GABAergic ventrolateral pre­optic nucleus neurons are involved in the mediation of the anesthetic hypnosis induced by propofol.

Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades, however the mechanism of anesthetic­induced unconsciousness remains to be fully elucidated. It has previously been demonstrated that anesthetics exert sedative effects by acting on endoge-nous sleep­arousal circuits. However, few studies focus on the ventrolateral pre­optic (VLPO) to locus coeruleus (LC) sleep­arousal pathway. The present study aimed to investigate if VLPO is involved in unconsciousness induced by propofol. The present study additionally investigated if the inhibitory effect of propofol on LC neurons was mediated by activating VLPO neurons. Microinjection, target lesion and extracellular single­unit recordings were used to study the role of the VLPO­LC pathway in propofol anesthesia. The results demonstrated that GABAA agonist (THIP) or GABAA antagonist (gabazine) microinjections into VLPO altered the time of loss of righting reflex and the time of recovery of righting reflex. Furthermore, propofol suppressed the spontaneous firing activity of LC noradrenergic neurons. There was no significant difference observed in firing activity between VLPO sham lesion and VLPO lesion rats. The findings indicate that VLPO neurons are important in propofol­induced unconsciousness, however are unlikely to contribute to the inhibitory effect of propofol on LC spontaneous firing activity.

Melanocortins mimic the effects of leptin to restore reproductive function in lean hypogonadotropic ewes.

BACKGROUND/AIMS: Leptin restores gonadotropic function in lean hypogonadotropic animals by an unknown mechanism. We aimed to test the hypothesis that restoration of gonadotropic function is a result of an upregulation of central acetylated melanocortin production. METHODS AND RESULTS: Lean ovariectomised (OVX) ewes received intracerebroventricular (i.c.v.) infusions of leptin (or vehicle) for 3 days, which upregulated proopiomelanocortin (POMC) mRNA and restored pulsatile luteinizing hormone (LH) secretion. A melanocortin agonist (MTII), but not naloxone treatment, reinstated pulsatile LH secretion in lean OVX ewes. We treated (i.c.v.) lean OVX ewes with leptin (or vehicle) and measured peptide levels and post-translational modification in the arcuate nucleus (ARC). Levels of beta-endorphin (beta-END) were lower in lean animals, with no effect of leptin treatment. Desacetyl-alpha-MSH was the predominant form of alpha-melanocyte-stimulating hormone (alpha-MSH) in the ARC and levels were similar in all groups. In another group of lean and normal-weight OVX ewes, we measured the different forms of alpha-MSH in ARC, hypothalamus (ARC-removed) and the preoptic area (POA). Acetylated alpha-MSH levels were lower in lean animals in the terminal beds of the hypothalamus and POA but not the ARC. CONCLUSIONS: Leptin corrects the hypogonadotropic state in the lean condition by upregulation of POMC gene expression, and may increase transport and acetylation of melanocortins to target cells in the brain. Melanocortin treatment restores LH secretion in lean animals.

The anterolateral projections of the medial basal hypothalamus affect sleep.

The role of the medial basal hypothalamus (MBH) and the anterior hypothalamus/preoptic area (AH/POA) in sleep regulation was investigated using the Halász knife technique to sever MBH anterior and lateral projections in rats. If both lateral and anterior connections of the MBH were cut, rats spent less time in non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). In contrast, if the lateral connections remained intact, the duration of NREMS and REMS was normal. The diurnal rhythm of NREMS and REMS was altered in all groups except the sham control group. Changes in NREMS or REMS duration were not detected in a group with pituitary stalk lesions. Water consumption was enhanced in three groups of rats, possibly due to the lesion of vasopressin fibers entering the pituitary. EEG delta power during NREMS and brain temperatures (Tbr) were not affected by the cuts during baseline or after sleep deprivation. In response to 4 h of sleep deprivation, only one group, that with the most anterior-to-posterior cuts, failed to increase its NREMS or REMS time during the recovery sleep. After deprivation, Tbr returned to baseline in most of the treatment groups. Collectively, results indicate that the lateral projections of the MBH are important determinants of duration of NREMS and REMS, while more anterior projections are concerned with the diurnal distribution of sleep. Further, the MBH projections involved in sleep regulation are distinct from those involved in EEG delta activity, water intake, and brain temperature.

Mice lacking the transient receptor vanilloid potential 1 channel display normal thirst responses and central Fos activation to hypernatremia.

Neurons of the organum vasculosum of the lamina terminalis (OVLT) are necessary for thirst and vasopressin secretion during hypersmolality in rodents. Recent evidence suggests the osmosensitivity of these neurons is mediated by a gene product encoding the transient receptor potential vanilloid-1 (TRPV1) channel. The purpose of the present study was to determine whether mice lacking the TRPV1 channel had blunted thirst responses and central Fos activation to acute and chronic hyperosmotic stimuli. Surprisingly, TRPV1-/- vs. wild-type mice ingested similar amounts of water after injection (0.5 ml sc) of 0.5 M NaCl and 1.0 M NaCl. Chronic increases in plasma osmolality produced by overnight water deprivation or sole access to a 2% NaCl solution for 48 h produced similar increases in water intake between wild-type and TRPV1-/- mice. There were no differences in cumulative water intakes in response to hypovolemia or isoproterenol. In addition, the number of Fos-positive cells along the lamina terminalis, including the OVLT, as well as the supraoptic nucleus and hypothalamic paraventricular nucleus, was similar between wild-type and TRPV1-/- mice after both acute and chronic osmotic stimulation. These findings indicate that TRPV1 channels are not necessary for osmotically driven thirst or central Fos activation, and thereby suggest that TRPV1 channels are not the primary ion channels that permit the brain to detect changes in plasma sodium concentration or osmolality.

[Effects of gypsum on the firing of pyrogen-treated thermosensitive neurons in PO/AH of cats].

AIM: To investigate the possible central mechanism of antipyretic effects of Chinese medicine gypsum. METHODS: Gypsum was injected after the fever model was established. The firing rate of thermosensitive neurons in preoptic-anterior hypothalamus(PO/AH) region was recorded by using extracellular microelectrode technique. RESULTS: The injection of pyrogen evoked decrease in firing rate of the warm-sensitive neurons and increase in the cold-sensitive neurons in the region of PO/AH; the changes of the firing rate of pyrogen- treated warm-sensitive and cold-sensitive neurons could be reversed by the injection of gypsum. CONCLUSION: The result may suggest that antipyretic action of gypsum is mediated by its influences on the thermosensitivity neurons in the region of PO/AH.

Neural substrate of cold-seeking behavior in endotoxin shock.

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 microg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 microg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel ("warmth receptor"). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 ("cold receptor"). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock.

The differential role of prostaglandin E2 receptors EP3 and EP4 in regulation of fever.

The innate immune system of mammals is able to detect bacteria when they infect local tissue or enter the blood stream, and initiate an immediate immune response. Prostaglandin (PG) E2 is considered as the most important link between the peripheral immune system and the brain. Due to four PGE2 receptors (EP receptors) and their differential expression in various areas of the hypothalamus and brain stem, PGE2 mediates different components of the acute phase reaction. A fever model is discussed in which the preoptic area contains the mechanisms for both hyperthermic and hypothermic responses and EP receptors in the median preoptic area (MnPO) modulate the thermogenic system. The neuron-specific modulation of EP receptors in the MnPO can be critically tested by using Cre-recombinase-mediated DNA recombination in genetically engineered mice. A concept for mice with conditional expression of EP3R and EP4R to investigate the different roles of those receptors in lipopolysaccharide (LPS)-induced fever is presented.

Role of the OVLT in the febrile response to circulating pyrogens.

The available data suggest that circulating endogenous pyrogens (EPs) probably do not penetrate the brain, but interact with sensory elements in the organum vasculosum laminae terminalis (OVLT) which may involve 5HT and SP as neurotransmitters. It is proposed that substance P (SP) may affect thermo-regulatory neurons in the preoptic area (POA) directly or induce the local synthesis of cytokines that secondarily act on these neurons. Recent evidence indicates that endothelial cells in the OVLT bind circulating cytokines to receptors on their luminal surface. This may result in the release of putative neuroregulators which then process the original signals inwardly to the POA, where they then affect neuronal functions leading to fever production. Thus, trans-BBB passage of cytokines is prevented, but the brain site mediating their pyrogenic effect is informed and the appropriate responses are activated. It is emphasized, however, that this suggested mechanism is still speculative.

Differential sensitivity in the sites of fever production by prostaglandin E1 within the hypothalamus of the rat.

1. The febrile sensitivity of male Sprague-Dawley rats to microinjections of prostaglandin E1 (PGE) was investigated at three different locations in the rostromedial hypothalamic region. These were the preoptic anterior hypothalamic area (PO-AH), the organum vasculosum laminae terminalis (OVLT) and the rostral third ventricle (3V). 2. Stainless-steel cannula guide tubes were implanted in the OVLT region of one group of animals, within the PO-AH area of a second group and into the third ventricle of a third group of rats. After their recovery, the febrile response of each group was tested to a variety of doses of PGE, each administered in a volume of 1 microliter sterile 0.9% saline, via a sterile cannula inserted into the implanted guide tubes. Metabolic, vasomotor and rectal temperature changes were monitored continuously for the duration of the fevers. 3. Surprisingly, not only did the introduction of PGE into the OVLT region produce fevers, but the sensitivity of this region to PGE in the production of fever greatly exceeded that of the PO-AH area and the third ventricle. Fevers produced by microinjection of PGE into the PO-AH and 3V were identical. 4. Doses of PGE as low as 0.5 ng injected into the OVLT produced fevers of 0.5 degrees C. The fever dose threshold for the OVLT region was one-fifth those of the PO-AH area and the 3V, and the slope of the OVLT dose-response curve was twice those of the PO-AH and the 3V dose-response curves. 5. This study demonstrates that there is an anatomically distinct, regional sensitivity in the febrile responsiveness to PGE within the hypothalamus. These results are interpreted as evidence that the site of action of PGE in the production of fever is located within or immediately adjacent to the OVLT region, rather than within the medial PO-AH neuropil as has been believed previously.

Hypothalamic neuronal activity associated with onset of pseudopregnancy in the rat.

The electrical activity of several hypothalamic sites, before and following cervical stimulation, was examined in an attempt to evaluate the central nervous system processes involved in the induction of pseudopregnancy in the rat. Cervical stimulation, resulting in pseudopregnancy, induced a sequence of neuronal changes at: 3.8, 4.4, 11.6, 20.1, 30.8, 44.5, 51.2, 51.7, 62.4, 85.1 and 111.5 min after stimulation in the preoptic area, lateral hypothalamus, ventromedial hypothalamus, preoptic area, suprachiasmatic nucleus, lateral hypothalamus, preoptic area, ventromedial hypothalamus, lateral hypothalamus and anterior hypothalamus, respectively. These results suggest that the preoptic region contains both the facilitatory neuronal mechanism and also an inhibitory system. The latter could tonically inhibit the expression of the nocturnal prolactin surge. We conclude that the sequence of neuronal events observed in various hypothalamic areas is in part responsible for the process which results in pseudopregnancy.

Preoptic-hypothalamic pathways controlling nocturnal prolactin surges, pseudopregnancy, and estrous cyclicity in the rat.

Frontal, dorsal, or sham deafferentations were placed at various locations within the hypothalamus in order to study the neural pathways involved in pseudopregnancy (PSP), estrous cyclicity, and prolactin (PRL) secretion in the rat. Dorsal or sham transections did not interfere with PSP or estrous cyclicity. Frontal cuts placed on day 3-4 of PSP between the posterior border of the optic chiasm and the anterior tip of the mediobasal hypothalamus (MBH) led to interruption of diestrus within 3-5 days. With frontal cuts placed more caudally in the MBH, and with frontal cuts placed rostrally at the anterochiasmatic area, the duration of PSP was within normal range. Irrespective of their effects on PSP, anterochiasmatic and retrochiasmatic cuts were associated with onset of persistent estrus, and MBH transections resulted in either persistent estrus in some rats or regular estrous cycles in the others. In deafferentated rats that showed persistent estrus, the basal plasma concentrations of PRL measured 3-4 weeks after ovariectomy were 2- to 3-fold higher than in deafferentated and sham-deafferentated animals that were cyclic before ovariectomy. Electrical vaginocervical stimulation induced secretion of nocturnal PRL surges in long-term ovariectomized rats with dorsal or sham transections, but not in those bearing frontal cuts, regardless of the neuroanatomical location of the frontal cut. These results suggest that (1) impulses generated at the uterine cervix must reach the medial preoptic area, a putative 'anti-surge center', and proceed from there to the MBH, in order to allow initiation of nocturnal PRL release.(ABSTRACT TRUNCATED AT 250 WORDS)

Lateralized functional relationship between the preoptic area and lateral hypothalamic reinforcement.

Electrical self-stimulation in the lateral hypothalamus of both hemispheres was recorded in 14 rats before and after administration of a unilateral ibotenic acid lesion of the cell bodies in the region of the lateral preoptic area. A significant decrease in the rate of self-stimulation at each of two stimulation intensities was found when the electrode was placed in the hemisphere in which the ibotenic acid lesion was made. This decrease remained constant over 21 days of testing. No changes were detected in rate of self-stimulation in the intact contralateral hemisphere. These results provide evidence for a role in lateral hypothalamic self-stimulation of intrinsic neurons located in the region of the lateral preoptic area.

Indomethacin pretreatment inhibits fever after anodal, but not cathodal, medial preoptic lesions in rats.

Pretreatment with indomethacin (15 mg/kg) prevented the fever occurring in unanesthetized rats immediately after unilateral anodal electrolytic lesions of the medial preoptic area. The drug had no effect on the fever if given before cathodal lesions. If given after the lesions, when the fever had begun to develop, indomethacin lowered anodal body temperature back to baseline for varied lengths of time and attenuated cathodal fever.

[Insomnia following a lesion of the paramedial preoptic area is reversible by inactivation of the posterior hypothalamus in the cat]. / L'insomnie consécutive à la lésion de la région préoptique paramédiane est réversible par inactivation de l'hypothalamus postérieur chez le chat.

The bilateral intratissular injection of muscimol, an agonist of gamma amino butyric acid (GABA), induced a transient hypersomnia (slow wave sleep and paradoxical sleep) in an insomniac cat whose paramedial preoptic area had been previously bilaterally destroyed.

The anterior wall of the third cerebral ventricle and homeostatic responses to dehydration.

Within the anterior wall of the third cerebral ventricle, structures are found which have been implicated in the regulation of fluid and electrolyte balance. These structures include the subfornical organ (SFO), preoptic medianus nucleus (PMN) and the organum vasculosum of the lamina terminalis (OVLT). In sheep, the OVLT rises from the ventricular floor over the optic chiasma and occupies most of the midline ventricular wall up to the level of anterior commissure. It contains a plexus of blood vessels at its base which possess fenestrated endothelial cells, and appears to lack ependyma. The SFO of sheep bulges into the third ventricle above the anterior commissure and the PMN is situated between the SFO and OVLT, surrounding the rostral edge of the midline anterior commissure. Like most mammals, water deprivation in sheep results in hypertonicity of body fluids, thirst and graded increase in plasma concentration of vasopressin (AVP). Dehydration also causes a natriuresis in these animals. In sheep with combined ablation of OVLT/PMN tissue, the volume of water drunk, the increases in plasma vasopressin (AVP) level, and the natriuresis in response to dehydration were considerably attenuated, and extreme hypernatremia resulted. Additionally, ablation of OVLT/PMN tissue almost abolished water drinking and AVP secretion in response to systemic infusion of hypertonic NaCl, but did not diminish AVP secretion in response to haemorrhage. In other animals, the OVLT and PMN were individually ablated. While partial osmoregulatory deficits were observed in each case, these deficits were smaller than those observed with combined OVLT/PMN ablation. In contrast to these results, the homeostatic responses to dehydration were not diminished in sheep with combined SFO/PMN lesions.(ABSTRACT TRUNCATED AT 250 WORDS)