeared to have spatial properties. The manuscript reported on the activity of 76 neurons. Only three of these cells showed a maximal firing rate in a particular part of the testing platform, irrespective of the animal s, or the experimenter s, behavior. Five additional cells appeared to respond in some way, when the animal was in a moderate state of arousal, was situated in the correct part of the testing platform, and for 4 of the 5, was receiving, in addition, the appropriate sensory stimulus. One of these cells required that the animal was, simultaneously lightly but firmly restrained by a hand placed over its back with thumb and index finger [the experimenter s] on its shoulder and upper arm. Needless to say, the initial reaction to O Keefe and Dostrovsky s paper varied from cautious skepticism to disdainful indifference to outright cynicism. In fact, none of those who were recording hippocampal activity in freely behaving rats at that time rushed into their laboratories to attempt to replicate the phenomenon. The next piece of evidence for the cognitive map hypothesis did not appear until 4 years later, when the first lesion study testing the theory was published (O Keefe et al., 1975). This paper, while less startling in its claims than the unit recording paper, also evoked little notice among the then current hippocampologists. Some notice was taken of a chapter by Nadel and O Keefe (1974) that laid out the basic ideas for the cognitive map theory. However, it was hard to ignore a provocative review article by Nadel et al. (1975) that challenged the use of a more traditional response inhibition model of hippocampal function to interpret the behavioral effects of hippocampal lesions. Also, around , a photocopied preprint of the book was circulated underground among a small circle of the hippocampal cognoscenti, much in the clandestine manner of a radical political tract in a fascist regime. Even though the theory was beginning to attract some interest, it was only one of a number of seemingly plausible theories of

3 348 BEST AND WHITE hippocampal function at that time. In addition to a role in spatial navigation, the hippocampus was implicated in orienting behavior (Grastyan, 1959), habituation (Hirano et al., 1970), short-term memory (Milner and Penfield, 1955), learning (Olds and Hirano, 1969), information processing (Adey, 1967), behavioral arousal (Green and Arduini, 1954; Mink et al., 1967), voluntary movement (Vanderwolf, 1969), response inhibition (Douglas, 1967), and rhythmic behavior (Komisaruk, 1970). Hippocampal recording studies continued to examine other phenomena such as orienting behavior (Vinogradova, 1970; Mays and Best, 1975), stages of sleep and arousal (Noda et al., 1969; Olmstead et al., 1973), learning (Best and Best, 1976; Segel et al., 1972), and various behaviors (Ranck, 1973). On considering the possible value of the different theories in the literature at that time, James Olds (personal communication) offered the opinion that theories of hippocampal function were nearly as numerous as the paradigms that had been used to elaborate its function. In 1973, Ranck reported a study of the relationship between hippocampal cellular activity and various behaviors, using an approach that he called neuroethology. The term was meant to capture the idea of carefully observing the animal s behavior, and noting the particular behavior the animal exhibited around the time that the cell fired. He found that the activity of individual hippocampal neurons fell into a small number of classes, each with a very specific relationship to various aspects of the animal s behavior. For example, one type of cell called an approachconsummate cell, might fire as the animal approached a food cup and started eating. Another type, called a motion punctuate cell, might fire as the animal terminated a specific behavior. One cell even fired as the rat bit the experimenter. One conclusion that can be drawn from Ranck s study is that the neuroethological approach does not produce verbal economy. It requires a very high ratio of words per cell. The manuscript is 85 pages long! However, a very important contribution of Ranck s paper was the observation that there are two distinct classes of cellular activity in the hippocampus: the complex spike cells, which have been demonstrated to be the pyramidal cells (the primary output cells of the hippocampus), and theta cells, which are now known to be interneurons (see also Fox and Ranck, 1975, 1981). While Ranck s extensive study revealed a wide variety of behavioral correlates, it found no tight relationship between cellular activity and the animal s location in the environment. It was not until 1976 that the first full-length manuscript on hippocampal place cells appeared in print (O Keefe, 1976). This study reported on 50 hippocampal neurons, 26 of which exhibited place field activity, and 16 of which were theta cells. For six place cells, location alone was necessary but not sufficient to evoke maximal activity. These cells, labeled misplace cells, fired maximally during exploratory behavior through the place field. A subsequent study demonstrated that the place fields of hippocampal neurons were affected in predictable and logical ways by various environmental manipulations (O Keefe and Conway, 1978). For example, removal or movement of any one room cue did not disrupt place field activity, yet rotation of the majority of room cues surrounding the rat caused a predictable relocation of the place fields. The fields maintained the same juxtaposition to the room cues as before rotation. These studies provided compelling evidence for the existence of place field activity, and began to stimulate the study of place cells in other laboratories. The first study outside of O Keefe s laboratory to demonstrate the existence of place cells was not originally designed to do so. It was a rank accident. During the summer that Richard Nixon resigned the presidency, Best and Ranck collaborated on a study in Ranck s laboratory at the University of Michigan, to reexamine Ranck s (1973) behavioral categories of hippocampal neurons. The goal was to use a more systematic method of data collection and obtain a more objective classification of behavioral correlates than Ranck had found in his previous study. They made videotapes of their recording sessions, which they eventually showed to naïve observers (students who had just completed Best s course in psychobiology at the University of Virginia). One of the first complex spike cells that Best and Ranck encountered appeared to fire when the animal approached a cup of water and drank. Ranck immediately recognized the cell as an approach-consummate cell. However, it also fired when the animal approached the location of the water cup, even when the cup was missing. Ranck now recognized the cell as an approachconsummate-mismatch cell. The cell did not fire when the rat found the water cup in a different place. Ranck now saw the cell as a motion-punctuate cell. We have it on reliable authority that Best, who had until that time cynically dismissed the very idea of place cells, recognized the cell as having place field properties. Best now decided to determine if Ranck was a clever enough neuroethologist to notice the cell s relationship to the rat s location, as he lured the animal through the place field with food and water, and chased the animal through the field by pinching its tail. Just as Best was about to give up, Ranck blurted out, Oh, this is going to make John O Keefe so happy. We understand that Ranck s version of this story is a bit different. When one sees a hippocampal neuron fire in its place field, it is hard to imagine how anyone could miss the relationship. It is very difficult to convey in words the compelling nature of place field activity. Even the oscilloscope traces or false color rate maps presented in many of the manuscripts fail to capture the distinctly close relationship between the activity of the place cell and its typically very small and circumscribed place field. The same cell that fires over 20 times a second inside its place field can be very quiescent outside of the place field, often firing less than once a minute. Interestingly, even the naïve observers of Best and Ranck s videotapes recognized the place field activity of most of the complex spike cells, and agreed upon the location of the fields (Best and Ranck, 1975, 1982). The first study outside of O Keefe s lab that was specifically designed to investigate place field activity was performed by Olton et al. (1978a), using the radial arm maze, an apparatus developed by Olton and Samuelson (1976), Olton had discovered that animals with lesions of the hippocampus or related structures were incapable of effectively foraging for food on the radial arm maze (Olton et al., 1978b). The maze seemed an appropriate environment in which to study hippocampal place cells systematically, because it permitted a completely objective analysis of the location of place fields. As the animal traversed the maze, there was little question as to which arm the animal occupied when the cells fired.

4 HIPPOCAMPAL PLACE CELL RESEARCH 349 While Olton eventually adopted the position that the role of the hippocampus was to provide the substrate for working memory, rather than cognitive maps, the radial arm maze has played a major role in studies of cognitive mapping. It has become one of the most widely used apparatuses for the study of cognition in the rat. A symposium entitled The hippocampus as a spatial analyzer was presented at the 1977 meeting of the Society for Neuroscience. The main thrust of that symposium was the demonstration that place field activity was indeed a reliable and replicable property of hippocampal pyramidal cells. By the late 1970s and early 1980s, once the existence of place cells had clearly been established, researchers began to focus on more fundamental questions regarding the nature of place cell activity. For instance, what types of environmental information does the brain rely on to determine the animal s location in space? Is a particular sensory modality dominant for an animal to determine its location, or are a variety of types of sensory information equally weighted? Are place cells driven solely by information currently in the environment, or can place cell activity be influenced by such factors as memory or motivational state? Do these cells truly represent spatial locations, or could it be that the hippocampus is involved in a more general process, of which building spatial maps is simply one example? Subsequent work has addressed questions about the specific nature of environmental information that permits the animal to know its location in space. It appears that stable visual cues, when present, provide the preferred source of information used to support place cell activity. When only one salient visual cue is present, it can exert control over the location of a place field. Rotations of that cue are accompanied by rotations of the place field (Muller and Kubie, 1987). When a small set of proximal maze cues and distal wall cues are provided, visual cues still predominate, and size of the place fields and the within-field firing rates of the cells can be predictably and reversibly altered by the removal of individual visual cues (Hetherington and Shapiro, 1997). It has also been demonstrated that, in an environment in which the configuration of visual cues remains constant, the locations of place fields are extremely stabile for long periods of time, in one case up to 153 days (Thompson and Best, 1990). In the absence of visual information, it appears that subjects can utilize whatever information is available to attempt to locate themselves in the environment. Hippocampal place cells are found to have well-defined, reliable place fields in blindfolded and deafened rats on a radial arm maze. The place fields of some cells are determined by proximal cues on the maze. Other cells show place fields that rely upon internal data, such as vestibular or proprioceptive information, to track their location in their internal map of the environment (Hill and Best, 1981). Recent work has also demonstrated that, even when stable visual cues are present, place field activity can be influenced by salient tactile and olfactory information (Shapiro et al., 1997). The activity of place cells is not simply determined by the nature of the sensory information impinging on the animal at the time it is in the place field. Place cells are not merely sensory neurons, exclusively under the control of stimuli currently in the environment. Under certain conditions, place field activity can be more strongly influenced by the animal s recent experiences than by current external stimuli in the environment (Quirk et al., 1990). Further evidence that hippocampal place cells are not merely sensory neurons, but are highly influenced by various intra-head variables, is provided by O Keefe and Speakman (1987), who trained rats on a radial arm maze to select a goal-arm that was defined by its location with respect to set of salient distal cues. The set of cues was rotated to a different position prior to the beginning of each trial. Subjects rapidly learned to choose the correct goal-arm, and the activity of most of the place cells rotated with the cues. On some trials, the cues were removed before subjects were allowed to choose the goal-arm. Most of the time, the rats were capable of choosing correctly, and the place fields remained constant relative to the now absent cues. So, even in the absence of the cues, the subject s memory of the room layout was sufficient to maintain both the accuracy of choice behavior and the location specific firing of the place cells. On other trials, when the cues were removed prior to placing the subjects on the maze, choice accuracy obviously fell to chance. However, on these trials the locations of the place fields were far from random. Their locations were highly predictable based upon the location of the arm that the subject chose as the goal-arm. The cells fired when the animal evidently thought he was in the place field. If hippocampal place cells are the substrate of the cognitive map, then lesions of the hippocampus should selectively disrupt spatial behaviors that rely upon a functioning cognitive map, and lesions of inputs to the hippocampus should disrupt both spatial behavior and place field activity. Studies of the effects of lesions of hippocampal connections on place cell activity have not produced a clear picture. Some studies have found reliable effects of fimbria-fornix and entorhinal cortex lesions on place-field activity. Entorhinal lesions virtually abolish place field activity in hippocampal neurons (Miller and Best, 1980). Fimbria fornix lesions reduce the precision of place field activity by increasing the rate of activity outside the field and increasing the field size. They also change the nature of the external stimuli that influence field location (Miller and Best, 1980; Shapiro et al., 1989). However, a number of studies on the effects of lesions of the medial septal nucleus, dentate gyrus, and various hippocampal regions have failed to find reliable changes in the nature of place field activity (McNaughton et al., 1989; Mizumori et al., 1989). Despite the compelling nature of place field activity, and the effects of hippocampal lesions on spatial navigation tasks, there is considerable evidence from lesion and recording studies that the concept of a cognitive map might not totally capture the function of the hippocampus. Hippocampal lesions have been found to cause disruption in some explicitly non-spatial tasks, for which a cognitive mapping strategy appears to be irrelevant. Such lesions disrupt performance on certain non-spatial working memory tasks (Rawlins et al., 1993) and tasks that require non-spatial configural or contextual processing, such as occasion setting tasks, in which one stimulus indicates whether another stimulus will be reinforced (Eichenbaum and Weiner, 1989; Sutherland and Rudy, 1989). Other studies have shown a close relationship between

5 350 BEST AND WHITE hippocampal pyramidal cell activity and factors other than the rat s location in space (Eichenbaum et al., 1987; Hampson et al., 1993). In rabbits, hippocampal neurons show well-defined reliable conditioned responses very early in conditioning, prior to the elaboration of conditioned behavioral responses (Berger et al., 1980; Seager et al., 1997). The effects of hippocampal lesions on non-spatial performance, coupled with the non-spatial correlates of hippocampal pyramidal cell activity, suggest that the hippocampus might be involved in a more general fundamental process, of which cognitive mapping is a specific example. While the Cognitive Mapping Theory might require some minor revisions, it has stood the test of time. It clearly meets Popper s requirements for a good theory (Popper, 1959). It is testable, and it has generated a substantial amount of informative research. 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