Activation of medial hypothalamic orexin neurons during a Go/No-Go task.

Orexin neurons (Orx; also referred to as hypocretin) are found exclusively in the hypothalamus, and release the neuropeptides orexin A and orexin B (also referred to as hypocretin 1 and 2) throughout the CNS. With its widespread targets, the orexin system is involved in a number of functions including, but not limited to stress, reward, wakefulness, and food seeking. Our laboratory has previously proposed that the dorsomedial hypothalamus (DMH) and perifornical (PFA) orexin neurons function in stress and arousal whereas those in lateral hypothalamus (LH) participate in reward processes (Harris and Aston-Jones, 2006). In the current study, we compared Fos activation in orexin neurons located in medial hypothalamus (DMH and PFA) to those in LH during a Go/No-Go task for a highly palatable food reward, a task that would likely activate regions for arousal/attention as well as reward. The Go/No-Go paradigm is a useful behavioral tool to measure behavioral inhibition, impulsivity, learning, and reaction time. Our results revealed increased activation of medial hypothalamic orexin neurons correlated with greater accuracy on the Go/No-Go task. No correlation was found between Go/No-Go accuracy and activation of lateral hypothalamic orexin neurons. This study supports a functional dichotomy of medial vs lateral orexin neurons, and indicates a role for medial orexin neurons in behavioral performance that requires response inhibition.

Role of medial hypothalamic orexin system in panic, phobia and hypertension.

Orexin has been implicated in a number of physiological functions, including arousal, regulation of sleep, energy metabolism, appetitive behaviors, stress, anxiety, fear, panic, and cardiovascular control. In this review, we will highlight research focused on orexin system in the medial hypothalamic regions of perifornical (PeF) and dorsomedial hypothalamus (DMH), and describe the role of this hypothalamic neuropeptide in the behavioral expression of panic and consequent fear and avoidance responses, as well as sympathetic regulation and possible development of chronic hypertension. We will also outline recent data highlighting the clinical potential of single and dual orexin receptor antagonists for neuropsychiatric conditions including panic, phobia, and cardiovascular conditions, such as in hypertension.

QRFP administration into the medial hypothalamic nuclei improves memory in rats.

Even though several of RFamide peptides have been shown to modify memory and learning processes in different species, almost nothing is known regarding cognitive effects of recently discovered neuropeptide QRFP. Considering multiple physiological functions of QRFP, localization of QRFP-synthesizing neurons in the hypothalamus and its' widely spread binding sites within the CNS, the present study was designed to investigate the possible role of QRFP in the consolidation of spatial memory. As target area for microinjection, the medial hypothalamic area, including dorsomedial (DMN) and ventromedial (VMN) nuclei, has been chosen. At first, the effects of two doses (200 ng and 400 ng) of QRFP were investigated in Morris water maze. After that receptor antagonist BIBP3226 (equimolar amount to the effective dose of neuropeptide) was applied to elucidate whether it can prevent effects of QRFP. To reveal possible changes in anxiety level, animals were tested in Elevated plus maze. The higher dose of QRFP (400 ng) improved short-term memory consolidation in Morris water maze. Pretreatment with antagonist BIBP3226 abolished cognitive effects of QRFP. The neuropeptide did not affect anxiety level of rats. This study provides unique evidence regarding the role of QRFP in the consolidation of memory and gives the basis for further investigations of neuropeptide's cognitive effects.

The alpha- and beta-noradrenergic receptors blockade in the dorsal raphe nucleus impairs the panic-like response elaborated by medial hypothalamus neurons.

Dorsal raphe nucleus (DRN) neurons are reciprocally connected to the locus coeruleus (LC) and send neural pathways to the medial hypothalamus (MH). The aim of this work was to investigate whether the blockade of α1-, α2- or ß-noradrenergic receptors in the DRN or the inactivation of noradrenergic neurons in the LC modify defensive behaviours organised by MH neurons. For this purpose, Wistar male rats received microinjections of WB4101, RX821002, propranolol (α1-, α2- and ß-noradrenergic receptor antagonists, respectively) or physiological saline in the DRN, followed 10 min later by MH GABAA receptor blockade. Other groups of animals received DSP-4 (a noradrenergic neurotoxin), physiological saline or only a needle insertion (sham group) into the LC, and 5 days later, bicuculline or physiological saline was administered in the MH. In all these cases, after MH treatment, the frequency and duration of defensive responses were recorded over 15 min. An anterograde neural tract tracer was also deposited in the DRN. DRN neurons send pathways to lateral and dorsomedial hypothalamus. Blockade of α1- and ß-noradrenergic receptors in the DRN decreased escape reactions elicited by bicuculline microinjections in the MH. In addition, a significant increase in anxiety-like behaviours was observed after the blockade of α2-noradrenergic receptors in the DRN. LC pretreatment with DSP-4 decreased both anxiety- and panic attack-like behaviours evoked by GABAA receptor blockade in the MH. In summary, the present findings suggest that the norepinephrine-mediated system modulates defensive reactions organised by MH neurons at least in part via noradrenergic receptors recruitment on DRN neurons.

Sleeve Gastrectomy Rescuing the Altered Functional Connectivity of Lateral but Not Medial Hypothalamus in Subjects with Obesity.

BACKGROUND: Lateral and medial hypothalamus (LH and MH) play important roles in energy balance. Changed hypothalamic function has been found in subjects with obesity. However, the effect of bariatric surgery on the function of the two sub-regions has been poorly investigated. METHODS: Thirty-eight subjects with obesity and 34 age- and sex-matched normal-weight controls were included. Seventeen of the 38 subjects underwent laparoscopic sleeve gastrectomy. Functional magnetic resonance imaging data and metabolic parameters were collected to investigate functional connectivity networks of the two hypothalamic sub-regions as well as the influence of sleeve gastrectomy on the two networks in subjects with obesity. RESULTS: Compared to normal-weight controls, pre-surgical subjects had increased functional connectivity (FC) in the reward region (putamen) within the LH network, and increased FC in somatosensory cortical area (insula), as well as decreased FC in the cognitive control regions (prefrontal regions) within the MH network. After the surgery, post-surgical FC of the putamen within the LH network changed towards the patterns found in the control group. Furthermore, the changes in fasting glucose before and after the surgery were associated with the changes in FC of the putamen within the LH network. CONCLUSIONS: The FC within the LH and MH networks were changed in subjects with obesity. Part of these altered FC was rescued after the surgery.

Anatomical projections of the dorsomedial hypothalamus to the periaqueductal grey and their role in thermoregulation: a cautionary note.

The DMH is known to regulate brown adipose tissue (BAT) thermogenesis via projections to sympathetic premotor neurons in the raphe pallidus, but there is evidence that the periaqueductal gray (PAG) is also an important relay in the descending pathways regulating thermogenesis. The anatomical projections from the DMH to the PAG subdivisions and their function are largely elusive, and may differ per anterior-posterior level from bregma. We here aimed to investigate the anatomical projections from the DMH to the PAG along the entire anterior-posterior axis of the PAG, and to study the role of these projections in thermogenesis in Wistar rats. Anterograde channel rhodopsin viral tracing showed that the DMH projects especially to the dorsal and lateral PAG. Retrograde rabies viral tracing confirmed this, but also indicated that the PAG receives a diffuse input from the DMH and adjacent hypothalamic subregions. We aimed to study the role of the identified DMH to PAG projections in thermogenesis in conscious rats by specifically activating them using a combination of canine adenovirus-2 (CAV2Cre) and Cre-dependent designer receptor exclusively activated by designer drugs (DREADD) technology. Chemogenetic activation of DMH to PAG projections increased BAT temperature and core body temperature, but we cannot exclude the possibility that at least some thermogenic effects were mediated by adjacent hypothalamic subregions due to difficulties in specifically targeting the DMH and distinct subdivisions of the PAG because of diffuse virus expression. To conclude, our study shows the complexity of the anatomical and functional connection between the hypothalamus and the PAG, and some technical challenges in studying their connection.

Direct versus indirect actions of ghrelin on hypothalamic NPY neurons.

OBJECTIVES: Assess direct versus indirect action(s) of ghrelin on hypothalamic NPY neurons. MATERIALS AND METHODS: Electrophysiology was used to measure ion channel activity in NPY-GFP neurons in slice preparations. Ca2+ imaging was used to monitor ghrelin activation of isolated NPY GFP-labeled neurons. Immunohistochemistry was used to localize Trpm4, SUR1 and Kir6.2 in the hypothalamus. RESULTS: Acylated ghrelin depolarized the membrane potential (MP) of NPY-GFP neurons in brain slices. Depolarization resulted from a decreased input resistance (IR) in ~70% of neurons (15/22) or an increased IR in the remainder (7/22), consistent with the opening or closing of ion channels, respectively. Although tetrodotoxin (TTX) blockade of presynaptic action potentials reduced ghrelin-induced changes in MP and IR, ghrelin still significantly depolarized the MP and decreased IR in TTX-treated neurons, suggesting that ghrelin directly opens cation channel(s) in NPY neurons. In isolated NPY-GFP neurons, ghrelin produced a sustained rise of [Ca2+]c, with an EC50 ~110 pM. Pharmacologic studies confirmed that the direct action of ghrelin was through occupation of the growth hormone secretagogue receptor, GHS-R, and demonstrated the importance of the adenylate cyclase/cAMP/protein kinase A (PKA) and phospholipase C/inositol triphosphate (PLC/IP3) pathways as activators of 5' AMP-activated protein kinase (AMPK). Activation of isolated neurons was not affected by CNQX or TTX, but reducing [Na+]o suppressed activation, suggesting a role for Na+-permeable cation channels. SUR1 and two channel partners, Kir6.2 and Trpm4, were identified immunologically in NPY-GFP neurons in situ. The actions of SUR1 and Trpm4 modulators were informative: like ghrelin, diazoxide, a SUR1 agonist, elevated [Ca2+]c and glibenclamide, a SUR1 antagonist, partially suppressed ghrelin action, while 9-phenanthrol and flufenamic acid, selective Trpm4 antagonists, blocked ghrelin actions on isolated neurons. Ghrelin activation was unaffected by nifedipine and ω-conotoxin, inhibitors of L- and N-type Ca2+ channels, respectively, while Ni2+, mibefradil, and TTA-P2 completely or partially inhibited ghrelin action, implicating T-type Ca2+ channels. Activation was also sensitive to a spider toxin, SNX-482, at concentrations selective for R-type Ca2+ channels. Nanomolar concentrations of GABA markedly inhibited ghrelin-activation of isolated NPY-GFP neurons, consistent with chronic suppression of ghrelin action in vivo. CONCLUSIONS: NPY neurons express all the molecular machinery needed to respond directly to ghrelin. Consistent with recent studies, ghrelin stimulates presynaptic inputs that activate NPY-GFP neurons in situ. Ghrelin can also directly activate a depolarizing conductance. Results with isolated NPY-GFP neurons suggest the ghrelin-activated, depolarizing current is a Na+ conductance with the pharmacologic properties of SUR1/Trpm4 non-selective cation channels. In the isolated neuron model, the opening of SUR1/Trpm4 channels activates T- and SNX482-sensitive R-type voltage dependent Ca2+ channels, which could contribute to NPY neuronal activity in situ.

Cholinergic neurons in the dorsomedial hypothalamus regulate food intake.

OBJECTIVE: Central cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake. METHODS: To selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice. We also generated transgenic mice expressing channelrhodopsins in cholinergic neurons with the Cre-LoxP technique. To delete the Chat gene exclusively in the DMH, we injected an AAV carrying a Cre recombinase transgene into the DMH of floxed ChAT mice. Food intake was measured with and without selective stimulation of DMH cholinergic neurons. RESULTS: Mice lacking the Chat gene in the DMH show reduced body weight as compared to control. Chemogenetic activation of DMH cholinergic neurons promotes food intake. This orexigenic effect is further supported by experiments of optogenetic stimulation of DMH cholinergic neurons. DMH cholinergic neurons innervate pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Treatment with acetylcholine (ACh) enhances GABAergic inhibitory transmission to ARC POMC neurons that is blocked by the muscarinic receptor antagonist. Direct activation of cholinergic fibers in the ARC readily stimulates food intake that is also abolished by the muscarinic receptor antagonist. CONCLUSION: ACh released from DMH cholinergic neurons regulates food intake and body weight. This effect is mediated in part through regulation of ARC POMC neurons. Activation of muscarinic receptors on GABAergic axon terminals enhances inhibitory tone to ARC POMC neurons. Hence, this novel DMHACh â†’ ARCPOMC pathway plays an important role in the control of food intake and body weight.

Interaction between novel oscillation within the ventromedial hypothalamus and the sympathetic nervous system.

The ventromedial hypothalamus (VMH) is known to play an important role in feeding behavior and the control of sympathetic nerve activity (SNA). We report the identification of novel neuron groups that showed oscillations on both sides of the VMH in hypothalamus slice preparations from juvenile rats of postnatal days 5-14. We detected spontaneous rhythmic burst activity with a frequency of around 0.06Hz typically in the dorsolateral region of the VMH (i.e., VMH oscillation) using optical recordings (voltage and calcium imaging), field potential recordings and intracellular membrane potential recordings. The oscillation was also confirmed after isolation of the VMH from other hypothalamic structures. The frequency of oscillation was increased by lowering the glucose concentration of the superfusate. To evaluate the relation between VMH oscillation and SNA, we simultaneously recorded VMH oscillation, SNA from the thoracic sympathetic nerve trunk and phrenic nerve discharge (Phr) in the decerebrate and arterially perfused in situ preparation from juvenile rats of postnatal days 5-11. Power spectral analysis in the arterially perfused in situ rat preparation revealed similar peak values to those of slice preparations within the low-frequency range between the VMH oscillation and sympathetic nerve trunk activity. In addition, we analyzed cross-correlations between the VMH, SNA and Phr. The results revealed that a predominant positive correlation of the VMH activity with the SNA existed with an average time lag of 2.4s, suggesting the presence of functional couplings between the VMH and SNA (and respiratory center) in the lower brainstem and spinal cord. We hypothesize that the VMH oscillation might be involved in low-frequency modulation of the SNA.

Molecular basis for regulating seasonal reproduction in vertebrates.

Animals that inhabit mid- to high-latitude regions exhibit various adaptive behaviors, such as migration, reproduction, molting and hibernation in response to seasonal cues. These adaptive behaviors are tightly regulated by seasonal changes in photoperiod, the relative day length vs night length. Recently, the regulatory pathway of seasonal reproduction has been elucidated using quail. In birds, deep brain photoreceptors receive and transmit light information to the pars tuberalis in the pituitary gland, which induces the secretion of thyroid-stimulating hormone. Thyroid-stimulating hormone locally activates thyroid hormone via induction of type 2 deiodinase in the mediobasal hypothalamus. Thyroid hormone then induces morphological changes in the terminals of neurons that express gonadotropin-releasing hormone and facilitates gonadotropin secretion from the pituitary gland. In mammals, light information is received by photoreceptors in the retina and neurally transmitted to the pineal gland, where it inhibits the synthesis and secretion of melatonin, which is crucial for seasonal reproduction. Importantly, the signaling pathway downstream of light detection and signaling is fully conserved between mammals and birds. In fish, the regulatory components of seasonal reproduction are integrated, from light detection to neuroendocrine output, in a fish-specific organ called the saccus vasculosus. Various physiological processes in humans are also influenced by seasonal environmental changes. The findings discussed herein may provide clues to addressing human diseases, such as seasonal affective disorder.

Effective Modulation of Male Aggression through Lateral Septum to Medial Hypothalamus Projection.

Aggression is a prevalent behavior in the animal kingdom that is used to settle competition for limited resources. Given the high risk associated with fighting, the central nervous system has evolved an active mechanism to modulate its expression. Lesioning the lateral septum (LS) is known to cause "septal rage," a phenotype characterized by a dramatic increase in the frequency of attacks. To understand the circuit mechanism of LS-mediated modulation of aggression, we examined the influence of LS input on the cells in and around the ventrolateral part of the ventromedial hypothalamus (VMHvl)-a region required for male mouse aggression. We found that the inputs from the LS inhibited the attack-excited cells but surprisingly increased the overall activity of attack-inhibited cells. Furthermore, optogenetic activation of the projection from LS cells to the VMHvl terminated ongoing attacks immediately but had little effect on mounting. Thus, LS projection to the ventromedial hypothalamic area represents an effective pathway for suppressing male aggression.

Effects of direct QRFP-26 administration into the medial hypothalamic area on food intake in rats.

The RFamide peptide family comprises a number of biologically active peptides sharing RF motif at their C-terminal end. These peptides are involved in the control of multiple physiological functions including regulation of metabolism and feeding behavior. QRFP-43 as well as its 26-aminoacid residue QRFP-26 are able to cause orexigenic effect when administered to the rodents' cerebral ventricles. QRFPs have been suggested as the endogenous ligands of the previously orphan GPR103 receptors. GPR103 receptors share amino acid identity with other receptors of neuropeptides involved in feeding (NPY, NPFF, galanin). QRFP-26 expressing neurons and binding sites are densely present in the rat medial hypothalamus (MHA), an area directly responsible for the regulation of feeding. QRFP-26 was delivered to the target area by direct intrahypothalamic microinjection, and the consumption of liquid food was measured over a 60 min period. Both doses (100 and 200 ng) significantly increased food intake. Non-specific receptor antagonist BIBP3226 eliminated the orexigenic effect caused by QRFP-26 administration. Effective doses of QRFP-26 did not modify general locomotor activity and behavioral patterns examined in the open-field test. This study is the first reporting feeding modulating effects following direct intrahypothalamic QRFP-26 administration.

Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior.

OBJECTIVES: The aim of this study was to analyze the impact of deep brain stimulation (DBS) of the posteromedial hypothalamus (pHyp) on seizure frequency in patients with drug-resistant epilepsy (DRE) associated with intractable aggressive behavior (IAB). METHODS: Data were collected retrospectively from nine patients, who received bilateral stereotactic pHyp-DBS for the treatment of medically intractable aggressive behavior, focusing on five patients who also had DRE. All patients were treated at the Colombian Center and Foundation of Epilepsy and Neurological Diseases-FIRE (Chapter of the International Bureau for Epilepsy), in Cartagena de Indias, Colombia from 2010 to 2014. Each case was evaluated previously by the institutional ethical committee, assessing the impact of aggressive behavior on the patient's family and social life, the humanitarian aspects of preserving the safety and physical integrity of caregivers, and the need to prevent self-harm. Epilepsy improvement was measured by a monthly seizure reduction percentage, comparing preoperative state and outcome. Additional response to epilepsy was defined by reduction of the antiepileptic drugs (AEDs). Aggressive behavior response was measured using the Overt Aggression Scale (OAS). RESULTS: All the patients with DRE associated with IAB presented a significant decrease of the rate of epileptic seizures after up to 4 years follow-up, achieving a general 89.6% average seizure reduction from the state before the surgery. Aggressiveness was significantly controlled, with evident improvement in the OAS, enhancing the quality of life of patients and families. SIGNIFICANCE: In well-selected patients, DBS of the pHyp seems to be a safe and effective procedure for treatment of DRE associated with refractory aggressive behavior. Larger and prospective series are needed to define the pHyp as a target for DRE in different contexts.

Frequency and Spatial and Temporal Characteristics of Neuronal Spike Activity in Dorsal Hippocampal Field CA1 in Behaviorally Active and Passive Rats after Stimulation of the Lateral and Ventromedial Hypothalamus.

We studied the neuronal mechanisms of the various emotional and motivational states in Wistar rats with different behavioral activities. Stimulation of the ventromedial hypothalamus had more pronounced effect on the frequency of action potentials in neurons of the dorsal hippocampus than stimulation of the lateral hypothalamus. However, stimulation of the lateral hypothalamus produced stronger effect on spatial and temporal characteristics of fi ring pattern than stimulation of the ventromedial hypothalamus. Neurons of the dorsal hippocampus in active rats were less sensitive to stimulation of the lateral and ventromedial hypothalamus than in passive animals.

NMDA and AMPA/kainate glutamatergic receptors in the prelimbic medial prefrontal cortex modulate the elaborated defensive behavior and innate fear-induced antinociception elicited by GABAA receptor blockade in the medial hypothalamus.

The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) and amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptors of the prelimbic (PL) division of the medial prefrontal cortex (MPFC) on the panic attack-like reactions evoked by γ-aminobutyric acid-A receptor blockade in the medial hypothalamus (MH). Rats were pretreated with NaCl 0.9%, LY235959 (NMDA receptor antagonist), and NBQX (AMPA/kainate receptor antagonist) in the PL at 3 different concentrations. Ten minutes later, the MH was treated with bicuculline, and the defensive responses were recorded for 10 min. The antagonism of NMDA receptors in the PL decreased the frequency and duration of all defensive behaviors evoked by the stimulation of the MH and reduced the innate fear-induced antinociception. However, the pretreatment of the PL cortex with NBQX was able to decrease only part of defensive responses and innate fear-induced antinociception. The present findings suggest that the NMDA-glutamatergic system of the PL is critically involved in panic-like responses and innate fear-induced antinociception and those AMPA/kainate receptors are also recruited during the elaboration of fear-induced antinociception and in panic attack-related response. The activation of the glutamatergic neurotransmission of PL division of the MPFC during the elaboration of oriented behavioral reactions elicited by the chemical stimulation of the MH recruits mainly NMDA receptors in comparison with AMPA/kainate receptors.

Development of the medial hypothalamus: forming a functional hypothalamic-neurohypophyseal interface.

The medial hypothalamus is composed of nuclei of the tuberal hypothalamus, the paraventricular nucleus of the anterior hypothalamus, and the neurohypophysis. Its arrangement, around the third ventricle of the brain, above the adenohypophysis, and in direct contact with the vasculature, means that it serves as an interface with circulating systems, providing a key conduit through which the brain can sample, and control, peripheral body systems. Through these interfaces, and interactions with other parts of the brain, the medial hypothalamus centrally governs diverse homeostatic processes, including energy and fluid balance, stress responses, growth, and reproductive behaviors. Here, we summarize recent studies that reveal how the diverse cell types within the medial hypothalamus are assembled in an integrated manner to enable its later function. In particular, we discuss how the temporally protracted operation of signaling pathways and transcription factors governs the appearance and regionalization of the hypothalamic primordium from the prosencephalic territory, the specification and differentiation of progenitors into neurons in organized nuclei, and the establishment of interfaces. Through analyses of mouse, chick, and zebrafish, a picture emerges of an evolutionarily conserved and highly coordinated developmental program. Early indications suggest that deregulation of this program may underlie complex human pathological conditions and dysfunctional behaviors, including stress and eating disorders.

Unilateral thalamic Vim and GPi stimulation for the treatment of Holmes' tremor caused by midbrain cavernoma: case report and review of the literature.

A 30-year-old man with brainstem cavernoma experienced hemorrhage and was operated in 2008. Six months after the operation, the patient presented with new complaints of left arm tremor namely Holmes' tremor. Neurological examination also revealed left-sided internuclear ophthalmoplegia, left-sided mild paresis, and increased deep tendon reflexes of the left upper extremity, truncal ataxia, and dysarthria. Brain magnetic resonance imaging showed a postoperative cavity and gliosis at the level of the superior and inferior colliculus in the right tegmentum and right red nucleus with extension to the substantia nigra. Fahn-Tolosa-Marin tremor rating scale (TRS) for his left upper extremity (Part A, score 6) was 11 for the proximal and the distal arm. After the failure of medical treatment, the patient underwent right globus pallidum internus and ventral intermediate thalamic nucleus deep brain stimulation. There were no side effects related to the stimulation. Final TRS months after operation was 3 for the proximal and 4 for the distal arm.

Fatigue is mediated by cholinoceptors within the ventromedial hypothalamus independent of changes in core temperature.

We investigated brain mechanisms modulating fatigue during prolonged physical exercise in cold environments. In a first set of studies, each rat was subjected to three running trials in different ambient temperatures (T(a)). At 8 °C and 15 °C, core body temperature (T(core)) decreased and increased, respectively, whereas at 12 °C, the T(core) did not change throughout the exercise. In another set of experiments, rats were randomly assigned to receive bilateral 0.2 µL injections of 2.5 × 10(-2) M methylatropine or 0.15 M NaCl solution into the ventromedial hypothalamic nuclei (VMH). Immediately after the injections, treadmill exercise was started. Each animal was subjected to two experimental trials at one of the following T(a) : 5 °C, 12 °C or 15 °C. Muscarinic blockade of the VMH reduced the time to fatigue (TF) in cold environments by 35-37%. In all T(a) studied, methylatropine-treated rats did not present alterations in T(core) and tail skin temperature compared with controls. These results indicate that, below the zone of thermoneutrality, muscarinic blockade of the VMH decreases the TF, independent of changes in T(core). In conclusion, our data suggest that VMH muscarinic transmission modulates physical performance, even when the effects of thermoregulatory adjustments on fatigue are minimal.

[Pathogenesis of narcolepsy: from HLA association to hypocretin deficiency]. / Zur Pathogenese der Narkolepsie: Vom HLA-Typus als Risikoprofil zum Hypocretinmangel als Ursache.

Narcolepsy is a rare and chronic sleep disorder, characterised by excessive daytime sleepiness. Frequently associated signs are cataplexy, sleep paralysis and hypnagogic or hypnopompic hallucinations. Advances in understanding the pathogenesis of the disease have essentially been elucidated during the last fifteen years. The most significant finding has been the discovery of hypocretin-1 and -2 in 1998. Hypocretin-containing cells have widespread projections throughout the entire CNS and play a crucial role in the regulation of the sleep-wake cycle. They also contribute to olefaction and to the regulation of food intake. Animal models and human studies concordantly show that the disturbed hypocretin system is the probable cause of narcolepsy. However, it remains unclear why there is neuronal death of hypocretin-producing cells in the lateral hypothalamus. As the HLA-allele DQB1*0602 is associated with narcolepsy and hypocretin deficiency, an autoimmune reaction against hypocretin-producing neurons has been vigorously discussed. Newly discovered gene polymorphisms as well as previously unknown pathogenetic mechanisms, linking the sleep-wake cycle with the immune system, may also contribute to the pathogenetic cascade. Worthy of mention in this context is, e.g., the "insulin-like growth factor"-binding protein 3 (IGFBP3), whose overexpression causes a down-regulation of the hypocretin production. Substitution of the deficient neuropeptides by hypocretin agonists may become the causal treatment strategy of the future, if an adequate administration route can be found. Presently, animal trials, including genetic therapy, cell transplantations or the administration of hypocretin receptor agonists, are underway.

The effect of chronic immobilization stress on leptin signaling in the ovariectomized (OVX) rat.

Previous studies have shown that both 17ß-estradiol (E2) treatment and chronic stress may attenuate post-OVX weight gain in the female rat. However, the interaction between E2 and stress is unclear. This study examined the effect of E2 treatment and chronic immobilization stress on body weight. Adult OVX Sprague-Dawley rats were randomly assigned to one of four treatment groups in a 2X2 factorial design examining hormone treatment [vehicle (VEH) or E2, sc] and stress (no stress vs stress 60 min/day for 22 days). After 22 days, E2 significantly inhibited weight gain and food intake in OVX rats. In contrast, chronic stress reduced body weight only in control OVX animals but did not affect food intake. E2 reduced circulating leptin levels in non-stressed animals, but not in animals subjected to chronic immobilization. Western blot analysis indicated that E2 treatment increased leptin receptor (Ob-Rb) expression in the medial basal hypothalamus (MBH); however, this treatment also increased suppressor of cytokine signaling 3 (SOCS3), which is an inhibitor of leptin signaling. Chronic immobilization stress blunted the E2-induced increase in Ob-Rb and SOCS3 levels. These results suggest that chronic stress counteracts E2 effects on leptin signaling in the MBH without altering body weight.