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HIPPOCAMPUS, VOL. 2, NO. 3, PAGES 307-322,JULY 1992 Spatial Responsiveness of Monkey Hippocampal Neurons to Various Visual and Auditory Stimuli Ryoi Tamura, Taketoshi Ono, Masaji Fukuda, and Kiyomi Nakamura Department of Physiology, Faculty of Medicine, T o y a m a Medical a n d Pharmaceutical University, Toyama, Japan ABSTRACT To investigate involvement of the hippocampal formation in spatial information processing, activity of neurons in the hippocampal formation of the conscious monkey was recorded during presentation of various visual and auditory stimuli from several directions around the monkey. Of 1,047 neurons recorded, 106 (10.1%) responded to some stimuli from one or more directions. Of these 106 neurons with directionally differentiating responsiveness, 49 responded to visual stimulation, 35 to auditory stimulation, and 22 to both. Among 81 neurons, each tested with more than 10 different stimuli, one type responded independent of the nature of the stimulus (nonselective, n = 39), and responses of the other type depended on the nature of the stimulus (selective, n=42). To investigate effects of change in spatial relations between test stimuli and background stimuli fixed on the monkey or fixed in the environment, 59 of 106 neurons were tested while the experimental apparatus holding the stimulus was moved relative to the monkey. Of these 59 neurons, 36 changed their responsiveness; 7 maintained the magnitude of their responses but changed the response direction with the movement of the apparatus, 5 changed direction regardless of the movement, and 24 did not change direction, but decreased or extinguished responses from the preferred direction. Thirty-two of 106 neurons were also tested by rotating the monkey. The directionally differentiating responsiveness of 1 1 neurons followed the monkey (egocentric neurons), that of 9 remained in place in the environment (allocentric neurons), and responses of 12 were reversibly extinguished when the monkey was rotated. The results suggest that these hippocampal neurons may be involved in identification of relations among various kinds of stimuli in different spatial frameworks (egocentric or allocentric) and this identification may be developed from multiple sensory modalities. Key words: hippocampal formation, single unit recording, spatial memory, egocentric neurons, allocentric neurons It is now widely accepted that the hippocampal formation (HF) is involved in spatial memory as well as nonspatial memory. Humans with damage in the medial temporal lobe, including the HF, exhibit spatial memory deficits (Smith and Milner, 1981; 1984; 1989; Cave and Squire, 1991). In the monkey, bilateral lesions in the H F system impair performance in several kinds of spatial tasks (Zola-Morgan and Squire, 1986; Rupniak and Gaffan, 1987; Parkinson et al., 1988). In the rat, bilateral lesions in the H F system also impair performance in spatial tasks (Olton et al., 1978; Moms et al., 1982). Unit-recording studies of the rat H F suggest the existence of “place units” in the H F that respond preferentially to particular locations of the animal in the field (O’Keefe and Correspondence and reprint requests to Professor Taketoshi Ono, Department of Physiology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Toyama 930-01, Japan. Dostrovsky, 1971; O’Keefe and Nadel, 1978; Muller et al., 1987; Breese et al., 1989; Foster et al., 1989). Unit-recording reports indicate that some primate H F neurons respond in spatial tasks (Watanabe and Niki, 1985; Cahusac et al., 1989; Miyashita et al., 1989; Rolls et al., 1989; Feigenbaum and Rolls, 1991). These unit-recording studies in the monkey H F suggest that some neurons in the H F may be involved in spatial learning or memory developed from vision. As suggested in a previous study of the rat hippocampus (O’Keefe and Conway, 1978), place-specific activity change in place units can depend not only on vision but also on other sensory modalities, such as audition. However, relations between neuronal responses of the monkey H F to spatial factors and properties of stimuli (such as sensory modalities or a kind of stimulation have not been ascertainedin one sensory The H F has reciprocal connections with both the posterior region of the inferior parietal cortex and the prefrontal as- 307 308 HZPPOCAMPUS VOL. 2, NO. 3, JULY 1992 sociation cortex, which are involved in spatial information processing (Teuber, 1964; Pohl, 1973; Petrides and Iversen, 1979; Andersen and Mountcastle, 1983; Passingham, 1985; Andersen, 1987; Goldman-Rakic, 19871, mainly via the parahippocampal cortices (PH) (Jones and Powell, 1970; Van Hoesen, 1982; Amaral, 1987; Tranel et al., 1988). Recent results indicate that the HF, and the system to which it belongs, are essential for acquisition, relation, combination, and conjunction among stimuli (Eichenbaum et al., 1988; Squire et al., 1989; Sutherland and Rudy, 1989; Wiener et al., 1989) and such functions are important for allocentric spatial mapping. A computational theory suggests the possibility that egocentric representation of information is converted to allocentric form in the hippocampus (O’Keefe, 1990). Assuming that there are neurons in the monkey H F that respond to stimuli presented in a particular local context (or configuration of background stimuli), responsiveness of such neurons may also depend on some reference stimuli as well. Furthermore, if reference stimuli are fixed to the animal or things that move with the animal, responses of neurons may have “egocentric” properties, and if reference stimuli are fixed in the environment, responses of neurons may have “allocentric” properties. It was thus thought to be useful and important to investigate whether there are neurons in the monkey H F that respond to some spatial aspects of stimuli presented, and if there are such neurons, which relations between stimuli are represented in their responses. In this study, we analyzed the responses of single neurons in the monkey H F to the presentation of various test stimuli, visual or auditory or both, from various directions relative to the monkey. To investigate relations between test stimuli and reference stimuli further, the same tests were performed either while keeping the monkey fixed and changing part of the environment, or while moving the monkey relative to a fixed environment. A preliminary report of this work has appeared elsewhere (Tamura et al., 1990), and some supporting evidence has recently been reported (Feigenbaum and Rolls. 1991). MATERIALS AND METHODS Except for differences in some parts of the experimental design and the stimulus presentation paradigm, the experimental methods were essentially the same as those used in the accompanying paper (Tamura et al.). Therefore, the Materials and Methods section has been minimized: the reader is referred to the accompanying paper (pp. 287-306) and our previous papers (Ono et al., 1980; 1981; 1989; Fukuda et al., 1986; Nishijo et al., 1988a; 1988b; Yamatani et al., 1990). Experimental design and stimulus presentation The monkeys normally sat in a chair facing an apparatus (Fig. 1). The apparatus had a front panel and two wings of aluminum plate that could be easily detached. The panel had a window (Wm, about 10 cm x 20 cm) covered by a oneway-mirror shutter. Each wing also had a window (W1 or Wr, about 15 cm x 15 cm). Behind each window was a stage for setting objects. The normal arrangement of the experimental room is shown in Figure 1A. The apparatus was in front of the monkey (M). The experimenter(s) (H) usually sat in front of the monkey to its right and was hidden by a wing of the apparatus. In this situation, various visual and auditory stimuli were presented to the monkey from several directions. Many different objects chosen from a pool of about 1,000, as well as some parts of the human body, were used as visual stimuli. Sometimes food (raisin, a piece of apple, cookie, etc.) was given to the monkey to retain its attention to the presented objects. Since, in the experimental situation reported here, the monkey’s limb movements (e.g., reaching his hands to foods) were restricted by attaching an acrylic plate in front, the foods were placed directly in the monkey’s mouth by the experimenter. The range that the monkey could see was restricted to about 280” from the center by attaching opaque acrylic plates at the sides of its face. Usually each object was presented by the experimenter putting it on the stage behind the window for about 2.0 seconds. The distance between the monkey’s face and the object was usually about 40 cm. Sometimes the same object was also presented by the experimenter’s hand, which approached closer to the monkey. When large objects, such as the human body, were presented, the wings were detached or the experimental apparatus in front of the monkey was completely removed. When the apparatus was removed and the room light was on, the monkey could see the white walls of the room in front and to the left anterior, and the recording setup to the right anterior (Fig. 1A). In this situation, the experimenter could walk around the monkey, stop at various places, and display various actions, such as sitting, standing, or presenting an object by hand that had been shown in the experimental apparatus. Many different kinds of sounds were used for auditory stimulation, including meaningful or complex sounds (step sound, clap, human voice, crash, etc.) and computer-synthesized sounds (harmonic rich sounds or pure tones) using a sound board (PC-9801-26K, NEC). Meaningful or complex sounds were usually presented by some act of the experimenter (stepping, clapping, vocalizing, crashing metal materials, etc). Computer-synthesized sounds were presented through speakers arranged around the monkey. Each sound source (experimenter’s act or speaker) was usually located about 80 cm from the monkey’s head except for sound from fixed sources, such as the sound of opening or closing the entrance door. The intensity of computer-synthesized sounds was usually controlled to about 80 dB. Intensities of complex sounds made by the experimentcr were estimated to range between 70 and 90 dB. Most auditory stimuli were presented from various directions around the monkey by moving the source of the sound. If a stimulus was considered to contain both visual and auditory components, we attempted to separate the modalities by attenuating the intensity of the sound or by masking it with white noise, or by reducing illumination to a minimum to restrict the monkey’s vision. When activity of a single neuron in the H F or PH was detected, a few kinds of objects or human actions were presented as visual stimuli at the left anterior (about 45” from the anterior-posterior plane), anterior, and right anterior positions (Fig. 1B). Each visual stimulus was presented five or more times at each position before the next object was presented. A few kinds of sounds were similarly presented five or more times each from the left anterior, anterior, right anterior, right posterior, posterior, and left posterior directions. MONKEY HIPPOCAMPAL RESPONSES TO SPACE / Tarnura et al. AII AC 1- 309 / - PC 9 8 0 1 I ,1 Task Control ' H ) Am piifier et c. -.-/ ATAC-450 (On Llna A M I Y S ~ ) I wr\ Wm H : Human M : Monkey 0 : Object S : Speaker Door I B J Anterior Left Anterior Left P o s t e r i o r t I Posterior Right P o s t e r i o r ___ -. VISUAL AUDITORY Fig. 1. Schema of experimental situation. (A) Arrangement of 4 m x 6 m experimental room. Monkey sat in a chair facing a front panel. Monkey's limb movements were restricted by plate attached in front of its body. Two wings (left wing and right wing) were at left and right sides of the front panel. There was a window in the front panel (Wm) and one in each wing (Wl, Wr). Experimenter(s) were usually at right anterior of the monkey to observe behavior of the monkey and direct on line analysis of unit activity. Various kinds of objects (0)were presented to monkey from left anterior (WI), anterior (Wm), or right anterior (Wr) directions as visual stimuli. Various kinds of sounds were presented to monkey from one of eight speakers (S) set around monkey as auditory stimuli. Entrance door to room was behind monkey. (B) Directions of visual and auditory stimulation sources. Various kinds of visual and/or auditory stimuli were presented from several directions around the monkey. Solid lines, visual stimulation; broken lines, auditory stimulation. M, monkey; H, experimenter(s); 0, objects presented; S, speakers used for computer-generated auditory stimuli; AC, air conditioner. If neuronal activity changed when the relative direction of the origin of a stimulus was changed, then more detailed relations between the directionally differentiating responsiveness and the kind of stimulation were examined using various kinds of visual and auditory stimuli. We use the term directionally differentiating since the neurons responded differently when stimuli were presented from different positions (or directions) around the monkey. This phrase is then used to describe responses of these neurons as they are subjected to corresponding procedures. Stimulus presentations were separated by intervals of at least 30 seconds. After these tests were concluded, and if the neuron being recorded was thought to have directionally differentiating responsiveness, we tested its responses in the following two procedures. Procedure 1 The experimental apparatus in front of the monkey was moved to several places in the experimental room. Since the experimental apparatus was usually located in front of the monkey and covered a large part of its visual field, this apparatus was considered to have many visual stimuli that could be dominant landmarks (references) for locational information of test stimuli. If the neuron did not change responses 31 0 HPPOCAMPL~S VOL. 2, NO. 3, JULY 1992 in this procedure, it was deemed to be responding to relations between a test stimulus and background stimuli other than those on the experimental apparatus. If the responses of the neuron followed movement of the apparatus, the neuron could have been responding to relations between test stimuli and stimuli on the experimental apparatus. Background stimuli is a general term meaning stimuli that could provide spatial reference for the test stimulus. Therefore, background stimuli include all stimuli fixed in the environment (experimental room), on the monkey, and all visible parts of the restraining device. Procedure 2 The monkey chair was rotated 45” to the left and then 45” to the right of the experimental apparatus, and the test stimuli remained in their initial positions. If the responses follow this rotation, as in Figure 9A, the neuron was considered to respond to some spatial relation between the test stimulus and some stimuli that rotated with the monkey. If the responses remained constant relative to the environment, as in Figure 9B, the neuron was considered to respond to some spatial relation between the test stimulus and some stimuli that were fixed in the environment. Recording and data analysis Most of the recording technique and data analysis were the same as those described in the accompanying paper (pp. 287306). Briefly, single-unit activity was recorded from the HF and PH. Neuronal activity was processed in a window discriminator and displayed as peristimulus time histograms using minicomputers on-line and off-line. During auditory stimulation, the stimuli themselves triggered data collection by converting sounds to electrical start signals through a microphone near the monkey’s head. For visual stimulation, the experimenter pressed a foot switch to trigger collection of data when stimuli were presented. Neuronal responses for the first 1.0 seconds after presentation were averaged for each of several stimulus presentations. Responses to the presented stimuli were compared by one-way analysis of variance (ANOVA) with significance at Pc.05. Latency of each response to the stimulus was measured mainly for auditory stimulation off-line since timing of auditory stimulation could be precisely determined from recorded sound data, whereas timing of visual stimulation, especially of human actions, could not be precisely determined. During recording sessions, eye movement of the monkey was monitored through a monochrome television camera or electrooculograms (EOG) or both, as well as directly by the experimenter. During recording sessions, behavior of the monkey was also monitored through a color television camera or electromyograms (EMG) or both, as well as directly by the experimenter. RESULTS Animal behavior All monkeys usually turned their attention to a visual stimulus when it was presented. Since the head was restrained, only the eyes of the monkeys could move in the direction of a visual stimulus. When food was presented, the monkeys would usually fix their eyes on it until they got it or it was withdrawn. No other consistent overt behavior was noticed when visual stimuli were presented. When auditory stimuli were presented, they did not usually exhibit any consistently overt behavior or eye movement, except when a loud or frightening sound was made. General properties of HF neurons with directionally differentiating responsiveness Of 1,047 neurons tested in the HF and PH, 106 (10.1%) responded (all by excitation) preferentially to the presentation of visual andlor auditory stimuli from a particular direction(s) around the monkey. Many of the neurons responded phasically , but a few responded tonically during stimulus presentation. Judging from EOGs, television monitoring, and inspection of experimenter, there was no clear correlation between visual responses of most neurons and initial eye position or eye movement. Responses of these neurons did not correlate to particular movements of the monkey, such as arm or leg movements. The spike activity of some of these neurons was complex, that is, a decrementing series of spikes at short intervals (2.0-5.0 ms) with 0.4-0.6 ms spike durations and low spontaneous firing rates (<2.0 spikesls). However, many of the neurons with directionally differentiating responsiveness did not show typical complex spike activity, but showed irregular bursting with shorter spike duration of spikes (0.2-0.5 ms) and slightly higher spontaneous firing rates (0.5-18.1 spikeds). Neurons that showed regular firing activity with short spike duration (0.2-0.3 ms) and high frequency of spontaneous firing (> 10.0 spikesh) usually did not have directionally differentiating responsiveness. There was no overlap between the neurons with directionally differentiating responsiveness described in this paper and neurons that responded to the sight of objects during performance of the object discrimination task described in the accompanying paper (Tamura et al., 1992). Relations among sensory modalities, kinds of stimuli, responsiveness, and direction Of these 106 neurons with directionally differentiating responsiveness, 49 responded to visual stimulation, 35 responded to auditory stimulation, and 22 responded to both visual and auditory stimulation. The relations among sensory modalities, neuronal responses, and orientation are shown in Figure 2. The number of neurons in each category that also responded in the other modality are shown in parentheses. The vision-responsive neurons tended to respond to stimulation presented from the right anterior direction, and the sound-responsiveness neurons tended to respond more to stimulation presented from the posterior. Of the 22 visual plus auditory neurons with directionally differentiating responsiveness, the visual and auditory responses of 11 overlapped (4,left anterior; 2, anterior; 5, right anterior) and responses of 11 did not overlap direction. Of the 106 neurons, 81 could be tested with more than 10 kinds of stimuli, and these 81 neurons were divided into two groups. In one group, responsiveness was independent of the nature (or kind) of the stimulus in one sensory modality (non- MONKEY HIPPOCAMPAL RESPONSES TO SPACE / Tarnura et al. I A (2) A (1 1) Fig. 2. Relations among sensory modalities, neuronal responses, and stimulus orientation. Ordinates, numbers of neurons with directionally differentiating responsiveness that respond in each position. Hatched areas (V), neurons with visual responses; solid areas (A), neurons with auditory responses. Number in parentheses below each column indicate number of neurons in that column that are bimodal. Totals may exceed those in text because of overlap. selective group, n = 39). In the other group, responsiveness depended on the nature of the stimulus, and these neurons tended to respond more to some stimuli than to others (selective group, n = 42). Of 49 visual neurons, 34 were tested with more than 10 kinds of stimuli and 21 of 34 were classified into a nonselective group. Responses of a visual nonselective neuron are shown in Figure 3. This neuron, located in the CAI area of the HF, was tested with 1 1 kinds of visual stimuli (not all shown) and 4 kinds of auditory stimuli. It responded phasically to visual stimuli presented from the right anterior direction (Ac, B), and did not respond to the same visual stimuli presented from any other direction (Aa, Ab). This neuron did not respond to any of four kinds of auditory stimuli presented from any direction (Aa-f, pure tone; B, human voice, step, clap, pure tone). Thus the responses of this neuron were nonselective to the kind of visual stimuli tested, but they were selective to the direction of stimulation (right anterior) and to sensory modality (vision). As shown in Figure 4, there seemed to be no clear relation between the response of this neuron and eye movement. For example, there was no significant eye movement in the second presentation of apple (A2) and second presentation of stick (C2) since the monkey had already directed its eyes toward right anterior, and there was significant movement to the right in the other presentations. However, the responses of the neuron were almost the same in all of these situations. The other 13 of 34 visual neurons were classified into a selective group (1 1 responded strongly to particular human movements and 2 responded to the sight of rewarding objects). Responses of a typical, visual selective neuron are shown in Figure 5. This neuron, located in the CAl area of 31 1 the HF, was tested with 15 kinds of visual stimuli and 8 kinds of auditory stimuli (not all shown). It responded selectively to human action (standing up or sitting down) in the right anterior position (A,B), but not to any of 14 other kinds of visual stimuli or 8 kinds of auditory stimuli (B). This neuron did not respond to any other test stimuli presented from any direction (A). When room illumination was reduced to a minimum or the monkey was prevented from seeing human action by an opaque plate, responses to human action at right anterior were completely extinguished (B, human action in dark). The response magnitude of this neuron to the presentation of visual stimuli did not depend on the length of the period that the monkey fixed his eyes on the visual stimulus, since the monkey almost always fixed his eyes longer on rewarding objects, such as a piece of apple, raisin, or cookie, than on human action. However, responses to human action were much stronger than the responses to these rewarding objects. Of 35 auditory neurons, 32 were tested with more than 10 kinds of stimuli, and 14 of 32 could be classified as nonselective. Responses of an auditory nonselective neuron are shown in Figure 6. This neuron, located in the CA3 area of the HF, was tested with six kinds of visual stimuli and seven kinds of auditory stimuli. It responded strongly to auditory stimuli presented from the left posterior direction (A). It also responded weakly to auditory stimuli from the posterior direction, but not if they were presented from any other direction. This neuron did not respond to any of six kinds of visual stimuli presented from anterior directions. Magnitudes of responses were almost the same for all kinds of different auditory stimuli presented from the left posterior direction (B) (ANOVA, P > . 1). Other auditory neurons (18 of 32) were classified as selective. All of these neurons exhibited strongly selective responses to complex sounds made by the experimenter: seven responded to a step, four to the sound of a chair moving, two to the sound of a door opening, two to a data recorder being switched, two to board tapping, one to the sound of paper crumpling. Responses of an auditory selective neuron are shown in Figure 7. This neuron, located in the dentate gyrus, was tested with 8 kinds of visual stimuli (not shown) and 10 kinds of auditory stimuli. The neuron responded strongly to sounds related to human movement presented from posterior directions (A, B); the strongest response was to the door being opened in the posterior direction (B). When the directionally differentiating responsiveness of this neuron was further tested by using a human voice, a clap, or a pure tone, responses to the human voice and clap diminished as the source of the stimulus approached the anterior direction. There were no responses to a pure tone from any direction nor to any auditory stimulation from anterior directions within the monkey's vision ( k80" from the center) (A). Judging from EOGs and television monitoring, there was no correlation between eye movement and responses of these auditory neurons. Of 22 neurons that responded to both visual and auditory stimuli, 15 were tested with more than 10 kinds of stimuli. Of these 15 neurons, 4 were classified as nonselective and 11 as selective (all 1 1 responded strongly to human action such as walking and to complex sounds made by the experimenter). 31 2 HZPPOCAMPUS VOL. 2, NO. 3, JULY 1992 U I I I I 1 I I I I I II Syringe I ,I, Stick 0 -1 f 0 1 2 I . II Posterior I1 I r -1 aec 8- Q) Q) a c 4- 2 I 0 3 sec -0 0 L P) Y 5 '0 E v) v) E a I T T OI 6- 1 a E > I I 0 -al Q) I1 I c c aQ 0 .- n I 1' t I Q) U f I Ill Left Posterior aec Y I I 3 2 1 I I m I I /I i s e c3 e \ I I> 1 I ,I I. I -1 1 II , 11 111 I I I 111 I1 I I", I T P 0 .c h N r 0 0 0 v P) C 0 I- E L if 2- E lu a I 0Stimuli P r e s e n t e d Fig. 3 . Responses of visual nonselective neuron. (A) Directionally differentiating responsiveness to visual and auditory stimuli shown as raster displays. Visual stimuli (e.g., apple, syringe, and stick) were presented from left anterior (a), anterior (b), and right anterior (c) directions. Auditory stimuli (e.g., pure tone) were presented from six directions (a-0. Note phasic responses to visual stimuli presented from right anterior direction (c). Abscissa, time (sec); vertical line in each plot indicates time 0 when each stimulus was presented; horizontal line above abscissa, period of stimulus presentation (2 seconds). P, front panel. Other descriptions as for Figure 1 . (B) Comparison of visual nonselective responses to various kinds of visual or auditory stimuli presented from right anterior direction. This neuron responded to all visual stimuli tested with almost the same response magnitude when presented from right anterior, but not from other directions, and did not respond to auditory stimuli. Each histogram, mean and SEM of response size of five presentations of each stimulus. (Response size defined as difference between 1 .O second measurement of firing number before stimulus presentation and 1.O second measurement of firing number during stimulus presentation.) MONKEY HIPPOCAMPAL RESPONSES TO SPACE / Tamura et al. A Apple Bill 1\- I I1 II J------- IH 31 3 perimental apparatus was fixed. Changing the location of the experimental apparatus modified the responses of 36 of 59 neurons. For 12 of these neurons, the direction of maximum response changed (7 neurons changed the direction according to the movement of the apparatus and 5 changed the direction independent of the movement). For the other 24, the preferred direction did not change, but responses in the preferred direction were very weakened, or the directionally differentiating responses were reversibly extinguished. The responsiveness of a neuron whose responsiveness was completely extinguished by moving the apparatus is shown in Figure 8. This is the same neuron shown in Figure 5. The strong responses to human action presented from the right anterior direction (Aa) were completely extinguished when the experimental apparatus, which was considered to be a part of the environment, was removed to a place where the monkey could not see it (Ab). The response magnitude also depended on the precise location of the apparatus when the monkey could see it. When the apparatus was moved about 5 cm to either the left or the right, responses in the preferred direction were steeply diminished irrespective of the relations between the test stimulus and the experimental apparatus (Fig. 8Ac, B), and when the apparatus was moved more than 10 cm to the left or 15 cm to the right, responses were completely extinguished (Fig. SAb, B) although the visibility of the human action was not changed. When the monkey was rotated, the directionally differentiating responsiveness of 11 neurons followed the monkey. We designate these neurons as “egocentric,” because the directions of their responses followed the rotation of the monkey, and these responses were considered to represent relations between the test stimulus and background stimuli on the monkey or on the restraining device that rotated with the monkey. An example of responsiveness of an egocentric neuron is shown in Figure 9A. This neuron responded strongly to both visual and auditory stimuli related to human movement, such as walking, presented from the right anterior position. The responses to walking at the right anterior were weakened but not extinguished when all of the lights in the experimental room were turned off or when the monkey was prevented by a screen from seeing the human walking (not shown). Thus, the directionally differentiating responsiveness of this neuron may include both vision and audition. The responsiveness to a human walking at the right anterior (Aa) followed the monkey when it was rotated 45” to the left (Ab) or to the right (Ac). Electroculograms and television monitoring of eye movement did not show correlation between responses of these egocentric neurons and eye movement. The directionally differentiating responsiveness of nine neurons remained in place in the environment and did not follow the monkey. We designated these neurons as “allocentric,” because the directions of their responses did not follow the rotation of the monkey but remained constant relative to the environment, and these responses were considered to represent relations between test stimulus and background stimuli fixed in the environment. An example of the responses of an allocentric neuron is shown in Figure 9B. This neuron also responded to visual or auditory stimulation caused by human actions (walking) presented from right anterior (Ba). Responses to human action presented from the right anterior 2u II 1111 I 111 III I11111 3 b - - II -I,-------- B Syringe 1- 11 II I 1 I I I1 a 1 I I I 2 I 1111 I 3 M c Stick ’ c 1111I I I I 111 I *m Ill 111 II I I 4 Ill II 3JI -1 R I 0 I 1 I 2 I 3 sec Fig. 4. Relation between neuronal responses to visual stimulation (upper rastergrams) and electrooculograms (EOGs, lower traces). These neuronal responses are those to the visual stimulation from the right anterior direction in Figure 3 but shown relative to EOGs. There were no clear correlations between eye movement and directionally differentiating neuronal responses even if the visual stimulus was the sight of a rewarding (A, apple), an aversive (B, syringe), or a neutral (C, stick) object. EOG, upward deflection, movement to left (L); downward deflection, movement to right (R). Abscissa, time (sec); time 0, each stimulus was presented; horizontal line above abscissa, period of stimulus presentation (2 seconds). Spontaneous firing rates and response latencies of each type of neuron are summarized in Table I . Dependence of responsiveness on relations between test stimulus and background stimuli Fifty-nine of 106 neurons were tested by changing the location of experimental apparatus in front of the monkey while the monkey’s position was fixed in the environment. Thirtytwo of 106 neurons were also tested by rotating the chair in which the monkey was seated while the location of the ex- 314 HZPPOCAMPUS VOL. 2, NO. 3, JULY 1992 A 20- - . 15- N m I m r .- 0 0 0 0 10- Y Q n Q c 1 m IT 0 .L .- -n 5 - O n a L :0 I C .-C .Y) m .-O L O Y o E O P . LT 0 v) 0 UJ .-C L % v) Y V c .- v) T Stimuli P r e s e n t e d -5- Fig. 5. Responses of visual selective neuron. (A) Comparison of responses to human movement (from left anterior and right anterior directions) and pure tone from six directions. This neuron responded strongly when human sat down or stood up at right anterior. There were no responses to human movements from left side directions or to auditory stimulation from any direction. (B) Comparison of responses to various visual or auditory stimuli presented from right anterior direction. This neuron responded selectively to human movement (sitting down or standing up). l h e r e were no responses to presentation of other stimuli, nor were there responses when all room lights were turned off and illumination was minimized (human movement in dark). Each histogram, mean and SEM of response size of six presentations of each stimulus. Hatched area in A and B, responses to human movement: filled area in A and B, responses to pure tone. Other descriptions as for Figures 1 and 3. A --+P B ia A Q m ‘m8 Q Y .- Q u) - 6 Q 6 a cn4 E ..-IL L r 2 2 (D a2 z 0 0 Q c u) II * 0 c *I Q Q v) 6 6 L 0 L Stimuli Presented Fig. 6. Responses of auditory nonselective neuron. (A) Comparison of responses to stimuli presented around monkey. Visual stimuli (e.g., apple) were presented from left anterior, anterior, and right anterior directions. Auditory stimuli (e.g., pure tone) were presented from six directions. This neuron responded to auditory stimuli presented from left posterior direction. (B) Comparison of responses to several auditory stimuli presented from left posterior direction. This neuron responded to all auditory stimuli tested from the left posterior direction with almost the same response magnitude. Each histogram, mean and SEM of response size of six presentations of each stimulus. Dotted area in A, responses to sight of apple; filled area in A and B, responses to pure tone. Calibration at right side of bottom histogram (responses to auditory stimuli from posterior direction) in A, firing rate. Other descriptions as for Figures 1 and 3. A l- T B c a, U Q .-rn 0 Q) N L 0 0 15 c 0 v) \ UJ xn 10 a l- .- P, C Q .-a 3 (d E T Q) 0 0 Y 0 0 r v) v 2 T N I 0 Q) > Q) P, n r +0 CI) c 0. I- P -Q 0 P v) Q) Q cn 0 c L 7 n 5 En .-C L iio C (d Stimuli P r e s e n t e d Q) 2 -5 Fig. 7. Responses of auditory selective neuron. (A) Comparison of responses to human voice (hatched area), clap (dotted area), and 1,000 Hz pure tone (filled area) from various directions. This neuron responded to several kinds of auditory stimuli when presented from posterior directions, but not to visual stimuli (not shown) from anterior directions. (B) Comparison of responses to various auditory stimuli presented from posterior direction. This neuron responded strongly to sound of door being opened behind monkey, moderately to human voice, tapping, and clap, and weakly to step and crash. There were no responses to computer-synthesized complex sounds nor to pure tone. Other descriptions as for Figures 1 and 3. 31 6 HIPPOCAMPUS VOL. 2, NO. 3, JULY 1992 Table 1. Spontaneous Firing Rates and Response Latencies of Each Type of Neuron Visual No. of neurons Visual and Auditory Auditory NS S NS S NS S Spontaneous firing rate Range (spikesis) Mean f SEM (spikesis) 21 13 14 18 4 11 0.0-18.3 3.6 k 0.8 0.0-5.1 1.4 f 0.5 0.0-5.5 2.2 k 0.6 0.0-4.8 2.1 f 0.3 0.4-1 1.4 4.4 -c 1.3 0.0-2.8 1.2 f 0.4 Response latency Range (ms) Mean i SEM (ms) No. of neurons 150-190 173 f 10 3 240 240 1 80-240 134 k 19 11 140-460 264 -+ 30 140-240 190 i 15 3 160k280 225 i 24 4 13 NS, nonselective neurons; S , selective neurons. Recording sites were weakened but not extinguished when all of the lights in the experimental room were turned off or when the monkey was prevented by a screen from seeing the human movement (not shown). The responsiveness to walking at the right anterior direction (Ba) remained fixed in the environment and did not follow the monkey when the monkey was rotated 45" to the left (Bb) or to the right (Bc). Response magnitude was decreased to about half of the original when the monkey was rotated 45" to the left and could not see the human because of the restriction of monkey's vision to ?So". These responses to walking at the right are considered to be responses to the auditory component of the stimulus (step). The directionally differentiating responsiveness of 12 other neurons was reversibly extinguished when the monkey was rotated. Recording sites of all neurons sampled are depicted in Figure 10. None of the three monkeys was significantly different from the other two, nor was any of the six hemispheres significantly different from any of the other five (chi-square test, P > . l ) . Therefore, recording sites from both hemispheres of three monkeys are plotted on representative sections of the left hemisphere. The recording sites of each type of neuron are depicted in Figure 1 1 and summarized in Table 2. These neurons were located throughout the rostrocaudal extent of the HF, but tended to be located caudally (chi-square test, fY.01). There were no clear relations between the subfields in the H F and sensory modalities nor between the subfields 0 5 .-.- L LL C I : 0 5 C cm *I -p I :- -5 I 15 Left 1 10 5 0 5 10 15 cm Right U Fig. 8. Effects of change of environment on responsiveness of the neuron shown in Figure 5. (A) Effects of change of front panel location. Strong responses to human movement (hatched area) at right anterior position (a) extinguished when front panel was moved from sight (b) or attenuated when it was moved about 5 cm to left (c). There were no responses to pure tone (filled area). (B) Analysis of effect of small location change of front panel on directionally differentiating responsiveness. Responsiveness of this neuron was strongest when panel was in its usual position (0 cm), attenuated as panel was moved from usual position, and extinguished when panel was moved more than 10 cm left or more than 15 cm right. Each point, mean and SEM of response size of six presentations of each stimulus. Abscissa, distance (cm) from usual position. MONKEY HIPPOCAMPAL RESPONSES TO SPACE / Tarnura et al. A a Usual Situation - b 45"Rotation t o L e f t - 4 5 " R o t a t i o n to Right c 45"Rotation to Righ! T B a Usual Situation c 31 7 b 1 \ 45"Rotation to L e f t Fig. 9. Effects of monkey rotation on responsiveness of neurons. (A) Egocentric neuron. (Aa) Strong responses to human walking at monkey's right anterior while the monkey was in its usual position. (Ab) Directionally differentiating responsiveness to human movement after monkey was rotated 45" left from its initial position. (Ac) Directionally differentiating responsiveness to human movement after monkey was rotated 45" right from its initial position. Note that responsiveness to human movement at right anterior (a) followed monkey (b and c). (B) Allocentric neuron. (Ba) Directionally differentiating responsiveness to human walking; there were strong responses at right anterior. (Bb) Directionally differentiating responsiveness to human walking (step sound) remained fixed in environment after monkey was rotated 45"left from initial position. (Bc) Directionally differentiating responsiveness remained fixed in environment after monkey was rotated 45" right from initial position. Each histogram in A and €3, mean and SEM of response size of five and three (A and B, respectively) presentations of each stimulus. Hatched areas, responses to human movement. Filled circles in B, no responses to stimuli presented (spontaneous firing rate of this neuron was almost 0). Other descriptions as for previous figures. and nonselective or selective nature of the neurons. In the subicular complex, the number of neurons that changed their directionally differentiating responsiveness when the location of the experimental apparatus was changed exceeded the number of stable neurons that did not change (8 of 10 changed, 2 of 10 stable), but there were no clear differences between the numbers of these neurons in other areas (dentate gyrus: 7 of 13 changed, 6 of 13 stable; CA3: 8 of 16 changed, 8 of 16 stable; CAI: 10 of 17 changed, 7 of 17 stable; EC: 2 of 2 changed; PH: 1 of 1 changed). The 11 egocentric neurons were located in the dentate gyrus (n = 4) and in the CA3 (n = 2) and CAI (n = 5) subfields. The nine allocentric neurons were located in the dentate gyrus (n = 3), the CAI subfield (n = 4), and the subicular complex (n=2). The 12 neurons that reversibly extinguished their directionally differentiating responsiveness with rotation of the monkey were located in the dentate g y m (n = 2), CA3 (n = 3), CAI (n = 6), and subicular complex (n = 1). DISCUSSION Relations between directionally differentiating responsiveness and sensory modalities The neurons with directionally differentiating responsiveness tended to respond to visual stimuli presented from the right anterior direction and to auditory stimuli presented from the posterior. This tendency was observed in all three monkeys. The reasons for this discrimination are not entirely clear, but it seems reasonable that vision should depend on stimuli presented within the visual field, and audition might be more valuable to the monkey when stimuli cannot be seen. Also, since the experimenters were usually positioned at the right front of the monkey during most experiments (training sessions and recording sessions for operant tasks), this location may have achieved special importance to the monkey. It is also probable that the monkey has spent more time with its attention directed to its right anterior than in any other 318 HIPPOCAMPUS VOL. 2, NO. 3, JULY 1992 Fig. 10. Recording sites of sampled neurons. Solid circles, neurons with directionally differentiating responsiveness; dots, neurons without directionally differentiating responsiveness. DG, dentate gyms; CA1 and CA3, hippocampal subfields; SUB, subicular complex; EC, entorhinal cortex; PH, parahippocampal cortices. Number below each section: distance (mm) anterior from interaural line. direction in the experimental room. If learning or memory should be related to neuronal activity, it might be possible that the increased time of attention to that area caused the difference seen in the number of neurons, that is, more neurons represent relations to various combinations of stimuli that were seen in the right anterior. The tendency of neurons to respond to visual stimuli presented from the anterior direction cannot be explained by leftright difference of hemispheres since there was no significant difference in the incidence of recording rate in the left and right hemispheres. It is also difficult to believe that H F neurons have this tendency by nature or that this tendency was observed in all three monkeys by chance. Rather it seems reasonable that this tendency may be formed in the experimental condition of training and recording sessions. Existence of neurons that respond to visual or auditory stimuli or both is not surprising, since the HF receives input mainly from multimodal or so-called supramodal cortical areas (Swanson, 1983; Amaral, 1987). This means that, consistent with a previous study of the rat hippocampus (O'Keefe and Conway, 1978), some neurons in the HF of the monkey may be involved in the representation of relations between stimuli through both vision and audition. Nonselective and selective neurons Nonselective neurons responded to different kinds of stimulus presentation in one or both sensory modalities with almost the same response magnitude. The responses of these stimulus nonselective neurons might partly reflect attention. However, even if a visual stimulus was not presented, the monkey often glanced toward the space where we believed it expected the next stimulus to be put, thus directing its attention to that space. Visual nonselective neurons never responded consistently in this situation. Therefore, these neurons did not respond even if the monkey did direct its attention to that space and perceive only background stimuli. MONKEY HIPPOCAMPAL RESPONSES TO SPACE / Tamura et al. 319 I I L A 19 I L PH'-- A 17 -- A 15 A 13 Nonselective A Visual Selective 0 Auditory Nonselective = Auditory Selective 0 Visual and Auditory Nonselective Visual and Auditory Selective * Visual A 11 A 9 Fig. 1 1 . Recording sites of different types of neurons with directionally differentiating responsiveness. Sensory modality of neurons: visual, triangles; auditory, squares; visual and auditory, circles. Selectivity of neurons: nonselective, open; selective, solid. Other description as for Figure 10. Table 2. Recording Sites of Each Neuron Type Recording Sites Visual (NS, S) Auditory (NS, S) Visual and Auditory (NS, S) Total Directional Neurons (NS, S) Total Neurons Sampled 20 (10, 10) 22 (10, 12) 25 (12, 13) 11 (6, 5 ) 2 (1, 1) 1 (0,1) 220 205 369 81 (39, 42) 1047 114 51 88 NS, nonselective neurons; S, selective neurons: DG, dentate gyrus; CA3 and CAI, subfields of hippocampus proper; SUB, subicular complex; EC, entorhinal cortex; PH, parahippocampal cortices. 320 HIPPOCAMPUS VOL. 2, NO. 3, JULY 1992 However, these neurons required that visual stimulation, ment of the apparatus might represent relations between test stimuli, background stimuli fixed on the apparatus, and other such as an object, be presented from a particular location. Selective neurons responded more to some stimuli than to background stimuli. However, other factors might have inothers in at least one sensory modality. Hippocampal neurons fluenced the responsiveness, such as suppression by particwith selective (or differential) responses have been previ- ular stimuli that could not be seen in the usual position. Responsiveness of egocentric neurons is considered to repously reported (Wible et al., 1986; Rolls et al., 1989; Wiener et al., 1989; Creutzfeldt, 1990; Vidyasagar et al., 1991; Ta- resent relations between the test stimulus and background mura et al., 1992). Furthermore, there were some reports stimuli fixed to the monkey or the restraining device, whereas (Creutzfeldt, 1990; Vidyasagar et al., 1991) of hippocampal responsiveness of allocentric neurons is considered to inneurons that were activated by presentation of particular volve representation of relations between the test stimulus human actions during what they called the “raisin show.” and background stimuli fixed in the room. Responsiveness of This report is very similar to the present results in that se- neurons that is extinguished by rotation of the monkey may be involved in representation of relations between the test lective neurons tended to respond to human action. Two visual information-processing pathways have been re- stimulus, background stimuli apparent after rotation of the ported (Mishkin, 1972). One is the dorsal pathway, which is monkey, and stimuli fixed in the room, though it is also posinvolved in analysis of the location of objects, and the other sible that some other factors might influence the responsiveis the ventral pathway, which is involved in analysis of the ness. To represent a visible object in an egocentric (head-cenphysical properties of objects. For detecting a particular location in which a particular object is located, interaction be- tered) framework, it is necessary to combine and compute tween these two pathways is necessary. The H F and PH the information about location of the image of the object on would be positions in which such interaction could occur, a visual field, eye position, neck position, and so on. Some since anatomical studies (Jones and Powell, 1970; Van Hoe- neurons in the neocortical areas have been reported to resen, 1982; Amaral, 1987; Tranel et al., 1988) show inputs to spond to retinotopic space, eye position, or combinations of the H F via the PH from the visual and auditory association these two factors (for review, see Andersen, 1987). However, cortices after processing perception of physical properties there is still no evidence to suggest neurons in the neocortical (Rolls et al., 1977; Gross et al., 1979; Sato et al., 1980; Fuster areas that represent aspects of spatial factors in the egocentric and Jervey, 1982; Ungerleider and Mishkin, 1982; Desimone framework or allocentric framework. Present results suggest et al., 1984; Miyashita, 1988; Miyashita and Chang, 1988), that neurons in the monkey H F or PH may relate stimuli in and from the posterior parietal and prefrontal cortices, after an egocentric framework or an ailocentric framework. Thereanalysis of spatial information (Teuber, 1964; Pohl, 1973; Pe- fore, some computation or conversion of information from trides and Iversen, 1979; Andersen and Mountcastle, 1983; the primary step of spatial representation (such as retinotopic Passingham, 1985; Andersen, 1987; Goldman-Rakic, 1987). space) to a more complicated spatial representation (such as Responsiveness of the visual selective neurons might reflect egocentric or allocentric space) may be made between the results of such interaction. It has been reported that bilateral sensory association cortices and the H F and PH, or within lesions of the H F impaired performance in a spatial memory the H F and PH. Further studies are necessary to investigate task (Parkinson et al., 1988) that required object-place as- such computation or conversion. sociation, so we can imagine that association between a stimACKNOWLEDGMENTS ulus and its location in space, as reflected in responses of the selective group, would be formed in the HF. The authors wish to thank Dr. A. Simpson, Showa University, for help in preparing the manuscript, and Mrs. M. Dependence of responsiveness on relations Yamazaki and Mrs. A. Tabuchi for typing. between test stimulus and background cues Supported in part by the Japanese Ministry of Education, Responsiveness of neurons that was not modulated by Science and Culture, Grants-in-Aid for Scientific Research changing the location of experimental apparatus may repre02404023 and 02255106, by a Bioscience Grant for Internasent relations between the test stimulus and background stimtional Joint Research Project from the NEDO, Japan, and by uli, other than those fixed on the apparatus. Responsiveness Brain Science Foundation, Japan. of the neurons that was changed by movement of the apparatus may represent relations between the test stimulus and References background stimuli fixed on the apparatus, and these might correspond to neurons with responses in the frame-of-ref- Amaral, D. G. (1987) Memory: Anatomical organization of candidate brain regions. In Handbook of Physiology, The Nervous System, erence of allocentric coordinates reported by Feigenbaum V.B. 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