LE JOURNAL CANADIEN DES SCIENCES NEUROLOG1QUES

The Dorsomedial Hypothalamic Nucleus In Autonomic And Neuroendocrine Homeostasis

LEE L. BERNARDIS

SUMMARY: Median eminence and ven­ dorsal and a ventral one. Monoamine- INTRODUCTION tromedial hypothalamus have in the past containing systems approach the DMN The localization of diencephalic been the principal foci of research in from the lateral hypothalamus and the "centers" controlling both extra- neuroendocrine and neurovisceral con­ bulk of these fibers are carried in the pituitary homeostatic functions (i.e. trol mechanisms. The present report medium forebrain bundle from their cells provides an overview of work involving of origin in the brain stem. Studies of the food and water intake) and neuroen­ the dorsomedial hypothalamic nucleus vascular supply indicate that both VMN docrine (i.e. hypothalamo-pituitary) (DMN). This structure is located dorsal and DMN receive their blood supply relationships has revealed consider­ to the ventromedial hypothalamic nuc­ from the internal carotid artery. It has able functional specificity of fairly leus (VMN) and extends antero- been recently demonstrated that the well-defined areas and fiber tracts. posteriorly from the plane of the largest DMN is involved in the control of food Thus, the medial hypothalamus has cross section of the VMN to the plane of intake and possibly water intake as well. been implicated in satiety ("satiety the dorsal premammillary nucleus. Fib­ Discrete lesions in the DMN have center") and the lateral ers from the DMN pass with the periven­ caused hypophagia and hypodipsia, and hypothalamus in feeding ("feeding tricular system and the dorsal longitudi­ implantation of epinephrine and center") (Anand and Brobeck, nal fasciculus of Schiitz and have been norepinephrine in this area has initiated traced to the midbrain tegmentum and eating. Many years ago, electrical stimu­ 1951). The supraoptic and paraven­ reticular formation. Intrahypothalamic lation of this area was reported to cause tricular nuclei of the hypothalamus connections involve intensive networks eating. Although DMN lesions cause have been recognized as the forma­ between DMN, lateral hypothalamic hypodipsia, they do not result in the tion sites of anti-diuretic hormone nucleus (LHN) and VMN. Regarding reduced water/food intake ratios that are (Hild and Zetler, 1953) and of oxyto­ neurotransmitters, recent studies indi­ so characteristic of the VMN syndrome. cin (Olivecrona, 1957), and finally, cate that the DMN receives noradrener­ DMN lesions are also followed by re- the ventromedial hypothalamus has gic innervation along two pathways, a (Please turn to page 57) been demonstrated to be involved in the control of growth hormone (GH) secretion (Bernardis and Frohman, RESUME: Dans le passe, I'eminence catecholaminerigique), vasculaire et 1967; Frohman and Bernardis, mediane et V hypothalamus physiologique (demonstration recente du 1968). ventromedian ont le plus regu I'attention role du NDM dans le controle de des chercheurs. Le present travail a pour I'apport calorique et liquidien; role dans The median eminence (ME) has but de faire une revue de nos connais- le "resetting" du controle autunome been the principal focus of most in­ sances au sujet du noyau hypothalami- central; dans le controle de la LTH et vestigators attention (for reviews see que dorsomedian (NDM), tant du point possiblement du facteur inhibiteur de Knigge, Scott and Weindl, 1972; de vue anatomique (voies et fibres de I'hormone de croissance et enfin role Martini, Motta and Fraschini, 1970; connections) qu'histochimique (impor­ important dans le controle de certains Nalbandov, 1963) since interference tance de I 'innervation mecanismes neurovisceraux). with its structural integrity invari­ ably results in functional disruption of all adenohypophyseal hormone secretion. However, the concept that the hypophysiotrophic princi­ ples — releasing and inhibiting fac­ tors — are formed in the ME has Departments of Surgery and Pathology, State University of New York at Buffalo, Buffalo, New been questioned (Mess, Fraschini, York 14215, U.S.A. Motta and Martini, 1967) and the concept has been advanced that the This review was written and some of the reported studies were conducted while the author was sup­ ME is merely a stopover point from ported by General Medical Sciences Grant GM which the hypophysiotrophic princi­ 15768, National Institutes of Health. ples formed in more distant areas of Reprint requests to Dr. L. L. Bernardis, State the hypothalamus are released into University of New York at Buffalo, 462 Grider St. Buffalo N.Y. 14215 U.S.A. the primary portal plexus. Areas

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beyond the limits of the ME which MedioMedi'ol Strio CorticohypothalamiCorticohypotriolamic exert hypophysiotrophic activity Medullar!* TrocTrodl have been well demonstrated by the definition of the hypophysiotrophic area (HTA) by Halasz and his co­ workers (Halasz, Pupp and Uhlarik, 1962). For the aforementioned reasons l it the majority of neuroendocrine Stria Termina Preoptic studies have been concentrated on Component r Periventricula the basal hypothalamus and the Nucleui, ant. HTA, and little attention has been part. directed toward the dorsal neurons of the hypothalamus. In an attempt to correct this the present review addresses itself to the dorsomedial hypothalamus, in particular the dor­ somedial hypothalamic nucleus (DMN), and represents an attempt to integrate many as yet uncoordi­ nated findings in many subdiscip- Oorsol Supraoptic Commissure, lines into a structural-functional Ventral Part Gestalt view of this diencephalic Hypoth. N. area. Figure 1: View of the rat hypothalamus showing relationship of nuclei and fiber tracts (Modified after Krieg, 1932). ANATOMY, HISTOLOGY The DMN are located dorsal to to the VMN, DMN and LHN in her the influence of fibers from the re­ the ventromedial hypothalamic nuc­ studies in monkeys with thalamic ticular zone of the thalamus. Fibers lei (VMN) and Krieg (1932) disting­ dorsomedial lesions. radiating from — and converging on uishes two subdivisions, the nucleus — the area between the medial lem­ dorsomedialis pars ventralis and The pars dorsalis ... "a poorly niscus and the cerebral peduncle pars dorsalis. The former borders on defined and inconspicuous cell group" . . . extends from the turn dorsally as what Krieg (1932) the VMN, separated by a cell-free has termed submamillothalamic fib­ zone, and is anteriorly and dorsally paraventricular nucleus to the me­ dial margin of the zona incerta and ers. Other fibers turn ventrally as continued with the pars dorsalis of commissura supraoptica dorsalis the nucleus. In its posterior aspect it nucleus reticularis thalami, along a line joining the mamillothalamic pars dorsalis (commissure of is in contact with the nucleus post­ Ganser) and as the fasciculus erior hypothalami. (Figure 1) tract and the fornix (Krieg, 1932). Dorsally the pars dorsalis borders on hypothalamicus. By this term Krieg The fornix column and the com- the nucleus reuniens thalami and the designated certain fibers which turn missura supraoptica dorsalis, pars nucleus centralis thalami while post­ ventrally either ventral or dorsal to dorsalis form the lateral borders. eriorly it fuses with the pars ven­ the fornix and do not decussate. He Axons have been described as pas­ tralis of the DMN. The cells of this noted that they passed medially be­ sing dorsally with the periventricular part of the DMN are indefinite in tween the medial lemniscus and the axons into the periventricular fibers, their connections and the axons pass medial forebrain bundle and became the main bundle of which passes probably with the periventricular lost in the region of the VMN. He through the nucleus (Krieg, 1932). fibers. The constituent cells of both thought that they were intermingled This original work has been con­ pars ventralis and pars dorsalis are with, but in general were caudal to, firmed by recent evidence which is small but the cell nuclei of the pars Ganser's commissure and noted that summarized in Sutin's (1966) re­ ventralis are somewhat larger than they probably synapsed in the view. Periventricular fibers indeed those of the pars dorsalis (Krieg, VMN. Other fibers cross the midline pass from the ventral premamillary 1932). Medially, the DMN borders as commissura interventralis nucleus, posterior periventricular on the ependyma of the third ventri­ thalami. nucleus and the DMN and it is clear cle but its cells do not have the Krieg's (1932) description indi­ that powerful relations exist bet­ intimate contact as found in the ar­ cates that the fiber connections to ween the DMN and the periventricu­ cuate nucleus. and from the DMN were poorly un­ lar system, which is probably its derstood at that time but he sus­ major outflow. It should also be FIBER CONNECTIONS pected that the axons of the DMN noted that Showers (1958) has re­ The nucleus dorsomedialis gener­ probably passed with periventricular ported periventricular degeneration ally is considered as coming under fibers, together with fibers from the

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periventricular, suprachiasmatic, pars dorsalis of the older literature. TV TM ventromedial, arcuate and posterior Similar findings were reported by hypothalamic nuclei. Other efferent Petrovicky (1967). Lesions in the descending fibers have been re­ DMN were followed by degenera­ ported to travel in the dorsal lon­ tion in the vicinity of the third ven­ gitudinal fasciculus of Schiitz (fas­ tricle and could be traced as far as ciculus longitudinalis dorsalis) and the central gray of the midbrain and to extend caudalward to Gudden's the nucleus centralis superior of dorsal segmental nucleus (Ariens Bechterew. Kappers, Huber and Crosby, 1960). The DMN also receives fibers The latter authors assumed a con­ from a lateral direction, the field tinuation of this system, after H2 of Forel (lenticular fasciculus), synapsing in that nucleus, to visceral which passes over the fornix and motor cell groups in the brain stem. thus reaches the DMN. These The fiber flow from the DMN studies in the Macaque brain also through the periventricular system showed that numerous single fibers (Krieg, 1932) has been confirmed by and bundles of fibers pierce the bor­ recent findings. Millhouse (1969) has der tracts between the lateral described that "path neurons" — so hypothalamic zone and the dor- Figure 2: The MFB at the level of the called because of their location in somedial area (Smialowski, 1973). ventromedial hypothalamic nucleus. the pathway of the medial forebrain Intrahypothalamic fiber connec­ Path neuron a, in lateral hypothalamus bundle (MFB, fasciculus medialis (HL), is typical of the neurons located tions involving the DMN have been telencephali) — course with axons along the MFB. Its wide ranging den­ studied by Guillery (1957), who dorsomedially into the periventricu­ dritic tree spreads out into the medial found moderate fiber degeneration lar system. The latter, it should be zone nuclei and internal capsule (IC) through the lateral hypothalamic recalled, is continuous with the dor­ and extends nearly to the pial surface. nucleus and into the diagonal band sal longitudinal fasciculus of Schiitz Neurons in the ventromedial of Broca following lesions in the hypothalamus (HM) such as cell b, and represents a major efferent, de­ DMN. He also noted that fibers from have dendrites reaching into HL. As scending hypothalamic pathway. the zona incerta entered the lateral seen here (and schematically in the top In a more recent description of the hypothalamic area. The latter con­ illustration, cells 1 and 2), there is an hypothalamic fiber system Ban nections will be discussed from a impressive co-mingling of dendrites (1964) indicated that ascending fib­ between lateral hypothalamus (path functional standpoint in the section neurons) and the medial zone nuclei at ers to the DMN had been traced in on food intake. The findings of this level, the ventro medial (HM) and the tracts coming from the mesence­ Matano, Sakai and Ban (1969) are the dorsomedial (HD) hypothalamic phalic gray, which also supply the also relevant. The Japanese workers nuclei M, mammillothalamic tract; paraventricular and posterior noted that the DMN send dendrites TM, midline thalamus; TV, ventral hypothalamic nuclei. Some descend­ into the lateral hypothalamic area, a thalamus. Transverse section, 16 day ing fibers from both VMN and DMN finding that has been substantiated rat, rapid Golgi methods. From Mill- have been traced contralateral^ by Millhouse (1969) who found . . . house, 1969. through the supramamillary decus­ "impressive co-mingling of de­ sation and terminate dorsal to the ndrites between the lateral nucleus oculomotorius. Other de­ hypothalamus (path neurons) and method. He noted that both the core scending fibers have been found to the medial zone nuclei at this level, of the VMN and the cell-poor zone course through the dorsal part of the the ventromedial (HM) and dor- surrounding it were free of degenera­ pedunculus mamillaris to the ventral somedial (HD) hypothalamic nuc­ tion and concluded that "the lateral part of the midbrain tegmentum. lei." hypothalamic projection to the dor­ The above findings have also been Millhouse also noted that collater­ somedial hypothalamus does not confirmed by Johnson (1965) who als of path neurons at the level of the seem to be continued to any signific­ described degenerating fibers after VMN arch over the VMN into the ant extent by a link between the DMN lesions as being traceable to periventricular zone, and along their dorsomedial and ventromedial nuc­ the midbrain tegmentum through course there are additional collater­ lei." Similarly, Eager, Chi and Wolf hypothalamo-tegmental tracts. als which synapse with dendrites of (1971) clearly demonstrated that de­ Other degenerating fibers from the both the VMN and DMN (Mil­ generation after lateral hypothalamic DMN were shown to course caud- lhouse, 1969). This is particularly lesions passes into the DMN. They ally to the midbrain tegmentum as well shown in Figure 2. also noted that their findings of a the dorsal hypothalamo-tegmental Recently, Chi (1970) reported ter­ pathway from the lateral tract and to terminate in the mid­ minal degeneration in the DMN and hypothalamus to the VMN, which brain reticular formation, the nuc­ dorsal hypothalamic area following reciprocates a previously postulated leus mesencephalicus profundus LHN lesions, using the Fink-Heimer VMN-LHN pathway, (Arees and

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Mayer, 1967; Mayer and Arees, ily in the ventro-lateral reticular accumulation of fluorescence in the 1968) lends anatomical support to formation, the ventral part of the lateral hypothalamic area, indicating the concept that the VMN and LHN midline raphe and the lateral part of the likely direction from which areas of the hypothalamus act as the periventricular and central gray monoamine-containing systems ap­ reciprocal centers in the control of matter. In addition, Fuxe (1965) has proach these regions. The identifica­ feeding and possibly other motivated found three small groups of tion of the lateral hypothalamic area behavior. More recently, Eager, Chi catecholamine-containing cells in or as a region from which such fibers and Wolf, (1971) have clearly shown near the hypothalamus. One of these approach the medial hypothalamus that degeneration after lateral lies dorsal to and in the DMN which, supports studies (Anden, Dahl­ hypothalamic lesions passes into the together with the external layer of strom, Fuxe, Larsson, Ohlsen and DMN, and Chi (1970) has reported the ME, contains very high concen­ Ungerstedt, 1966) which demon­ terminal degeneration in the DMN trations of dopamine. In all regions strate that the medial forebrain bun­ following LHN lesions, using the of the rat brain where monoamine- dle carries the bulk of monoamine- Fink-Heimer method, which allows containing cells have been de­ containing fibers from their cell the demonstration of degenerating scribed, they can be visualized in bodies in the brain stem to the axon terminals of fibers of a wide thiocholine-stained material that diencephalon. caliber range. Following lesions of contains small amounts of True The hypothalamus in general and the DMN he found a great deal of Cholinesterase (AChE). Possibly, terminal degeneration in the VMN. the DMN in particular have also these neurons are cholinoceptive. been shown to contain cholinergic Some of the best Golgi studies of More recently, Jonsson, Fuxe and fibers. One of the two the areas under discussion can be Hokfelt (1972) have performed deaf- cholinesterase-containing pathways found in Szentagothai, Flerko, Mess ferentation studies in rats and found (AChE) in the rat forebrain was and Halasz' (1968) book. Particu­ that complete deafferentation pro­ found by Shute and Lewis (1963) to larly noteworthy are the sections in duced an almost complete disap­ arise from the substantia nigra and which dendrites are shown to extend pearance of catecholamine- ventral tegmental area of the mid­ from a single VMN cell onto de­ containing nerve terminals in all brain and to travel through the ndrites and cells in the DMN and parts of the hypothalamic island, ex­ hypothalamus and subthalamus en- laterally into the LHN, indicating a cept the ME. This island, among route to the basal forebrain area. very close link between these zones. other structures, included the DMN. This pathway contains only AChE. The latter, as alluded to above, will No depletion was found in the exter­ Their axons can be traced rostrally enter into our discussion of the in­ nal layer of the ME. The authors to the globus pallidus and the ventral fluence of the DMN on food intake concluded that the hypothalamic part of the reticular thalamic nuc­ control. noradrenergic innervation arises leus. Not only AChE-containing It has been known for some time mainly along two pathways: one cells, but also fibers of passage can that the amygdala connect with the pathway probably enters dorsally be seen in most of the dorsal VMN via the stria terminalis (Gloor, and sends fibers medially into the hypothalamic areas. These data sug­ 1956; Raisman, 1970; Field, 1972). dorsal part of the hypothalamus, in­ gest a strong involvement of both The DMN also receives its nervous nervating the DMN and the paraven­ catecholamines, i.e. dopamine, and supply from the stria. Heimer and tricular nuclei. The other pathway of acetylcholine as transmitters in Nauta (1969) have analyzed the ter­ runs ventrally and sends fibers me­ and to the DMN. minal area of the stria which, as they dially along the ventral surface of the brain to innervate the VMN and also VASCULAR SUPPLY, EPENDYMAL state, is often described as a cell- CONNECTIONS poor zone. They found it contained a probably the internal layer of the ME and part of the periventricular Recent findings have suggested considerable number of neuronal that the hypothalamic neurons con­ perikarya. They noted a large system. It may be deduced from these findings that the DMN receive vey their hypophysiotrophic princi­ number of dendrites radiating into ples not directly into the primary this zone, mostly from the VMN, a dual output: from the first- mentioned, direct pathway and also plexus of the portal system in the but also from the DMN and the ME, but rather via the cerebral spi­ arcuate nuclei. from the second, periventricular system-related pathway. The latter, nal fluid in the third ventricle. From NEUROTRANSMITTERS it will be recalled, is likely involved there, the releasing and inhibiting Studies on the nature of the in impulse transmission from the factors reach the primary portal neurotransmitters subserving im­ DMN (Gurdjian, 1927; Krieg, 1932). plexus and thence the pulse transmission in the adenohypophyseal parenchyma. hypothalamus (Dahlstrom and Fuxe, The origin of monoamine- This view has been strongly sup­ 1964; Anden, Dahlstrom, Fuxe and containing fibers in the rat has re­ ported by Knigge's findings and has Larsson, 1965; Fuxe, 1965) have cently been studied by Smith and been well reviewed (Knigge, Scott demonstrated that momoamine- Fink (1972). Lesions involving the and Weindl, 1972). The transport containing ascending pathways arise VMN, DMN and the paraventricular involves a special type of ependymal from groups of cells located primar­ nuclei were followed by a marked cells, the tanycytes (Horstmann,

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scribed by Brugger influence food intake differently from the classical lateral area, and that more signifi­ cance should be attached to the mediodorsal rather than the lateral hypothalamic area. Recognizing the discrepancy bet­ ween the two localizations, Larsson (1954) reinvestigated the problem, using the unanesthetized sheep and goat as the experimental animals. Hyperphagia was induced by stimu­ lation in the area of the DMN, and it was mostly limited to the period of stimulation. Delgado and Anand's animals, on the other hand, did not Figure 3: Vascular supply of the dorsomedial (DM) and ventromedial (VM) hypo­ increase food intake until the second thalamic nuclei (DM) dorsomedial nucleus, (VM) ventromedial nucleus, (ARC) arcuate nucleus and (IC) internal carotid artery. Modified after Scremin, 1970. postoperative day. The latter au­ thors indicate that the lateral hypothalamic area stimulated in their experiments is crossed by the 1954). These cells leave the soma in rine and autonomic nature could be medial forebrain bundle and fuses the ependymal lining and penetrate provoked in areas away from the caudally with the zona incerta and well into the neuropil, differing principal lesion site by suppressing substantia nigra. The former, it will structurally and chemically from the their vascular supply. Areas falling be recalled, sends fibers into the more familiar cuboidal-columnar into this category are the supraoptic lateral hypothalamic area and bor­ ependymal lining cells. Millhouse nucleus, the anterior dorsolateral ders on the DMN pars dorsalis (Guil- (1971) has recently also shown that, hypothalamus and the posterior dor­ lery, 1957; Matano, Sakai and Ban, proceeding from the dorsal wall to solateral hypothalamus lateral to the 1969). the ventral aspect of the third ven­ DMN and VMN. It appears then tricular wall, the density of the tany- that the VMN and DMN are not Recent studies in the rat on the cytes appears to be greater. Thus, affected by lesions at different sites effect of the DMN on the control of the distribution of these specialized around them. cells is different for the area in the FOOD INTAKE Figure 4: Food intake (hyperphagia, dorsomedial and the ventromedial bulimia), elicited by electrical stimula­ The "classical" hypothalamic hypothalamic nuclei. tion of the dorsal intermediate areas involved in food intake control hypothalamus (Horsley-Clarke coor­ The vascular supply of the DMN have been characterized as the ven­ dinates: F +10.0, H — 4.0, ML 1.5 to has been well described in a recent tromedial "satiety center" and the 2.0). Sagittal section, about 1.5 mm study by Scremin (1970). Fig. 3. lateral hypothalamic "feeding from the midline. The active area Principally, the hypothalamus in the center." (Anand and Brobeck, 1951). (solid circles) is situated between the rat is supplied by vessels originating However, evidence implicating fornix and the mammillothalamic in the internal carotid, the posterior more dorsal ana medial tract, somewhat closer to the latter. communicating and the cerebral ar­ hypothalamic structures which was (AC) anterior commissure, (F) fornix, (TM) tract of Meynert, (CM) mammal- teries, the veins showing a similar published in the early forties by the distrubution. lary body, (VM) ventromedial nuc­ Hess group in Zurich (Brugger, leus, (MT) mammallothalamic tract The author raises an important 1943) is seldom referred to. Ten (MI) massa intermedia, (TO) optic point: the effects of experimental years before Delgado and Anand tract. (From Brugger, 1943, redrawn, lesions in the hypothalamus have (1953) reported that electrical stimu­ Akert, 1961). been assumed to be due to the loss of lation of the lateral hypothalamic nerve cells and nerve fibers within area induced feeding in the cat, the area of the lesion. Based on his Brugger (1943) obtained "ausges- data in the rat's hypothalamus, prochene Fressgier" — a voracious Scremin points out that "the possi­ drive to eat — also in the cat, follow­ bility of the involvement of areas ing electrical stimulation of the area distant to the primary lesion by the between the fornix and the mamil­ destruction of blood vessels crossing lothalamic tract, corresponding to through the lesioned area has not the DMN area. been discussed so far in the papers In an excellent review, Akert dealing with hypothalamic lesions". (1961) pointed out that the medial Thus, disturbances of neuroendoc­ and lateral hypothalamic loci de­

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food intake have yielded results in TABLE 1 keeping with the stimulation studies Parameter Group 1 Group 2 Group 3 of Briigger (1943) and Larsson (1954). Electrolytic lesions primarily Treatment* VMNL DMNL CON destroying the DMN, but impinging N 9 7 8 on the posterior hypothalamus as Body weight well, resulted consistently in change (GM) 152 + 10 68 ±15**** 115±2 hypophagia and hypodipsia. This Body length was first noted in the weanling change (MM) 82 ±7 64±8 107 ±3 female rat (Bernardis, Box and Total food** Stevenson, 1963) and was subse­ intake (Days 1-30) 23 + 1.1 j 1 +| -j**** 19±0.4 quently studied in more detail in Food intake both weanling and adult rats of both (Days 1-6) 14± 1.7 6±1.6*** 18±0.8 sexes. (Bernardis, 1970; Bernardis Food intake and Frohman, 1971; Bernardis, (Days 24-30) 22 ±1.8 11 1.8*** 19 ±1.2 1972a; Bernardis, 1972b). Total water 16±2 4**** 33± 1.7 It is worth recalling that some intake (Days 1-30) 30± 1.9 studies have suggested a sex differ­ Water intake 9 + 1.2** ence in food intake following ven­ (Days 1-6) 21 ±3.9 28± 1.2 tromedial hypothalamic manipula­ Water intake tion (Valenstein, Cox and (Days 24-30) 28 ±4.6 15±3.3* 34 ±1.9 Kakolewski, 1969). It has been Total water/Total noted that hypophagia and reduced Food intake ratio 1.31 ±0.08 1.45 ±0.12 1.69 ±0.09 weight gain occur in both sexes after Carcass fat DMN lesions (weanling - Bernardis (% Wet body weight) 35 ±3.5 12 ±2 5**** 12±0.1 1970, 1972b mature - Bernardis, Carcass water 1972a). (% Wet body weight) 47 ±2.7 65 ± 1.7**** 64 ±0.3 Lean body mass Studies in the author's laboratory (% Wet body weight) 18±0.8 23 +0 7**** 24±0.2 have also shown that DMN lesions disrupt the normal diurnal feeding Total food intake/Lean body mass 1.33 ±0.12 0.50 ±0.02**** 0.82 ±0.02 and weight gain pattern in weanling rats. The DMN rats showed their Lean body mass/Food intake 0.80 ±0.07 2.44 ±0.42*** 1.22 ±0.03 usual hypophagia but distributed their feeding over both dark and light periods of the day. Similar findings Table 1: The table juxtaposes data on food and water intake, ponderal and linear were made for the weanling VMN- growth, and body composition in rats with ventromedial and dorsomedial lesioned rat, thus demonstrating that hypothalamic lesions and sham-operated controls. the area subserving "cycling" of * VMNL — lesions in the ventromedial hypothalamic nuclei feeding and weight gain is rather DMNL — lesions in the dorsomedial hypothalamic nuclei large and covers both VMN and CON — sham-operated controls DMN and perhaps goes beyond ** All food and water intake data are presented in gm/day these hypothalamic loci. *** Mean±S.E.M. The fact that the classical localiza­ Comparisons between Groups 1 and 2, respectively, and Group 3: tion studies on the feeding loci in the p 0.05 hypothalamus found the DMN to be p 0.02 j 0.^1 a silent area (Anand and Brobeck, p 0.001 1951) appears disturbing and might necessitate a reinterpretation. The Comparisons between Groups 1 and 2: p<0.05* principal questions arising from the p<0.02** new findings are: 1) does an area p<0.01*** thus far unresponsive to manipula­ p<0.001**** From Bernardis, 1970. tion by lesioning technique exert the described hypophagic effect on its own, i.e. independent of lateral hypothalamus suggests that DMN called that Guillery (1957) has re­ hypothalamic area involvement, or lesions, in addition to destroying the ported fiber degeneration after DMN 2) does the DMN syndrome repres­ DMN proper, injure neuronal cir­ lesions through the lateral ent an attenuated, lateral cuits originating in the DMN and hypothalamic area and into the hypothalamic syndrome? Considera­ terminating in the lateral diagonal band of Broca, and that tion of the circuitry in this part of the hypothalamic area. It should be re­ zona incerta fibers enter the lateral

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critical analysis of the fiber tracts that involve the DMN and its im­ mediate neuronal neighbors, princi­ pally the VMN and the lateral hypothalamic nuclei, and the possi­ ble interrelationship between the DMN and both the lateral hypothalamic area and the zona in­ certa (Gurdjian, 1927; Krieg, 1932; Ariens Kappers, Huber and Corsby, 1936; Guillery, 1957; Ban, 1964; Arees and Mayer, 1967; Mayer and Arees, 1968; Szentagothai, Flerko, Mess and Halasz, 1968; Heimer and Nauta, 1969; Millhouse, 1969; Christ, 1969). Nevertheless, the pos­ sibility cannot be excluded that con­ nections between the VMN and DMN might play a role in normal food intake and in the hypophagia that follows DMN lesions. These connections appear to play a role in Figure 5: Localization of implant placements against the background of the DeGroot the relationship between the VMN (1959) coordinate system of the rat brain. Filled circles indicate consistently good and the lateral hypothalamic area on effects of both adrenergic and cholinergic stimulation, white stars inside filled circles one hand and the DMN and the indicate consistently excellent effects of both adrenergic and cholinergic effects; lateral hypothalamic area on the black stars represent predominantly adrenergic placements. Black triangles indicate other (Arees and Mayer, 1967; negative placements. (V) third ventricle, (ARH) arcuate nucleus, (VMH) ventrome­ dial nucleus, (MFB) medial forebrain bundle, (LHA) lateral hypothalamic area, Mayer and Arees, 1968) (See also (DMN) dorsomedial hypothalamic nucleus, (OT) optic tract, (ZI) zona incerta, (RE) Eager, 1971 and Chi, 1970; Chi and nucleus reuniens thalamic, (RH) thalamic rhomboideus nucleus, (MD) thalamic Wolf, 1971). Perhaps the most im­ mediodorsal nucleus, (AM) thalamic anteromedial nucleus, (VA) thalamic ventral portant papers relevant to the or­ nucleus pars anterior, (VE) ventral thalamic nucleus, (MT) mammillothalamic tract, ganization of the medial (EP) entopeduncular nucleus, (GE) thalamic gelatinosus nucleus, (PH) posterior hypothalamus have been published hypothalamic nucleus, (VM) ventral thalamic nucleus, pars medialis, (PC) cerebral recently by Millhouse (1973a, peduncle, (PMV) ventral premammary nucleus, (LM) medial lemniscus. From 1973b). Resting on evidence ob­ Grossman, 1962. tained by Golgi studies, they relate well with the 1969 paper on the lat­ eral hypothalamus and show the var­ hypothalamic area. Undoubtedly, cholinergic substances (acetyl­ ious interdigitations of synaptic pro­ the zona incerta is also injured by choline and carbachol) induced cesses between lateral, ventrome­ even precisely placed DMN lesions. drinking in the same loci in the same dial, periventricular and dorsome­ This might explain why, following animals. He pointed out . . . "posi­ dial hypothalamic zones. The DMN injury, food intake is pro­ tive points in the dorsal portion of studies indicate that VMN dendrites foundly decreased but not entirely this distribution seem to be concen­ are long and branch infrequently, abolished. The latter change, trated closer to the midline . . .", i.e. and that the dendritic trees of the aphagia, is a consequence of the not located in the classical lateral VMN cells do not show a particular lateral hypothalamic syndrome. hypothalamic feeding area. orientation. The trees of a single (Anand and Brobeck, 1951; Bernar- An additional point in distinguish­ neuron stretch out across the dor- dis and Frohman, 1970; Teitelbaum ing between the lateral and the dor­ soventral and mediolateral aspect of and Epstein, 1962). somedial syndrome is the need for the VMN, and many of the dendrites The Bernardis data are also re­ tube feeding in the rat with lateral protruding through and beyond the concilable with the findings by hypothalamic lesions during the first capsule of the VMN can be followed Grossman (1962) in which he de­ few postoperative days. Rats with into the lateral hypothalamus, the monstrated that placement of DMN lesions, whether weanling or DMN, and to the ventral pial sur­ epinephrine and norepinephrine in mature, do not require tube feeding face. Medial axons from both VMN an area between the fornix and the at any time after the placement of and DMN extend into the ventral mamillothalamic tract — the the lesions. and perhaps dorsal lateral "Briigger area" — and lateral and Undoubtedly, consideration of the hypothalamic area. From dorsal to the VMN induced feeding role of the DMN in the control of Millhouse's latest study there is no in satiated rats.Implantation of food intake will have to include a direct evidence that medial axons

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actually synapse on lateral To this must be added the data by position (Bernardis, Box and hypothalamic neurons. Grossman (1962) on the initiation of Stevenson, 1963; Bernardis, 1970; The interrelationship between the drinking in satiated rats by the im­ Bernardis and Frohman, 1970; Ber­ DMN and the lateral hypothalamic plantation of cholinergic substances nardis, 1972a; Bernardis, 1972b). area and between the DMN and the into the DMN. As with food intake, Unless DMN lesions affect food in­ VMN in mature rats alluded to the question must be asked as to take and activity simultaneously it above is of interest in the light of whether the observed effect on could be speculated that the latter is DeGroot's findings (1967). He has water intake might not be related to an adjustment to the former to spare reported that placement of VMN le­ injury to connecting and interdigitat- calories for anabolic processes. sions followed by lateral ing circuits of the "thirst center" in Hypoactivity has also been de­ hypothalamic lesions resulted in re­ the lateral hypothalamic area and its scribed after the destruction of me­ duced food intake and weight gain. related neurons. It is especially dial and lateral hypothalamic areas When the lateral hypothalamic le­ noteworthy that Millhouse has re­ by lesions larger than the ones in the sions were placed prior to the VMN cently stated (1973b) that "the axons Bernardis studies (Gladfelter and lesions, both food intake and weight of the dorsomedial hypothalamic Brobeck, 1962). However, destruc­ gain remained low (1967). Recent nucleus might be significant in integ­ tion of the mamillothalamic tract, experiments in weanling rats bearing rating eating and drinking be­ the medial forebrain bundle, the for­ double lesions show that DMN le­ havior." nix and the periventricular area sions had an attenuating effect on elsewhere in the hypothalamus did LOCOMOTOR ACTIVITY not cause a decrease in locomotor food intake and weight gain only The extensive analyses by Richter when they had been placed prior to activity. The authors suggested that (1927, 1952, 1967) of biological impulses from these areas leave the the VMN lesions. (Bernardis, rhythms and spontaneous activity Chlouverakis, Schnatz and hypothalamus either by a very dif­ patterns have shown that a wide fuse pathway, or by a dorsal or lat­ Frohman, 1974). The latter data also variety of endocrine manipulations show that destruction of the lateral eral route. It is conceivable that the including hypophysectomy fail to af­ lesions in the Bernardis studies in­ hypothalamic feeding neurons has fect the "24-hour clock" in the rat. terrupted dorsal pathways efferent consequences different from those Using changes in running-wheel ac­ from Gladfelter's and Brobeck's following DMN lesions and this tivity as criterion, he noted that . . . area(s) (1962) rather than destroying might also be taken-as pointing to a "the clock possibly is located a primary "activity center." These different functional capacity. somewhere in the hypothalamus." authors emphasized that activity WATER INTAKE Indeed, Brooks (1946) demonstrated changes in their animals occurred Consumatory behavior is not only that the hypothalamic area in ques­ independently of food and water in­ affected by DMN lesions in terms of tion might be the VMN, since le­ take; the opposite is true for the reduced food intake but also water sions in this area in mature rats DMN lesioned rat. intake (Bernardis, 1970). It is of in­ brought about a state of hypoactiv- terest, however, that the DMN le­ ity. In combination with hyper- HYPOTHALAMO-PITUITARY sions do not cause a reduced phagia, it might contribute to the RELATIONSHIPS water/food intake ratio, a change profound obesity in this type of ex­ As mentioned in the introductory that is characteristic of the VMN perimental animal. Bernardis (1972c) section of this review, most studies syndrome (weanling rat — Bernar­ confirmed hypoactivity following addressing themselves to an explora­ dis, 1970; Bernardis and Frohman, VMN lesions in the weanling rat tion of hypothalamic sites involved 1971; Bernardis, 1972b; mature rat which, it should be recalled, is nor- in the control of the — Montemurro and Stevenson, mophagic with normal weight gain adenohypophysis have been con­ 1957). It is also worth noting that but increased carcass fat (Bernardis fined to the basal hypothalamus, DMN lesioned rats show normal and Frohman, 1967; Bernardis, specifically the ME. Although carcass water content (Bernardis, 1970; Bernardis and Frohman,; Halasz' work has pointed to a wider 1970) and that both male and female 1970; Bernardis and Frohman, 1971; involvement of hypothalamic struc­ mature DMN rats excrete a given Bernardis, 1972c; Bernardis, 1973a; tures than merely the ME, the water load at the same rate as ap­ Bernardis, 1973b). Hypophysiotrophic Area (HTA) by propriately sham-operated controls While in the intact rat decreased definition does not include the DMN (Bernardis, 1972a). These findings food intake or fasting is followed by (Halasz, Pupp and Uhlarik, 1962). are in contrast to the data reported hyperactivity (Slonaker, 1925; Wald Within the last few years, evi­ by Montemurro and Stevenson and Jackson, 1944; Campbell and dence has accumulated that the (1957) who located an area in the rat Sheffield, 1953; Stevenson and DMN is involved in hypophysiot­ lateral hypothalamus, the destruc­ Rixon, 1957), the (hypophagic) rophic function. Lesion studies have tion of which causes adipsia and weanling as well as mature DMN rat suggested that the DMN might be hypodipsia but is different from the displays hypoactivity, which is ac­ involved in the control of prolactin lateral hypothalamic "feeding companied by decreased body (LTH) secretion. After destruction center" (Anand and Brobeck, 1951). weight gain but normal body com­ of an area involving the VMN, DMN

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TABLE 2 found reductions in both ponderal and linear growth but normal body Parameter Group 1 Group 2 Group 3 VMNL (25)» DMNL (7) SCON (S) 1 vs 2 1 vs 3 2 vs 3 composition (Bernardis, 1970; Ber­ nardis and Frohman, 1970; Bernar­ Plasma GH (Mg/ml) 35.2^5.4** 91.6^24.4 77.8^14.9 0.01 0.01 ns*** dis and Frohman, 1971). Follow-up A Body Weight (gm) 137^ 8 68^15 115^2 0.001 ns 0.01 studies revealed normal plasma glu­ A Body Length (mm) 77^3 64#?8 107^3 ns 0.001 0.001, Food Intake (gm/day) 20.4^1.0 11.3^1.7 19.4 #0.4 0.001 ns 0.001 cose and insulin (Bernardis and Carcass Fat (% dry wt.) 60^2 32^5 37 4 0.001 0.001 ns Frohman, 1970, 1971) and trig­ Strain: Holtzman * VMNL — lesions in the ventromedial lyceride and cholesterol levels (Ber­ hypothalamic nuclei nardis and Schnatz, 1970). One of DMNL — lesions in the dorsomedial hypo­ the most remarkable features of this Age at operation: 28 days syndrome is the fact that plasma GH thalamic nuclei Duration of levels are normal or slightly elevated experiment: 31 days SCON — sham-operated controls (Bernardis, 1973). Time of year: Nov.-Dec. ( ) population Oxygen consumption, thyroid and Lesion current: 1.0 mAmp ** Mean^S.E.M. testes weights were normal, but ad­ Lesion time: 12.5 sec. *** statistically not significant renal weights were smaller in the DMN lesioned rats (Bernardis, Table 2: Plasma Growth Hormone (GH) levels and somatic parameters in rats with lesions in the ventromedial and dorsomedial hypothalamic nuclei, respectively, and 1972a, 1972b). Changes in the secre­ of sham-operated controls. From Bernardis, 1973. tions of these glands have not been reported following DMN lesions, but evidence to be discussed indicates it is unlikely that the growth retarda­ and the arcuate nuclei, prolonged cuate nucleus decreased. From the tion in the DMN rat is due to de­ diestrus and active corpora lutea fourth day of pseudopregnancy ficiencies in the secretions of the were observed in the rat MUA decreased in the DMN, the above glands. Rather, it was prop­ (Nikitovitch-Winer, 1970). Subse­ anterior hypothalamic area and the osed (Bernardis, 1972a, 1972b; Ber­ quent studies by Everett and Quinn hippocampus. nardis and Goldman, 1972) that the (1966) showed that the mechanism(s) While the VMN has been impli­ growth reduction is due to decreased initiating and maintaining pseudop­ cated in the control of growth and food intake. Normal or even ele­ regnancy in rats is (are) easily distin­ Growth Hormone (GH) secretion vated GH levels cannot bring about guished from the mechanism(s) con­ (Hetherington and Ranson, 1942; normal growth under this condition. trolling ovulation. Pseudopregnancy Reichlin, 1961; Smith, 1927), proof Most recent studies by Nakayama was precipitated by stimulation of. . for the participation of a specific et al (Nakayama, Tseng and Bernar­ . "sites near the dorsomedial nuc­ area, i.e. the VMN, has been forth­ dis, 1973; Nakayama, Bernardis and leus . . ." — a sign of LTH secretion coming only recently. Bernardis and Tseng, 1974), however, have shown — and did not induce ovulation. The Frohman (1967) were the first to that the DMN are involved in GH latter was brought about by stimula­ report that destruction of the VMN dynamics. Using an ultrastructural- tion of the preoptic area which failed without injury to the ME brought quantitative approach the authors to induce pseudopregnancy. This about a decrease of both pituitary suggested that the DMN might be differential response provided and plasma GH levels. Subsequent involved in the control of Growth further evidence for the existence of lesion (Frohman and Bernardis, Hormone Inhibiting Factor (GIF). two separate hypothalamic 1968; Bernardis and Frohman, 1970) This factor has been postulated by mechanisms that can be selectively and stimulation (Toivola and Gale, Krulich, Dhariwal and McCann stimulated and in turn activate cells 1973) studies have confirmed these (1968) and Krulich and McCann in the HTA to produce Prolactin original findings and moved the (1969) and its origin was thought to Inhibiting Factor (PIF) and Luteiniz­ VMN into the focal point of GH be outside the ME (Krulich, Qui- ing Hormone Releasing Factor control. jada, and liner, 1971). Nakayama (LHRF). Indications that the VMN may not and his co-workers measured three The DMN was also implicated in be the sole hypothalamic locus in­ ultrastructural parameters of the the pseudopregnancy — LTH con­ volved in GH dynamics appeared in pituitary GH-synthesizing machin­ trol scheme by data from cervical the early sixties, when it was re­ ery: the surface area of the GH- stimulation experiments. Kawakami ported that profound growth reduc­ synthesizing cell, the number of sec­ and Ibuki (1972) stimulated the cer­ tion occurred when weanling rats retory granules per cell, and the vix of mature rats on the day of received electrolytic lesions in the mean diameter of the secretory estrus to induce pseudopregnancy DMN (Bernardis, Box and Steven­ granules. In previous studies, and found an increase in multiple son, 1963). A recent re-investigation Nakayama and Nickerson (1973) unit activity (MUA) in the anterior of this problem confirmed the origi­ used this approach to demonstrate hypothalamic area and the DMN for nal report. DMN lesions that do not that high circulating levels of GH — several hours. The MUA of the ar­ injure the VMN are followed by pro­ as in rats bearing the Furth MtTIO

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tumor — caused significant reduc­ growth and obesity. The authors in­ 300 Hours Days tions in GH cell granule number, terpreted their findings to indicate VMN Ratas surface area of the GH cell, and that . . . "neural elements responsi­ 260 / granule diameter. Application of this ble for growth reside in the VM m/i method to the study of GH cells in region and that these elements re­ 220 —v pituitaries from rats with VMN and ceive inhibitory connections from other structures ..." The removal i DMN lesions demonstrated 180 DMN Rats (Nakayama, Tseng and Bernardis, of these inhibitory connections by x 1973; Nakayama, Bernardis and horizontal knife cuts as used by \ Palka, Liebelt and Critchlow (1971) 140 Tseng, 1974) that destruction of the -I—I- -I- VMN was followed by an increase of are comparable to the DMN lesions 2 8 24 2 7 14 in the Bernardis (1973b) and 30% above control levels in the 390r Hours Days number of secretory granules, mean Nakayama (Nakayama, Tseng and diameter of the secretory granule Bernardis, 1973; Nakayama, Ber­ VMN Rats I nardis and Tseng, 1974) studies, in­ 370 and surface area of the GH- m^. synthesizing cell. This was taken as asmuch as both types of intervention an indication of a state of prolonged interrupted connections between the 350 inhibition of granule release and is dorsal and ventral circuits, i.e. bet­ compatible with the currently held ween the dorsomedial area and the 330 view that GRF (Growth Hormone VMN. The lack of growth promo­ tion, both in terms of weight and Releasing Factor) forming neurons 310 length, in all of the Bernardis studies are located in or near the VMN. is undoubtedly due to the profound 2 8 24 2 Destruction of the DMN, on the and consistent hypophagia that other hand, caused the opposite characterizes the DMN rat (Bernar­ Figure 6 Upper Panel — Changes in the changes in GH cells: the number of dis, Box and Stevenson, 1963; Ber­ mean diameter of the largest secretory secretory granules decreased rapidly nardis, 1970; Bernardis, 1972a, granule in each somatotroph of VMN- after the hypothalamic operation and 1972b; Bernardis and Goldman, and DMN- lesioned rats sacrificed 2,8, reached its lowest point 24 hours and 24 hours and 2,7, and 14 days after 1972; Bernardis, 1973; Bernardis operation (Experiment 2). The cross- afterwards — 33% below control Chlouverakis, Schnatz and levels. The secretory granules re- hatched horizontal band shows the Frohman, 1974). mean diameter of the largest granule accumulated slowly but were still and its standard error in the sham- 20% below control levels 19 days Hypoglycemia has been recog­ operated control rats. The vertical after the placement of the DMN le­ nized as the adequate stimulus for lines in each point depict the standard sions. The changes in the pituitaries GH secretion (Roth, Glick, Yalow error of the mean. of rats with DMN lesions were in­ and Berson, 1963). The synthetic terpreted as indicating a state of glucose analog, 2-deoxy-D-glucose Lower Panel — Changes in the mean hypersecretion, a rapid outpouring (2DG), when given to animals and number of secretory granules per of secretory granules from pituitary man, causes an enzymatic inhibition somatotroph cross section in the stores. This is attributed to a lack of of glucose metabolism (Tower, 1958) VMN- and DMN- lesioned rats sac­ inhibition, possibly due to a lack of that yields the same response as rificed 2,8, and 24 hours and 2,7, and GIF (Growth Hormone Inhibitory insulin administration (Houpt and 14 days after the hypothalamic opera­ tion (Experiment 2). The cross- Factor) whose formation site and/or Hance, 1971; Smith and Root, 1969). In an attempt to define the location hatched horizontal band shows the storage locus must then be in the mean granule count and its standard DMN or their immediate dorsal in the hypothalamus of the error in the sham-operated controls. hypothalamic vicinity. chemoreceptors that might be acti­ The vertical lines in each point show vated by 2DG or hypoglycemia, the standard error of the mean. Mod­ The data on changes in secretory Himsworth, Carmel and Frantz ified after Nakayama et al., 1974. granules and GH cells as provided (1972) have injected 2DG into vari­ by Nakayama and the plasma GH ous hypothalamic areas of macacca data following DMN lesions (Ber­ mulatta. While the injection sites nardis, 1973b) gain more meaning alongside the midpart of the lateral and significance when interpreted in VMN were effective in increasing the light of findings by the Critchlow plasma GH levels, injections into the group (Palka, Liebelt and Critchlow, DMN were consistently ineffective. 1971). Horizontal knife cuts through Although these sites differ from the hypothalamus that divided the those established by lesion (Bernar­ VMN into ventral and dorsal halves dis and Frohman, 1967; Frohman were the most effective — among a and Bernardis, 1968) and stimulation number of types of cuts — in causing studies (Frohman, Bernardis and increased ponderal and linear Kant, 1968; Bernardis and Frohman,

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1971; Martin, 1972; Tiovola and hypothalamus. Subsequent studies concede that their data does not Gale, 1972, 1973), the authors indi­ by Ifft (1962, 1964) utililized changes permit conclusions regarding the cate the fibers pass medially from in nucleolar size, rather than nuclear adrenalectomy-initiated reversal of the stimulated region to the VMN size, and related these changes to iodine uptake, they hypothesize that (Arees and Mayer, 1967; Nauta and changes in various hypothalamic it might be due to concomitant Haymaker, 1969). The fact that the neurons. An increase in nucleolar adreno-cortical stimulation, con­ DMN area is unresponsive to hypog­ size was attributed to an increase in ceivably caused by increased ACTH lycemia agrees with Bernardis' neuronal activity. In his 1964 study, or adrenocortical hormone secre­ (1973b) findings that DMN lesions Ifft manipulated the endocrine sys­ tion. do not cause a decrease in plasma tem by extirpation of the pituitary, These findings have been con­ GH levels, and with the Bernardis the thyroid, ovaries, adrenals and firmed by Martin and Reichlin (1972) and Frohman (1971) data that elec­ adrenal medulla. The nucleoli of the who could not find a positive re­ trical stimulation of the DMN fails to DMN did not show changes five sponse in plasma Thyroid Stimulat­ bring about a rise in circulating GH. days post hypophysectomy, but ing Hormone (TSH) after DMN showed changes 60 days after While adrenal function for years stimulation. They did find a positive hypophysectomy. The VMN nuc­ response in one of their animals that has been known to be influenced and leoli were decreased in size at five controlled by a hypothalamic princi­ had been stimulated longer than the days, but not sixty days after other, non-responsive rats. The re­ ple — Corticotrophin Releasing Fac­ hypophysectomy. Neither ovariec­ tor (CRF, Saffran and Schally, 1955) sults of lesion studies are also in tomy nor thyroidectomy affected keeping with the above findings. that acts via pituitary ACTH and is VMN and DMN nucleolar size, and found jn ample amounts in the ME, Mess, Zanisi and Tima (1970) could both adrenalectomy and adrenal not find changes in Thyrotropin Re­ recent findings suggest the existence demedullation increased nucleolar of an extra-pituitary control system leasing Factor (TRF) seven days size in both VMN and DMN. The after the placement of DMN lesions. as well. Following electrical stimula­ changes in the DMN in particular tion of the ventromedial as well as have to be interpreted in the light of While the DMN are undoubtedly the dorsomedial areas in the dog, alterations observed in other involved in the secretion of Prolactin an augmentation of adrenal blood hypothalamic nuclei and it is particu­ (LTH) as previously indicated, both flow and pressure was noted, the larly noteworthy that hypophysec­ the tonic and cyclic mechanisms former not necessarily depending tomy, adrenalectomy and adrenal controlling Luteinizing Hormone on the latter. While in non- demedullation initiated changes in (LH) appear to be unrelated to DMN hypophysectomized dogs there was all of the 16 hypothalamic nuclei activity. This was shown by studies no correlation between blood flow examined. Thus, the nucleolar size of the Sawyer group (Gallo, Johnson, and adrenal corticoid release, such changes in the DMN appear to be Goldman, Whitmoyer and Sawyer, a correlation existed after hypophy- affected in a generalized and nons­ 1971) who demonstrated an increase sectomy. The authors (Kovach, pecific manner, but this might be in multiple unit activity (MUA) in Moos, Kiltay and Desrius, 1970) expected from data on lesion and the arcuate nuclei and the VMN interpret the coordination of this stimulation studies to be discussed following electrochemical stimula­ response in the light of a "dor­ subsequently. Unfortunately Ifft did tion of the ventral hippocampus. somedial sympathetic vasodilator not use insulin hypoglycemia, a They also observed a depression of relay" described by Folkow, specific and potent stimulus for the plasma LH Wz and 3 hours following Johansson and Oberg (1959) at secretion of GH. This might have stimulation. No increase in MUA which level the response is likely thrown some interesting light on the was found in the DMN, the ME and organized. It is also recalled that, role of at least the VMN in GH the zona incerta. with ACTH concentrations lower dynamics. Hyperglycemia, on the METABOLIC CONTROL than the physiological minimum, other hand, might have set in motion The control of intermediary cortisteroid response is changed in a chain of events that could have metabolism is generally thought to response to altered blood flow (Ur- implicated the DMN in the be executed by enzymes which have quhart, 1965). aforementioned role in GIF secre­ been activated — or induced — by Some years ago, Szentagothai, tion. hormones. The latter are either sec­ Flerko, Mess and Halasz (1968) used The involvement of the DMN in reted by the pituitary directly, e.g. changes of cell nucleus size in the thyroid function control has been GH (Second Order Neuroendocrine various hypothalamic nuclei as an examined by Vertes, Vertes and System), Scharrer (1966), or require indicator of functional activity of the Kovacs (1965). Electrical stimula­ the action of a pituitary trophic hor­ neurons. They derived their conclu­ tion of the nucleus in its anterior mone on a target gland that in turn sions from experiments in which aspect was followed by a decrease in releases the hormone, e.g. Thyroid manipulation of the endocrine milieu thyroidal I131 uptake. After ad­ Stimulating Hormone (TSH) and was followed by profound altera­ renalectomy, however, stimulation Thyroid Hormone (Third Order tions in cell nucleus size, reflecting in the DMN was followed by a grea­ Neuroendocrine System) (Scharrer, neuronal activity in the ter uptake of I131. While the authors 1966).

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Previous investigations in the cen­ framework of its somatic- (Goldman, Schnatz, Bernardis and tral nervous system control of in­ physiological potential, is better Frohman, 1972). Studies in the termediary metabolism of carbohyd­ equipped to exist with smaller DMN rat, on the other hand, have rate and lipid have shown that in amounts of substrate for its shown that body composition is weanling rats with VMN lesions the metabolism than is the calorie- normal (Bernardis, 1970), and that epididymal fat pad oxidizes and in­ restricted sham-operated control." hypophagia and subnormal body corporates glucose and palmitate This more efficient adaptation to re­ weight gains co-exist in the face of with great avidity, while oxidation of duced calories is speculated to be normoinsulinemia and normog- the latter metabolite is decreased due to a "resetting" of central au­ lycemia (Bernardis and Frohman, (Goldman, Bernardis, Frohman and tonomic mechanisms which need not 1971). Evidently, the destruction of Schnatz, 1968; Goldman, Schnatz, necessarily exert their effect via two neuronal assemblies so closely Bernardis and Frohman, 1970; adenohypophyseal secretions (Ber­ appositioned in the hypothalamus Goldman, Schnatz, Bernardis and nardis and Goldman, 1972). brings about entirely different Frohman, 1971). The importance of metabolic responses. The question It has been noted that lesions in as to why the weanling DMN rat has this finding is emphasized by the fact the VMN of the mature rat are fol­ that the above changes are evident in a normal carcass fat content in view lowed by a profound increase in of the reduced food intake is difficult hypophysectomized (Goldman, body weight (Brobeck, Tepperman Schnatz, Bernardis and Frohman, to interpret. Possibly, the DMN rat and Long, 1943; Hetherington and preserves energy by reducing its ac­ 1970) and streptozotocin-diabetic Ranson, 1942; Smith, 1927), this rats (Goldman, Schnatz, Bernardis tivity which thus might account for a being due to increased lipogenesis. It normal fat storage in view of re­ and Frohman, 1972). To clarify and was long thought that the latter was define the hypothalamic site in­ duced food intake (Bernardis, 1972a, simply due to the hyperphagia which 1972b). volved in the initiation of this characterizes the mature VMN rat. phenomenon, the studies were ex­ Subsequent work, however, has in­ The foregoing review has attemp­ tended to the weanling rat with dicated that mature rats with VMN ted to show that a hypothalamic DMN lesions (Bernardis and Gold­ lesions become hyper-insulinemic area, removed from the median emi­ man, 1972). It should be recalled that (Hales and Kennedy, 1964) and insu­ nence and thus the portal circula­ the latter hypothalamic model shows lin is well known to be a potent tion, exerts a profound influence on normal plasma glucose, insulin, lipogenic hormone. Subsequent both adenohypophyseal and ex- growth hormone, triglyceride and work has also shown that both obes­ trapituitary control mechanisms of cholesterol levels (see above). ity and hyperinsulinemia develop in homeostasis. tube-fed hypophysectomized rats Epididymal fat pads from rats with CONCLUDING REMARKS with VMN lesions, indicating that DMN lesions placed shortly after The data of this review indicate the endocrine pancreas is involved weaning showed significantly lower that an area of the hypothalamus in hypothalamic obesity and demon­ incorporation of palmitate into that up to now has received rela­ strating that hyperinsulinemia can phospholipid and diglyceride in tively little attention — the Dor- develop in the absence of hyper­ comparison with ad libitum-fed, somedial Hypothalamic Nuclei phagia and pituitary hormones (Han sham-operated controls, whereas in­ (DMN) — exerts profound influ­ and Frohman, 1970). corporation into triglyceride was un­ ences on a wide spectrum of altered. It is of interest to note that The weanling VMN rat, on the homeostatic mechanisms. It is in­ these parameters are normal in the other hand, does not gain more volved in extrapituitary-autonomic fat tissue of controls that were fed weight than its sham-operated con­ control systems: food and water in­ the same amount of food eaten by trol but is hyperinsulinemic and take, diurnal cyclicity, spontaneous the (hypophagic) DMN-lesioned normoglycemic and normophagic activity, metabolism in terms of the rats. and has a higher carcass fat content fate of both intermediates and cir­ The data for the diaphragm are with lower lean body mass and water culating substrates, and adrenal quite different. The DMN-operated (Bernardis and Frohman, 1967, Ber­ function by affecting adrenal blood rats incorporated significantly less nardis, 1970, Bernardis and flow. It is also involved in glucose into total lipid and glycogen, Frohman, 1970). While it was first hypothalamo-pituitary relationships while in comparison with pair-fed thought (Frohman and Bernardis, of neuroendocrine nature: control or controls the DMN rats showed no 1968) that the increased lipogenesis modulation of Luteotrophic Hor­ significant alterations when com­ was due to the high insulin levels — mone (LTH) and growth and pared with ad libitum-fed controls. hyperplagia per se had to be ex­ Growth Hormone possibly by mod­ The authors noted that. . . "striking cluded—it was subsequently demon­ ulating Growth Hormone Inhibiting somatic changes are not matched by strated that obseity and the above Factor (GIF). Most of the paramet­ similarly striking changes in the in­ metabolic changes occur in the ab­ ers measured show reponses of dif­ termediary metabolism of glucose sence of pituitary (Goldman, ferent direction and magnitude when and palmitate." They hypothesized Schnatz, Bernardis and Frohman, compared with parameters obtained that the DMN rat . . . "within the 1970) and an endocrine pancreas from Ventromedial Hypothalamic

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Nucleus (VMN) — manipulated correlation between adrenal blood flow BERNARDIS, L. L. and FROHMAN, L. A. rats, at least in weanling animals. and adrenal corticoid release in (1970): Effect of lesion size in the ven­ hypophysectomized dogs. This has been tromedial hypothalamus on growth hor­ Although the data on intranuclear mone and insulin levels in the weanling rat. and intrahypothalamic fiber connec­ interpreted as a coordinated response at the level of a "dorsomedial sympathetic Neuroendocrinology 6:319-328. tions unequivocally point to an ex­ vasodilator relay" rather than a "true" BERNARDIS, L. L. and FROHMAN, L. A. tensive degree of interdigitation of neuroendocrine effect via corticotropin (1971): Plasma growth hormone responses the DMN circuits with these or other releasing factor (CRF). Experiments to electrical stimulation of the hypothalamic areas, particularly the that failed to demonstrate a relationship hypothalamus in the rat. Neuroendocrinol­ ogy 7:193-201. VMN, the endocrine and metabolic between the DMN and the tonic and data indicate a great deal of cyclic control of luteinizing hormone re­ BERNARDIS, L. L., and SCHNATZ, J. D. leasing factor (LHRF) are discussed. (1970): Localization in the ventromedial localization-specificity. The latter hypothalamus of an area affecting plasma type of data therefore suggest that The data reviewed indicate the existence lipid levels. Journal of Neuro-Visceral Re­ the currently fashionable aversion to in the dorsomedial hypothalamus of an lations 32:522-537. the "center concept" of area that exerts a profound influence on BERNARDIS, L. L. (1972a): Hypophagia, hypothalamic control localization many aspects of neurovisceral and some hypodipsia and hypoactivity following elec­ neuroendocrine control systems. trolytic lesions in the dorsomedial may have to be revised, at least in hypothalamic nuclei of mature rats of both terms of functional specificity. Ob­ sexes. Journal of Neural Transmission viously, two so closely appositioned REFERENCES 33:1-10. neuronal assemblies subserve en­ ANAND, B. L. and BROBECK, J. R. (1951): BERNARDIS, L. L. (1972b): Hypophagia, tirely different, if not opposite Hypothalamic control of food intake in rats hypodipsia and hypoactivity following dor­ homeostatic functions. and cats. Yale Journal of Biology and somedial hypothalamic lesions. Physiology Medicine 24:123-140. and Behavior 8:1151-1164. ANDEN, N. E., DAHLSTROM, A., FUXE, BERNARDIS, L. L. (1972c): Hypoactivity as SUMMARY K., and LARSSON, K. (1965): Further a possible contributing cause of obesity in (Continued from page 45) evidence for the presence of nigro- the weanling rat ventromedial syndrome. neostriatal dopamine neurons in the rat. Canadian Journal of Physiology and Phar­ duced spontaneous activity (running American Journal of Anatomy 116:329-333. wheel), but this reduced activity is not macology 50:370-372. accompanied by increased weight gain ANDEN, N. E., DAHLSTROM, A., FUXE, BERNARDIS, L. L. and GOLDMAN, J. K. K., LARSSON, K., OLSON, L. and UN- and accretion of adipose tissue, the lat­ (1972): Growth and Metabolic changes in GERSTEDT, U. (1966): Ascending weanling rats with lesions in the dorsome­ ter being consistently observed in the monoamine neurons to the telencephalon VMN rat. Rather, carcass fat remains dial hypothalamic nuclei. Experimental and diencephalon. Acta Physiologica Scan- Brain Research 15:424-429. normal in the DMN rat and carcass dinavica 67:313-326. protein is either normal or slightly in­ BERNARDIS, L. L. (1973): Disruption of AKERT, K. (1961): Diencephalon: In: Elec­ diurnal feeding and weight gain cycles in creased. Many of the aforementioned trical Stimulation of the Brain, Sheer, D.E., changes in weanling rats with DMN le­ weanling rats by ventromedial and dor­ ed. Austin Hogg Foundation for Mental somedial hypothalamic lesions. Physiology sions, however, are not matched by simi­ Health, University of Texas Press, pp. and Behavior 10:855-861. lar alterations in the intermediary 288-310. metabolism of carbohydrate and lipid. BERNARDIS, L. L. (1973): Normal plasma AREES, E. A. and MAYER, J. (1967): growth hormone levels in growth-retarded Possibly this is due to a "resetting" of a Anatomical connections between medial weanling rats with dorsomedial central autonomic control system that and lateral regions of the hypothalamus hypothalamic lesions. Experimental Brain makes it possible for the DMN rat to concerned with food intake. Science Research 18:374-382. 157:1574-1575. adapt more efficiently to a reduced in­ BERNARDIS, L. L., CHLOUVERAKIS, flux of substrate, i.e. the consistent ARIENS KAPPERS, C. U., HUBER, G, C, C, SCHNATZ, J. D., FROHMAN, L. A. hypophagia. From a review of the litera­ and CROSBY, E. C. (1960): The compara­ (1974): Effect of dorsomedial hypothalamic ture it appears that the DMN and their tive anatomy of the nervous system of lesions before and after placement of circuitry are involved in only a few vertebrates, including man. Hafner Publish­ obesity-producing ventromedial neuroendocrine, i.e. hypothalamo- ing Company. (Originally published in 1936 hypothalamis lesions in the weanling male in two volumes). hypophyseal control mechanisms. Both rat. Brain Research 69:67-75. lesion and cervical stimulation experi­ BAN, T. (1964): The hypothalamus, espe­ BROBECK, J. R., TEPPERMAN, J. and cially on its fiber connections, and the ments suggest an involvement of the LONG, C. N. H. (1943): Experimental septo-preoptic-hypothalamic system. Med­ hypothalamic hyperphagia in the albino rat. DMN in the control of LTH. Circums­ ical Journal of Osaka University, 15, 1-83. tantial evidence points to the DMN as a Yale Journal of Biology and Medicine BERNARDIS, L. L., BOX, B. M. and 15:831-853. possible formation and I or storage site of STEVENSON, J. A. F. (1963): Growth growth hormone inhibiting factor (GIF). following hypothalamic lesions in the BROOKS, C. M. (1946): The relative impor­ Although DMN rats show reduced pon- weanling rat. Endocrinology 72:684-692. tance of changes in activity in the develop­ deral and linear growth, they have been ment of experimentally produced obesity in BERNARDIS, L. L. and FROHMAN, L. A. the rat. American Journal of Physiology found to have normal or elevated plasma (1967): Plasma and pituitary growth hor­ 147:708-716. growth hormone (GH) levels. Both lesion mone levels in rats with hypothalamic le­ and stimulation studies have yielded the BRUGGER, M. (1943): Fresstrieb als sions. Endocrine Society Annual Meeting, hypothalamisches Symptom, Helvetica impression that the DMN is not involved p. 86. Physiologica Acta 1:183-198. in thyroid, i.e., thyrotropin stimulating BERNARDIS, L. L. (1970): Participation of hormone releasing factor (TSHRF) con­ the dorosmedial hypothalamic nucleus in CAMPBELL, B. A. and SHEFFIELD, F. D. trol. Electrical stimulation of the DMN the "feeding center" and water intake cir­ (1953): Relation of random activity to food has been reported to result in a positive cuitry of the weanling rat. Journal of deprivation. Journal of Comparative Neuro-Visceral Relations 31:387-398. Physiological Pharmacology 46:320-322.

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