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Previous studies have suggested that a decreased inhibitory input onto neurons within the posterior hypothalamus (PH), a known pressor area, may contribute to hypertension in the spontaneously hypertensive rat (SHR). Recent experiments from this laboratory have shown that neurons in the PH of the SHR have an altered and elevated discharge frequency compared to those in the normotensive rat. In addition, biochemical studies have reported that there is a decreased concentration of the inhibitory neurotransmitter, GABA, in the hypothalamus of the SHR. The objective of the present study was to assess any variations in GABAergic modulation of cardiovascular activity in SHRs compared to normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Arterial pressure and heart rate responses to microinjections of the GABA synthesis inhibitor 3-mercaptopropionic acid (3-MP) into the posterior hypothalamic area of anesthetized young (6–8 weeks) and mature (11–16 weeks) hypertensive and normotensive rats were recorded. Microinjection of 3-MP elicited increases in arterial pressure of 17.4 ± 3.9 mmHg, 18.1 ± 7.8 mmHg, 16.9 ± 6.4 mmHg, and 10.4 ± 3.5 mmHg in the mature WKY, mature SD, young WKY, and young SHR, respectively. In addition, heart rate was elevated by 33.2 ± 21.9 beats/min, 70.0 ± 25.3 beats/min, 56.3 ± 15.0 beats/min and, 45.9 ± 10 beats/min in the mature WKY, adult SD, young WKY, and young SHR groups, respectively. In contrast, microinjection of 3-MP into the posterior hypothalamus of adult SHRs produced no significant change in arterial pressure (−5.0 ± 1.8 mmHg) or heart rate (+5.3 ± 6.1 beats/min). In three of the adult SHRs, cardiovascular responses to electrical stimulation in the PH were compared to responses elicited by microinjection of 3-MP into the same PH site. Electrical stimulation produced large increases in both arterial pressure and heart rate; however, microinjection of 3-MP produced no significant changes in cardiovascular activity. These results indicate that spontaneously hypertensive rats have a deficiency in the tonic GABAergic input onto posterior hypothalamic neurons. This alteration may contribute to the maintenance of the elevated blood pressure in spontaneously hypertensive rats.

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center.

Identification of active networks involved in behavior is central to understanding brain function as an emergent property. Functional magnetic resonance imaging (fMRI) allows the identification of areas with increased or decreased activity, but the cellular correlates to changes in fMRI response is still controversial. Deep brain stimulation of the posterior hypothalamic nucleus (PH) is known to facilitate locomotor behaviors and rescue locomotion in rodent models of parkinsonian akinesia by an unknown mechanism. Here, we performed 9.4 T fMRI during deep brain stimulation of PH in the anesthetized rat as a model system to explore the network substrates for its behavioral consequences. In addition, multi-unit and field potential recordings were made to examine the physiological correlates to changes in fMRI response. The most robust and reliable MR signal increases were observed in the somatosensory and motor cortices, with minor limbic and sparse thalamic activation. Electrophysiological experiments demonstrated that increased fMRI response in the neocortex corresponds to general increases in spiking activity, decreased slow oscillations and increased delta band activity. Forelimb movements evoked by intracortical microstimulation had reduced thresholds and larger representational (motor map) areas during and following PH stimulation. These findings identify the sensorimotor cortices as major contributors for behavioral effects of PH stimulation, and that coincident increase in spiking, synaptic activity and MR signal reflect functional facilitation of neocortical output.

Object The aim of this study was to review the indications for and results of deep brain stimulation (DBS) of the posterior hypothalamus (pHyp) in the treatment of drug-refractory and severe painful syndromes of the face, disruptive and aggressive behavior associated with epilepsy, and below-average intelligence. The preoperative clinical picture, functional imaging studies, and overall clinical results in the literature are discussed. Methods All patients underwent stereotactic implantation of deep-brain electrodes within the pHyp. Data from several authors have been collected and reported for each clinical entity, as have clinical results, adverse events, and neurophysiological characteristics of the pHyp. Results The percentage of patients with chronic cluster headache who responded to DBS was 50% in the overall reported series. The response rate was 100% for short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and for chronic paroxysmal hemicrania, although only 2 patients and 1 patient, respectively, have been described as having these conditions. None of the 4 patients suffering from refractory neuropathic trigeminal pain benefited from the procedure (0% response rate), whereas all 5 patients (100%) affected with refractory trigeminal neuralgia (TN) due to multiple sclerosis (MS) and undergoing pHyp DBS experienced a significant decrease in pain attacks within the first branch of cranial nerve V. Six (75%) of 8 patients presenting with aggressive behavior and mental retardation benefited from pHyp stimulation; 6 patients were part of the authors' series and 2 were reported in the literature. Conclusions In carefully selected patients, DBS of the pHyp can be considered an effective procedure for the treatment of refractory trigeminal autonomic cephalalgias, aggressive behavior, and MS-related TN in the first trigeminal branch. Only larger and prospective studies along with multidisciplinary approaches (including, by necessity, neuroimaging studies) can lead us to better patient selection that would reduce the rate of nonresponders.

We have previously reported that endothelin-1 and -3 modulate different steps of noradrenergic transmission in the hypothalamus. We showed that endothelins modify neuronal norepinephrine transport activity through the regulation of the kinetic constant and internalization. In the present work we sought to define the endothelin receptors and intracellular mechanisms involved in the down-regulation of neuronal norepinephrine uptake induced by endothelin-1 and -3 in the rat posterior hypothalamic region. Results showed that endothelin-1 reduced norepinephrine uptake through ET(B) receptors, whereas endothelin-3 through a non-conventional or atypical endothelin receptor. In both cases, the effect on norepinephrine uptake was coupled to protein kinase A and C as well as nitric oxide pathways. However, neither protein kinase G nor intracellular or extracellular calcium and calcium/calmodulin-dependent protein kinase II were involved. In addition, the same intracellular mechanisms participated in the reduction of nisoxetine binding (norepinephrine transporter internalization index) induced by both endothelins. Present findings reveal the underlying mechanisms involved in the regulation of the neuronal norepinephrine transporter by endothelins and further support the role of these peptides in the modulation of noradrenergic transmission at the presynaptic nerve endings in the posterior hypothalamus.

Oestrogen is formed in the female dove brain. The aim of this study was to determine whether (a) the catalytic properties of the brain aromatase are similar to the ovarian enzyme and (b) aromatase activity in the female brain changes during the reproductive cycle and is influenced by steroids and environmental stimuli. The results show that female preoptic aromatase has a higher substrate affinity than the enzyme in ovarian follicles (apparent Km: preoptic area, 7 nmol/l; ovarian follicles, 29 nmol/l), but a lower activity in the preoptic area (Vmax: preoptic area, 290 fmol/mg tissue per h; ovarian follicles, 843 fmol/mg tissue per h). In intact females with developing follicles, oestradiol-17β formation was higher in the posterior hypothalamus than the preoptic area. Females in a later stage of reproductive development (yolked follicles) had a different distribution of oestrogen formation with increased aromatase activity in the preoptic area. Preoptic and posterior hypothalamic aromatase activity of females paired with males for 10 days was positively correlated (r = 0·84, P = 0·0001; r = 0·75, P = 0·001 respectively) with ovarian development. Females with undeveloped ovaries which interacted with males had higher preoptic aromatase activity than visually isolated females with similar ovarian development, suggesting that behavioural stimuli have direct effects on brain aromatase activity which are independent of the ovary. Oestradiol benzoate treatment increased preoptic and posterior hypothalamic aromatase activity in intact and ovariectomized females, and testosterone propionate treatment increased anterior hypothalamic aromatase activity, but did not affect other areas, indicating that the distribution of induced aromatase activity is steroid-specific. Oestrogen treatment in ovariectomized or intact females did not replicate the maximal hypothalamic aromatase activity seen when the ovary contained yolked follicles. We conclude that brain aromatase activity is related directly to ovarian condition during the reproductive cycle of the female dove. As in the male, steroids have a role in the regulation of oestrogen formation in the female hypothalamus; behavioural stimuli are also likely to be involved in the control of the brain enzyme. Journal of Endocrinology (1992) 134, 385–396

The effects of verapamil or diltiazem on pressor responses to posterior hypothalamic stimulation, injected noradrenaline or tyramine were studied in urethane-anaesthetized normotensive, deoxycorticosterone acetate (DOCA), renal and spontaneously hypertensive rats at the early and established phases of hypertension. Pressor responses to the pressor stimuli were significantly enhanced in the early and established phases of hypertension when compared with the normotensives. While the magnitude of pressor responses in the established phase of renal or spontaneously hypertensive rats was significantly higher (P < 0·05) than the corresponding value in the early phase, in contrast, the pressor response in the early phase of DOCA hypertension was significantly higher than that of the established phase. Verapamil or diltiazem significantly (P < 0·005) inhibited pressor responses to injected noradrenaline or tyramine in all groups of rats but not that to hypothalamic stimulation, irrespective of the stage of hypertension. When the probable mechanism of the hypothalamic pressor response's resistance to the calcium antagonists was studied in-vitro, ATP significantly (P < 0·005) inhibited the relaxant effect of the calcium antagonists in the rat aortic strips. Our data indicate that verapamil or diltiazem is ineffective in inhibiting the pressor response to posterior hypothalamic stimulation. The probable mechanism of the resistance and the clinical implication of the findings are discussed.

The purpose of this study was to quantitate the constrictor responses of pre- vs. postglomerular microvessels during brief increases in renal nerve activity by directly observing the intact microcirculation. To validate the use of the rat hydronephrotic kidney model for this purpose, the vascular reactivity of hydronephrotic kidneys, and normal kidneys was assessed to adrenergic and neural stimulation by quantitating whole kidney blood flow velocity changes elicited by intravenous administration of norepinephrine, electrical stimulation of the posterior hypothalamus, and direct renal nerve stimulation. Hydronephrotic and nonhydronephrotic kidneys responded comparably to norepinephrine and posterior hypothalamic stimulation; however, the hydronephrotic kidneys were less responsive than normal kidneys to direct renal nerve stimulation. In the microcirculatory experiments, stimulation of the splanchnic nerve (2-8 Hz) induced a frequency-dependent constriction of interlobular arteries and afferent arterioles. Preglomerular vessel diameters decreased by 42-53% during the 8-Hz stimulation, whereas the efferent arteriolar diameters did not significantly change. Thus, constriction of preglomerular vessels mediates, in large part, the changes in renal hemodynamics evoked by increases in renal sympathetic nerve activity.

Trigeminal neuralgia is a disorder characterized by paroxysmal pain arising in one or more trigeminal branches; it is commonly reported in multiple sclerosis. In multiple sclerosis patients the ophthalmic branch may be frequently involved and the risks carried by neurosurgical ablative procedures are higher including major adverse effects such as corneal reflex impairment and keratitis. The objective of this works is to assess the role of posterior hypothalamus neuromodulation in the treatment of trigeminal neuralgia in multiple sclerosis patients. Five multiple sclerosis patients suffering from refractory recurrent trigeminal neuralgia involving all three trigeminal branches underwent deep brain stimulation of the posterior hypothalamus. The rationale of this intervention emerges from our earlier success in treating pain patients suffering from trigeminal autonomic cephalalgias. After follow-up periods that ranged from 1 to 4 years after treatment, the paroxysmal pain arising from the first trigeminal branch was controlled, whereas the recurrence of pain in the second and third trigeminal branches necessitated repeated thermorhizotomies to control in pain in two patients after 2 years of follow-up. In conclusion, deep brain stimulation may be considered as an adjunctive procedure for treating refractory paroxysmal pain within the first trigeminal division so as to avoid the complication of corneal reflex impairment that is known to follow ablative procedures.

In the diurnal unstriped Nile grass rat ( Arvicanthis niloticus ) access to a running wheel can trigger a shift in active phase preference, with some individuals becoming night-active (NA), while others continue to be day-active (DA). To investigate the contributions of different neural systems to the support of this shift in locomotor activity, we investigated the association between chronotype and Fos expression during the day and night in three major nuclei in the basal forebrain (BF) cholinergic (ACh) arousal system – medial septum (MS), vertical and horizontal diagonal band of Broca (VDB and HDB respectively) −, and whether neural activation in these areas was related to neural activity in the orexinergic system. We also measured Fos expression in dopaminergic and non-dopaminergic cells of two components of the reward system that also participate in arousal – the ventral tegmental area (VTA) and supramammillary nucleus (SUM). NAs and DAs were compared to animals with no wheels. NAs had elevated Fos expression at night in ACh cells, but only in the HDB. In the non-cholinergic cells of the BF of NAs, enhanced nocturnal Fos expression was almost universally seen, but only associated with activation of the orexinergic system for the MS/VDB region. For some of the areas and cell types of the BF, the patterns of Fos expression of DAs appeared similar to those of NAs, but were never associated with activation of the orexinergic system. Also common to DAs and NAs was a general increase in Fos expression in non-dopaminergic cells of the SUM and anterior VTA. Thus, in this diurnal species, voluntary exercise and a shift to a nocturnal chronotype changes neural activity in arousal and reward areas of the brain known to regulate a broad range of neural functions and behaviors, which may be also affected in human shift workers.

The neuronal pathways, through which prolactin secretion is regulated during lactation, have still not been fully explored. Studies indicate that the suckling stimulus travels through the spinal cord, the brain stem, and then reaches the hypothalamus. The focus of this present experiment is to further explore the neuronal connections between the brain stem and the arcuate nucleus that may be involved in suckling-induced prolactin release. Ante- and retrograde tracing techniques were used. To chemically characterize the explored neurons neuropeptide immunohistochemistry was applied. Previous studies have indicated that the peripeduncular nucleus is a relay of the suckling stimulus in the midbrain, conveying the information to the hypothalamus. In our experiments, we have found an additional cell group in the subparafascicular parvocellular nucleus located just behind the posterior thalamus that projects to the arcuate neurons. The injection of the retrograde tracer into the ventrolateral part of the arcuate nucleus labeled cells in the lateral subdivision of the subparafascicular parvocellular nucleus. Anterograde tracing from the subparafascicular parvocellular nucleus resulted in fiber labeling in the arcuate nucleus in close apposition with dynorphin immunopositive neurons. Double labeling revealed that a subpopulations of the subparafascicular parvocellular neurons projecting to the arcuate nucleus contained tuberoinfundibular peptide of 39 residues or calcitonin gene-related peptide. The presented findings suggest that the ascending fibers from the subparafascicular parvocellular nucleus might be in the pathway involved in the suckling-induced prolactin release.

INTRODUCTION Deep brain stimulation of the posterior hypothalamic region (PHR) is an emerging technique for the treatment of medically intractable cluster headache. Few reports have analyzed single unit neuronal recordings in the human PHR. We report properties of spontaneous neuronal discharge in PHR for 6 patients who underwent DBS for cluster headaches. METHODS Initial target coordinates, determined by magnetic resonance imaging stereotactic localization, were 2 mm lateral, 3 mm posterior, and 5 mm inferior to the midpoint of the anterior commissure-posterior commissure plane. A single microelectrode penetration was performed beginning 10 mm above the anatomic target, without systemic sedation. Single units were discriminated off-line by cluster cutting in principal components space. Discharge rates, interspike intervals, and oscillatory activity were analyzed and compared between ventromedial thalamic and hypothalamic units. RESULTS Six patients and 24 units were evaluated. Units in the PHR had a slow, regular spontaneous discharge with wide, low-amplitude action potentials. The mean discharge rate of hypothalamic neurons was significantly lower (mean +/- standard deviation, 13.2 +/- 12.2) than that of medial thalamic units (28.0 +/- 8.2). Oscillatory activity was not detected. Microelectrode recording in this region caused no morbidity. CONCLUSION The single-unit discharge rate of neurons in the PHR of awake humans was 13.2 Hz and was significantly lower than medial thalamic neurons recorded dorsal to the target. The findings will be of use for microelectrode localization of the cluster headache target and for comparison with animal studies.

Background It is well documented that several general anesthetics, including propofol, potentiate glycine receptor function. Furthermore, glycine receptors exist throughout the central nervous system, including areas of the brain thought to be involved in sleep. However, the role of glycine receptors in anesthetic-induced hypnosis has not been determined. Methods Experiments were conducted in rats where the loss of righting reflex (LORR) was used as a marker of the hypnotic state. Propofol-induced LORR was examined in the presence and absence of strychnine (a glycine receptor antagonist), GABAzine (a gamma-aminobutyric acid A receptor antagonist), as well as ketamine (an antagonist of N-methyl-D-aspartic acid subtype of glutamate receptors). Furthermore, the effects of propofol on the currents elicited by glycine and gamma-aminobutyric acid were analyzed in neurons isolated from the posterior hypothalamus of rats. The effects of strychnine and GABAzine on propofol-induced currents were also evaluated. Results Strychnine and GABAzine dose-dependently reduced the percentage of rats exhibiting LORR induced by propofol. Furthermore, strychnine significantly increased the onset time and reduced the duration of LORR induced by propofol. In contrast, strychnine did not affect the LORR induced by ketamine. In addition, propofol markedly increased the currents elicited by glycine and GABA of hypothalamic neurons. Conversely, strychnine and GABAzine both profoundly attenuated the current induced by propofol. Conclusion Strychnine, the glycine receptor antagonist, dose-dependently reduced propofol-induced LORR in rats and propofol-induced current of rat hypothalamic neurons. These results suggest that neuronal glycine receptors partially contribute to propofol-induced hypnosis.

The supramammillary nucleus (SuM) in the hypothalamus is proposed to regulate the function of the hippocampus through distinct fiber connection. Several investigations suggest that the SuM is relevant to anxiety and defensive behavior. Function of the SuM, however, is not known exactly. In order to demonstrate the spatial activation of the SuM in physiologically behaving rats, we investigated Fos induction in the SuM by exposure to novel environment. To correct uneven background in microscopic preparations, we applied a convolution filter, resulting in reliable automatic counting of Fos-positive neurons and analyzed the distribution of Fos-positive neurons in the whole region of SuM. A large number of Fos-positive neurons were observed throughout the entire SuM after rats exposed to a novel open field. A three-dimensional density map revealed that density of the Fos-positive neurons was highest in the medial SuM, especially in its core regions. Based on these results we suggest that the medial SuM modulates defensive behavior and that the lateral SuM modulates emotional and memory functions of the hippocampus.

5-Hydroxytryptamine1A (5-HT1A) receptor agonists have been shown to inhibit the activity of hippocampal, cortical, and dorsal raphé neurons. We tested urapidil and a new 5-HT1A agonist, CM 57493 [4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridine ], for their neuroprotective activity in models of focal and global cerebral ischemia in rodents. After middle cerebral artery-occlusion (MCA-0) in mice, the infarct size was reduced dose dependently by both urapidil and CM 57493. In MCA-occluded rats, CM 57493 (1 and 5 mg/kg) reduced the cortical infarct volume by 30% and application of 10 mg/kg CM 57493 led to a 40% reduction in the cortical infarct volume. The striatal damage could not be influenced by CM 57493 treatment. Furthermore, 1 and 5 mg/kg CM 57493 significantly reduced the neuronal damage within the CA1 sector of the rat hippocampus after 10 min of forebrain ischemia followed by 7 days of recovery. Measurement of cerebral and rectal temperature revealed that the neuroprotective effect of CM 57493 was not caused by a hypothermic effect. We assume that the neuroprotective activity of 5-HT1A agonists is mediated by an inhibitory action on neurons.

Unilateral microinjection of neuropeptide Y (NPY) into the posterior hypothalamic nucleus was previously found to evoke a sympathoexcitatory-mediated increase in mean arterial pressure (MAP) in urethan-anesthetized rats. In this study, the effect of unilateral injection of NPY into the posterior hypothalamic nucleus on the cardiovascular system of conscious, freely moving rats was determined. Microinjection of NPY (0.2-2.4 nmol) or the cholinergic agonist carbachol (0.5-5.5 nmol) resulted in concentration-dependent increases in MAP. Pretreatment of animals with 7.5 mg/kg iv of the ganglionic blocker pentolinium resulted in a blockade of the increase in MAP evoked by microinjection of NPY (2.4 nmol) or carbachol (3.3 nmol). Despite their similarity of effects on MAP, NPY and carbachol evoked different changes in heart rate. NPY increased heart rate, whereas carbachol evoked a biphasic change in heart rate that consisted of an initial increase followed by a decrease. In addition, carbachol caused increases in both hindquarter and mesenteric vascular resistances, whereas NPY caused a short-lasting increase in mesenteric resistance and a tendency toward an increase in hindquarter resistance. Both NPY and carbachol increased total peripheral resistance while NPY decreased stroke volume. Cardiac output was not significantly affected by either NPY or carbachol, although NPY had a tendency to decrease cardiac output. These results suggest that microinjection of NPY or carbachol into the posterior hypothalamic nucleus of conscious rats evokes an increase in MAP primarily as a result of sympathoexcitation and that NPY and carbachol selectively affect autonomic nervous system control of the cardiovascular system.

Diurnal changes of LH secretion in sexually immature hens of 9, 11, 13 and 15 weeks of age consisted of 25–40% increases in the mean concentrations of LH in plasma between 15.00 and 18.00 h, i.e. between 2 h before and 1 h after the onset of darkness. During this time there was a tendency for the mean contents of LHRH-I in the anterior hypothalamus and posterior hypothalamus to increase by 21–74% and 20–56% respectively. In hens of 9 and 15 weeks, diurnal changes in the plasma concentration of LH closely paralleled those of LHRH-I content in the posterior hypothalamus. In contrast, the diurnal rhythm of LH secretion in hens of 11 and 13 weeks was more marked and plasma concentrations of LH continued to rise steeply between 18.00 and 21.00 h, i.e. between 1 and 4 h after the onset of darkness. At 11 weeks, this was associated with a reduction (PPPPP It is concluded that a diurnal rhythm of release of LHRH-I may drive the diurnal rhythm of LH secretion. Thus, in sexually immature hens of 9 and 15 weeks and laying hens in which diurnal changes in plasma LH were small there were parallel changes in the content of LHRH-I in the posterior hypothalamus. However, where the plasma concentration of LH was increased substantially, as at 11 weeks, there was a decline in the hypothalamic contents of LHRH-I. A simultaneous fall in the hypothalamic content of LHRH-II raises the possibility of a causal relationship between the activities of LHRH-II, LHRH-I and the release of LH. Journal of Endocrinology (1991) 130, 457–462

The posterior hypothalamic receptors involved in the cardiovascular responses to electrical stimulation of the rostral ventrolateral medulla were investigated in urethane-anaesthetized rats. Electrical stimulation of the rostral ventrolateral medulla produced a significant increase in systolic blood pressure. This response was significantly attenuated by the prior administration of d,l-propranolol (20 micrograms), clonidine (8 micrograms), atropine (8 micrograms) or methysergide (10 micrograms) into the posterior hypothalamus, but not by cimetidine (11 micrograms), chlorpheniramine (12 micrograms), naloxone (10 micrograms) or a vasopressin V1 antagonist (100 ng). The effect of clonidine (8 micrograms) on the pressor response to stimulation of the rostral ventrolateral medulla was antagonized by idazoxan (66 micrograms). These results confirm that the cardiovascular changes elicited by stimulation of the rostral ventrolateral medulla area are, in part, centrally modulated by alpha 2 and beta-adrenoceptors in the posterior hypothalamus which exert respectively, inhibitory and stimulatory effect. Furthermore the results indicate the involvement of posterior hypothalamic cholinergic and serotonergic receptors in the pressor response produced by stimulation of the rostral ventrolateral medulla.

Previous research in mice has shown that an uncontrollable stressor, but not a controllable stressor, depresses responding for rewarding electrical stimulation of the brain (ESB) (33). We reexamined this effect in rats by determining rate-intensity functions for rewarding brain stimulation 24 h and 48 h following stressor exposure. In each rat, two electrodes, one on each side of the brain, were aimed at the posterior, lateral hypothalamus. Self-stimulation rate-intensity functions were obtained for each electrode; stimulation of one electrode always caused stronger activity than equivalent stimulation of the other. If the rats had been stressed with uncontrollable shock the preceding day, their responding was significantly depressed to stimulation at the weaker electrode site but not the stronger electrode site. However, if the rat had control over the stressor, then rate-intensity functions were unchanged. Repeating the test for rate-intensity function 48 h after exposure to the stressor showed no effect of prior stress on self-stimulation. This work suggests that relatively brief exposure to an uncontrollable stressor can leave a residual, 24-h depressive influence on reward system substrates. Some effects of exposure to uncontrollable stressors on acquisition and maintenance of responding for rewards may be due, therefore, to attenuation of reward strength.

Experiments were undertaken to determine if sympatho-inhibition produced by ketanserin is due to antagonism of central nervous system alpha 1-adrenoceptors rather than central 5-HT2 receptors and if (like prazosin) it produces sympatho-inhibition indirectly via a central (presynaptic) alpha 2-adrenoceptor mechanism. Administration of ketanserin (0.03-3.0 mg/kg i.v.) caused a dose-related depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the hypothalamus in pentobarbital anesthetized cats. No effect of ketanserin was observed on electrodermal responses evoked by preganglionic sympathetic nerve stimulation nor did the more specific 5-HT2 receptor antagonist, cinanserin, produce a central sympatholytic effect at dosages up to 3 mg/kg i.v. Pretreatment with alpha 2-adrenoceptor blockers yohimbine, idazoxan, or rauwolscine significantly antagonized ketanserin-induced sympatho-inhibition. Depletion of central nervous system (CNS) monoamines totally prevented ketanserin-induced sympatho-inhibition although clonidine (30 micrograms/kg i.v.) continued to be effective. These results suggest that ketanserin acts in the CNS to reduce sympathetic reactivity by blocking alpha 1-adrenoceptors and not 5-HT2 receptors. In this regard, ketanserin appears to act in a manner similar to other alpha 1-adrenoceptor antagonists (e.g. prazosin and indoramin) by an apparent presynaptic facilitation of alpha 2-adrenoceptor mediated tonic inhibition descending from the lower brainstem.

To determine whether noradrenergic projections to the posterior hypothalamus via baroreflex are altered in the hypertensive state, the extracellular norepinephrine (NE) content of the posterior hypothalamus was measured in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) after sinoaortic denervation (SAD) or sham operation. In WKY, blood pressure (BP) and extracellular NE content 24 h after SAD were significantly higher than those of sham-operated rats. Contrarily, SAD did not increase both BP and NE in the posterior hypothalamus of SHR. These results suggest that the noradrenergic pathway via the baroreflex is impaired in SHR. This mechanism may play an important role in the development and maintenance of hypertension in SHR.

Several studies have provided evidence that suprapontine structures are involved in modulating the respiratory response to increases in carbon dioxide. However, the actual neuroanatomical site(s) responsible for this effect has not been identified. Therefore, the purpose of the present study was to determine if the posterior hypothalamus is one rostral site involved in the modulation of the respiratory response to hypercapnia. Phrenic nerve responses to progressive step increases in end-tidal PCO2 were recorded before and after unilateral microinjection of gamma-aminobutyric acid (GABA) antagonists into the posterior hypothalamus of anesthetized cats, which were paralyzed and ventilated. Microinjection of the antagonists reduced the apneic threshold to lower values of end-tidal PCO2. In addition, phrenic nerve responses to changes in CO2 above the apneic threshold were augmented following microinjections of the GABA antagonists. This augmentation resulted from larger respiratory frequency responses with slight increases in the tidal phrenic response. Microinjection of a GABA agonist into the same hypothalamic site reversed the effects of the GABA antagonist. Microinjection of the GABA agonist without a preceding antagonist injection had no effects. These results suggest that the respiratory responses to increases in PCO2 above the apneic threshold are modulated by neurons in the posterior hypothalamus in anesthetized cats. This hypothalamic modulation involves a GABAergic mechanism.

Bilateral administration of 6-hydroxydopamine in the medial fore-brain bundle at the level of the posterolateral hypothalamus in rats resulted in hypokinesia, muscular rigidity and tremor as determined by various behavioral assessment procedures. These neurological signs were accompanied by marked decreases in the concentrations of dopamine and its main metabolites dihydroxyphenylacetic acid and homovanillic acid in both striatum and nucleus accumbens. Administration of apomorphine (1 mg/kg) or L-Dopa (60 mg/kg) reversed or totally abolished the hypokinesia, rigidity and tremor in lesioned animals. Together, the present findings demonstrate that bilateral intrahypothalamic administration of 6-OHDA results in the appearance of the three cardinal symptoms of Parkinson's disease in rats. This model should prove to be valuable for both the study of the neuropathological processes underlying the neurological signs of this disease and the screening of potential antiparkinson agents.

To examine whether baroreceptor reflex regulation by the posterior hypothalamus becomes modified with age, we compared baroreceptor reflex sensitivity and hypothalamic responsiveness in 2- and 10-month-old rats anesthetized with urethane-chloralose. Hypothalamic regulation of baroreceptor reflex sensitivity was assessed by recording responses to intravenously infused phenylephrine and afferent aortic nerve stimulation after sham operation or electrolytic destruction of the posterior hypothalamus. Regardless of age, reflex bradycardia and sympathoinhibition elicited during pressor responses to phenylephrine, as well as all cardiovascular and sympathetic nerve responses to afferent aortic nerve stimulation, were stronger in rats with bilateral hypothalamic lesions than in age-matched, sham-operated controls. Distinctively, because baroreceptor reflex sensitivity differed with age only in sham-operated controls but not in lesioned rats, we concluded that age-related differences in baroreceptor reflex sensitivity had been abolished by posterior hypothalamic lesions. Other experiments were then performed to compare responses to graded electrical stimulation of the posterior hypothalamus in baroreceptor-intact rats. Pressor and sympathoexcitatory responses to hypothalamic stimulation were larger, and stimulus thresholds were lower at 10 than at 2 months of age thereby suggesting that hypothalamic responsiveness had increased with age. Our results are in accord with the interpretation that aging exacerbates the baroreceptor reflex suppression normally exerted by the posterior hypothalamus.

Norepinephrine(NE) release in posterior nucleus(PH) of the hypothalamus was examined before and during acute shaker (oscillation) stress in sinoaortic denervated(SAD) and sham-operated(SO) rats. NE in PH extracellular fluid of freely moving rats was collected by microdialysis and measured by sensitive radioenzymatic assay. Three days after SAD or SO operation, mean arterial pressure(MAP) and heart rate(HR) were significantly higher in SAD rats than SO rats. Baseline levels of NE in PH dialysate were also significantly elevated in SAD rats. Although five minutes of shaker stress elicited pressor and tachycardic responses coupled with increased NE release in PH of both groups, the increases in MAP and dialysate NE were larger in SAD than SO rats. These findings indicate that noradrenergic neurons in the PH respond to stress-induced stimuli and receive tonic input from baroreflex pathways.

Olfactory information modulates innate and social behaviors in rodents and other species. Studies have shown that the medial nucleus of the amygdala (MEA) and the ventral premammillary nucleus (PMV) are recruited by conspecific odor stimulation. However, the chemical identity of these neurons is not determined. We exposed sexually inexperienced male rats to female or male odors and assessed Fos immunoreactivity (Fos-ir) in neurons expressing NADPH diaphorase activity (NADPHd, a nitric oxide synthase), neuropeptide urocortin 3, or glutamic acid decarboxylase mRNA (GAD-67, a GABA-synthesizing enzyme) in the MEA and PMV. Male and female odors elicited Fos-ir in the MEA and PMV neurons, but the number of Fos-immunoreactive neurons was higher following female odor exposure, in both nuclei. We found no difference in odor induced Fos-ir in the MEA and PMV comparing fed and fasted animals. In the MEA, NADPHd neurons colocalized Fos-ir only in response to female odors. In addition, urocortin 3 neurons comprise a distinct population and they do not express Fos-ir after conspecific odor stimulation. We found that 80% of neurons activated by male odors coexpressed GAD-67 mRNA. Following female odor, 50% of Fos neurons coexpressed GAD-67 mRNA. The PMV expresses very little GAD-67, and virtually no colocalization with Fos was observed. We found intense NADPHd activity in PMV neurons, some of which coexpressed Fos-ir after exposure to both odors. The majority of the PMV neurons expressing NADPHd colocalized cocaine- and amphetamine-regulated transcript (CART). Our findings suggest that female and male odors engage distinct neuronal populations in the MEA, thereby inducing contextualized behavioral responses according to olfactory cues. In the PMV, NADPHd/CART neurons respond to male and female odors, suggesting a role in neuroendocrine regulation in response to olfactory cues.

The field of neuromodulation is emerging as a promising and alternative therapeutical option for many drug-resistant clinical conditions, including painful syndromes such as refractory chronic cluster headache (CCH) and trigeminal neuralgia. We here report a series of patients who have undergone Deep Brain Stimulation (DBS) of Posterior Hypothalamus for chronic cluster headache, trigeminal neuralgia and atypical facial pain, matching their corresponding clinical results and also suggesting a role for Great Occipital Nerve Stimulation (which is a much less invasive procedure) in the treatment of CCH. According to us, the refinement of surgical techniques and of metabolic and functional brain neuroradiological investigations will lead to a refinement of the therapeutical strategies in such patients.

Recently, functional imaging data have underscored the crucial role of the hypothalamus in trigemino-autonomic headaches, a group of severe primary headaches. This prompted the application of hypothalamic deep-brain stimulation (DBS), with the intention to preventing cluster headache (CH) attacks in selected severe therapy-refractory cases. To date, a total of 50 operated intractable CH patients, one patient with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and three with atypical facial pain, have been reported. However, it is not apparent why the spontaneous bursts of activation in the inferior posterior hypothalamus result in excruciating head pain, whereas continuous electrical stimulation of the identical area is able to prevent these attacks. Recently, this issue has been addressed by examining 10 operated chronic CH patients, using H215O-positron emission tomography and alternately switching the hypothalamic stimulator on and off. The stimulation-induced activation in the ipsilateral posterior inferior hypothalamic grey (the site of the stimulator tip) as well as activation and de-activation in several cerebral structures belonging to neuronal circuits usually activated in pain transmission. These data argue against an unspecific antinociceptive effect or pure inhibition of hypothalamic activity as the mode of action of hypothalamic DBS and suggest functional modulation of the pain-processing network.

金沢大学医薬保健研究域医学系, Stress-induced analgesia (SIA) is a key component of the defensive behavioral "fight-or-flight" response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased input resistance, and blocked the firing of action potentials in Hcrt neurons. N/OFQ postsynaptic effects were consistent with opening of a G protein-regulated inwardly rectifying K+ (GIRK) channel. N/OFQ also modulated presynaptic release of GABA and glutamate onto Hcrt neurons in mouse hypothalamic slices. Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did not exhibit SIA, although analgesia was induced by i.c.v. administration of Hcrt-1. N/OFQ blocked SIA in wild-type mice, while coadministration of Hcrt-1 overcame N/OFQ inhibition of SIA. These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA.

We previously reported that endothelin-1 and endothelin-3 modulate norepinephrine neuronal release and tyrosine hydroxylase activity and expression in the hypothalamus. In the present study we sought to establish the role of endothelin-1 and -3 in the regulation of norepinephrine uptake in the anterior and posterior hypothalamus. Results showed that in the anterior hypothalamus endothelin-3 increased neuronal norepinephrine uptake whereas endothelin-1 decreased it. Conversely, in the posterior hypothalamic region both endothelins diminished the neuronal uptake of the amine. Endothelins response was concentration dependent and maintained at all studied times. Endothelins also modified the kinetic and internalization of the NE neuronal transporter. In the anterior hypothalamic region endothelin-3 increased the V(max) and the B(max) whereas endothelin-1 decreased them. However, in the posterior hypothalamic region both endothelins diminished the V(max) as well as B(max). Neither endothelin-1 nor endothelin-3 modified neuronal norepinephrine transporter K(d) in the studied hypothalamic regions. These findings support that in the posterior hypothalamic region both endothelins diminished neuronal norepinephrine transporter activity by reducing the amine transporter expression on the plasmatic membrane. Conversely, in the anterior hypothalamic region endothelin-3 enhanced neuronal norepinephrine transporter activity by increasing the expression of the transporter on the presynaptic membrane, whereas endothelin-1 induced the opposite effect. Present results permit us to conclude that both endothelins play an important role in the regulation of norepinephrine neurotransmission at the presynaptic nerve endings in the hypothalamus.

Deep brain stimulation (DBS) of the posterior hypothalamus was found to be effective in the treatment of drug-resistant chronic cluster headache. We report the results of a multicentre case series of six patients with chronic cluster headache in whom a DBS in the posterior hypothalamus was performed. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to published coordinates 2 mm lateral, 3 mm posterior and 5 mm inferior referenced to the mid-AC-PC line. Microelectrode recordings at the target revealed single unit activity with a mean discharge rate of 17 Hz (range 13-35 Hz, n = 4). Out of six patients, four showed a profound decrease of their attack frequency and pain intensity on the visual analogue scale during the first 6 months. Of these, one patient was attack free for 6 months under neurostimulation before returning to the baseline which led to abortion of the DBS. Two patients had experienced only a marginal, non-significant decrease within the first weeks under neurostimulation before returning to their former attack frequency. After a mean follow-up of 17 months, three patients are almost completely attack free, whereas three patients can be considered as treatment failures. The stimulation was well tolerated and stimulation-related side-effects were not observed on long term. DBS of the posterior inferior hypothalamus is an effective therapeutic option in a subset of patients. Future controlled multi-centre trials will need to confirm this open-label experience and should help to better define predictive factors for non-responders.

Deep brain stimulation (DBS) of the posterior hypothalamic area is a new treatment option for patients with refractory chronic cluster headache (CCH). A review of the literature reveals that studies based on large numbers of patients, long-term observations and controlled randomised trials are still lacking. In 2006 a case report of the first patient in Germany to be operated on to allow DBS was published, and we now present a report of this patient's course in the first 6 months after the operation; in addition, a current literature review is discussed. In July 2005 a DBS lead was placed in the left posterior hypothalamic area of this 39-year-old woman with CCH. Stimulation on demand achieved complete suppression of the cluster attacks, and the patient no longer needed medication. After about 8 months a decreasing effect of the stimulation, with only about 50% reduction of cluster attacks, and stimulation-induced side effects were observed. Neither reprogramming of the stimulation parameters nor pharmacological therapy with on-demand and long-term medication reduced the frequency or severity of CCH attacks to the level experienced in the early postoperative stage. Because of intolerable subjective side effects and tension-related pain at the site of the connection cable, in September 2006 the whole system was explanted at the patient's request.DBS in the posterior hypothalamic area is an invasive treatment option for use in cases with CCH that is refractory to any pharmacological therapy. As demonstrated by this case report, it is not possible to give a prognosis concerning its long-term efficacy: despite the initial excellent benefit there can be a reduction and even a loss of the effect of stimulation. The clinical results and long-term follow-up observations of the few cases published so far need to be evaluated in a larger multicentre trial with a double-blind study design.

Neuroimaging studies in cluster headache (CH) patients have increased understanding of attack-associated events and provided clues to the pathophysiology of the condition. They have also suggested stimulation of the ipsilateral posterior inferior hypothalamus as a treatment for chronic intractable CH. After 8 years of experience, stimulation has proved successful in controlling the pain attacks in almost 60% of chronic CH patients implanted at various centres. Although hypothalamic implant is not without risks, it has generally been performed safely. Implantation affords an opportunity to perform microrecordings of individual posterior hypothalamic neurons. These studies are at an early stage, but suggest the possibility of identifying precisely the target site by its electrophysiological characteristics. Autonomic studies of patients undergoing posterior hypothalamic stimulation provide further evidence that long-term stimulation is safe, revealing that it can cause altered modulation of the mechanisms of orthostatic adaptation without affecting the baroreflex, cardiorespiratory interactions or efferent sympathetic and vagal functions. Chronically stimulated patients have an increased threshold for cold pain at the site of the first trigeminal branch ipsilateral to the stimulated side; when the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, suggesting that long-term stimulation is required to induce sensory and nociceptive changes. Posterior inferior hypothalamic stimulation is now established as a treatment for many chronic CH patients. The technique is shedding further light on the pathophysiology of the disease, and is also providing clues to functioning of the hypothalamus itself.

We have previously shown that the atrial natriuretic peptide (ANP) content of the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR-S) is higher than that of Wistar-Kyoto (WKY) rats. ANP has been shown to inhibit neuronal norepinephrine release and to reduce the excitability of hypothalamic neurons. This study tested the hypothesis that blockade of endogenous ANP in the anterior hypothalamus by local microinjection of a monoclonal antibody to ANP (MAb KY-ANP-II) lowers blood pressure in SHR-S. Purified MAb KY-ANP-II (0.055 and 0.55 micrograms) or control mouse IgG in 200 nl saline was microinjected into the anterior hypothalamic area (AHA) of conscious SHR-S and control WKY rats. As a further control, Mab KY-ANP-II (0.55 microgram) was microinjected into the posterior hypothalamic area (PHA) of SHR-S. Anterior hypothalamic microinjection of MAb KY-ANP-II caused significant dose-related decreases in mean arterial pressure (MAP) and heart rate (HR) in SHR-S but not in WKY rats. Control injections of equal volumes of IgG had no effect on MAP or HR. Microinjection of Mab KY-ANP-II into PHA produced no significant alteration in MAP or HR in SHR-S. These data provide the first demonstration that endogenous ANP in a region of brain known to influence cardiovascular function mediates BP and HR control in the rat. These findings suggest that the increased endogenous ANP in the anterior hypothalamus of SHR-S may be involved in the central regulation of BP in the model.

A microdialysis probe, implanted in the posterior hypothalamus (PH) was used to examine changes of extracellular norepinephrine (NE) in freely moving rats from which mean arterial pressure (mAP) and heart rate (HR) were continuously monitored. Artificial cerebrospinal fluid (aCSF) was pumped through the probe and 10-microliters dialysate samples were collected at 5-minute intervals and analyzed for NE by radioenzymatic assay. High sodium chloride (NaCl)-aCSF solution elicited pressor and tachycardiac responses and locomotor activity coupled with significant increases in levels of dialysate NE. The latter and the associated cardiovascular effects were significantly attenuated by perfusate lidocaine (0.5%). When alpha-adrenergic receptors in PH were blocked by phenoxybenzamine (0.165 M), high NaCl-aCSF released NE but the associated cardiovascular effects were attenuated. In addition, intravenous ganglionic blockade with hexamethonium (25 mg/kg) also attenuated cardiovascular responses during the high NaCl-aCSF perfusion of PH. These results indicate that PH is one of the important areas for central actions of NaCl and that the cardiovascular and locomotor responses produced by central NaCl, in part, depend on neuroadrenergic activity in PH.

Neurons in the tuberomammillary nucleus (TM) of the rat hypothalamus were immunolabelled for the enzyme adenosine deaminase (ADA) and investigated by electron microscopic immunohistochemical techniques. ADA-immunoreactivity was distributed throughout the somal and dendritic cytoplasm of TM neurons and in the karyoplasm of most, but not all of these neurons. Immunoreactive axons were rarely observed within the tightly packed cell clusters of the TM subdivisions examined. Dense deposition of immunoreaction product together with reasonable preservation of morphological detail facilitated identification of immunoreaction product together with reasonable preservation of morphological detail facilitated identification of immunoreactive profiles and allowed characterization of the ultrastructural features of labelled neurons and the relationships of these with each other and with surrounding unlabelled neuronal and glial elements. Immunolocalization of ADA therefore represents a reliable and convenient method for the identification of TM neurons in EM studies of their ultrastructure and synaptic interactions.

The effects of a small posterior hypothalamic deafferentation (PHD) on adrenocortical responses to peripheral neural stimuli were investigated in rats. PHD inhibited the rise in plasma corticosterone (CS) following photic and acoustic stimulation, but did not affect the adrenocortical response following sciatic nerve stimulation. PHD did not change the content of norepinephrine in the paraventricular nucleus of the hypothalamus, however, it reduced the serotonin content by about 30%. The possible role of serotonin or of another tonic caudal input into the hypothalamus for the activation of the pituitary-adrenocortical axis, following certain neural stimuli, is discussed.

The effects of amphetamine on the extinction of intracranial self-stimulation (ICSS) and on postextinction ICSS performance were examined in rats implanted with electrodes either in medial prefrontal cortex (mPFC) or in the posterior hypothalamus-ventral tegmental area (PH-VTA). Lever-pressing for ICSS was allowed to stabilize in daily 15-minute sessions before each animal was exposed to 5 minutes of extinction (responding without reward). Animals were administered either 0.25 mg/kg d-amphetamine or saline before baseline, extinction and lower in PH-VTA animals compared with saline-treated controls. Rates did not change immediately after extinction but, one day later, postextinction sessions. After amphetamine treatment, the number of lever presses during extinction was higher in mPFC animals and rates had increased in all saline-treated animals (both PH-VTA and mPFC animals) and had decreased in all amphetamine-treated animals. These findings demonstrated that the effects of amphetamine on the extinction of ICSS were different in cortical and hypothalamic sites, possibly because of regional differences in stimulus-evoked reinforcement and inhibitory processes.

It was found in chronic experiments in cats, using the recording of local blood flow and oxygen tension (pO2) in the anterior and posterior hypothalamus in the sleep-wakefulness cycle, that when the phases of sleep are alternated, the changes in these parameters are in different directions: the level of blood flow and the frequency of fluctuation of the pO2 during paradoxical sleep increase in the posterior hypothalamus, while they decrease in the anterior hypothalamus. On the other hand, the opposite pattern is observed during slow-wave sleep. The multidirectionality of the changes in local blood flow level and in the frequency of fluctuations of pO2 in one and the same sleep phase indicate that they are of local origin and must be governed by functional-metabolic shifts in these structures; the functional state of the posterior hypothalamus during paradoxical sleep is assessed on this basis.

The synaptic connections between histaminergic neurons and substance P (SP) afferents in the caudal magnocellular nucleus (CM) of the hypothalamus were examined using an immunoelectron microscopic mirror method. SP-immunoreactive (SP-IR) terminals made synaptic contacts with the somata, somatic spines and dendrites of histidine decarboxylase immunoreactive (HDC-IR) neurons. This suggests that SP afferents exert monosynaptic influence on the central histaminergic neuronal system.

The purpose of the present study was to evaluate the effects of alpha-2u-globulin, a sex-dependent male rat urinary protein on pituitary-gonadal functions and hypothalamic monoamine contents in male mice. Adult male mice, maintained under standardized laboratory conditions (L:D, 14:10) were injected subcutaneously with alpha-2u-globulin at a dose of 1 mg/animal/day or with vehicle daily for 14 days and killed 16 h after the last injection. Plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) and testicular levels of T were measured by radioimmunoassays. The concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in medial basal hypothalamus (MBH) and anterior hypothalamus (AH) were measured by high performance liquid chromatography. Administration of alpha-2u-globulin led to a significant increase in plasma FSH and LH levels (P less than 0.05) as well as in plasma and testicular T levels (P less than 0.025). In the MBH of alpha-2u-globulin treated mice, there were significant elevations of NE (P less than 0.025), DA (P less than 0.01) and 5-HT (P less than 0.025) contents. In the AH, both DA (P less than 0.025) and 5-HT (P less than 0.01) contents were decreased while NE content remained unaltered. These results indicate that administration of alpha-2u-globulin can lead to a significant stimulation of pituitary-testicular axis and that this effect may be mediated through alteration of hypothalamic monoamines.

The dorsal premammillary nucleus (PMd) has a critical role on the expression of defensive responses to predator odor. Anatomical evidence suggests that the PMd should also modulate memory processing through a projecting branch to the anterior thalamus. By using a pharmacological blockade of the PMd with the NMDA-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5), we were able to confirm its role in the expression of unconditioned defensive responses, and further revealed that the nucleus is also involved in influencing associative mechanisms linking predatory threats to the related context. We have also tested whether olfactory fear conditioning, using coffee odor as CS, would be useful to model predator odor. Similar to cat odor, shock-paired coffee odor produced robust defensive behavior during exposure to the odor and to the associated context. Shock-paired coffee odor also up-regulated Fos expression in the PMd, and, as with cat odor, we showed that this nucleus is involved in the conditioned defensive responses to the shock-paired coffee odor and the contextual responses to the associated environment.

The purpose of this study was to look at the connectivity of the posterior inferior hypothalamus in a patient implanted with a deep brain stimulating electrode using probabilistic tractography in conjunction with postoperative MRI scans. In a patient with chronic cluster headache we implanted a deep brain stimulating electrode into the ipsilateral postero-medial hypothalamus to successfully control his pain. To explore the connectivity, we used the surgical target from the postoperative MRI scan as a seed for probabilistic tractography, which was then linked to diffusion weighted imaging data acquired in a group of healthy control subjects. We found highly consistent connections with the reticular nucleus and cerebellum. In some subjects, connections were also seen with the parietal cortices, and the inferior medial frontal gyrus. Our results illustrate important anatomical connections that may explain the functional changes associated with cluster headaches and elucidate possible mechanisms responsible for triggering attacks.

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes characterised by intense pain and associated activation of cranial parasympathetic autonomic outflow pathways out of proportion to the pain. The TACs include cluster headache, paroxysmal hemicrania and SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing). The pathophysiology of these syndromes involves activation of the trigeminal-autonomic reflex, whose afferent limb projects into the trigeminocervical complex in the caudal brainstem and upper cervical spinal cord. Functional brain imaging has shown activations in the posterior hypothalamic grey matter in TACs. This paper reviews the anatomy and physiology of these conditions and the brain imaging findings. Current treatments are summarised and the role of neuromodulation procedures, such as occipital nerve stimulation and deep brain stimulation in the posterior hypothalamus are reviewed. Neuromodulatory procedures are a promising avenue for these highly disabled patients with treatment refractory TACs.

Chronic high frequency stimulation (HFS) of the posteromedial hypothalamus (PMH) has been the first direct therapeutic application of functional neuroimaging data in a restorative reversible procedure for the treatment of an otherwise refractory neurological condition; in fact, the target coordinates for the stereotactic implantation of the electrodes have been provided by positron emission tomography (PET) studies, which were performed during cluster headache attacks. HFS of PMH produced a significant and marked reduction of pain attacks in patients with chronic cluster headache (CCH) and in one patient with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The episodes of violent behaviour and psychomotor agitation during the attacks of CCH supported the idea that the posteromedial hypothalamus could be also involved in the control of aggressiveness; this has been previously suggested, in the seventies, by the results obtained in Sano's hypothalamotomies for the treatment of abnormal aggression and disruptive behaviour. On the basis of these considerations, we have performed HFS of the PMH and controlled successfully violent and disruptive behaviour in patients refractory to the conventional sedative drugs. Finally, we also tested the same procedure in three patients with refractory atypical facial pain, but unfortunately, they did not respond to this treatment.

Cluster headache (CH) is a primary headache with excruciatingly painful attacks that are strictly unilateral. About 10% of cases experience no significant remission, and about 15% of these do not respond to medication, so surgery is considered. Neuroimaging studies show that the posterior inferior hypothalamus is activated during CH attacks and is plausibly the CH generator. We report on 16 chronic CH patients, with headaches refractory to all medication, who received long-term hypothalamic stimulation following electrode implant to the posterior inferior hypothalamus. After a mean follow-up of 23 months, a persistent pain-free to almost pain-free state was achieved in 13/16 patients (15/18 implants; 83.3%) a mean of 42 days (range 1–86 days) after monopolar stimulation initiation. Ten patients (11 implants) are completely pain-free. A common side effect was transient diplopia, which limited stimulation amplitude. In one patient, a small non-symptomatic haemorrhage into the 3rd ventricle occurred following implant, but regressed 24 h later. Persistent side effects are absent except in one patient with bilateral stimulation, in whom stimulation was stopped to resolve vertigo and worsened bradycardia, but was resumed later without further problems. Hypothalamic stimulation is an effective, safe and well tolerated treatment for chronic drug-refractory CH. It appears as a valid alternative to destructive surgical modalities, and has the additional advantage of being reversible.

Central diabetes insipidus is rare in children. Characteristic features include polyuria and polydipsia due to arginine vasopressin deficiency. The differential diagnosis of polyuric states may be difficult. Etiologic diagnosis of central diabetes insipidus may be an equally difficult task.To specify the difficulties encountered in the diagnosis of central diabetes insipidus and to point out features of the etiologic work-up and of long-term follow-up of children with idiopathic central diabetes insipidus.A retrospective study of 12 children admitted with a polyuria/polydipsia syndrome to the pediatric - consultation and emergency unit of the children's hospital of Tunis between 1988 and 2005. Children with acquired nephrogenic central diabetes insipidus were excluded. Fourteen-hour fluid restriction test and/or desmopressin test were used without plasma vasopressin measurement.Eight patients were classified as having central diabetes insipidus, which was severe in seven children and partial in one girl. One patient was classified as having primary polydipsia. The diagnosis remains unclear in three patients. The etiological work-up in eight patients with central diabetes insipidus enabled the identification of Langerhan's-cell histiocytosis in two patients and neurosurgical trauma in one. The cause was considered idiopathic in five patients. The median follow-up of the five patients with idiopathic central diabetes insipidus was five years two months plus or minus six years seven months (range five months, 14.5 years). During this follow-up, neither brain magnetic resonance imaging scans findings nor anterior pituitary function have changed.Fluid restriction and desmopressin tests did not enable an accurate distinction between partial diabetes insipidus and primary polydipsia. Regular surveillance is warranted in patients with idiopathic central diabetes insipidus to identify potential etiologies.

Objective To evaluate the structure and quality of sleep and the circadian rhythm of body core temperature (BcT degrees ) in patients with drug-resistant chronic cluster headache (CH) before and during deep brain stimulation (DBS) of the posterior hypothalamus. Background Chronic CH is a severe primary headache and frequently associated with disturbances in sleep. Posterior hypothalamus DBS is performed as an effective treatment of drug-resistant chronic CH. The effects of posterior hypothalamus DBS on sleep and the circadian rhythm of BcT degrees are unknown. Methods Three male patients with chronic drug-resistant CH underwent 48-hour consecutive polysomnography (PSG) by means of the VITAPORT system with determination of BcT degrees by means of a rectal probe. Recordings were done before electrode implantation in the posterior hypothalamus and after optimized DBS of posterior hypothalamus. Results Before electrode implantation PSG showed nocturnal CH attacks, reduced sleep efficiency, fragmented sleep and increased periodic limb movements in sleep (PLMS). During DBS nocturnal CH attacks were abolished and sleep efficiency and PLMS improved. BcT degrees circadian rhythm was normal both before and during DBS. Conclusions Our data show that DBS of posterior hypothalamus in drug-resistant chronic CH is effective in curtailing nocturnal CH attacks, and is associated with improved sleep structure and quality. Chronic CH displays a normal circadian rhythm of BcT degrees, unchanged during hypothalamic DBS.

GPCR101 is a recently identified orphan G protein-coupled receptor (GPCR) expressed abundantly in the human and mouse hypothalamus. In the absence of a ligand, a direct approach to determine the function(s) of this receptor is not possible. However, clues to the possible functions of GPCR101 may yield from information on the distribution of the receptor and the effect of in vivo manipulation upon the expression level of the receptor. In situ hybridisation on mouse brain sections revealed GPCR101 expression in a number of nuclei, including the amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, as well as in the arcuate nucleus, posterior hypothalamus and paraventricular nucleus of the hypothalamus. Food-deprivation was found to increase GPCR101 mRNA level in the posterior hypothalamus and amygdala. In obese mice bearing the ob gene mutation, GPCR101 mRNA level decreased in the posterior hypothalamus and remained unaltered in the amygdala. By contrast, in both nuclei, GPCR101 mRNA level did not change significantly in obese ob/ob mice after intraperitoneal injection of leptin or in mice fed with a high fat diet. These data suggest that GPCR101 mRNA expression in the posterior hypothalamus and amygdala is regulated by a factor(s) other than leptin. Dual in situ hybridisation was used to establish the relationship between GPCR101 and neuropeptides expressed in the hypothalamus. In the arcuate nucleus, GPCR101 mRNA was expressed in approximately half of the population of neurones expressing the mRNA for the anorexigenic neuropeptide, pro-opiomelanocortin, which suggests a potential functional relationship.