Involvement of endothelins in deoxycorticosterone acetate-salt hypertension through the modulation of noradrenergic transmission in the rat posterior hypothalamus.

NEW FINDINGS: 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.

Blunted autonomic response in cluster headache patients.

BACKGROUND: Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls. METHODS AND MATERIALS: Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis. RESULTS: CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (-2.86 vs. -13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, -0.05 vs. -0.17, p < 0.05). CONCLUSIONS: CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.

SUNCT, SUNA and trigeminal neuralgia: different disorders or variants of the same disorder?

PURPOSE OF REVIEW: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) and trigeminal neuralgia are considered different disorders, thus grouped in separate sections of the International Classification of Headache Disorders 3 beta. However, the clinical, radiological and therapeutic overlap between SUNCT, SUNA, and trigeminal neuralgia has challenged this traditional view. This review summarizes the available clinical and pathophysiological evidence on whether SUNCT, SUNA and trigeminal neuralgia should be considered separate entities or variants of the same disorder. RECENT FINDINGS: Data on the clinical phenotype and effective management strategies in SUNCT and SUNA syndromes have shown striking similarities with trigeminal neuralgia. Moreover, studies exploring radiological findings supported the hypothesis of common aetiological and pathophysiological basis between SUNCT/SUNA and trigeminal neuralgia. However, a limitation of most studies is that they have included small samples of patients and therefore any conclusions need to be drawn cautiously. SUMMARY: Despite being considered distinct conditions, emerging clinical and radiological evidence supports a broader nosological concept of SUNCT, SUNA, and trigeminal neuralgia. These conditions may constitute a continuum of the same disorder, rather than separate clinical entities. Further evidence is required to shed light on this nosological issue, given its potential impact on clinical practice and further research studies in this area.

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

BACKGROUND: SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. CASE: Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. CONCLUSION: This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

[Hypothalamic deep brain stimulation for treatment of cluster headache]. / Stymulacja podwzgórza w leczeniu klasterowego bólu glowy.

Extremely severe, unilateral, recurrent facial pain and headache, accompanied by autonomic symptoms and signs, can be identified as cluster headache attacks (CH). Despite optimal pharmacological treatment, 20% of patients will not achieve satisfactory improvement. The severity of pain is so extreme that CH has been a cause of multiple suicidal attempts among patients ineffectively treated because of CH. Hypermetabolism of ipsilateral posterior hypothalamus observed in PET studies led to multiple attempts of deep brain stimulation (DBS) utilization in CH treatment. The authors present current opinions about DBS treatment in CH. A socioeconomic analysis of neuromodulatory treatment of CH is presented.

Pathophysiology of trigeminal autonomic cephalalgias.

Cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are primary headaches recently classified together as trigeminal autonomic cephalalgias (TACs). The causes of these headaches have long been debated, with "peripheral" hypotheses in opposition to "central" hypotheses. The available information indicates that the pain originates from within the brain in cluster headache. The hypothalamic activation observed during TAC attacks by use of functional neuroimaging, and the success of hypothalamic stimulation as a treatment, confirm that the posterior hypothalamus is crucial in the pathophysiology of these headaches. The posterior hypothalamus is now known to modulate craniofacial pain, and hypothalamic activation occurs in other pain disorders, suggesting that this brain area is likely to have a more complex role in the pathophysiology of TACs than that of a mere trigger. Hypothalamic activation might play a part in terminating rather than triggering attacks, and might also give rise to a central permissive state, allowing attacks to take place.

Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus.

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration.

Hypothalamic deep-brain stimulation: target and potential mechanism for the treatment of cluster headache.

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 H(2)(15)O-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.

Lessons from 8 years' experience of hypothalamic stimulation in cluster headache.

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.

[Central diabetes insipidus: diagnostic difficulties]. / Diabète insipide central: difficultés diagnostiques.

UNLABELLED: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Sympathetic hyperactivity during hypothalamic stimulation in spontaneously hypertensive rats.

To determine whether sympathetic hyperactivity of hypothalamic origin contributes to keep blood pressures high in spontaneous hypertension, aortic pressures and sympathetic nerve spike potentials were recorded during electrical stimulation of the posterior hypothalamus in urethane-anesthetized normotensive or hypertensive rats. Basal sympathetic nerve activity was higher in spontaneously hypertensive rats than in either normotensive or deoxycorticosterone acetate-salt hypertensive ones even before stimulation began. Blood pressure elevations produced by hypothalamic stimulation were always preceded by substantial increases in amplitude and rate of neural firing. Changes in amplitude could not be quantified, but rates of neural firing accelerated much more in spontaneous hypertensives than in normotensives during stimulation with 50- and 100-muA currents. Similar differences between deoxycorticosterone acetate-salt hypertensives and either normotensives or spontaneous hypertensives were not statistically significant. Nerve activity invariably became quiescent immediately after hypothalamic stimulation was discontinued, and recovery from this poststimulatory inhibition was faster in spontaneously hypertensive than in normotensive rats. Although spontaneous hypertensives generally also had stronger pressor responses to various sympathomimetic stimuli, responses to hypothalamic stimulation were enhanced to a greater extent than those to either norepinephrine or sympathetic nerve stimulation. Because this selectivity indicates participation of mechanisms other than augmented cardiovascular reactivity, further enhancement of responsiveness to hypothalamic stimuli was attributed to the associated increase in sympathetic nerve firing. These results are in accord with the hypothesis that the blood pressure elevation in rats with established spontaneous hypertension is a result, at least in part, of sympathetic hyperactivity emanating from the posterior hypothalamus.

Neuromodulatory approaches to the treatment of trigeminal autonomic cephalalgias.

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 of the posteromedial hypothalamus in facial pain syndromes and behaviour disorders.

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.

Connectivity of an effective hypothalamic surgical target for cluster headache.

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.

Inactivation of the medial mammillary nucleus attenuates theta rhythm activity in the hippocampus in urethane-anesthetized rats.

Although the importance of the mammillary body for memory and learning processes is well known, its exact role has remained vague. The fact, that many neurons in one nucleus of the mammillary body in rats, i.e. the medial mammillary nucleus (MM), fires according with hippocampal theta rhythm, makes this structure crucial for a theta rhythm signaling in so-called extended hippocampal system. These neurons are driven by descending projections from the hippocampal formation, but it is still unknown whether the mammillary body only conveys theta rhythm or may also modulate it. In the present study, we investigated the effect of pharmacological inactivation (local infusion of 0.5µl of 20% procaine hydrochloride solution) of the MM on hippocampal theta rhythm in urethane-anesthetized rats. We found that intra-MM procaine microinjections suppress sensory-elicited theta rhythm in the hippocampus by reduction of its amplitude, but not the frequency. Procaine infusion decreased the EEG signal power of low theta frequency bands, i.e. 3-5Hz, down to 9.2% in 3-4Hz band in comparison to pre-injection conditions. After water infusion (control group) no changes of hippocampal EEG signal power were observed. Our findings showed for the first time that inactivation of the MM leads to a disruption of hippocampal theta rhythm in the rat, which may suggest that the mammillary body can regulate theta rhythm signaling in the extended hippocampal system.

Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity.

OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and surrounding structures to be avoided such as the RN. PH units can be distinguished from ventral thalamic units based on their response to focal microstimulation. The RN has a characteristic higher firing rate and a pattern of beta oscillations in the spike trains. The effect of the anesthetic administered should be considered when using microelectrode recordings. The results of this study, along with previous reports, suggest that PH DBS may be an effective treatment for aggression.

GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity.

The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction.

Physical exercise decreases neuronal activity in the posterior hypothalamic area of spontaneously hypertensive rats.

Recently, physical exercise has been shown to significantly alter neurochemistry and neuronal function and to increase neurogenesis in discrete brain regions. Although we have documented that physical exercise leads to molecular changes in the posterior hypothalamic area (PHA), the impact on neuronal activity is unknown. The purpose of the present study was to determine whether neuronal activity in the PHA is altered by physical exercise. Spontaneously hypertensive rats (SHR) were allowed free access to running wheels for a period of 10 wk (exercised group) or no wheel access at all (nonexercised group). Single-unit extracellular recordings were made in anesthetized in vivo whole animal preparations or in vitro brain slice preparations. The spontaneous firing rates of PHA neurons in exercised SHR in vivo were significantly lower (8.5 +/- 1.6 Hz, n = 31 neurons) compared with that of nonexercised SHR in vivo (13.7 +/- 1.8 Hz, n = 38 neurons; P < 0.05). In addition, PHA neurons that possessed a cardiac-related rhythm in exercised SHR fired significantly lower (6.0 +/- 1.8 Hz, n = 11 neurons) compared with nonexercised SHR (12.1 +/- 2.4 Hz, n = 18 neurons; P < 0.05). Similarly, the spontaneous in vitro firing rates of PHA neurons from exercised SHR were significantly lower (3.5 +/- 0.3 Hz, n = 67 neurons) compared with those of nonexercised SHR (5.6 +/- 0.5 Hz, n = 58 neurons; P < 0.001). Both the in vivo and in vitro findings support the hypothesis that physical exercise can lower spontaneous activity of neurons in a cardiovascular regulatory region of the brain. Thus physical exercise may alter central neural control of cardiovascular function by inducing lasting changes in neuronal activity.

Immediate hypotensive after-effects of posterior hypothalamic lesions in awake rats with spontaneous, renal, or Doca hypertension.

If the posterior hypothalamus contributes to elevate blood pressure in hypertension by increasing sympathetic vasomotor activity, then lesions of the posterior hypothalamus should lower blood pressure more in hypertensive than in normotensive rats. To test this hypothesis without complications caused by anaesthesia, aortic pressures were recorded from indwelling catheters in awake rats before and after selective hypothalamic destruction. In normotensive rats rats, bilateral lesions of the medial areas of the posterior hypothalamus always lowered blood pressure while those in the anterior hypothalamus slightly increased it. Heart rate responses varied widely and did not seem to contribute to the blood pressure changes. Posterior hypothalamic lesions of approximately the same size had significantly greater hypotensive after-effects in renal and spontaneously hypentensive rats than in normotensive or Doca hypentensive ones. These results imply that sympathetic overactivity emanating from posterior hypothalamic centres contributes to the blood pressure elevation in spontaneous or chronic renal hypentension but not in Doca hypertension. However, because of inherent weaknesses in the 'lesion method' and the complexity of blood pressure regulation in awake animals, other explanations are possible.

Reorganization of supramammillary-hippocampal pathways in the rat pilocarpine model of temporal lobe epilepsy: evidence for axon terminal sprouting.

In mesial temporal lobe epilepsy (MTLE), spontaneous seizures likely originate from a multi-structural epileptogenic zone, including several regions of the limbic system connected to the hippocampal formation. In this study, we investigate the structural connectivity between the supramammillary nucleus (SuM) and the dentate gyrus (DG) in the model of MTLE induced by pilocarpine in the rat. This hypothalamic nucleus, which provides major extracortical projections to the hippocampal formation, plays a key role in the regulation of several hippocampus-dependent activities, including theta rhythms, memory function and emotional behavior, such as stress and anxiety, functions that are known to be altered in MTLE. Our findings demonstrate a marked reorganization of DG afferents originating from the SuM in pilocarpine-treated rats. This reorganization, which starts during the latent period, is massive when animals become epileptic and continue to evolve during epilepsy. It is characterized by an aberrant distribution and an increased number of axon terminals from neurons of both lateral and medial regions of the SuM, invading the entire inner molecular layer of the DG. This reorganization, which reflects an axon terminal sprouting from SuM neurons, could contribute to trigger spontaneous seizures within an altered hippocampal intrinsic circuitry.