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Biomedical subjects

C B Saper

Publications and source records attributed to C B Saper.

At least 73 records · Page 4Linked to original sources
PubMed1998

Unraveling the central nervous system pathways underlying responses to leptin.

Here we summarize recent progress in the biology of leptin, concentrating on its central nervous system (CNS) actions. The product of the ob gene, leptin is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis and neuroendocrine responses. Leptin regulates energy homeostasis, as its absence in rodents and humans causes severe obesity. We consider the physiological mechanisms underlying leptin action, along with several novel hypothalamic neuropeptides that affect food intake and body weight. The molecular causes of several other obesity syndromes are discussed to illuminate how the CNS regulates body weight. We describe neural circuits that are downstream of leptin receptors and propose a model linking populations of leptin-responsive neurons with effector neurons underlying leptin's endocrine, autonomic and behavioral effects.

Brain↗
PubMed1998

Vagus nerve stimulation.

Left vagus nerve stimulation (VNS) is a promising new treatment for epilepsy. In 1997, VNS was approved in the United States as an adjunctive treatment for medically refractory partial-onset seizures in adults and adolescents. For some patients with partial-onset seizures, the adverse effects of antiepileptic drugs (AEDs) are intolerable; for others, no single AED or combination of anticonvulsant agents is effective. Cerebral resective surgery is an option to pharmacotherapy in some cases, but many patients with partial-onset seizures are not optimal candidates for intracranial surgery. VNS entails implantation of a programmable signal generator--the Neuro-cybernetic Prosthesis (NCP)--in the chest cavity. The stimulating electrodes of the NCP carry electrical signals from the generator to the left vagus nerve. Although the mechanism of action of VNS is not known, controlled studies have shown that it is safe and well-tolerated by patients with long-standing partial-onset epilepsy. Side effects, which are generally of mild to moderate severity, almost always disappear after the stimulation settings are adjusted. Encouraging results have also been reported in pediatric patients.

Adolescent↗
PubMed1998

Microinjection of a cyclooxygenase inhibitor into the anteroventral preoptic region attenuates LPS fever.

Considerable evidence supports the role of prostaglandins in fever production, but the neuroanatomic sites of prostaglandin synthesis that produce fever remain unknown. With the use of a novel microinjection technique, we injected the cyclooxygenase inhibitor ketorolac into the preoptic area (POA) to determine which preoptic regions produce the prostaglandins required for fever. Initial experiments demonstrated that intravenous ketorolac blocked the fever normally produced by lipopolysaccharide (LPS) 5 micrograms/kg i.v. Microinjection of ketorolac into the POA had no effect on body temperature, and injection of artificial cerebrospinal fluid into the POA did not alter LPS fever. Injection of ketorolac into the anteroventral POA markedly decreased the fever produced by LPS, compared with injections into more rostral, caudal, or dorsal locations. These observations indicate that prostaglandin synthesis in the anteroventral preoptic region is necessary for the production of fever.

Analgesics, Non-Narcotic↗
PubMed1997

Effects of sleep on wake-induced c-fos expression.

We investigated the effects of sleep on wake-induced c-fos expression in the cerebral cortex of rats and c-fos-lacZ transgenic mice. In the cortex of rats, the levels of c-Fos, detected both by immunocytochemistry and Western blot, remained high during 6 or 12 hr of enforced wakefulness but declined rapidly (within 1 hr) with increasing time of recovery sleep. Similarly, in the transgenic mice in which lacZ expression is driven from the c-fos promoter, beta-galactosidase activity was high after enforced wakefulness and declined with increasing amounts of sleep. These results suggest that the decrease in c-Fos protein in cortical neurons during sleep may be attributable to cessation of c-fos expression, activation of a process that degrades the wake-induced c-Fos, or both.

Animals↗
PubMed1997

Connections of the hippocampal formation in humans: I. The mossy fiber pathway.

The hippocampal formation has been one of the most extensively studied cortical regions in rats, yet little is known about the anatomical connections of the hippocampus in primates, especially humans. With the use of an antibody against the calcium-binding protein, calbindin-D28K, in normal autopsy tissue and the neuronal tracers biocytin or biotinylated dextrans in in vitro slice preparations from tissue removed during surgery for intractable epilepsy, we examined the human hippocampal mossy fiber pathway. The injections of biocytin into the dentate granule cell layer labeled neurons in a Golgi-like manner, revealing the presence of basal dendrites on about 30% of the granule cells. The granule cell axons, the mossy fibers, initially formed a diffuse plexus of fibers in the polymorphic layer before organizing into fiber fascicles in the hilar pyramidal region. These fiber fascicles were much more prominent rostrally than caudally. Within the hilus and proximal portions of the extrahilar CA3 field, the mossy fibers ran through the pyramidal cell layer, and while near the transition to field CA2, the fibers turned superficially and crossed the pyramidal layer to run in the stratum lucidum. All of these features, seen following injections of tracer into hippocampal slices from the brains of epileptics, were confirmed by calbindin-staining of mossy fibers in normal brains. Biocytin-labeled mossy fiber axons revealed two characteristic types of enlargements: small varicosities and larger expansions. The expansions were found throughout the neuropil and were highly irregular, diaminobenzidine-dense profiles that had pleiomorphic modes of attachment to the parent axon. Electron microscopic images of these biocytin labeled expansions revealed that they were large synaptic boutons bearing asymmetric synapses. This study indicates that the human mossy fiber pathway shows some minor deviations from the rodent brain but little difference from monkeys. We argue that these changes mirror a phylogenetic growth of the CA3 pyramidal neurons (subfield CA3c) into the hilus rather than an evolutionary change of the mossy fiber pathway. This growth of subfield CA3c and the increase in mossy fibers running through the pyramidal layer (and a presumed accompanying increase in proximal basal dendritic contacts) may reflect a growing role of the projection from the dentate granule cells to subfield CA3c and from there to field CA1 in the primate hippocampus.

Adult↗
PubMed1997

Connections of the hippocampal formation in humans: II. The endfolial fiber pathway.

We investigated the anatomical connections of the pyramidal neurons located within the hilar region of the dentate gyrus of the human hippocampus, neurons which do not have a rodent equivalent. The myeloarchitectural patterns of the human hippocampus indicated the presence of a distinct fiber pathway, the endfolial fiber pathway, in the stratum oriens of the hilus and field CA3. By using the fluorescent lipophilic dye DiI in formalin-fixed human hippocampal tissue, we demonstrated that this is a continuous fiber pathway between the deep hilar region and CA2. This fiber pathway did not enter the fimbria or alveus along the entire distance of the traced pathway and ran exclusively in the stratum oriens of the hilus and CA3. Tracing studies with biocytin in in vitro human hippocampal slices indicated that the hilar and CA3 pyramidal neurons contributed to this pathway. Out distally in field CA3, the long transverse fibers became short and choppy, suggesting that they were beginning to move out of the plane of the tissue slice. Numerous fibers from this pathway were seen crossing the pyramidal layer. Based on comparative studies, we propose that the endfolial fiber system is a component of the hilar Schaffer collateral system in humans. The presence of a significant Schaffer collateral system from the pyramidal neurons in the hilar region would indicate that these neurons are anatomically related to the CA3 pyramidal neurons. Therefore, we suggest the inclusion of the human hilar pyramidal neurons within Lorente de No's field CA3 and, in particular, within subfield CA3c.

Adult↗
PubMed1997

Neurochemical architecture of the human striatum.

The striatum of the human brain has a highly differentiated neurochemical architecture visible in stains for many of the neurotransmitter-related molecules present in the striatum. The distributions for these chemical markers have never been analyzed comprehensively. We compared the distributions of multiple neurochemical markers in a serial-section analysis of the caudate nucleus, the putamen, and the ventral striatum in normal human brains. The cholinergic system was identified with choline acetyltransferase (ChAT). The organization of the cholinergic fiber system was compared with that of striatal systems expressing immunoreactivity for calbindin D28k, met-enkephalin, substance P, tyrosine hydroxylase, and parvalbumin. Each striatal region analyzed displayed a unique neurochemical organization. In the dorsal caudate nucleus, the distribution of all markers followed the classical striosome/matrix organization as previously reported. In the dorsal putamen, ChAT-staining was less intense, and striosomes were delineated primarily by unstained fiber bundles. In the ventral caudate nucleus/nucleus accumbens region, the boundaries of ChAT-stained regions were not always visible with stains for calbindin, enkephalin, and substance P. The ventral putamen displayed a similar organization, except in its lateral part, where ChAT-poor regions were often found adjacent to, rather than in register with, regions expressing low levels of the other markers (calbindin, enkephalin, substance P, and tyrosine hydroxylase). Our findings suggest that, in addition to the classical striosome-matrix organization visible in the dorsal caudate nucleus and putamen, there is further neurochemical differentiation in a large ventral part of the caudate nucleus and putamen and in the ventral striatum-nucleus accumbens proper. The more complex relationships among the different neurochemical systems in the ventral striatum may reflect the increase in size in the primate of striatal regions associated with association and limbic cortex.

Adult↗
PubMed1997

Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages.

Production of prostaglandins is a critical step in transducing immune stimuli into central nervous system (CNS) responses, but the cellular source of prostaglandins responsible for CNS signalling is unknown. Cyclooxygenase catalyzes the rate-limiting step in the synthesis of prostaglandins and exists in two isoforms. Regulation of the inducible isoform, cyclooxygenase 2, is thought to play a key role in the brain's response to acute inflammatory stimuli. In this paper, we report that intravenous lipopolysaccharide (LPS or endotoxin) induces cyclooxygenase 2-like immunoreactivity in cells closely associated with brain blood vessels and in cells in the meninges. Neuronal staining was not noticeably altered or induced in any brain region by endotoxin challenge. Furthermore, many of the cells also were stained with a perivascular microglial/macrophage-specific antibody, indicating that intravenous LPS induces cyclooxygenase in perivascular microglia along blood vessels and in meningeal macrophages at the edge of the brain. These findings suggest that perivascular microglia and meningeal macrophages throughout the brain may be the cellular source of prostaglandins following systemic immune challenge. We hypothesize that distinct components of the CNS response to immune system activation may be mediated by prostaglandins produced at specific intracranial sites such as the preoptic area (altered sleep and thermoregulation), medulla (adrenal corticosteroid response), and cerebral cortex (headache and encephalopathy).

Animals↗
PubMed1997

Mechanisms of CNS response to systemic immune challenge: the febrile response.

The acute-phase reaction is the multisystem response to acute inflammation. The central nervous system (CNS) mediates a coordinated set of autonomic, endocrine and behavioral responses that constitute the cerebral component of the acute-phase reaction. However, the mechanisms of immune signaling of the CNS remain controversial. Emerging evidence indicates that different parts of the acute-phase reaction are initiated by distinct mechanisms and in different brain regions. Cytokines produced as a result of local infections (for example, in the abdominal or thoracic cavities) might activate vagal sensory fibers, resulting in sickness behavior and fevers. Additionally, circulating immune stimuli might activate meningeal macrophages and perivascular microglia along the borders of the brain, eliciting the local production of prostaglandins and responses such as fever, anorexia, sleepiness, and activation of the hypothalamo-pituitary-adrenal (HPA) axis. The biological importance of these responses might favor the existence of multiple parallel CNS pathways that are engaged by cytokines.

Animals↗
PubMed1997

Leptin activates neurons in ventrobasal hypothalamus and brainstem.

Leptin is a circulating protein secreted by adipocytes which has profound feeding, metabolic, and neuroendocrine effects. Leptin receptors have been localized to the hypothalamus, but the anatomic sites responsible for mediating the effects of circulating leptin have not been demonstrated. We report that systemic administration of leptin activates nuclear groups in the ventrobasal hypothalamus, including the ventromedial, dorsomedial, and ventral premammillary hypothalamic nuclei. Leptin also activated the parvicellular subdivisions of the paraventricular hypothalamic nucleus that project to parasympathetic and sympathetic preganglionic neurons. Finally, leptin administration activated the superior lateral parabrachial subnucleus, a nuclear group containing cholecystokinin neurons that project to the ventrobasal hypothalamus. These findings indicate that circulating leptin activates specific nuclear groups in the hypothalamus and brainstem known to regulate complex physiological responses during times of substrate availability.

Animals↗
PubMed1996

Activation of neurons projecting to the paraventricular hypothalamic nucleus by intravenous lipopolysaccharide.

The central nervous system interacts with the immune system to coordinate several components of the acute phase response, although the specific neuroanatomical pathways that mediate these responses are still uncharacterized. However, neurons in both the autonomic and endocrine components of the paraventricular hypothalamic nucleus (PVH) are characteristically activated in different models of immune stimulation. In the current study, we have used intravenous administration of lipopolysaccharide (LPS; 5 or 125 micrograms/kg) to induce the acute phase response. We subsequently coupled immunohistochemistry for Fos (as a marker of neuronal activation) with retrograde transport of the neuroanatomical tracer cholera toxin-b from the PVH. Several of the activated cell groups directly projected to the paraventricular nucleus, including the visceromotor (infralimbic) cortex, median preoptic nucleus, ventromedial preoptic area, bed nucleus of the stria terminalis, parabrachial nucleus, ventrolateral medulla, and nucleus of the solitary tract. These findings indicate that immune system stimulation activates cell groups from multiple nervous system levels that project to the paraventricular nucleus. We hypothesize that the activation of specific autonomic and endocrine elements of the PVH may be due to the activity of distinct afferents that converge on the PVH from multiple components of the central autonomic control system. Our results are consistent with the hypothesis that the PVH plays a key role in integrating diverse physiological cues into the varied manifestations that constitute the cerebral component of the acute phase response.

Acute-Phase Reaction↗
PubMed1996

Ventromedial preoptic prostaglandin E2 activates fever-producing autonomic pathways.

Fever is thought to be initiated by pyrogenic cytokines inducing the production of prostaglandin E2 (PGE2) in the preoptic area (POA); PGE2 may act as a paracrine mediator that stimulates the neural pathways that raise body temperature. This essential role for prostaglandins in fever first was proposed 25 years ago, but the specific preoptic cell groups at which PGE2 acts and the pathways through which fever is produced remain poorly understood. To better define the role of preoptic PGE2 in fever, we developed a new method for combining acute brain injections with Fos immunohistochemistry. We microinjected a threshold dose of PGE2 to construct an anatomically detailed map of fever-producing preoptic sites. The most pyrogenic preoptic sites were clustered along the ventromedial aspect of the POA, surrounding and just anterior to the organum vasculosum of the lamina terminalis. We then used Fos immunohistochemistry to identify the pattern of neural activation induced by fever-producing preoptic injections of PGE2 and compared it with the Fos pattern seen after systemic immune stimulation. PGE2 fever was accompanied by Fos induction in the ventromedial POA and the parvicellular subnuclei of the paraventricular nucleus of the hypothalamus (PVH). In contrast to the Fos pattern seen after intravenous lipopolysaccharide administration, PGE2 injection did not induce Fos in the circumventricular organs or the magnocellular subnuclei of the PVH. These observations establish a potential site of PGE2 action during fever and help define candidate pathways through which fever occurs.

Animals↗
PubMed1996

Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration.

The central nervous system, particularly the hypothalamus, is intimately involved in the coordination of various aspects of the inflammatory response, including the generation of fever. We used intravenous injections of bacterial cell wall lipopolysaccharide (LPS; 5 or 125 micrograms/kg) to stimulate the acute phase response and mapped the resultant distribution of Fos-like immunoreactivity in the rat brain. In addition, we compared the patterns of Fos distribution with the thermoregulatory responses elicited by the LPS. Administration of LPS resulted in a dose- and time-dependent pattern of Fos-like immunoreactivity throughout the rat brain consistent with a coordinated autonomic, endocrine, and behavioral response to the LPS challenge that was most pronounced 2 hours following injection. Specifically, Fos-like immunoreactivity was observed in key autonomic regulatory nuclear groups, including the insular and prelimbic cortices, paraventricular hypothalamic nucleus, parabrachial nucleus, nucleus of the solitary tract, and the rostral and caudal levels of the ventrolateral medulla. In addition, a significant sustained elevation of Fos-like immunoreactivity was observed in a cell group adjacent to the organum vasculosum of the lamina terminalis, which we termed the ventromedial preoptic area. This sustained elevation of Fos-like immunoreactivity coupled with the alterations in body temperature elicited by LPS leads us to hypothesize that the ventromedial preoptic area may be a key site for the initiation of fever during endotoxemia.

Animals↗
PubMed1996

Injections of okadaic acid, but not beta-amyloid peptide, induce Alz-50 immunoreactive dystrophic neurites in the cerebral cortex of sheep.

In an attempt to produce an animal model of neurofibrillary degeneration of the Alzheimer type, okadaic acid (a phosphatase inhibitor) and beta-amyloid peptide (1-40) were microinjected into the cerebral cortex of six adult sheep. After survivals varying from 1 day to 3 months, the injection sites and adjacent areas were evaluated using light microscopic immunocytochemistry. Near sites of implantation of crystalline okadaic acid, the Alz-50 monoclonal antibody stained twisted, dystrophic neurites. None of the beta-amyloid peptide injections caused neurofibrillary pathology. However, immunohistochemical analysis revealed no detectable beta-amyloid peptide remaining in the neuropil, even at 1 day, indicating rapid clearance of the beta-amyloid peptide. The induction of Alz-50 immunoreactive dystrophic neurites by okadaic acid in sheep represents a novel animal model of Alzheimer's neurofibrillary pathology.

Amyloid beta-Peptides↗
PubMed1996

Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide.

Cyclooxygenase (COX) is an enzyme involved in the biosynthesis of prostaglandins and is one of the principle targets of non-steroidal anti-inflammatory drugs. Two isoforms of this enzyme are known to exist in the brain; one of these (type 1 COX or COX1) is constitutively expressed, whereas the other form of the enzyme, which is inducible, has been called type 2 COX (COX2). We have used systemic administration of bacterial lipopolysaccharide (LPS) as a model of the acute phase response to study the expression of COX2 in the murine CNS. We observed COX2 expression in neurons of several regions of the normal murine telencephalon. Robust expression of COX2 mRNA was induced in perivascular cells between 45 min and 6 h after LPS injection. The role of prostaglandins produced by these perivascular cells in the cerebral components of the acute phase response remains to be elucidated.

Animals↗
PubMed1996

Activation of ventrolateral preoptic neurons during sleep.

The rostral hypothalamus and adjacent basal forebrain participate in the generation of sleep, but the neuronal circuitry involved in this process remains poorly characterized. Immunocytochemistry was used to identify the FOS protein, an immediate-early gene product, in a group of ventrolateral preoptic neurons that is specifically activated during sleep. The retrograde tracer cholera toxin B, in combination with FOS immunocytochemistry, was used to show that sleep-activated ventrolateral preoptic neurons innervate the tuberomammillary nucleus, a posterior hypothalamic cell group thought to participate in the modulation of arousal. This monosynaptic pathway in the hypothalamus may play a key role in determining sleep-wake states.

Animals↗
PubMed1996

Cholinergic innervation in the human striatum: a three-compartment model.

The mammalian striatum is divided into compartments that are anatomically and neurochemically distinct. The dorsal striatum has been described as containing two compartments, striosomes and matrix, while the ventral striatum is thought to have a more complex, multi-compartmental organization. In this study, we sought to characterize the compartmentalization of the dorsal and ventral portions of the human striatum using choline acetyltransferase as a marker. Image analysis was used to assess relative densities of immunostaining, and three distinct, choline acetyltransferase-immunostained compartments were demonstrated: intensely immunostained, moderately immunostained and weakly immunostained areas. The dorsomedial portion of the striatum was made up of moderately immunostained regions embedded within a densely immunostained background, thus manifesting the characteristic striosome/ matrix organization of the dorsal striatum. However, the ventral and lateral two-thirds of the striatum were made up of a mixture of densely immunostained, moderately immunostained and weakly immunostained areas, with the moderately immunostained region forming the bulk of the background tissue, and smaller, densely immunostained and weakly immunostained regions embedded within it. These compartments were compared to regions defined by distinct levels of acetylcholinesterase immunostaining in adjacent sections; the staining patterns produced by the two cholinergic markers were found to be identical except in some portions of the nucleus accumbens, where acetylcholinesterase immunostaining was found to be more intense than choline acetyltransferase immunostaining. The immunoreactive somata were mapped within sections stained for choline acetyltransferase taken from different rostrocaudal levels of the striatum, and the distributions and densities of immunoreactive somata within these three cholinergic compartments were determined. In general, the densities of cholinergic somata roughly correlated with immunostaining intensity of regions, e.g. the most intensely immunostained compartment also had the highest densities of cholinergic somata. However, in the rostroventral striatum, the densities of cholinergic somata in the weakly immunostained compartment roughly equalled the densities of cholinergic somata in the moderately immunostained compartment, suggesting that local axonal arborizations of cholinergic cells may differ in density or orientation between the two compartments, or, alternatively, that some of the cholinergic cells in the weakly immunostained compartment may project outside of the striatum. The large proportion of striatum displaying ventral striatal characteristics (a complex, multi-compart-mental organization) in humans relative to that observed in other mammals suggests that the role of the ventral striatum may be expanded and more highly differentiated in the human brain.

Adult↗