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Biomedical subjects

C B Saper

Publications and source records attributed to C B Saper.

At least 19 recordsLinked to original sources
PubMed2001

Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation.

The suprachiasmatic nucleus (SCN), the circadian pacemaker for the brain, provides a massive projection to the subparaventricular zone (SPZ), but the role of the SPZ in circadian processes has received little attention. We examined the effects on circadian rhythms of sleep, body temperature, and activity in rats of restricted ibotenic acid lesions of the ventral or dorsal SPZ that spared the immediately adjacent paraventricular hypothalamic nucleus (PVH) and the SCN. Ventral SPZ lesions caused profound reduction of measures of circadian index of sleep (by 90%) and locomotor activity (75% reduction) but had less effect on body temperature (50% reduction); dorsal SPZ lesions caused greater reduction of circadian index of body temperature (by 70%) but had less effect on circadian index of locomotor activity (45% reduction) or sleep (<5% reduction). The loss of circadian regulation of body temperature or sleep was replaced by a strong ultradian rhythm (period approximately 3 hr). Lesions of the PVH, immediately dorsal to the SPZ, had no significant effect on any circadian rhythms that we measured, nor did the lesions affect the baseline body temperature. However, the fever response after intravenous injection of lipopolysaccharide (5 microg/kg) was markedly decreased in the rats with PVH lesions (66.6%) but not dorsal SPZ lesions. These results indicate that circadian rhythms of sleep and body temperatures are regulated by separate neuronal populations in the SPZ, and different aspects of thermoregulation (circadian rhythm and fever response) are controlled by distinct anatomical substrates.

Activity Cycles↗
PubMed2001

Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke.

Idiopathic narcolepsy usually results from a loss of the hypothalamic neuropeptide orexin (hypocretin), but the cause of secondary narcolepsy resulting from focal brain lesions is unknown. The authors describe a young man who developed narcolepsy after a large hypothalamic stroke. His lesion included much of the hypothalamic region in which orexin is produced, and his CSF concentration of orexin was low. The authors hypothesize that a loss of orexin neurons or their relevant targets may be the specific neuropathology causing this and many other cases of secondary narcolepsy.

Adult↗
PubMed2001

Differential expression of orexin receptors 1 and 2 in the rat brain.

Orexins (hypocretins) are neuropeptides synthesized in the central nervous system exclusively by neurons of the lateral hypothalamus. Orexin-containing neurons have widespread projections and have been implicated in complex physiological functions including feeding behavior, sleep states, neuroendocrine function, and autonomic control. Two orexin receptors (OX(1)R and OX(2)R) have been identified, with distinct expression patterns throughout the brain, but a systematic examination of orexin receptor expression in the brain has not appeared. We used in situ hybridization histochemistry to examine the patterns of expression of mRNA for both orexin receptors throughout the brain. OX(1)R mRNA was observed in many brain regions including the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. OX(2)R mRNA was prominent in a complementary distribution including the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial nucleus, paraventricular nucleus, and ventral premammillary nucleus. The differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX(2)R receptor in regulating sleep state stability.

Animals↗
PubMed2001

Characterization of CART neurons in the rat and human hypothalamus.

Cocaine- and amphetamine-regulated transcript (CART) is a recently described neuropeptide widely expressed in the rat brain. CART mRNA and peptides are found in hypothalamic sites such as the paraventricular nucleus (PVH), the supraoptic nucleus (SON), the lateral hypothalamic area (LHA), the dorsomedial nucleus of the hypothalamus (DMH), the arcuate nucleus (Arc), the periventricular nucleus (Pe), and the ventral premammillary nucleus (PMV). Intracerebroventricular administration of recombinant CART peptide decreases food intake and CART mRNA levels in the Arc are regulated by leptin. Leptin administration induces Fos expression in hypothalamic CART neurons in the PVH, the DMH, the Arc, and the PMV. In the current study, we used double label in situ hybridization histochemistry to investigate the potential direct action of leptin on hypothalamic CART neurons and to define the chemical identity of the hypothalamic CART neurons in the rat brain. We found that CART neurons in the Arc, DMH, and PMV express long form leptin-receptor mRNA, and the suppressor of cytokine signaling-3 (SOCS-3) mRNA after an acute dose of intravenous leptin. We also found that CART neurons in the parvicellular PVH, in the DMH and in the posterior Pe coexpress thyrotropin-releasing hormone (TRH) mRNA. CART neurons in the magnocellular PVH and in the SON coexpress dynorphin (DYN), and CART cell bodies in the LHA and in the posterior Pe coexpress melanin-concentrating hormone (MCH) and glutamic acid decarboxylase (GAD-67) mRNA. In the Arc, a few CART neurons coexpress neurotensin (NT) mRNA. In addition, we examined the distribution of CART immunoreactivity in the human hypothalamus. We found CART cell bodies in the PVH, in the SON, in the LHA, in the Arc (infundibular nucleus) and in the DMH. We also observed CART fibers throughout the hypothalamus, in the bed nucleus of the stria terminalis, and in the amygdala. Our results indicate that leptin directly acts on CART neurons in distinct nuclei of the rat hypothalamus. Furthermore, hypothalamic CART neurons coexpress neuropeptides involved in energy homeostasis, including MCH, TRH, DYN, and NT. The distribution of CART cell bodies and fibers in the human hypothalamus indicates that CART may also play a role in the regulation of energy homeostasis in humans.

Adult↗
PubMed2001

Fos expression in orexin neurons varies with behavioral state.

The neuropeptide orexin (also known as hypocretin) is hypothesized to play a critical role in the regulation of sleep-wake behavior. Lack of orexin produces narcolepsy, which is characterized by poor maintenance of wakefulness and intrusions of rapid eye movement (REM) sleep or REM sleep-like phenomena into wakefulness. Orexin neurons heavily innervate many aminergic nuclei that promote wakefulness and inhibit REM sleep. We hypothesized that orexin neurons should be relatively active during wakefulness and inactive during sleep. To determine the pattern of activity of orexin neurons, we recorded sleep-wake behavior, body temperature, and locomotor activity under various conditions and used double-label immunohistochemistry to measure the expression of Fos in orexin neurons of the perifornical region. In rats maintained on a 12 hr light/dark cycle, more orexin neurons had Fos immunoreactive nuclei during the night period; in animals housed in constant darkness, this activation still occurred during the subjective night. Sleep deprivation or treatment with methamphetamine also increased Fos expression in orexin neurons. In each of these experiments, Fos expression in orexin neurons correlated positively with the amount of wakefulness and correlated negatively with the amounts of non-REM and REM sleep during the preceding 2 hr. In combination with previous work, these results suggest that activation of orexin neurons may contribute to the promotion or maintenance of wakefulness. Conversely, relative inactivity of orexin neurons may allow the expression of sleep.

Animals↗
PubMed2001

Passages 2001.

Explore the source record for details and available documents.

Neurosciences↗
PubMed2000

Relationship of EP(1-4) prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses.

The action of prostaglandin E(2) (PGE(2)) in the preoptic area is thought to play an important role in producing fever. Pharmacologic evidence suggests that, among the four subtypes of E-series prostaglandin (EP) receptors, i.e., EP(1), EP(2), EP(3), and EP(4), the EP(1) receptor mediates fever responses. In contrast, evidence from mice with EP receptor gene deletions indicates that the EP(3) receptor is required for the initial (<1 hour) fever after intravenous (i.v.) lipopolysaccharide (LPS). To investigate which subtypes of EP receptors mediate systemic infection-induced fever, we assessed the coexpression of Fos-like immunoreactivity (Fos-IR) and EP(1-4) receptor mRNA in nuclei in the rat hypothalamus that have been shown to be involved in fever responses. Two hours after the administration of i.v. LPS (5 microg/kg), Fos-IR was observed in the ventromedial preoptic nucleus, the median preoptic nucleus, and the paraventricular hypothalamic nucleus. In these nuclei, EP(4) receptor mRNA was strongly expressed and the Fos-IR intensely colocalized with EP(4) receptor mRNA. Strong EP(3) receptor mRNA expression was only seen within the median preoptic nucleus but Fos-IR showed little coexpression with EP(3) receptor mRNA. EP(2) receptor mRNA was not seen in the PGE(2) sensitive parts of the preoptic area. Although approximately half of the Fos-immunoreactive neurons also expressed EP(1) receptor mRNA, EP(1) mRNA expression was weak and its distribution was so diffuse in the preoptic area that it did not represent a specific relationship. In the paraventricular nucleus, EP(4) mRNA was found in most Fos-immunoreactive neurons and levels of EP(4) receptor expression increased after i.v. LPS. Our findings indicate that neurons expressing EP(4) receptor are activated during LPS-induced fever and suggest the involvement of EP(4) receptors in the production of fever.

Animals↗
PubMed2000

Hypothalamic arousal regions are activated during modafinil-induced wakefulness.

Modafinil is an increasingly popular wake-promoting drug used for the treatment of narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast modafinil-induced wakefulness with spontaneous wakefulness, we administered modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that modafinil may promote waking via activation of TMN and orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.

Animals↗
PubMed2000

Lipopolysaccharide activates specific populations of hypothalamic and brainstem neurons that project to the spinal cord.

Sympathetic preganglionic neurons receive direct, monosynaptic input from a series of well defined nuclei in the brainstem and the hypothalamus. These premotor cell groups coordinate sympathetic control with ongoing endocrine and behavioral response. However, it is not known precisely which populations of sympathetic premotor neurons are activated during specific responses, such as fever after intravenous lipopolysaccharide (LPS). We used the activation of c-fos protein expression in spinally projecting neurons during intravenous LPS fever as a model for examining the functional organization of this system. Intravenous LPS (5 microg/kg) induced Fos-like immunoreactivity in sympathetic preganglionic neurons in the spinal cord as well as several sympathetic premotor nuclei, including the paraventricular nucleus of the hypothalamus, rostral and caudal levels of the ventrolateral medulla, and the nucleus of the solitary tract. After injecting Fluorogold into the intermediolateral column at the T1-L1 spinal levels, neurons that were both Fos immunoreactive and retrogradely labeled were found only in the dorsal parvicellular division of the paraventricular nucleus in the hypothalamus, the rostral ventrolateral medulla (C1 adrenergic cell group), and the A5 noradrenergic cell group in the brainstem. The same pattern of double-labeling was seen from injections at each spinal cord level. These findings suggest that only a limited pool of hypothalamo-sympathetic neurons contribute to the fever response and that they may do so by contacting specific populations of preganglionic neurons that are distributed across a wide range of spinal levels. The anatomical specificity of the paraventriculo-spinal projection is thus functional rather than topographic.

Animals↗
PubMed2000

Chemical characterization of leptin-activated neurons in the rat brain.

Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.

Animals↗
PubMed2000

Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance.

BACKGROUND: Working memory (WM) deficits in schizophrenia have been associated with dorsolateral prefrontal cortex (DLPFC) dysfunction in neuroimaging studies. We previously found increased DLPFC activation in schizophrenic versus normal subjects during WM performance (Manoach et al 1999b). We now have investigated whether schizophrenic subjects recruit different brain regions, particularly the basal ganglia and thalamus, components of frontostriatal circuitry thought to mediate WM. METHODS: We examined regional brain activation in nine normal and nine schizophrenic subjects during WM performance using functional magnetic resonance imaging. Subjects performed a modified version of the Sternberg Item Recognition Paradigm that included a monetary reward for correct responses. We compared high and low WM load conditions to each other and to a non-WM baseline condition. We examined activation in both individual subjects and averaged group data. RESULTS: Relative to normal subjects, schizophrenic subjects exhibited deficient WM performance, at least an equal magnitude of right DLPFC activation, significantly greater left DLPFC activation, and increased spatial heterogeneity of DLPFC activation. Furthermore, only the schizophrenic group activated the basal ganglia and thalamus, even when matched for task performance with the normal group. CONCLUSIONS: Aberrant WM performance and brain activation in schizophrenia may reflect dysfunction of frontostriatal circuitry that subserves WM. Future studies will elucidate the contribution of the anatomical components of this circuitry to WM deficits.

Adult↗
PubMed2000

Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep.

Neurons in the ventrolateral preoptic nucleus (VLPO) in rats show c-fos activation after sleep and provide GABAergic innervation of the major monoamine arousal systems, suggesting that they may be a necessary part of the brain circuitry that produces sleep. We examined the effects on sleep behavior in rats of cell-specific damage to the VLPO by microinjection of ibotenic acid. Severe lesions of the central cell cluster of the VLPO ( approximately 80-90% cell loss bilaterally) caused a 60-70% decrease in delta power and a 50-60% decrease in nonrapid-eye-movement (NREM) sleep time (p < 0.001). The number of remaining Fos-immunoreactive neurons in the VLPO cell cluster was linearly related to NREM sleep time (r = 0.77; p < 0.001) and total electroencephalogram delta power (r = 0. 79; p < 0.001) but not to rapid-eye-movement (REM) sleep (r = 0.35; p > 0.10). Lesions in the region containing scattered VLPO neurons medial or dorsal to the cell cluster caused smaller changes in NREM sleep time (24.5 or 15%, respectively) but were more closely associated with loss of REM sleep (r = 0.74; p < 0.01). The insomnia caused by bilateral VLPO lesions persisted for at least 3 weeks. Lesions of the VLPO caused no change in mean body temperature or its circadian variation; after small lesions of the ventromedial preoptic nucleus, body temperature showed normal circadian variation but a wider temperature range, and sleep behavior was not affected. These experiments delineate distinct preoptic sites with primary effects on the regulation of NREM sleep, REM sleep, and body temperature.

Animals↗
PubMed2000

Leptin regulation of neuroendocrine systems.

The discovery of leptin has enhanced understanding of the interrelationship between adipose energy stores and neuronal circuits in the brain involved in energy balance and regulation of the neuroendocrine axis. Leptin levels are dependent on the status of fat stores as well as changes in energy balance as a result of fasting and overfeeding. Although leptin was initially thought to serve mainly as an anti-satiety hormone, recent studies have shown that it mediates the adaptation to fasting. Furthermore, leptin has been implicated in the regulation of the reproductive, thyroid, growth hormone, and adrenal axes, independent of its role in energy balance. Although it is widely known that leptin acts on hypothalamic neuronal targets to regulate energy balance and neuroendocrine function, the specific neuronal populations mediating leptin action on feeding behavior and autonomic and neuroendocrine function are not well understood. In this review, we have discussed how leptin engages arcuate hypothalamic neurons expressing putative orexigenic peptides, e.g., neuropeptide Y and agouti-regulated peptide, and anorexigenic peptides, e.g., pro-opiomelanocortin (precursor of alpha-melanocyte-stimulating hormone) and cocaine- and amphetamine-regulated transcript. We show that leptin's effects on energy balance and the neuroendocrine axis are mediated by projections to other hypothalamic nuclei, e.g., paraventricular, lateral, and perifornical areas, as well as other sites in the brainstem, spinal cord, and cortical and subcortical regions.

Animals↗
PubMed2000

Calcitonin gene-related peptide-like immunoreactivity marks putative visceral sensory pathways in human brain.

Calcitonin gene-related peptide serves as a neuromodulator in several ascending visceral sensory pathways from the parabrachial nucleus to the thalamus, amygdala and the visceral sensory cortex in rats, but these pathways have not been studied in primates. We have examined the distribution of calcitonin gene-related peptide-like immunoreactive innervation of the corresponding areas of the human brain, including the cortex, diencephalon and brainstem. We report the finding of three populations of calcitonin gene-related peptide-like immunoreactive cells that are homologous to those that have been characterized in the rat: the external lateral and external medial parabrachial subnuclei and the posterior intralaminar thalamic complex, including the subparafascicular, lateral subparafascicular and peripeduncular nuclei. In addition, scattered calcitonin gene-related peptide-like immunoreactive cells were found in the periventricular hypothalamus. Calcitonin gene-related peptide-like immunoreactive terminals were found in regions homologous to the projection areas of the external medial and external lateral parabrachial subnuclei in the rat, including the ventroposterior parvicellular nucleus of the thalamus, the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the insular cortex; and in the terminal field of the posterior intralaminar thalamic complex, including the amygdalo-striatal transition region and the insular cortex. These results suggest that, similarly to other species, calcitonin gene-related peptide may also serve as a marker for ascending visceral sensory pathways in the human brain.

Amygdala↗