TWO TYPES OF PATTERN OF HIPPOCAMPAL ELECTRICAL ACTIVITY INDUCED BY STIMULATION OF HYPOTHALAMUS AND SURROUNDING PARTS OF RABBIT'S BRAIN

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1 TWO TYPES OF PATTERN OF HIPPOCAMPAL ELECTRICAL ACTIVITY INDUCED BY STIMULATION OF HYPOTHALAMUS AND SURROUNDING PARTS OF RABBIT'S BRAIN Shizuo TORII* Department of Physiology, School of Medicine, Toho University, Tokyo The pattern of hippocampal electrical activity, including both regular slow waves (5-7 cycles per second) and fast waves (15-30 cycles per second), is a matter of controversial discussion. In 1954 GREEN and ARDUINI described that the regular slow waves of the hippocampus appeared in arousal state. Thereafter, this finding has been confirmed by several authors (LIB ERSON and AKERT 1955; GANGLOFF and MONNIER 1956; MACLEAN 1957; TORII and SUGI 1960). On the other hand, there are few reports regarding the fast waves of the hippocampus (BRlJCK et al. 1959; GRASTYAN et al. 1959), and the significance of this wave as well as the relationship between two types of hippocampal electrical activity has not yet been elucidated. When studying the hippocampal electrical activity accompanying the cardiovascular responses to electrical stimulation of the hypothalamus, preoptic region and limbic structures, the author found the existence of close correlation between the hippocampal electrical activity and autonomic activity, and inferred that the slow and fast waves of the hippocampus represent the sympathetic and parasympathetic activity, respectively (TORII and KAWAMURA 1960). On the basis of this assumption it is thought probable that the two types of patterns of hippocampal electrical activity may be induced from the separate system within the brain. It is also possible that these systems may have an intimate relationship with the central representation of the autonomic nervous system in the hypothalamus confirmed by RANSON and his coworkers (1939) and HESS (1936). The present paper deals with the localization of these two systems within the brain of the rabbit. METHODS Twenty-eight rabbits were used in this study. All animals were immobilized with d-tubocurarine. After tracheotomy and canulation the animal was placed in a stereotaxic apparatus (Todai-Noken type), the scalp incised, and a large part of the skull removed. The exposed brain was covered with a pool of warm liquid paraffin. For Received for publication October 8, 1960.

2 148 S. TORII recording, bipolar parallel electrodes were used. They consisted of insulated steel wires, 200 ƒê in diameter, placed side by side about 500,u apart with only the cut cross section of tips bared. An eight-channel ink writing electroencephalograph (Nihon Koden, Model ME-5D) was used for bipolar recording with common earth. Stimulation was carried out with concentric bipolar electrodes consisting of 0.3 mm. stainless steel wire within a 0.8 mm. stainless steel pipe, insulated to about 0.5 mm. of their tips which were spaced 1 mm. apart. Square wave stimuli were used with a pulse duration of 1 msec. and intensities varying from 0.5 to 3 volts. Frequency was usually 100 cycles per second. At the end of the experiments the brain was removed and fixed in 10 per cent formalin. The locations of the electrodes were determined by the examination of serial sections with thionine. RESULTS The hippocampal electrical responses to direct stimulation of the brain: Three types of hippocampal electrical responses were induced from the hypothalamus and surrounding parts of the brain, fast wave, slow wave and intermediate responses. In FIG. 1 are shown these three patterns of responses to stimulation of the septal region. The term, fast wave response, is used here to represent low voltage fast activity at 15 to 300 cycles per second induced with frequencies of 100 cycles per second and pulses of one millisecond in duration (FIG. 1,A). Slow wave response is the same type of response as that previously described as arousal response by GREEN and ARDUINI (1954), consisting of high amplitude regular slow waves at 5 to 7 cycles per second (FIG. 1,C). The intermediate response SE PTAL STIMULATION FIG. 1. Examples of three types of hippocampal electrical activity induced by stimulation of the septum in a curarized rabbit. A: fast wave response ; B: intermediate response ; C: slow wave response. Horizontal bars indicate the period of stimulation.

3 HIPPOCAMPAL ELECTRICAL ACTIVITY FIG. 2. Sites of stimulation from which FIG. J. was prepared. (A 3 of the Sawyer, Everett and Green atlas). The symbols indicate the type of responses seen. œ: fast wave response ; : intermediate response ; : slow wave response. AC : anterior cornmissure ; AMYG. : amygdala ; C: caudate nucleus ; IC : internal capsule ; OCH : optic chiasm ; LPO : lateral preoptic area ; MPO : medial preoptic area ; SP : septum. is employed to that in which by increasing the stimulus intensity the slow wave response changes to the fast wave response (FIG. 1, B). In FIG. 2 are illustrated the sites of stimulation. Bipolar stimulating electrodes were inserted through the septum into the preoptic area at A-3 of the Sawyer, Everett and Green atlas. Electrical stimulation at +3 mm. vertical above the horizontal reference plane resulted in a pure fast wave response. Lowering the electrode to -2 mm. vertical below the horizontal reference plane a fast wave response was replaced by a SEPTAL STIMULATION FIG. 3. Stimulation of the septum produced a fast wave response in hippocampus and after-discharge was seen following stimulation of 1.0 volt for 5 seconds. Electrical activity of the motor cortex was also modified. LHIP : left hippocampus ; LMC : left motor cortex. The same abbreviations are used in the following figures.

4 S. TORII LAT. PREOPTIC STIMULATION 100 CPS. 1 MSEC. FIG. 4. Stimulation of the lateral preoptic area produced a fast wave response. Electrical activity of the motor cortex was not modified. LAT. HYPOTHALAMIC STIMULATION 100 CPS. 1 MSEC. FIG. 5. Stimulation of the lateral hypothalamic area produced a fast wave response. Frequency of the fast waves increasing stimulus intensity. Electrical activity of the motor cortex was modified. intermediate response. Further, when the electrode was placed at the wall of the third ventricle, a definite slow wave response was observed. The fast wave responses of the hippocampal electrical activity to stimulation of various parts of the brain are shown in FIG. 3, 4 and 5. The threshold stimulus for this type of response was usually 0.5 volts. When the intensity of the stimulus was small, an abrupt diminution in amplitude of the slow waves

5 HIPPOCAMPAL ELECTRICAL ACTIVITY (FIG. 3) or replacement with low voltage fast waves (FIG. 4) was seen. As the intensity of the stimulus became stronger, the frequency of the induced fast waves became somewhat faster. This is illustrated in FIG. 5, which shows that as the stimulus intensity is progressively increased from 0.8 to 1.0 volt, the frequency of the fast waves increased from 15 to 30 cycles per second. When the intensity of stimulus was sufficiently large or its duration prolonged, the hippocampal after-discharge following electrical stimulation was often seen. In FIG. 3, the after-discharge following electrical stimulation of the septum is shown. The most prominent part of the septum responsible for this type of response was the medial septal region. On the other hand, stimulation of the lateral part of the septum gave rise to the intermediate response. Also, upon appropriate stimulation, fast wave responses were produced by stimulation of the lateral preoptic area and lateral hypothalamic area (FIG. 4 and 5). In most instances, however, the intermediate responses were most easily elicited from stimulation of these regions. The mammillary body and anterior nuclei of the thalamus were stimulated on several occasions. In some cases, fast wave response was seen, though the result available is not sufficient to give a clear conclusion. It is interesting to note that the intermediate response was easily obtained by electrical stimulation of the reticular formation of the mid-brain. At threshold stimulation the slow wave response was elicited, and if the stimulus was a little greater, the slow wave showed diminution in amplitude and was replaced by fast RF STIMULATION 100 CPS, I MSEC FIG. 6. Stimulation of the dorso-lateral part and ventro-medial part of the midbrain reticular formation produced a slow wave response (A) and an intermediate response (B), respectively.

6 S. TORII CG STIMULATION 100 CPS. 1 MSEC. FIG. 7. Stimulation of the central gray evoked a slow wave response in the hippocampus and an arousal in the neocortex. POST. HYPOTHALAMIC STIMULATION 100 CPS. 1 MSEC. FIG. 8. Stimulation of the posterior hypothalamus evoked a slow wave response in the hippocampus. Electrical activity of the neocortex was not modified.

7 HIPPOCAMPAL ELECTRICAL ACTIVITY waves (FIG. 6,B). However, the slow wave response was also observed after stimulation of the dorso-lateral part of the reticular formation (FIG. 6,A). In all of the experiments the electrical activity of the motor cortex showed only minor modifications (FIGs. 3 and 5) or continued undisturbed (FIGs. 4 and 6). The slow wave responses of the hippocampal electrical activity to stimulation of the hypothalamus and surrounding areas are shown in FIGS. 7 and 8. The intensity of stimulation at threshold produced the regular slow wave activity at 7 cycles per second merely during stimulation. When the intensity of stimulation was increased, the slow waves gradually increased in frequency and amplitude and had a tendency to continue after cessation of stimulation. However, even if the stimulus was sufficiently strong, there was no tendency to decrease in amplitude. This type of response could be obtained most typically from the central gray matter (FIG. 7). An appropriate stimulation of the posterior hypothalamus also could produce a slow wave response in the hippocampus (FIG. 8). The electrical activity of the motor cortex showed an arousal pattern or continued undisturbed. Localization of areas responsive to stimulation: In an attempt to determine the localization of excitable areas within the brain, a systematic exploration of FIG. 9. Drawing of sections from the brain of the rabbit showing the location of points, stimulation of which caused fast responses in hippocampal electrical activity, black circles ; slow wave response, white squares ; intermediate responses, black triangles. Numbers and letters referred to the Sawyer, Everette and Green atlas,

8 S. TORII the hypothalamus and surrounding parts of the brain was made in the rabbit with the aid of above mentioned patterns of hippocampal electrical activity. The distribution of reactive points, stimulation of which caused fast wave responses in hippocampal electrical activity, is indicated by black circles in FIG. 9. Points yielding the intermediate response had approximately the same distribution and is indicated by black triangles. It will be noted from an examination of FIG. 9 that fast wave responses were obtained from the fimbria, septal region, lateral preoptic area and lateral hypothalamic area. The reactive zone was continued through the mammillary peduncle into the tegmentum of the mesencephalon dorsal to the red nucleus. The slow wave responses were obtained by stimulation of the medial preoptic area, medial part of the hypothalamus, posterior hypothalamus, central gray matter and dorso-lateral parts of the mesencephalon and is indicated by white squares. This type of response had tendency to locate more medially at the level of the hypothalamus and to lie more dorso-laterally at the level of the midbrain. DISCUSSION The present study has confirmed that three types of the hippocampal electrical activity are produced from direct stimulation of the brain. If it is postulated that the stimulus threshold is much lower on the side of the slow wave induced system than on the fast wave induced system, it seems possible that an intermediate response may be regarded to be due to simultaneous stimulation of two functional systems, fast and slow wave induced systems. The finding that intermediate responses can be easily obtained from the hypothalamic area and reticular formation where cells and fibers which belong to the separate functional unit are intermingled or densely packed may support this assumption. On the basis of these observations the author believes that there are two functional systems within the brain which can influence the electrical activity of the hippocampus, one running from the ventro-medial part of the tegmentum of the mid-brain through the lateral part of the hypothalamus to the medial septal region and fimbria, and the other running from the dorso-lateral part of the tegmentum through the central gray matter to the medial part of hypothalamic and preoptic area. These results suggest the possibility that there are two main ascending pathways from the mid-brain through the hypothalamus to the hippocampus. This view may be supported by the anatomical findings of GUILLARY (1957) and NAUTA (1958). NAUTA postulated that an ascending pathway that passes from the midbrain into the hippocampus was represented by two main fiber bundles: the dorsal longitudinal fascicles of SchUtz, and the system of the mammillary peduncle. The Schutz's system is composed mainly of fibers which ascend from the periaqueductal gray midbrain substance to the caudal region of the periventricular zone of the hypothalamus, and the system of the mammillary

HIPPOCAMPAL ELECTRICAL ACTIVITY peduncle appears to originate in the medial tegmental region and terminate massively in the mammillary body, but additional longer fiber through the medial forebrain

9 HIPPOCAMPAL ELECTRICAL ACTIVITY peduncle appears to originate in the medial tegmental region and terminate massively in the mammillary body, but additional longer fiber through the medial forebrain bundle to the medial nucleus of the septal region. According to GUILLARY ( 1957 ), the medial forebrain bundle is the fibers that form a part of the bundle in the lateral hypothalamic region, rostrally running through the lateral preoptic region and turning dorsomedially into the septum, and caudally continuing into the tegmental region of the midbrain, running just dorsal to the mammillary peduncle. This bundle is made up of ascending and descending fibers, and most of the ascending fibers end in the medial septal nucleus, but a few fibers also continue into the hippocampus. It is interesting to note that the cells of origin of the medial forebrain bundle do not lie in the central gray of the midbrain. This is in accord with the findings in this study that fast wave responses could not be elicited by stimulation of the central gray. It is tempting to postulate, therefore, that the slow and fast wave induced systems confirmed in this study correspond to the Schiitz's system and medial forebrain bundle, respectively. GREEN and ARUDUINI (1954) showed that hippocampal slow activity could be influenced by an ascending system that passes through the midbrain tegmentum, hypothalamus and septum. They did not distinguish two functional units within the ascending system to the hipocampus. Since the ascending system described by them includes the medial part of the hypothalamic and preoptic area, it may presumably correspond to the slow wave induced system in this study. It is well known that the descending component of these two fiber bundles appears to have an intimate relationship with the autonomic activity (MAGOUN, RANSON and HETHERINGTON 1938; WANG and RANSON 1939). According to a recent study in the rabbit by KUROTSU and his coworkers (Personal communication), the Schutz's system represents the descending pathway for the sympathetic nervous system and the medial forebrain bundle represents that for the parasympathetic nervous system. The author has reported in a previous paper (TORH and KAWAMURA 1960) that both pressor responses associated with the slow wave pattern and depressor responses associated with the fast wave pattern could be produced by stimulation of the hypothalamus and limbic structures. From this it may be inferred that the fast wave induced system passing through the medial forebrain bundle of the lateral hypothalamus is concerned with the parasympathetic activity and the slow wave induced system including the Schiitz's system is concerned with the sympathetic activity. Recently GRASTYAN et al. (1959) have stated that desynchronization of the hippocampus, corresponding to the fast wave pattern in this study, is an expression of enhanced activity and the rhythmic slow waves that of an inhibitory state. However, the present study suggests that the rhythmic slow wave is also an expression of enhanced activity of the sympathetic nervous system. It is impossible at the present time, however, to say the functional significance of the hippocampus in terms of the autonomic activity, as long as we do not know

10 S. TORII more about the subcortical projections of the hippocampus. Nevertheless, for neurophysiologists, the observations reported here might be of interest, since they will be able to be an indicator for exploring the central mechanism of the autonomic activity. SUMMARY 1. The two types of electrical activities of the hippocampus evoked by direct stimulation of the brain have been studied in unanesthetized rabbits, immobilized by tubocurarine. 2. The slow wave pattern of the hippocampal electrical activity, characterized by the regular slow waves at 5 to 7 cycles per second, was induced by direct stimulation of the medial preoptic area, medial hypothalamic region, central gray matter and dorso-lateral part of the tegmentum of the midbrain. 3. The fast wave pattern of the hippocampal electrical activity, characterized by low voltage fast waves at 15 to 30 cycles per second, was elicited by direct stimulation of the medial septum, lateral hypothalamus and medio-ventral part of the tegmentum of the midbrain. 4. The slow and fast wave pattern of the hippocampal electrical activity may represent activity of the separate system within the brain, sympathetic and parasympathetic activities. The author is deeply indebted to Professor T. TOKIZANE for his encouragement and many helpful suggestions. REFERENCES 1) BRUCKE, P., PETSCHE, H. PILLAT, B. UND DEISENHAMMER, E. Ein Schrittmacher in der medialen Septumregion des Kaninchengehirns. Pfliigers Archiv. 269: , ) GANGLOFF, H. AND MONNIER, M. Eletrographic aspect of an " arousal " or attention reaction induced in the unanesthetized rabbit by the presense of a human being. EEG Clin. Neurophysiol. 8: , ) GRASTYAN, E., LISSAK, K., MADARASZ, I. AND DONHOFFER, H. Hippocampal electrical activity during the development of conditioned reflexes. EEG. Clin. Neurophysiol. 11: , ) GREEN, J. D. AND ARDUINI, A. A. Hippocampal electrical activity in arousal. J. Neurophysiol. 17 : , ) GUILLARY, R. W. Degeneration in the hypothalamic connections of the albino rat. J. Anat., Lond. 91: , ) HESS, W. R. Hypothalamus und die Zentrum des autonomen Nervensystems : Physiologie. Arch. Psychiat. Nervenkr. 104: , ) LIBERSON, W. T. AND AKERT, K. Hippocampal seizure state in guinea pig. EEG. Clin. Neurophysiol. 7: , ) MACLEAN, P. P. Chemical and electrical stimulation of hippocampus in unrestrained animals. A.M.A. Arch. Neural, & Psychiat. 78 ; , 1957,

11 HIPPOCAMPAL ELECTRICAL ACTIVITY 9) MAGOUN, H. W., RANSON, S. W. AND HETHERINGTON, A. Descending connections from the hypothalamus. Arch. Neurol. & Psychiat. 39: , ) NAUTA, W. J. H. Hippocampal projections and related neural pathways to the midbrain in the cat. Brain. 81 : , ) RANSON, S. W. AND MAGOUN, H. W. The hypothalamus. Ergebn. Physiol. 41: 6-163, ) SAWYER, C. H., EVERETTE, J. V. AND GREEN, J. D. The rabbit diencephalon in stereotaxic coordinate. J. Comp. Neurol. 101: , ) TORII, S. AND SUGI, S. Electrical activity of hippocampus in unrestrained rabbits. Folia psychiat. neural. japon. 14: , ) TORII, S. AND KAWAMURA, H. Effects of amygdaloid stimulation on blood pressure and electrical activity of hippocampus. Jap. J. Physiol. 10: , ) WANG, S. C. AND RANSON, S. W. Descending pathways from the hypothalamus to the medulla and spinal cord. Observations on blood pressure and bladder responses. J. Comp. Neurol. 71: , 1939.

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