correlative neurosciences - [part a - fundamental mechanisms] - t. tokizane, et al., (elsevier, 1966)

The b-sympathetic zone corresponds to the medial hypothalamic area including the anterior, supraoptic, paraventricular, dorsomedial, ventromedial, posterior and the lateral mamillary nuc

P R O G R E S S I N B R A I N R E S E A R C H

VOLUME 21A CORRELATIVE N E U R O S C I E N C E S PART A: F U N D A M E N T A L M E C H A N I S M S

Tokyo New York London

Netherlands Central Institute for Brain Research, Anisterdam (The NetherlanrJs)

ELSEVIER PUBLISHING COMPANY

A M S T E R D A M / LONDON / NEW YORK

1966

T BAN, Department of Anatomy, Osaka University Medical School, Osaka (Japan)

T FURUKAWA, Department of Physiology, Osaka University Medical School, Osaka (Japan)

K HAMA, Department of Anatomy, School of Medicine, Hiroshima University, Hiroshima (Japan)

T HUKUHARA, Department of Pharmacology, Faculty of Medicine, University of Tokyo, Tokyo (Japan)

M ITO, Department of Physiology, Osaka University Medical School, Osaka (Japan)

M KATO, Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo, Tokyo (Japan)

Tokyo (Japan)

Medicine, University of Tokyo, Tokyo (Japan)

Y KATSUKI, Department of Physiology, Tokyo Medical and Dental University,

E KAWANA, Department of Neuroanatomy, Institute of Brain Research, Faculty of

H KUMAGAI, Department of Pharmacology, Faculty of Medicine, University of Tokyo, Tokyo (Japan)

Tokyo, Tokyo (Japan)

Medicine, University of Tokyo, Tokyo (Japan)

M KUROKAWA, Institute of Brain Research, Faculty of Medicine, University of

T KUSAMA, Department of Neuroanatomy, Institute of Brain Research, Faculty of

H MANNEN, Anatomical-Physiological Section, Institute of the Deaf, Tokyo Medical and Dental University, Tokyo (Japan)

(Japan)

K MIYAMOTO, Department of Physiology, Osaka University Medical School, Osaka

H NARUSE, Institute of Brain Research, Faculty of Medicine, University of Tokyo,

S NISHIOKA, Department of Physiology, Keio University School of Medicine, Tokyo (Japan)

(Japan)

(Japan)

K OTANI, Department of Anatomy, School of Medicine, Chiba University, Chiba

T OTSUKA, Department of Physiology, Keio University School of Medicine, Tokyo

Y SAITO, Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo Tokyo (Japan)

F SAKAI, Department of Pharmacology, Faculty of Medicine, University of Tokyo, Tokyo (Japan)

A SAKUMA, Department of Pharmacology, Institute of Cardiovascular Diseases, Tokyo Medical and Dental University, Tokyo (Japan)

N SHIMIZU, Department of Neuroanatomy, Institute of Higher Nervous Activity, Osaka University Medical School, Osaka (Japan)

Osaka (Japan)

University School of Medicine, Sendai (Japan)

Y TSUKADA, Department of Physiology, Keio University School of Medicine, Tokyo (Japan)

M SHIMOKOCHI, Department of Physiology, Osaka University Medical School,

H SUZUKI, Department of Physiology and Institute of Brain Diseases, Tohoku

N YOSHII, Department of Physiology, Osaka University Medical School, Osaka (Japan)

Other volumes in this series:

Volume 1 : Brain ~echanisms

Specific und aspecific Mechanisms of Sensory Motor ~ntegrut~on

Edited by G Moruzzi, A Fessard and H H Jasper

Volume 2: Nerve, Bruin and Memory Models

Edited by Norbert Wiener? and J P Schadt

Volume 3: The Rhinencephalon and Related Structures

Edited by W Bargmann and J P Schadi:

Volume 4: Growth and Maturation of the Brain

Edited by D P Purpura and J P Schadk

Volume 5 : Lectures on the Diencephalon

Edited by W Bargmann and J P Schade

Volume 6: Topics in Basic Neurology

Edited by W Bargmann and J P Schadt

Volume 7: Slow Electrical Processes in the Brain

by N A Aladjalova

Volume 8: Blogenic Amhes

Edited by Harold E Himwich and Williamina A, Himwich

Volume 9: The Developing Brain

Edited by Williamina A Himwich and Harold E Himwich

Volume 10: The Structure and Function ofthe Epiphysis Cerebri

Edited by 1 Ariens Kappers and J P Schadi:

Volume 11 : Organization of the Spinal Cord

Edited hy J C Eccles and J P Schade

Volume 12: Physiology of Spinal Neurons

Edited by J C Eccles and J P Schadi:

Volume 13 : Mechanisms of Neural Regeneration

Edited b y M Singer and J P Schadt

VlII

Volume 14: Degeneration Patterns in the Nervous System

Edited by M Singer and J P Schad6

Volume 15 : Biology of Neuroglia

Edited by E D P De Robertis and R Carrea

Volume 16 : Horizons in Neuropsychopharmacology

Edited by Williamina A Himwich and J P Schad6

Volume 17: Cybernetics of the Nervous System

Edited by Norbert Wiener1 and J P Schadk

Volume 18 : Sleep Mechanisms

Edited by K Akert, Ch Bally and J P Schadk

Volume 19: Experimental Epilepsy

Edited by T Tokizanc and J P Schad6

Volume 22: Brain Reflexes

Edited by E A Asratyan

Volume 23 : Sensory Mechanisms

Edited by Y Zotterman

Volume 24: Carbon Monoxide Poisoning

Edited by H Bow and I McA Ledingham

Volume 25: The cerebellum

Edited by C A Fox and R S Snider

Volume 26 : Developmental Neurology

Edited by C G Bernhard

Volume 21 : Structure and Function of the Limbic System

Edited by W Ross Adey and T Tokizane

1x

Preface

Medical and biological sciences in Japan have a long history As far back as 562 A D

medical books were introduced from China, initiating a long period of fruitful medical education and practice An important era of scientific interest in the struc-

ture and function of the nervous system began in 19 11 with the publication by Prof

Shiro Tashiro on the carbon dioxide production of nerve fibers Prof Genichi Kato

announced in 1920 his famous theory of non-decremental nerve conduction and presented all the evidence at the International Physiological Conference in 1926 His

research was a major breakthrough in the physiology of single nerve fibers He had a profound influence on the development of physiology in Japan and directing interest toward neurophysiology From that time on the majority of Japanese scientists have been engaged in research in the brain sciences

The present volume is the first of a set of two, containing reviews and surveys of brain research in the majot Japanese laboratories and institutes It particularly reflects the progress of Japanese research in the basic and clinical neurological sciences Part A covers important fields such as: neural regulations of autonomic functions, basic mechanisms of vision and hearing, histochemistry and submicroscopy of synapses and dendrites, enzymatic and metabolic parameters of behavior and con- vulsive states Part B will deal with clinical neurological studies and the relationship

of neuroanatomy, neurophysiology and neurochemistry to the clinical sciences

It is a rare occasion that one acquires an overall view of the research activities of a large country in such an important field of the medical sciences We trust this volume will provide a means of evaluating the level of brain research in Japan

The Editors

This Page Intentionally Left Blank

X I

List of contributors V

Preface IX

The septo-preoptico-hypothalamic system and its autonomic function

T Ban (Osaka, Japan) 1

Synaptic interaction at the Mauthner cell of goldfish T Furukawa (Osaka, Japan) 44

Neural mechanism of hearing in cats and monkeys Y Katsuki (Tokyo, Japan) 71

Relationship between activity of respiratory center and EEG H Kumagai, F Sakai, A Sakuma and T Hukuhara (Tokyo, Japan) 98

Metabolic studies on ep mouse, a special strain with convulsive predisposition M Kurokawa, H Naruse and M Kato (Tokyo, Japan) 11 2 Contribution to the morphological study of dendritic arborization in the brain stem H Mannen (Tokyo, Japan) 131

Central mechanism of vision K Motokawa and H Suzuki (Sendai, Japan) 163

Excitation and inhibition in ventrobasal thalamic neurons before and after cutaneous input deprivation H Nakahama, S Nishioka and T Otsuka (Tokyo, Japan) 180

N Shimizu and T Abe (Osaka, Japan) 197

N Yoshii, M Shimokochi, K Miyamoto and M Ito (Osaka, Japan) 217

K Hama (Hiroshima, Japan) 251

Y Tsukada (Tokyo, Japan) 268

T Kusama, K Otani and E Kawana (Chiba, Japan) 292

neurons H Akimoto and Y Saito (Tokyo, Japan) 323

Author index 352

Subject index 358

Histochemical studies of the brain with reference to glucose metabolism

Studies on the neural basis of behavior by continuous frequency analysis of EEG

Studies on fine structure and function of synapses

Amino acid metabolism and its relation to brain functions

Projections of the motor, somatic sensory, auditory and visual cortices in cats

Synchronizing and desynchronizing iduences and their interactions on cortical and thalamic

This Page Intentionally Left Blank

1

The Septo-Preoptico- Hypothalamic System

and its Autonomic Function

T A D A Y A S U B A N

Deparrtiient of Anaroniy, Osaka University Medical School, Osaka (Japan)

T H R E E Z O N E S I N T H E H Y P O T H A L A M U S

In 1935, Hasegawa reported that the body temperature rose after needle (0.1-0.2 mm

in diameter) puncture in Griinthal’s (1929) b cell-group of the hypothalamus in guinea- pigs On the other hand, Megawa reported in 1940 that needle puncture of Griinthal’s

a and c cell-groups of the hypothalamus and the lateral part of the midbrain teg- mentum in guinea-pigs showed a fall in body temperature The b cell-group also showed increases in blood sugar (Shimizu, 1941) and in number of leucocytes (Satani, 1943) with increased mononuclear leucocytes after needle puncture in rabbits, although

in the a and c cell-groups blood sugar (Shimizu, 1941) and leucocytes (Satani, 1943) decreased In these cases, the coagulation time of the blood was shortened and the sedimentation rate was raised by the puncture of the b cell-group, although the coagulation time was prolonged and the sedimentation rate was lowered by the punc-

ture of the a and c cell-groups (Iwakura, 1944; Kurotsu et al., 1943) Electrical stimu-

lation of the cell-groups mentioned above showed almost the same results as shown

by needle puncture These results prompted Kurotsu and his associates (1947) to propose the hypothesis that the wall of the third ventricle in the hypothalamus was physiologically divided into three zones medio-laterally, namely, a-parasympathetic, b-sympathetic and c-parasympathetic zones respectively The a-parasympathetic zone corresponds to the hypothalamic periventricular stratum (Simidu, 1942) and the medial mamillary nucleus, and the c-parasympathetic zone to the lateral hypotha- lamic area (the lateral hypothalamic nucleus) The b-sympathetic zone corresponds

to the medial hypothalamic area including the anterior, supraoptic, paraventricular, dorsomedial, ventromedial, posterior and the lateral mamillary nuclei, but the stimu- lation of the anteromedial part of the paraventricular nucleus near the periventricular stratum decreased the blood sugar level (Shimizu, 1941) The b and c zones are sepa-

rated from each other by the fornix (Fig l)

T B A N

Fig 1 Frontal sections of the septa1 region (SEP) and the preoptic and hypothalamic areas are shown from left to right ACA, anterior limb of the anterior commissure; AH, anterior hypothalamic nucleus; ARC, arcuate nucleus; CA, anterior commissure; CAU, caudate nucleus; CC, corpus

callosum; CI, internal capsule; CHOP, optic chiasm; COMH, commissura fornicis; CORA, Ammon's horn; DM, dorsomedial hypothalamic nucleus; DSM, supramamillary decussation ; F,

fornix; FM, fasciculus retroflexus; HYP, hypophysis; LH, lateral hypothalamic nucleus; ML, lateral mamillary nucleus; MM, medial mamillary nucleus; MT, mamillothalamic tract; PC, cerebral peduncle; PCA, posterior limb of the anterior commissure; PH, posterior hypothalamic nucleus;

PMD, dorsal premamillary nucleus; PMV, ventral premamillary nucleus; POL, lateral preoptic area; POM, medial preoptic area; PV, paraventricular hypothalamic nucleus; SCH, suprachias- matic nucleus; SM, supramamillary nucleus; SOP, supraoptic nucleus; SPVH, hypothalamic peri-

ventricular stratum; SPVP, preoptic periventricular stratum; STM, stria medullaris; STT, stria terminalis; SUB, subthalamic nucleus; TOL, lateral olfactory tract; TOP, optic tract; VL, lateral

ventricle; VM, ventromedial hypothalamic nucleus; VIII, third ventricle

19%) was increased by electrical stimulation of the nuclei in the medial hypotha- lamic area, but it was decreased after a longer latent period by stimulation with low frequency and voltage This decrease could not be prevented by administration of atropine, and it was slightly accelerated by administration of Imidalin The blood

pressure was decreased (Kurotsu et al., 1954c) by electrical stimulation with low frequency and, after bilateral adrenalectomies, was increased by the same stimulation However, even in normal rabbits, the same stimulation produced an increase in blood sugar, inhibition of gastric motility and a decrease in renal volume In hypophysecto- mized, thyroidectomized or adrenalectomized rabbits, the latent period was about 1.0 sec, which was similar to that in normal rabbits (Ban et al., 1953) The pressor response obtained by the stimulation was pronounced in bilaterally adrenalectomized rabbits In hypophysectomized rabbits, pressor response was rapid and the secondary rise of blood pressure became apparent as the stimulation was repeated This second- ary rise was not modified by extirpation of the thyroid gland, but disappeared after extirpation of the suprarenal glands Even when all three glands were extirpated, the

blood pressure still increased after medial hypothalamic stimulation (Ban et al.,

SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M 3 sure sometimes increased and then decreased When the basic level was markedly lowered by extirpation of the adrenal glands, stimulation of the lateral hypothalamic area did not produce a fall but a small rise of the pressure However, when the basic level was elevated again by intravenous injection of physiological saline solution, the

same stimulation decreased the blood pressure (Ban et at., 1953) These results suggest that the effect of nervous stimuli is subject to the internal environment of animals The electrocardiographic changes (Morimoto, 1951 ; Yuasa et a]., 1957) during medial hypothalamic stimulation under ether or chloralose anesthesia in rabbits were

as follow The R R intervals were shortened after a latent period of 0.5-1.0 sec The

RQ and QT intervals were also shortened and the P wave increased by the stimulation (Fig 2) Lateral hypothalamic stimulation markedly prolonged the R R intervals after

a latent period of 0.4-0.8 sec The PQ and QT intervals were also prolonged and the

P wave was decreased At the same time, sinus bradycardia, sinoauricular block or

auriculoventricular block was observed Sometimes auriculoventricular or ventricular automatism was recognized (Fig 2) These reactions induced by the stimulation of

the lateral hypothalamic nucleus were suppressed by bilateral vagotomies, but some- times slight temporary prolongation of R R intervals could be observed 4-10 sec after the beginning of the stimulation in bilaterally vagotomized rabbits, which might

be caused humorally Effects of stimulation of the periventricular stratum on the elec- trocardiogram were almost the same to those mentioned above

According to Iwakura (1944), an increase in fibrinogen and thrombin was demon- strated with a decrease in the coagulation time of blood after medial hypothalamic stimulation At the same time, the sedimentation rate was accelerated (Iwakura, 1944) and the total amount of protein, albumin and globulin, especially y-globulin, in serum increased (Morimoto, 1950) An increase in aspartic acid in serum was also demon- strated (Tazuke, 1951) On the other hand, after lateral hypothalamic stimulation, the coagulation time was prolonged and the sedimentation rate was retarded (Iwakura, 1944), and the total amount of protein, albumin and globulin in serum was gradually reduced (Morimoto, 1950)

Kotake asserted in 1930 that the method for estimating the serum-iodometric titra- tion value was the most suitable for ascertaining the state of intermediate metabolism

of protein Tazuke (Kurotsu et a]., 3954d), using this method, reported that thevalue

was rapidly increased by 40-90 % after medial hypothalamic stimulation, and stated that this increase was due to an increase in the ether-insoluble material and not t o an ether-soluble one such as a-ketonic acid From the results of these experiments, it is concluded that the medial hypothalamic area can accelerate protein metabolism and the lateral hypothalamic area as well as the periventricular stratum suppress it The total nonprotein nitrogen in blood also increased up to 30% after medial

hypothalamic stimulation (Kurotsu et at., 1954d) The total nonprotein nitrogen and

albumin in blood are closely related to renal function, which will be discussed later

At any rate, albuminuria was observed until 3 days after medial hypothalamic stim-

ulation in rabbits, even in anesthetized rabbits (Ban et at., 1951a) An increase in

blood sugar after medial hypothalamic stimulation has been mentioned above (Shimizu, 1941), but even when the hypophysis, thyroid and adrenal glands had been

4 T B A N

all extirpated, an increase in blood sugar occurred on stimulation (Kurotsu et al.,

1953~) This fact is very interesting for studying liver metabolism

The changes in the total cholesterol and lipid phosphorus in blood and total lipid

in serum induced by the stimulation of the ventromedial hypothalamic nucleus were

2

3

Fig 2 1 shows shortening of PR, PQ and QT and increase of P induced by the stimulation of the nucleus hypothalamicus posterior under ether anesthesia 2 shows shortening of RR and PQ and increase of P induced by the stimulation of the nucleus hypothalamicus ventromedialis under chlora-

lose anesthesia 3 shows the ventricular automatism induced by the stimulation of the nucleus

hypothalamicus lateralis under chloralose anesthesia

S E P T O - P R E O P T I C O - H Y P O T H A L A M I C S Y S T E M 5

measured by means of Bloor’s and Fiske-Subbarow’s methods and the phenol turbi- dity method of Kunkel and the results were as follow (Inoueetal., 1954).Totalcholester-

01 decreased in all 15 rabbits, lipid phosphorus decreased in 8, increased in 5 and

remained unchanged in 2 Total lipid decreased slightly in 7 rabbits and remained

unchanged in 5 After lateral hypothalamic stimulation, total cholesterol remained

almost unchanged, but slightly increased (8 mg/dl) in 3 out of 10 rabbits Lipid phosphorus increased in 1 1 out of 15 rabbits, remained unchanged in 3 and decreased

in 1 Total lipid in serum remained unchanged in 7 out of 12 rabbits, while it increased

in 5 (Inoue et al., 1954)

As to the histamine content in total blood (Kurotsu et al., 1955a; Tane et al., 1958)

measured by Code’s method, medial hypothalamic stimulation was inclined to lower the blood histamine, but an increase was observed in rabbits that died after the stimulation In bilaterally adrenalectomized rabbits, the same stimulation caused an increase in blood histamine as shown in thyroidectomized rabbits, but the histamine content tended to decrease on stimulation when adrenocortical extract (Interenin) was satisfactorily administered to the adrenalectomized rabbits In hypophysectomized rabbits, a decrease in blood histamine was observed on the same stimulation On the other hand, lateral hypothalamic stimulation produced an increase in blood histamine in all normal rabbits, whereas the same stimulation showed a decrease of blood histamine content in adrenalectomized or thyroidectomized rabbits In hy- pophysectomized rabbits, the same stimulation showed an increase in the same man- ner as in normal rabbits

Regarding the changes (Ban et al., 1951 b) of K+ and Ca2+ in total blood induced by the hypothalamic stimulation measured by Kramer-Tisdall’s method, K+ increased while Ca++ decreased slightly on ventromedial hypothalamic stimulation On lateral hypothalamic stimulation, K + decreased while Ca2+ was apt to increase

According to Okamoto and Oda (1952) mobilization of lymph from the lymph gland was accelerated by medial hypothalamic stimulation : the lymphocyte count

in the efferent lymphatic vessels was increased and the related lymph gland was reduced in size by the stimulation On the other hand, they (Okamoto and Oda, 1952) reported that production of lymph in the lymph gland was accelerated by lateral hypothalamic stimulation, because the lymphocyte count in the efferent lymphatic vessels remained almost unchanged and the related lymph gland was enlarged

(11) Cerebrospina1,fluid and choroid plexus (Kurotsu et al., 19536)

The cerebrospinal fluid pressure was markedly elevated up to 200 mm HzO in a glass tube (1.5 mm in diameter) immediately after the ventromedial hypothalamic nucleus was stimulated In the course of repetition of the stimulation, a marked antagonistic action occurred between the sympathetic and parasympathetic systems The stimulation resulted in positive globulin reaction and proportionate increases

i n cell count, total protein and sugar contents Portal permeability from blood into cerebrospinal fluid was increased by the stimulation At the same time, the vitamin C

content was noticeably lowered and the epithelial layer cells of the choroid plexus

6 T B A N

seemed to indicate enhancement of their secretion cytologically After repetition of the ventromedial hypothalamic stimulation, hydrocephalus internus could often be observed On the other hand, a decrease in cerebrospinal fluid pressure was observed down to -100 mm HzO when the lateral hypothalamic nucleus was stimulated No

changes occurred in permeability from blood to cerebrospinal fluid, in vitamin C or sugar contents Epithelial layer cells of the choroid plexus showed features which made it seem that secretory function was at rest cytologically

(III) Eye and intraorbital glands

When the medial hypothalamic area was stimulated in rabbits, exophthalmos and

mydriasis were observed (Ban et al., 1951a, b) At the same time, the intraocular pressure rose markedly (Nagai et al., 1951), even when the common carotid artery

was ligated This rise in pressure was believed to be due first to the contraction of Miiller’s muscles (Nagai, 1951) and then to an increase in blood pressure The total protein content in the aqueous humor (Nagai and Ito, 1951) and the permea- bility from blood to aqueous humor (Nagai and Morimoto, 1952) were also increased

by the same stimulation According to histochemical tests, glycogen in the retina de- creased during the stimulation and then increased after the stimulation (Matsumoto and Ishino, 1957) The lacrimal gland and Harder’s gland showed features of intra-

cellular production of secretion on stimulation (Kurotsu et al., 1956b) On the other hand, when the lateral hypothalamic nucleus was stimulated, enophthalmos and

miosis were observed (Ban et al., 1951a, b) At the same time, the intraocular pressure

fell slightly after the drop in the blood pressure, even when the common carotid ar- tery was ligated Thus the fall in the intraocular pressure was presumed to be due partly to a decrease in blood pressure and partly to extension of Miiller’s muscles

as well as pupillary constriction (Nagai et al., 1951) Glycogen in the retina seemed

to be increased, according to histochemical examination (Matsumoto and Ishino, 1957) After lateral hypothalamic stimulation, the lacrimal and Harder’s glands

showed features of secretion cytologically (Kurotsu et al., 1956b)

( I V ) Digestive system

In 1943, Fujita (1943; Fujita and Amano, 1943) in our laboratory reported that lateral hypothalamic stimulation in rabbits produced stomach bleeding which was prevented by bilateral vagotomies or administration of atropin before the stimu- lation In coeliac gangliectomized rabbits, marked stomach bleeding or ulcer (Fig 3) occurred after the same stimulation These phenomena were presumed to be produced

by rupture of the blood capillaries due to the high pressure of arterial blood caused

by venal constriction induced by muscular contraction of the gastric body Lateral hypothalamic stimulation increased the intragastrointestinal pressure and motility,

and produced hemorrhage in the gastric mucosa (Kurotsu et al., 1951c, 1952~) The impulse from the lateral hypothalamic nucleus to the stomach and small intestine was transmitted chiefly through the vagi, but the rectum had no relation with the vagi and

SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M 7

coeliac ganglia, because their extirpation did not modify the responses of the rectum

to lateral hypothalamicstimulation (Kurotsu el a/., 1951c, 1952~) The same stimula-

tion increased intraesophageal pressure (Kurotsu et a/., 1953a), but it decreased the motilities of the cardia and pylorus (Takeda and Ito, 1951)

According to Fujita (1943; Fujita and Amano, 1943), the stimulation ofthe medial hypothalamic area in rabbits produced small dotted bleeding in the stomach in 50%

Fig 3 Stomach ulcer induced by lateral hypothalamic stimulation in the coeliac gangliectomized

rabbit (Kurotsu e/ a/., 1951~)

which was prevented by extirpation of the coeliac ganglia but not influenced by bilateral vagotomies or administration of atropine Medial hypothalamic stimulation decreased the intragastrointestinal pressure and obliterated their motilities completely

through both coeliac ganglia (Kurotsu et a/., 195lc, 1952~) Intraesophageal pressure also showed a slight fall (Kurotsu et af., 1953a) but the cardiac and pyloric motilities

were increased by the same stimulation (Takeda and Ito, 1951) We sometimes observed minor bleeding or ulcers in the cardia or pylorusafter medial hypothalamic stimulation The complete obliteration of the rectal motility induced by the same stimulation had no relation with the coeliac ganglia

The sexual cycle in female rabbits markedly affected all responses to the hypothalam-

ic stimulation especially in the gastrointestinal system as well as genital organs (Kurotsu et a / , 1952b)

The alveolar cells of the parotid and submandibular glands in rabbits (Kurotsu

et a / , 1951 b), and the chief and parietal cells of the fundus gland (Amano, 1947) and

the surface epithelium cells in cats (Kurotsu eta/., 1954a), as well as the duodenal gland cells (Kurotsu et al., 1958a) and the acinus cells of the pancreas (Kurotsu, 1954) in

8 T B A N

rabbits, after lateral hypothalamic stimulation, all had features observable cytologi- cally in which they seemed to discharge their intracellular contents to the ducts, whereas after medial hypothalamic stimulation, they showed features in which they seemed to produce secretory substances in the cells The epithelium cells of the submandibular duct discharged supranuclear vacuoles to the duct and large vacuoles along the basic membrane to the intercellular space outside the duct after medial hypothalamic stimulation The former was taken to be the sympathetic salivary fluid and the latter to be an endocrine substance of the salivary gland On the other hand, the surface epithelium cells of the stomach also showed features in which they dis- charged the contents to the lamina propria after lateral hypothalamic stimulation This is likely to be an endocrine function of the gastric mucous membrane

( V ) Genital organs and ejection of milk

The electrical stimulation of the medial hypothalamic area, medial preoptic area or the midbrain central gray substance produced ovulation in mature rabbits (Kurotsu

et a/., 1950) In rabbits whose ovarial nerve or internal carotid nerves, including the superior cervical ganglia, were extirpated, or whose ovary was autotransplanted in the anterior chamber of the eye, follicular hematomata were also produced by the stimu- lation In pregnant or pseudopregnant rabbits as well as hypophysectomized rabbits (Kurotsu et al., 1952a), ovulation could not be observed after the same stimulation From these results we conclude that the gonadotropic stimulus in the hypothalamus was transmitted to the anterior lobe of the pituitary gland through the pituitary stalk

On the other hand, the lateral hypothalamic stimulation inhibited ovulation induced

by medial hypothalamic stimulation, but it could not prevent ovulation produced

by the injection of urine of pregnant women (Kurotsu e t a / , 1950)

The motility and tone of the uterus were increased by medial hypothalamic stimu-

lation, but these reactions varied according to the sexual cycle (Kurotsu e f a/., 1952b)

Three days after castration, spontaneous motility and reactions of the uterus to the hypothalamic stimulation disappeared, but they reappeared on administration of the follicular hormone Spontaneous motility of the uterus and its reactions to sympathet-

ic stimulation became evident in accord with disappearance of the corpora luteal function in pregnant or pseudopregnant rabbits The tone of the uterus was increased, while the frequency and amplitude of the uterine motility were decreased

by the lateral hypothalamic stimulation in normal mature rabbits (Kurotsu et a/.,

1952b)

Regarding the influence of the hypothalamus upon pregnancy in the rabbit (Tsutsui

et al., 1957), ventromedial hypothalamic stimulation at the last stage of pregnancy often caused delivery, but lateral hypothalamic stimulation had no effect on the delivery

or the puerperium The gestation was prolonged by bilateral destruction of the medial hypothalamic areas during pregnancy After bilateral destruction of the lateral hypo- thalamic areas at various stages of pregnancy, different changes were found as follow Destruction on the seventh day of pregnancy caused abortion without placentation Destruction on the 14th day of pregnancy produced necrotized uterine contents which

SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M 9

were absorbed or discharged later and promoted atrophy of the corpus luteum gravi-

darum Destruction on the 25th day of pregnancy caused premature labor However, even with this destruction of the lateral hypothalamic nuclei pregnancy safely could

be maintained by administration of more than 40 mg of progesterone, but not by administration of follicular hormone

Medial hypothalamic stimulation in rabbits on the 3rd postpartum day increased

the ejection of milk (Shimizu et al., 1956; Ban et al., 1958), t o the maximum value of

38 mm3 in a glass cannula of 0.8 mm in diameter inserted in a teat duct, which was almost equal to the value induced by 100 mU of oxytocin The same stimuldtion could not produce any ejection of milk in hypophysectomized rabbits, but it showed

a vigorous ejection in thyroidectomized rabbits It is probable that the medial hypo- thalamic stimulation induces milk ejection by the posterior pituitary hormone via the hypothalamohypophysial tract Stimulation of the lateral hypothalamic nucleus

or the periventricular stratum did not increase milk ejection Bilateral destruction of the ventromedial hypothalamic nuclei of rabbits at postpartum caused reduction of the mammary gland cells as early as the 4th day after the destruction and often the sucklings died Even though they could continue to live, their growth was not satis- factory In these cases, milk secretion could be maintained by administration of more

than 5 R.U of the anterior pituitary hormone (Hypophorin) after the bilateral destruc- tion of the medial hypothalamic areas On the other hand, bilateral destruction of the lateral hypothalamic nuclei maintained milk secretion well and all sucklings showed satisfactory growth

Histological changes in the testis and prostate in mature rabbits induced by ventro-

medial hypothalamic stimulation were as follow (Nakamura et al., 1962) In the semi- niferous tubules, marked dilatation of the lumen, discharge of spermium and reduc- tion of fat granules were observed, while in the interstitial cells, diminution of the cell body, disappearance of vacuoles and reduction of fat granules were observed

At the same time, the prostate showed marked secretory activity similar to that in apocrine glands Accordingly, Leydig’s interstitial cell as well as the prostate were presumed to secrete on medial hypothalamic stimulation

On the other hand, lateral hypothalamic stimulation induced contraction of the lumen, acceleration of spermatogenesis and increase of fat granules in the seminiferous tubules, while in the interstitial cells, swelling of the cell body and increase of vacuoles and fat granules were observed after the stimulation In the prostate also fat granules were increased

( V I ) Neurosecretion

In 1940, Kurotsu and Kondo reported the seasonal changes of neurosecretion, an increase in summer and a decrease in winter in the hypothalamus of the toad In rabbits, some neurosecretory granules were seen which were transmitted partly to the intracellular spaces of the pars tuberalis and the frontal part of the pars distalis via primary capillaries or the perivascular spaces or the hypophysial portal system, and partly to the intercellular spaces in the caudal part of the pars distalis via the poste-

- - - c

,

PI

PD

Fig 4 Hypothalamohypophysial neurosecretory pathways in the rabbit hypophysis (sagittal section)

HS, hypophysial stalk; NR, posterior lobe; PD, anterior lobe; PI, intermediate lobe; PT, pars

tuberalis; a, b and c, descending course of neurosecretory granules to the anterior lobe

retained in the axons (Shimazu et at., 1954) By irradiating rat heads with X-rays, neu-

rosecretory granules in the hypothalamus and hypophysis were increased in one or

two days (Tanimura, 1957)

During pregnancy, parturition and post-partum periods in rabbits, neurosecretory

material showed some changes as follow (Tanimura et at., 1960) Early in the preg- nancy the supraoptic and paraventricular nuclei contained many vacuoles and com- paratively few granules At mid-pregnancy, granules increased markedly in the nuclei, infundibular area and neurohypophysis Granules and droplets also invaded the intercellular spaces of the pars intermedia Immediately before parturition neuro- secretory granules decreased rapidly, and Herring-bodies of the neurohypophysis became vacuolated and irregularly shaped This decrease in neurosecretory material continued to the 7th day post-partum In rabbits which were allowed to suckle their young, neurosecretory granules in the hypothalamohypophysial system tended to increase from the 7th day

SE PTO- PR EO PTI C O - H Y P O T H A L A M I C SYSTEM 1 1

( VII) Urinary system

Ventromedial hypothalamic stimulation in normal rabbits anesthetized with urethane showed a marked diminution in renal volume recorded by an oncometer, followed

by a decreasing number of urine drops, and then marked dilatation of the kidney followed almost simultaneously by an increase in urine drops The same stimulation

in bilaterally splanchnicotomized, hypophysectomized or bilaterally adrenalec- tomized rabbits showed a marked decrease in renal volume, but it recovered without

exceeding the initial renal volume (Hirahara et al., 1953) On the other hand, lateral hypothalamic stimulatjon in normal rabbits showed an increase in renal volume followed by an increasing number of urine drops and then reduction of the renal

volume with diminution of urine drops In biIaterally splanchnicotomized, hypo-

physectomized or bilaterally adrenalectomized rabbits, the renal volume was increased

by the stimulation and recovered to the initial volume after the stimulation without any rebound response The number of urine drops in the former 2 groups was almost normal, but in the adrenalectomized rabbits, no urine drop was observed in the course of our experiments (Hirahara ef al., 1953)

The histological changes in the kidney after hypothalamic stimulation were as follow During the ventromedial hypothalamic stimulation, the majority of the renal corpuscles and the intracapsular spaces became smaller, and the permeability of the blood vessels decreased simultaneously Consequently the filtration activity was dimin- ished At the same time, the proximal convolution cells showed changes in their fine structures, in which the cells were presumed to absorb the filtrate from the lumina during the stimulation During lateral hypothalamic stimulation, the renal corpuscles became much larger, and the intracapsular spaces dilated strikingly up to 18 /.I in diameter The glomerular capillaries also dilated from 9 to I 1 p in diameter These features were taken to indicate promoted glomerular filtration, while the proximal con- volution cells showed changes in their finer structures, in which thecells were presumed

to discharge the absorbed substance into the blood vessels (Kurotsu et al., 1954b) These results show that the changes in the renal volume took place in parallel with the changes in dimensions of the renal corpuscles and the inner diameter of the urini- ferous tubules

In bilaterally adrenalectomized rabbits (Kurotsu et al., 1955b), the renal corpuscles seemed to decrease in size slightly during ventromedial hypothalamic stimulation, and then they gradually enlarged after the stimulation; whereas during the lateral hypothalamic stimulation they enlarged with dilated intracapsular spaces, and after the stimulation they gradually returned to their initial size The proximal convolution cells always showed features which suggested that they absorbed the filtrate and then discharged it to the blood stream It was also probable in these adrenalectomized rabbits that the changes in the renal volume were mainly due to changes in size of

the renal corpuscles and the other blood vessels The anuria following bilateral adrenalectomy, which continued even at the stage of the hypothalamic stimulation, was thought to be mainly due to the intensive fall of the general blood pressure and the absorption of the proximal convolution cells

12 T B A N

According to Yokoyama (Yokoyama et al., 1960) who studied urinary bladder

responses to the electrical stimulation of the hypothalamus in male mature rabbits

anesthetized with small doses of urethane (0.5-0.7 g per kg in body weight), the stimu-

lation of the medial hypothalamic area or the mamillary peduncle produced relaxation response only or relaxation response after an initial contraction, whereas stimulation

of the lateral hypothalamic area, mamillotegmental tract or the periventricular stra- tum produced a prompt, vigorous and sustained contraction as well as miosis and somatic urinary movement Stimulation of the boundary of the three zones showed almost biphasic responses

(VIII) Respiratory system

In 1951,Ban et al (1951a) reported hemorrhage of the lung induced by ventromedial hypothalamic stimulation in rabbits (Fig 5 ) Accordingly the effects of hypothalamic stimulation on the lung were studied histologically in rabbits (Kurotsu et al., 1956a)

Fig 5 Hemorrhage of the lung induced by the stimulation of the ventromedial hypothalamic

nucleus in the rabbit

After ventromedial hypothalamic stimulation, the alveolar lumina enlarged, walls thinned and capillaries contracted In 96 % of all cases, many scattered hemorrhages occurred at the beginning of the stimulation This hemorrhage was due to rupture

of the capillaries by an increase of blood pressure Immediately after the stimulation, bronchial and bronchiolar dilatations were observed Goblet cells of the bronchi and bronchioles were also distended, mitochondria increased in number, and then vacuoles began to appear Forty min after the stimulation, vacuoles began to be discharged

On the other hand, after lateral hypothalamic stimulation, narrowing of the alveolar

S E P T O - PR EOPTI C O - H Y P O T H A LAM I C SYSTEM 13

lumina, thickening and loosening of the walls and dilatation of the capillaries were observed Sometimes, leucocytes and emigrated cells were found to be more numerous

in the alveolar sacs Pulmonary hemorrhage occurred in 3 1 % in gross solitary form This hemorrhage was believed to occur through an increase in permeability of blood vessels Pulmonary edema accompanied by congestion was seen in the bleeding area Atelectasis was observed in 40 % Two out of 8 cases showed pneumonia-like features The bronchi constricted into asteroid shape, and the bronchial lumina were covered with mucous secretion Goblet cells were constricted and mucous secretion was observed in both apocrine and ecrine types

Shinoda studied the types of respiratory reactions induced by the hypothalamic stimulation (Shinoda et al., 1958) Electrical stimulation of the various nuclei of the medial hypothalamic area caused respiratory acceleration and also marked level- shifting towards inspiration At the same time, enlargement of the alveoli was per- ceived histologically (Kurotsu et al., 1956a) Strong stimulation caused various types

of panting with periodical gasping Stimulation, if repeated, caused marked con- tinuous acceleration in respiratory activity The effect was greatest after stimulation

of the ventromedial hypothalamic nucleus

On the other hand, electrical stimulation of the lateral hypothalamic nucleus and the periventricular stratum caused level-shifting towards expiration On the whole, weak stimulation gave slight and gradual decrease of respiratory activity (generally, decrease in frequency and amplitude), slightly stronger stimulation caused paroxys- mal hyperpnea with preponderance of expiration, and a strong one produced panting attended by marked inhibition of inspiration, also maintaining the shift towards expira- tion This panting was smaller in amplitude and shallow, extremely rapid and con- vulsive in respiration, with gasping hardly intermingled During these types of respir- ation, deflation of the alveoli of lungs was also perceived histologically (Kurotsu et al.,

I956a) Stimulation, if repeated, induced continuous decrease in respiratory activity This decrease, different from the one seen in the non-narcosis, non-stimulation and untreated, soon (1 5-20 min later) reached the same degree as in natural sleep, but had no such peculiarity of respiratory waves as was seen in natural sleep On stimu- lation of the periventricular stratum, the only peculiarity was that respiration was often made to stop by strong stimulation (Shinoda et at., 1958)

14 T B A N

lation TEAB (tetraethylammoniumbromide) administered to rabbits showed almost the same change in gaseous metabolism as seen in non-anesthetized rabbits Gaseous metabolism was increased by ventromedial hypothalamic stimulation even in thy- roidectomized, unilaterally adrenalectomized or hypophysectomized rabbits, but the increase was less than that in non-operated rabbits The increase in gaseous metabo- lism produced by the same stimulation in bilaterally adrenalectomized rabbits was much less than that of healthy rabbits Bilateral adrenalectomy caused a marked decrease in gaseous metabolism : therefore it was difficult to determine whether the decrease was due to bilateral adrenalectomy only, or partly due to the lateral hypotha- lamic stimulation

( X ) Endocrine glands and some other glands

According to histological and cytological studies on some gland cells induced by the hypothalamic stimulation, ventromedial hypothalamic stimulation in rabbits caused swelling of the cell body by vacuolization, whereas lateral hypothalamic stimulation induced shrinkage of the cell body, and the intercellular space became much dilated

in the medulla of the suprarenal gland (Kurotsu, 1954; Ishida, 1944) The thyroid follicular cells also showed an increase in vacuole and became taller, and the size of the follicle became smaller due to discharge of its contents on ventromedial hypothalamic stimulation, whereas after lateral hypothalamic stimulation, the cells became lower again due to gradual discharge of the vacuole contents to the follicular lumen, and the lumen became larger (Kurotsu, 1954; Fujita, 1947) The cytological changes of the anterior lobe of the hypophysis in rabbits studied by Heidenhain, Mallory and Gomori methods were as follow (Okada, 1954) Lateral hypothalamic stimulation caused accumulation of the secretion in the intercellular spaces Dilatation of the capillaries, dark cytoplasm and obliteration of the fine structure of the cells were observed The cell bodies shrunk and the intercellular space dilated markedly, while the ventromedial hypothalamic stimulation showed constriction of the capillaries and swelling of the cell body due to an increase in vacuoles and mitochondria Concomitantly, the inter- cellular spaces were reduced markedly

cells was induced, and the cell body became larger by vacuole formation after ventromedial hypothalamic stimulation, whereas lateral hypothalamic stimulation caused a de- crease in the number of b cells, and the cell body became smaller by discharging its content Even in bilaterally adrenalectomized rabbits, ventromedial hypothalamic stimulation induced an increase in the number of @ cells whereas lateral hypothalamic stimulation caused a decrease The cytological changes in the gland of the mucous membrane of the maxillary sinus induced by hypothalamic stimulation were as follow (Kato, 1958) After ventromedial hypothalamic stimulation, the serous gland cells

as well as the mucous gland cells showed secretory production, even in bilaterally adrenalectomized rabbits, whereas lateral hypothalamic stimulation produced a secretory discharge, even in bilaterally adrenalectomized rabbits Argentaffine cells (Kubo, 1960) in the epithelium of the digestive tube decreased in number on ventro-

In the pancreatic islets (Kurotsu et al., 1957), an increase in the number of

S E P T 0 - P R E 0 P T 1 C 0 - H Y P O T H A L A M I C S Y S T E M 15

medial hypothalamic stimulation This result was presumed t o be due to a decrease in argentaffinity by liquefaction of the granules

( X I ) Liver metabolism

Yamada ( I 950) reported that the bile capillaries were markedly enlarged with secre-

tory fluid, and in the liver cells granules containing iron decreased after stimulation

of the ventromedial hypothalamic nucleus On the other hand the bile capillaries remained narrow and granules containing iron increased after lateral hypothalamic stimulation Yamada concluded that the medial hypothalamic area might stimulate bile secretion by the liver cells, and the lateral hypothalamic nucleus might produce the secretion and expel the secretory fluid from the liver by narrowing the bile capillaries

in fasted rabbits After ventromedial hypothalamic stimulation, the acid phosphatase reaction increased in the liver cells and the alkaline phosphatase reaction increased markedly in the bile capillaries (Kurotsu et al., 1951a) The latter is believed to have

some relationship to the increase of the secretory fluid in the dilated bile capillaries (Yamada, 1950) in rabbits The gallbladder contracted, the folds of the mucous membrane increased and the secretion of its cells was cytologically promoted by ventromedial hypothalamic stimulation, whereas after lateral hypothalamic stimu- lation in the rabbit, the gallbladder became bigger, the folds of mucous membrane decreased and the ordinary epithelium cells appeared cytologically to absorb water (Matsui et a/., 1961)

In higher animals, certain hepatic enzymes that metabolize amino acids have been shown to be controlled by the hypothalamus (Shimazu, 1962, 1964a,b) Electrical stimulation of the ventromedial hypothalamic nucleus (20 sec stimulation, every 5 min for 18-20 h) in rabbits, resulted in about an 8-fold increase in activity of tryptophan pyrrolase in the liver homogenate; and lateral hypothalamic stimulation by the same method caused about a 5-fold increase in this enzyme activity Knox and Auerbach (1955) found the activity of this enzyme was increased by administration of cortisone,

and we found an increase of about 43 % of corticosteroid in blood after ventromedial

hypothalamic stimulation in rabbits Studies were made t o determine whether the effect of the hypothalamic stimulation on tryptophan pyrrolase was secondary by

causing an increase in adrenal activity Even in bilaterally adrenalectomized rabbits,

a 6-fold increase in enzyme activity over the control was recorded after stimulation

of either the ventromedial hypothalamic nucleus or the lateral hypothalamic nucleus These results indicate that the increase in the level of tryptophan pyrrolase observed after electrical stimulation of the hypothalamus is not a secondary effect of increased adrenal activity, but rather a primary effect of hypothalamic activity

To analyze in detail the induction of tryptophan pyrrolase by hypothalamic stimu- lation, the total amount of apoenzyme and the level of holoenzyme were measured differentially The activity of tryptophan pyrrolase was assayed on the cell sap fraction

of liver homogenate in the presence or absence of excess cofactor Rat liver micro- somes were used as a cofactor preparation Electrical stimulation of either the sympa- thetic or parasympathetic zone of the hypothalamus caused a marked elevation in

16 T B A N

the total amount of apoenzyme The level of holoenzyme was markedly increased after stimulation of the sympathetic zone (the medial hypothalamic area), but was only slightly increased after stimulation of the parasympathetic zone (the lateral hypotha- lamic area) Thus, the ratio of holoenzyme to apoenzyme was changed from 1/3 in normal rabbits to 1/2 and 1/5, respectively, in rabbits stimulated in the sympathetic zone and the parasympathetic zone

The activities of tyrosine transaminase and alanine transaminase (Shimazu, 1964a) were likewise elevated about 2- to 3-fold after electrical stimulation of the sympathetic zone But stimulation of the parasympathetic zone had no influence on these trans- arninases Serine dehydratase was affected by stimulation neither of the sympathetic zone, nor the parasympathetic zone

(XU) Mal$ormation

The influence of electrical stimulation or destruction of the mother’s hypothalamus

on development of her fetus was studied in rabbits, and the results were as follow

(Takakusu et al., 1962) Acute stimulation caused abnormalities chiefly of the central nervous system such as infoldings of the brain and a flexed spinal cord Besides these,

a few cases of herniation of the heart and hypodactyly were found Malformation

of the face was observed in one case whose mother’s ventromedial hypothalamic nucleus had been chronically stimulated during the middle stage of pregnancy In one case, whose mother’s fornix was destroyed unilaterally, syndactyly and oligodac- tyly were obtained A microcephaly (Fig 6) and herniation of the midbrain were produced by destruction of a large part of the hypothalamus and a part of the thalam-

us It was suggested that abnormal proliferation by inhibition of differentiation

Fig 6 Microcephaly induced by destruction of the mother’s hypothalamus in the rabbit

SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M 17

potency might be a factor in the genesis of malformation in the central nervous system The mother’s parasympathetic zone of the hypothalamus was thought to be important for the development of the trabeculae in the adrenal gland and thymus, and the sympathetic zone of the hypothalamus was believed to be necessary for their differen- tiation into parenchymal elements

The effects of electrical stimulation of the hypothalamus on the placenta and uterine vessels were studied in rabbits, and the following results were obtained (Takakusu

et al., 1964) Stimulation of the ventromedial hypothalamic nucleus, which belongs

to the sympathetic zone, produced dilatation of the uterine vein, narrowing of the villi, withdrawal of fetal blood from the villous capillaries, widening of the maternal blood spaces in the labyrinth, some fragmentation of the syncytium, and bleeding in the intermediate layer Stimulation of the lateral hypothalamic nucleus, which is the c-parasympathetic zone, induced little change in the uterine vessels, but resulted in con- tact of the syncytial layers, withdrawal of the maternal blood from the labyrinth and widening of the villi Accordingly, it was suggested that inhibition of oxygen and nutri- ment transport from the maternal blood to the fetal blood produced by changes in the placental circulation induced by the hypothalamic stimulation might be one of the causal mechanisms of malformations induced by maternal hypothalamic stimulation

or destruction The specific changes in the placenta mentioned above are similar to the initial feature of the placental change in the toxemia in pregnancy

( X I I I ) Waking, sleep and emotional behavior

I n 1951 it was reported (Ban et al., 1951b) that electrical stimulation of the ventro- medial hypothalamic nucleus in rabbits elicited the rage reaction, with which ovu-

lation (Kurotsu et al., 1950) occurred in mature female rabbits, while repeated stimu-

lations of the lateral hypothalamic nucleus (c-parasympathetic zone) induced sleep, and that bilateral destruction of the medial hypothalamic areas (b-sympathetic zone) could produce a state of predominance or super-predominance of the parasympathetic tonus, while bilateral destruction of the c-parasympathetic zones could produce a state of predominance or super-predominance of the sympathetic tonus (Fig 7) Accordingly, it was thought that sleep could be induced by the state of balance in which the level of the parasympathetic tonus became a little higher than that of the sympathetic after they had conflicted with one another, and that waking was the state

of balance in which the level of the sympathetic tonus was a little higher than that of the parasympathetic Further, it was reported (Ban et al., 1951 b) that rage or excitation might be produced in the state of super-dominance of the sympathetic, while lethargy

or narcolepsy might be induced in the state of super-dominance of the parasympa- thetic tonus These changes could be produced with hypothalamic emotion It is considered that rage or excitation developing from the waking state belongs to the positive emotional behavior, and that sleep developing from the waking state belongs

to the negative emotional behavior (Ban, 1964a) Electroencephalographic changes

(Ishizuka et al., 1954) in the hypothalamus in oestrus, anoestrus, pregnant and non-

pregnant rabbits also supported these hypotheses on the balance mechanisms

18 T B A N

Fig 7 Left above: rage reaction induced by stimulation of the ventromedial hypothalamic nucleus, and left below: sedate state induced by bilateral destruction of the same nuclei Right above: ex- citatory state induced by bilateral destruction of the lateral hypothalamic nuclei, and right below: sedate state induced by bilateral destruction of the ventromedial hypothalamic nuclei

Recently, Sano (1962) succeeded in obtaining most marked sedative effects in pa- tients with violent behavior by his postero-medial hypothalamotomy, namely by bilateral destruction of our b-sympathetic zones; and he also demonstrated our a- parasympathetic, b-sympathetic and c-parasympathetic zones in the hypothalamus of patients by electrical stimulation before his hypothalamotomy The sites of electrodes were decided with the help of X-ray photographs The EEG changes after the postero- medial hypothalamotomy were almost the same as those in the hypothalamotomized

rabbits which had been described by Sawyer et al (1961) It is interesting that o u r results with rabbits or cats are very similar to Sano’s results with man

( X I V ) Conditioned reflex induced by hypothalamic stimulation

We produced a conditioned reflex in the pupil, respiration, gastric motility and the general condition of rabbits by using electrical stimulation of the hypothalamus as unconditioned stimulus and sound as conditioned stimulus (Ban and Shinoda, 1956)

S E P T O - P R E O P T I C O - H Y P O T H A L A M l C S Y S T E M 19

Two forms of the conditioned reflex, namely the sympathetic conditioned reflex and

the parasympathetic conditioned reflex, were constructed by using separate reinforce-

ment of electrical stimulation of the ventromedial hypothalamic nucleus or the lateral

hypothalamic nucleus, each as the unconditioned stimulus The reinforcement was

given 20 times or so a day at intervals of 5 min In the sympathetic conditioned reflex,

mydriasis, exophthalmos, acceleration of respiration and inhibition of the stomach

Fig 8 (a) Conditioned EEG response in synipathetic conditioned reflex CS, conditioned stiniulation

(2 c/s) 5th day of the experiment (b) Conditioned EEG response in parasympathetic conditioned

reflex The gain from the lateral hypothalamic nucleus alone is recorded as well as a quarter of the

other three, for its response is extremely peculiar high voltage slow waves 5th day of the experiment

(c) The same animal that showed the responsive change of (b) showed differential inhibition under

the conditioned stimulation of a different rhythm (I c/s)

20 T B A N

movement (not easily produced) were induced by sound from the 3rd or 4th day of the reinforcement On the 7th or 8th day the response became maximal In the para- sympathetic conditioned reflex, miosis (not easily produced), enophthalmos, depres- sion of respiration and acceleration of stomach movements were all observed to be induced by sound

When the sympathetic conditioned reflex was gradually built up, sham-rage could

be induced by such a weak stimulation as could not ordinarily induce the sham-rage,

if it had only been applied to the medial hypothalamic area as an unconditioned stimu- lation that was adopted in the course of reinforcement Another remarkable obser- vation was that, if any kind of unconditioned reflex was combined in the course of reinforcement, there occurred a special change in the size of the effect of the condition-

ed reflex of the organ influenced by that unconditioned reflex For example, mydriasis was more easily produced by reinforcement in a dark room than in a lighted room Consequently it may be accepted that the hypothalamus has a dynamic adaptability

in its functioning

In conditioned EEG responses (Ban and Shinoda, 1960) which were established by electrical stimulation of the hypothalamus in rabbits as unconditioned stimulation, frequency-specific slow waves appeared conspicuously in the hypothalamus In the sympathetic conditioning, the frequency-specific harmonized slow waves carried super- imposed high frequency fast waves and the voltage might be slightly reduced (gener- alized desynchronization)

In the parasympathetic conditioning, on the other hand, high voltage slow waves

of 200-300 pV appeared without fast wave activity Both sympathetic and parasympa-

thetic conditioning established generalization, differentiation and extinction which were confirmed in the EEG responses (Fig 8)

An increase in the blood sugar level and the leucocyte count was observed in the sympathetic conditioned reflex which was formed by using the electrical stimulation

of the ventromedial hypothalamic nucleus as unconditioned stimulus (Ban and Shi- noda, 1961) On the other hand, a decrease in the blood sugar level and the leucocyte count was observed in the parasympathetic conditioned reflex which was built up through the electrical stimulation of the lateral hypothalamic nucleus as unconditioned stimulus From these results, we made it clear that the hypothalamic conditioning was also possible in the interoceptive reaction

F U N C T I O N O F T H E P R E O P T I C A N D S E P T A L A R E A S

The preoptic area belongs to the telencephalon and is closely related to the hypo- thalamus morphologically (Ban, 1963, 1964b) and functionally The boundary between the hypothalamus and the preoptic area is not distinct The preoptic area is divided into 3 cell groups, i.e., the lateral preoptic area, the medial preoptic area and the preoptic periventricular stratum which is in contact with the ependymal layer of the third ventricle (Fig 1) But their boundaries are not clear The lateral preoptic area, including the nucleus preopticus magnocellularis, is occupied chiefly by the medial fore- brain bundle and the interstitial nuclei of the bundle scattering in this area The medial

SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M 21

preoptic area is divided into the pars ventralis and pars dorsalis of the nucleus preop- ticus principalis Rostrally the preoptic area continues to the septal region The stria terminalis originating in the amygdala and partly in the periamygdaloid cortex enters the lateral preoptic area and the medial hypothalamic area from dorsal side (Ban and Omukai, 1959), and these connections were certified physiologically by Yuasa et al ( 1959)

Kurotsu et al (1950), Kurotsu et al (1958b), Sakai et af (1958), Shinoda et al

( 1958), Ban et a/ (1958) and Yokoyama et a/ (1 960) reported influences of the electri-

cal stimulation of the preoptic and septal areas on ovulation, blood pressure, gastric motility, respiratory movement, milk ejection and urinary bladder response in rabbits According to these experimental results, the septal region, the preoptic periventric-

Fig 9 Septo-preoptico-hypothalamic system (SPH system) of the rabbit brain Horizontal section through the septal region, preoptic area and hypothalamus Area parasympathica A consisting

of the septal region (SEP), preoptic periventricular stratum (SPVPI, hypothalamic periventricular stratum (SPVH) and medial niamillary nucleus (MM), and area parasympathica C consisting of the septal region, lateral preoptic area (APL) and lateral hypothalamic area (AHL) are marked by oblique lines Areas A and C unite in the septal region The medial preoptic area (APM), medial hypothalamic area (AHM) and lateral mamillary nucleus (ML) belong t o area sympathica B

AH, anterior hypothalamic nucleus; AHIP, anterior continuation of the hippocampus; BOLF, bulbus olfactorius; CAU, caudate nucleus; CE, external capsule; CI, internal capsule; DM, dorso- medial hypothalamic nucleus; F, fornix; HIP, hippocampus; PH, posterior hypothalamic nucleus;

PC, cerebral peduncle; PCMS, precommissural portion of the septum; PRM, premamillary nucleus;

PUT, putamen; VM, ventromedial hypothalamic nucleus

22 T B A N

ular stratum and the lateral preoptic area, including the medial forebrain bundle, showed parasympathetic reactions, and the medial preoptic area showed sympathetic reactions In accord with these findings, such preopticareas belonging to the telenceph-

Fig 10 Schematic summary of the courses and terminations of the medial forebrain bundle (MFB)

and A-group of fibers The small black squares show the site of the lesion

(A), A-group of fibers: ACA, anterior limb of the anterior commissure; AD, anterodorsal thalamic nucleus; AH, anterior hypothalamic nucleus; AHIP, anterior continuation of the hippocampus; AHM, medial hypothalamic area; AM, anteromedial thalamic nucleus; APL, lateral preoptic area; APM, medial preoptic area; AV, anteroventral thalamic nucleus; BOLF, olfactory bulb; (C), C-group

of fibers; CC, corpus callosum: D, nucleus of Darkschewitsch; EW, nucleus of Edinger-Westphal; HIP, hippocampus; HL, lateral habenular nucleus; H M , medial habenular nucleus; IS, interstitial nucleus of Cajal; LH, lateral hypothalamic nucleus; LT, lateral thalamic nucleus; MD, mediodorsal thalamic nucleus; ML, lateral mamillary nucleus; MM, medial mamillary nucleus; OA(P), pars posterior of the anterior olfactory nucleus; PCMS, precommissural portion of the septum; PT, pretectal nucleus; PTAE, parataenial nucleus; PVA, anterior paraventricular nucleus; RT, thalamic reticular nucleus; SGC, central gray substance; SH, septohippocampal nucleus; SPL lateral septal nucleus; SPM, medial septal nucleus; SPV, preoptic and hypothalamic periventricular stratum; STLL, stria longitudinalis lateralis; STLM, stria longitudinalis medialis; STM, stria medullaris;

TD, dorsal tegmental nucleus of Gudden; TOL, lateral olfactory tract; TUBO, olfactory tubercle;

111, oculomotor nucleus; IV, trochlear nucleus; VI, abducens nucleus

SEPTO-PREOPTICO-HYPOTHALAMIC SYSTEM 23

alon and locating rostrally to the hypothalamus are thought to be continuations

of 3 zones of the hypothalamus Namely, the medial preoptic area is a continuation

of the medial hypothalamic area (b-sympathetic zone), and the lateral preoptic area

is a continuation of the lateral hypothalamic area (c-parasympathetic zone) The pre- optic periventricular stratum is a continuation of the hypothalamic periventricular stratum (a-parasympathetic zone) And rostrally, the preoptic periventricular stratum and the lateral preoptic area are thought to be united with each other at the septal region

From the functional point of view, the septal, preoptic and hypothalamic areas can

be united into one system named the septo-preoptico-hypothdamic system or the SPH- system (Ban, 1963, 1964b), which can be divided into 3 areas longitudinally, namely

( I ) area parasympathica A or area A consisting of the septal region and the preoptic and hypothalamic periventricular layers, (2) area symparhica B or area B consisting

of the medial preoptic area and the medial hypothalamic area, and (3) area para- sympathica C or area C consisting of the septal region, the lateral preoptic area and the lateral hypothalamic area (Fig 9)

FIBER C O N N E C T I O N S IN T H E SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M

( I ) A-group of Jibers (tractus hypothalamicus periventricularis)

In our Marchi’s sections a few fine fibers from the lateral part of the septum pelluci- dum occupy the medial part of the diagonal band of Broca, proceed caudad in the periventricular stratum of the third ventricle wall, decrease in number and terminate

in the subependymal layer of the rostral part of the cerebral aqueduct On the way, some fibers enter the pars medianus of the medial mamillary nucleus These fine fibers

belong to our A-group of Jibers A few fine fibers, occupying the medial part of the

tract, originate in the medial forebrain bundle which belongs to our C-group offibers

and terminate in the subependymal layer of the cerebral aqueduct bilaterally (Fig 10)

So a part of the C-group of fibers joins the A-group of fibers at the rostral border of the midbrain Megawa (1960) recognized parasympathetic reactions by electrical stimulation of the subependymal layer of the midbrain central gray substance at the level of the superior colliculus

Ascending fibers of our A-group of fibers proceed in the periventricular stratum of the third ventricle wall to the level of the anterior hypothalamus, and on the way, ramify to the pars medianus of the medial mamillary nucleus

Masai et al (1953) demonstrated fine degenerated fibers from the lesion in the

cortical areas 6 and 8 to the subependymal layer These fibers are also included in our A-group of fibers: they are shown in Fig 11

( I / ) B-group offibers

The dorsal longitudinal fasciculus, which originates in the medial hypothalamic area and descends through the central gray substance, corresponds to the dorsales Langs-

of the central gray substance (below) These fibers belong to our A-group of fibers

biindel of Schiitz (1 891), which was found in the brain of progressive paralysis Gurdjian (1927) called these fibers the periventricular system of fibers, and divided

the system into the hypothalamic and the thalamic divisions He reported that the hypothalamic division originated in the ventral premamillary nucleus, posterior hypo- thalamic nucleus, ventromedial hypothalamic nucleus and the posterior hypotha- lamic periventricular nucleus; on the other hand the thalamic division was closely related to some cells near the nucleus reuniens Fibers of both divisions could be traced through the central gray substance to the tectum and medulla oblongata Ascending and descending fibers of the fasciculus obtained by us (Zyo et al., 1962)

by the Marchi technique are shown in Figs 12 and 13

( a ) Descending fibers of the hypothalamic component Fibers originating in the

ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, posterior hypothalamic nucleus and the dorsal premamillary nucleus, which all belong to the medial hypothalamic area, run dorsocaudad through the third ventricle wall to the central gray substance of the midbrain The fibers terminate in the central gray sub- stance at the level of the superior colliculus, and partly in the interstitial nucleus of Cajal If lesion exists dorsally to the supramamillary decussation, degenerated fibers being traced dorsocaudad to the central gray substance reach dorsally to the tegmental nucleus of Gudden decreasing in number, and in part, terminate in the pars dorsalis

of this nucleus The fiber-group sends the sympathetic impulses from the medial hypothalamic area (b-sympathetic zone) to the lower autonomic centers Therefore,

we call this fiber-group B-group of fibers

SEPTO-PREOPTICO-HYPOTHALAMIC S Y S T E M 25

Some descending fibers from the ventromedial and the dorsomedial hypothalamic nuclei are traced to the central gray substance contralaterally through the supra- mamillary decussation and terminate dorsally to the oculomotor nucleus (Fig 13)

In all our experiments no degenerated fibers were traced to the oculomotor nucleus, nucleus of Edinger-Westphal, nucleus of Darkschewitsch or the trochlear nucleus

Fig 12 Schematic summary of courses and terminations of the dorsal longitudinal fasciculus (FLD)

The small black round points show site of lesion

AH, anterior hypothalamic nucleus; AL, nucleus dorsalis vagi; AMB, nucleus ambiguus; CA

anterior commissure; CC, corpus callosum; CHOP, optic chiasm; COLI, inferior colliculus; COLS,

superior colliculus; CMT, medial central nucleus; CP, posterior commissure; D, nucleus of Dark-

schewitsch; DM, dorsomedial hypothalamic nucleus; EW, nucleus of Edinger-Westphal; FLD,dorsal

longitudinal fasciculus; HIP, hippocampus; HL, lateral habenularnucleus; HM, medial hypothalamic

nucleus; IC, nucleus intercalatus Staderini; IS, interstitialnucleusof Cajal; IP, interpeduncular nucle-

us; LAM, nucleus laminaris (pars anterior); LI, nucleus of locus incertus; ML, lateral mamillary

nucleus; MM, medial mamillary nucleus; PH, posterior hypothalamic nucleus; PMD, dorsal pre-

mamillary nucleus; PMV, ventral premamillary nucleus; PRH, nucleus prepositus hypoglossi; PVA,

anterior paraventricular nucleus; PVP, posterior paraventricular nucleus; RE, nucleus reuniens; RVM, subnucleus reticularis ventralis medullae oblongatae; SG, nucleus supragenualis; SM, supra-

mamillary nucleus; SOL, nucleus tractus solitarii; STPV, hypothalamic periventricular stratum; TD,

dorsal tegmental nucleus of Gudden; VM, ventromedial hypothalamic nucleus; 111, oculomotor nucleus; IV, trochlear nucleus; VI, abducens nucleus; VII, facial nucleus; VIIIL, VIIIM and VIIIS,

lateral, medial and superior vestibular nuclei ; XII, hypoglossal nucleus

The dorsal longitudinal fasciculus in which central gray substance was destroyed at the level of the superior colliculus, proceeds caudad ventrally to the cerebral aqueduct

as well as the fourth ventricle, and sends fibers to the pars dorsalis of the dorsal teg- mental nucleus of Gudden, the nucleus of locus incertus and the nucleus supragenualis (Meessen and Olszewski, 1949) Some fibers of the fasciculus terminate in the medial and lateral vestibular nuclei (Figs 12 and 13)

The dorsal tegmental nucleus of Gudden is divided into two parts, namely the small celled pars dorsalis and the large celled pars ventralis According to our findings

on their fiber connections, the pars dorsalis is connected with the dorsal longitudinal

26 T B A N

Fig 13 Horizontal aspect of the B-group of fibers including the dorsal longitudinal fasciculus (FLD), hypothalamicotegmental tract (THT), hypothalamiconigral tract (THN) and tegmentohypo- thalamic tract (TTH) Abbreviations are same as in Fig 12 VESI, VESL, VESM and VESS, inferior, lateral, medial and superior vestibular nuclei; XDI nucleus dorsalis vagi TTML shows the lateral

In other cases (Matano et al., 1964) degenerated fibers originating in each part of the vestibular nuclei proceed to the gray substance of the fourth ventricle floor, join the dorsal longitudinal fasciculus and descend laterally to the central canal to reach the rostra1 end of the cervical cord On the way, some of them terminate in the nucleus prepositus hypoglossi and the nucleus intercalatus (Fig 15)

SE P T O - P R E O P T I C O - H Y P O T H A LAM I C SYSTEM 27

3

Fig 14 Schematic summary of the courses and terminations of the mamillary peduncle (PM)

and mamillotegmental tracts observed in our experiments I , tr tegmentomamillaris intermedius;

2, tr tegmentomamillaris medialis; 3, tr tegmentomamillaris lateralis; 3', tr tegmentohypothala- micus; 4, tr hypothalamicotegmentalis; 4, tr hypothalamiconigralis; 5, tr mamillotegmentalis

lateralis: 6, tr mamillotegmentalis medialis; 8, tr tegmentopeduncularis

AHL, lateral hypothalamic area; AHM, medial hypothalamic area; F, fornix; FLM, medial long- itudinal fasciculus; FM, fasciculus retroflexus; IP, interpeduncular nucleus; LM, medial lemniscus;

ML, lateral mamillary nucleus; MM, medial mamillary nucleus; MT, mamillothalamic tract;

PC, cerebral peduncle; PM, mamillary peduncle; PYR, pyramidal tract ; SGC, central gray substance;

SM, supramamillary nucleus; SN, substantia nigra; SPVH, hypothalamic periventricular stratum;

TD, dorsal tegmental nucleus; TV, ventral tegmental nucleus; 111, oculomotor nucleus; IV, trochlear

nucleus

Rcferenrrs