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The need for increased sleep after traumatic brain injury is a common and disabling complaint, yet its etiology is unknown. Previous studies have demonstrated diffuse damage to various hypothalamic systems, but the integrity of the histaminergic tuberomammillary nucleus, a major arousal-promoting system located in the posterior hypothalamus, has never been examined in head trauma patients. Here, we demonstrate that severe head trauma is associated with a marked loss (41%) of histaminergic neurons. Reduced histamine signaling may contribute to increased sleep need, and therapies that enhance histaminergic tone may improve arousal after head trauma or other conditions.

What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate–salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate–salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)–salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA–salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA–salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA–salt rats, but ETB receptors showed no changes. These results show that ET-1 and ET-3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA–salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model. Fil: Abramoff, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina Fil: Guil, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina Fil: Morales, Vanina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina Fil: Hope, Sandra Ingrid. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bianciotti, Liliana Graciela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Vatta, Marcelo Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina

Prefrontal cortices have been implicated in autonomic function, but their role in this activity is not well understood. Orbital and medial prefrontal cortices receive input from cortical and subcortical structures associated with emotions. Thus, the prefrontal cortex may be an essential link for autonomic responses driven by emotions. Classic studies have demonstrated the existence of projections between prefrontal cortex and the hypothalamus, a central autonomic structure, but the topographic organization of these connections in the monkey has not been clearly established. We investigated the organization of bidirectional connections between these areas in the rhesus monkey by using tracer injections in orbital, medial, and lateral prefrontal areas. All prefrontal areas investigated received projections from the hypothalamus, originating mainly in the posterior hypothalamus. Differences in the topography of hypothalamic projection neurons were related to both the location and type of the target cortical area. Injections in lateral eulaminate prefrontal areas primarily labeled neurons in the posterior hypothalamus that were equally distributed in the lateral and medial hypothalamus. In contrast, injections in orbitofrontal and medial limbic cortices labeled neurons in the anterior and tuberal regions of the hypothalamus and in the posterior region. Projection neurons targeting orbital limbic cortices were more prevalent in the lateral part of the hypothalamus, whereas those targeting medial limbic cortices were more prevalent in the medial hypothalamus. In comparison to the ascending projections, descending projections from prefrontal cortex to the hypothalamus were highly specific, originating mostly from orbital and medial prefrontal cortices. The ascending and descending connections overlapped in the hypothalamus in areas that have autonomic functions. These results suggest that specific orbitofrontal and medial prefrontal areas exert a direct influence on the hypothalamus and may be important for the autonomic responses evoked by complex emotional situations.

Summary 1. We studied the ontogenetic development of GABAB receptors and their coupling to cyclic AMP formation in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rat brains. GABAB receptor binding to various brain regions was compared in age-matched SHR and WKY rats. 2. The specific [3H]-GABA binding to the posterior hypothalamus (PH) was significantly lower in not only 4 week old (normotensive) but also 11 week old (hypertensive) SHR, when compared with age-matched WKY. 3. Moreover, GABAB receptor agonists (baclofen and DN-2327)-induced suppression of adenylate cyclase activity also showed a decrease in 4 week old and 11 week old SHR PH. 4. We concluded that the number and the functional responsiveness of GABAB receptors in rat brains decrease in SHR, preceding blood pressure elevation. The activity of GABABergic mechanisms may be different in the brains of SHR and WKY rats.

SUMMARY 1. Radioligand binding studies using [3H]-prazosin (α1) and [3H]-yohimbine (α2) were undertaken to characterize central α-adrenoceptors in regions involved in blood pressure regulation. 2. Both α1- and α2-adrenoceptors were identified in the anterior and posterior hypothalamus and dorsal midline area of the caudal medulla oblongata of the rat. 3. The α1- or α2-adrenergic pharmacological specificity of the adrenoceptors was similar in each region, although their concentrations were different. 4. The concentration of α2-adrenoceptors in the anterior hypothalamus was decreased following sino-aortic denervation suggesting that some hypothalamic α2-adrenoceptors are associated with neurones of the baroreflex arc.

Hypothalamic involvement in visually conditioned heart rate change (established by pairing light and foot-shock) was studied in 128 pigeons by evaluating conditioning performance following lesions of various hypothalamic areas. Extensive destruction of the posterior hypothalamus severely impaired development of conditioned heart rate change. Anterior hypothalamic lesions also produced serious deficits, though not as severe as following posterior hypothalamic damage. Partial posterior hypothalamic, unilateral and tuberal lesions produced only minor to moderate deficits. The critical locus for profound impairment of conditioned response development appeared to be the medial hypothalamus, and it is suggested that more specifically it is the terminal field of the archistriatal projection upon the medial hypothalamus. It is concluded that the medial hypothalamus is essential for the development of defensively conditioned heart rate change, and based on previous findings it is suggested that the critical descending pathway for expression of this conditioned response involves the archistriatal projection upon the medial hypothalamus and subsequently a polysynaptic pathway through the ventral brainstem.

SUMMARY 1 Electrolytic lesions were made in various brain regions of the rat, and the effects of these lesions on nociceptive threshold and the antinociceptive actions of morphine were tested using a shock titration technique. 2 Lesions in the medial thalamus, the periaqueductal grey area, or the caudate nucleus, had no effect on the nociceptive threshold; whereas, lesions in the posterior hypothalamus resulted in a small but statistically significant increase in this threshold. 3 Morphine administered intraperitoneally to rats having histologically verified lesions in the posterior hypothalamus, the caudate nucleus or the periaqueductal grey area resulted in a 15–30% increase in the nociceptive threshold. This increase was similar to that observed in unoperated control rats. On the other hand, injections of morphine into animals having greater than 50% of the medial thalamus destroyed produced a highly significant increase of 95% in the threshold. This potentiation of the antinociceptive action of morphine was not observed in rats having less than 50% destruction of the medial thalamus.

The effect of Hydergine on intracranial self-stimulation was tested in male albino Holtzman rats. The rats had monopolar electrodes implanted in the medial forebrain bundle of the posterior hypothalamus. Hydergine was given orally at 40 and 80 mg/kg. A dose-dependent excitatory effect occurred which was rapid in onset, large, long-lasting, and evidenced in acute trials of the drug. The results suggest that a major portion of Hydergine's action in aged patients is stimulatory and antidepressant in nature.

Groups of pregnant rats were injected with two successive daily doses of 3H-thymidine from gestational day 13 (E13+14) until the day before birth (E21+22). This double labelling procedure was combined with an injection schedule of a single day delay between groups (E13+14; E14+15; E15+16. .I. The two injections assured the comprehensive labelling of prac- tically all neurons of a given structure prior to the onset of their differentiation (comprehensive labelling), whereas the progressive daily delay in injections made it possible to estimate the proportion of neurons formed in various regions of the hypothalamus on a single day. Hypothalamic areas or nuclei were assigned into four classes on the basis of their cytogenetic isochronicity. Struc- tures composed of the earliest arising (class 1) neurons constitute a lateral tier that includes the lateral preoptic and lateral hypothalamic areas, and the later- al mammillary nucleus. Structures composed of early arising (class 2) neurons form a heterogeneous collection of nuclear systems, including the paraventricu- lar, internuclear and supraoptic magnocellular neurons, and several intermedi- ate tier nuclei of the anterior and posterior hypothalamus. The late arising (class 3) and latest arising (class 4) nuclei constitute a periventricular system anteriorly and a more extensive region posteriorly. The latter two nuclear sys- tems may constitute the hypophysiotropic area of the hypothalamus. The nuclei of the mammillary system, which are produced sequentially, are distinguished from other hypothalamic structures by their more rapid generation time. Inter- nuclear labelling gradients were used to infer the neuroepithelial site of origin and settling pattern of neurons. Common sites of origin were indicated for the following structures: the magnocellular neurohypophysial neurons; the neu- rons of the dorsomedial and ventromedial nuclei; and the neurons of the tuberomammillary and arcuate nuclei. The sites of origin of these groups of nu- clei were related to specialized ventricular linings in the mature hypothalamus.

SUMMARY Experiments are described on cats in which convulsive and subconvulsive states were produced by topical application of strychnine to the cortex or by intravenous injection of picrotoxin or Metrazol. It is shown that the state of excitation of the sympathetic division of the hypothalamus has a profound effect on both types of convulsive discharges. An increase in the state of excitation of the hypothalamus is associated with an aggravation and generalization of existing convulsive discharges and with the precipitation of a seizure if the animal was in a subconvulsive condition before stimulation. This effect may be produced by stimulation of the posterior hypothalamus or of the reticular formation with square wave pulses at 90–100 c/sec or by nociceptive and proprioceptive stimuli which are known to impinge upon the hypothalamus and elicit increased diffuse hypothalamic-cortical discharges. A diminution in the baroreceptor reflexes through hypotensive drugs exerts a similar action. It is based on the fact that tonic activity of the baroreceptors restrains the posterior hypothalamus so that lessened discharges from the sino-aortic receptors lead to a release of the hypothalamus and an increase in the hypothalamic-cortical discharges. Whereas noradrenaline (or adrenaline) through raising the blood pressure and consequently the sino-aortic pressure, reduces the activity of the somatic nervous system in the normal animal and diminishes the convulsive activity when it is slight, it aggravates the convulsive state in heavily strychninized animals. These results are explained on the basis of the double action of noradrenaline: inhibitory via the baroreceptor reflexes and excitatory by direct action on hypothalamus and reticular formation. In highly excitatory states the latter action supervenes. Asphyxia evokes a generalized synchronized convulsive discharge after previous strychninization of the hypothalamus. It is suggested that the great resistance of the hypothalamus (and of the reticular formation) as compared to that of the cortex and the action of the adrenomedullary neurohumors which are discharged in asphyxia account for the role of the hypothalamus as a pacemaker under these conditions. Cortico-fugal impulses which are shown to cause an excitation of the hypothalamus and to increase its responsiveness to reflex stimulation are thought to be involved in the activation of the hypothalamus in states of emotion. The experiments described in this paper suggest the mechanisms through which emotional excitement may precipitate a seizure. RESUME Les experiences decrites furent effectuees chez des chats, et consistaient a produire des etats convulsifs ou convulsifs latents par l'application locale de strychnine sur le cortex cerebral, ou par l'injection intraveineuse de picrotoxine ou de metrazol. Il est demontre que l'excitabilite de la partie sympathique de l'hypothalamus a une influence profonde sur les deux types de decharge convulsive. Une elevation de l'etat d'excitation de l'hypothalamus est associee avec une aggravation et une generalisation des decharges convulsives existantes, et par la precipitation d'une crise si l'animal se trouvait dans un etat convulsif latent avant la stimulation. Cet effet peut etre produit par la stimulation de la partie posterieure de l'hypothalamus, ou de la formation reticulaire au moyen d'ondes rectilignes a une frequence de 90/100 par sec, ou par des stimulants nociceptifs ou proprioceptifs qui soient connus pour influencer l'hypothalamus et provoquer des decharges hypothalamico-corticales diffuses. Une diminution des reflexes barorecepteurs causee par des preparations hypertensives exerce une action similaire. Ceci se base sur l'activite tonique diminuee des barorecepteurs qui inhibe l'activite de l'hypothalamus posterieur; ainsi l'activite reflexe diminuee des recepteurs sino-aortiques libere l'hypothalamus de cette inhibition, et donne lieu a une augmentation des decharges hypothalamico-corticales. Alors que la noradrenaline, ou l'adrenaline, en elevant la tension arterielle et par consequent la tension dans les barorecepteurs sino-aortiques, inhibe l'activite du systeme nerveux somatique chez l'animal normal et diminue l'activite convulsive si celle-ci est faible, ces deux substances pharmacologiques aggravent l'etat convulsif chez des animaux fortement strychninises. Ces consequences peuvent s'expliquer sur la base de l'action double de la noradrenaline: inhibitrice par les reflexes barorecepteurs, excitatrice par action directe sur l'hypothalamus et la formation reticulaire. Dans des etats de haute excitabilite, c'est le dernier effet qui predomine. L'asphyxie provoque une decharge convulsive generalisee synchronisee apres strychninisation de l'hypothalamus. On suppose que la plus grande resistance de l'hypothalamus (et de la formation reticulaire) par rapport a celle du cortex, combinee a l'action des hormones de la medullo-surrenale qui sont liberees en cas d'asphyxie, doivent etre tenues pour responsable du role de l'hypothalamus comme animateur. Des impulsions corticofugales qui, comme il fut demontre, causent un etat de surexcitabilite de l'hypothalamus sont supposees etre responsables de l'activation de l'hypothalamus dans les etats emotifs. Les experiences decrites dans ce travail suggerent les mechanismes per lesquels un etat d'excitation emotionnelle peut aboutir a une crise epileptique.