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PubMed1984

Hypothalamic neurons responding to hemodynamic input and to stimulation in the pons may influence adrenocorticotropin release.

Experiments were designed to identify hemodynamically sensitive neurons in the mediodorsal hypothalamus and to determine if they were also sensitive to electrical stimulation of areas in the dorsal rostral pons that were implicated previously in the control of adrenocorticotropin (ACTH) release. Cats were anesthetized with chloralose and urethane, immobilized with gallamine, and artificially respired. Hemodynamic stimuli included constriction (CC) of the supradiaphragmatic inferior vena cava to reduce venous return and sinusoidal volume pulsation (RA) of the right atrium (1 ml peak at 1 Hz). Previously, CC was shown to facilitate and RA was shown to inhibit ACTH release. Electrical stimulation in the pons consisted of single shocks (500 microA DC, 0.05 msec, negative-to-tip) delivered on each of an array of three or four bipolar co-axial electrodes in the pons. Twenty-three neurons were tested with only RA. Of these, two were inhibited, two were facilitated, and 19 did not respond. Thirty-two neurons were tested with CC. Of these, nine were inhibited, nine were facilitated, and 14 did not respond. Seventeen neurons that responded either to RA or to CC were tested with stimulation in the pons. Of these, three were orthodromically activated and two were inhibited from a total of eight pontine sites. Six of the eight sites were within 300 microns of an area shown previously to contain neurons that responded to CC. Of 31 additional sites that were stimulated, but at which stimulation did not drive neurons that responded to hemodynamic stimuli, 26 were located more than 300 microns from this area (p less than 0.01, X2 test). The data suggest that some hypothalamic neurons involved in the hemodynamic control of ACTH release receive a projection from or through the dorsal raphe nucleus medially, and the ventral locus ceruleus, locus subceruleus, and underlying reticular formation laterally. However, other neurons may receive projections that bypass these regions.

Adrenocorticotropic Hormone↗

PubMed1994

C-PON immunoreactive neurons in the neostriatum of the hedgehog (Erinaceus europaeus): a correlated light- and electron-microscopic study.

The present study provides light- and electron-microscopic immunocytochemical data on the presence of neurons that are immunoreactive to the C-terminal flanking peptide of neuropeptide Y, C-PON, in the neostriatum of the hedgehog (Erinaceus europaeus). Positive neurons have mostly fusiform or round perikarya from which two to four poorly branched processes arise. Immunostained fibers and puncta are also evenly distributed throughout the neostriatum. Ultrastructurally, each neuron exhibits a deeply invaginated nucleus surrounded by abundant cytoplasm with a well-developed rough endoplasmic reticulum and Golgi apparatus. Positive neurons receive symmetric and asymmetric synapses from unlabeled terminals. The results of this study can be correlated with previous findings, as the C-PON-positive neurons of the hedgehog resemble medium-sized neostriatal neurons that are known to be local circuit neurons exhibiting C-PON in the rat. Thus, a high degree of C-PON neuronal system phylogenetic conservation and function can be postulated for the neostriatum of mammals.

Animals↗

PubMed1988

C-PON containing neurons in the rat striatum are also positive for NADPH-diaphorase activity. A light microscopic study.

The indirect immunofluorescence technique to detect endogenous C-flanking peptide of neuropeptide Y (NPY), C-PON, in combination with NADPH-diaphorase (NADPH-d) histochemistry, were applied to the same sections to establish whether C-PON containing cell bodies in the rat striatum can be labelled by their content of NADPH-diaphorase activity. NADPH-diaphorase activity proved to be a reliable marker for these positive C-PON neurons. Our results suggest that, in the rat striatum, C-PON, SOM and NPY co-exist in the same cells.

Animals↗

PubMed2005

Responsiveness to cholinesterase inhibitors in Alzheimer's disease: a possible role for the 192 Q/R polymorphism of the PON-1 gene.

Cholinesterase inhibitors (ChEIs) are the most established treatment strategy in Alzheimer's disease (AD). However, the responsiveness to these drugs is widely heterogeneous and the majority of AD subjects do not respond to treatment. Paraoxonase-1 (PON-1) is a potent endogenous ChEI and has been widely studied for its ability to hydrolyze environmental neurotoxins. Serum levels and biological activity of PON-1 display wide inter-individual variability and are strongly influenced by a common polymorphism at position 192 of the PON-1 gene. Here, we evaluated whether this gene variation is associated with differences in the ability of AD subjects to respond to therapy with ChEIs. We found that individuals that respond to ChEIs had a significantly higher frequency of the R allele, compared to non-responders (P<0.05). This study indicates that the 192 Q/R polymorphism of the PON-1 gene might influence responsiveness to ChEIs, with potentially important implications for the treatment of AD. Mutations of genes encoding for endogenous modulators of the cholinergic system should merit further investigation as prognostic indicators of individual response to treatment in AD subjects.

Aged↗

PubMedDate not supplied

Catalase/superoxide dismutase (SOD) and catalase/paraoxonase (PON) ratios may implicate poor glycemic control.

BACKGROUND: Previous studies suggest that elevated oxidative stress implicates poor glycemic control resulting in the development of diabetic complications. By evaluating the relationship between paraoxonase (PON) and antioxidant enzyme activities and glycemic control in diabetic patients with and without complications, we investigated whether there is a role of PON and/or antioxidant status in glycemic control. METHODS: A total of 107 patients with type 2 diabetes mellitus (DM) was included in the study. Seventy-five patients had complications including microangiopathy, proliferative retinopathy, and/or nephropathy while 32 had no complications. The control group consisted of 29 age- and sex-matched healthy persons. Serum superoxide dismutase (SOD) and catalase activities were measured according to Sun and Goth, respectively. Basal and salt-stimulated paraoxonase activities and arylesterase activity were determined using the method of Eckerson et al. RESULTS: There was an increase in the catalase activity and a decrease in the basal and salt-stimulated PON activity of patients when compared with controls, while no significant difference was observed in SOD activity. PON phenotypes had no effect on any parameter in patient and control groups. The ratio of catalase/SOD was 2.44 +/- 7.10 and 0.17 +/- 0.09 in diabetics and controls, respectively (p = 0.004); this was associated with an elevation in HbA1c levels. On the other hand, catalase/PON ratio was also enhanced in diabetic patients (2.8 +/- 5.2), showing a relationship with HbA1c levels compared to controls (0.29 +/- 0.3, p = 0.000). CONCLUSIONS: The data of this study reveal that enhanced catalase/SOD and catalase /PON ratios that are correlated with HbA1c levels are observed in diabetic patients; thus, these ratios may be used as markers of poor glycemic control and as risk factors in the development of diabetic complications.

Adult↗

PubMed2003

Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins.

The human paraoxonase-1 (PON-1) is a serum high-density lipoprotein-associated phosphotriesterase secreted mainly by the liver. This enzyme is able to hydrolyze toxic organophosphate xenobiotics, endogenous oxidized phospholipids, and homocysteine thiolactone. Physiologically, it is thought to protect against cardiovascular diseases. The level of PON-1 gene expression is a major determinant of paraoxonase-1 status but little is known regarding the regulation of this gene. We identified several transcription start sites and characterized the regulation of its promoter by fibrates and statins. In HuH7 human hepatoma cells, the PON-1 secreted enzymatic activity and mRNA levels were increased by fenofibric acid (approximately 70%) and decreased by several statins (approximately 50%). Transient and stable transfection assays in HuH7 cells indicated that the modulation of the mRNA and enzymatic activity levels could be accounted for by the regulation of the PON-1 gene promoter activity by these drugs. These effects are probably not mediated by the PPAR alpha because over-expression of this receptor decreased the fibrate effect and did not modify statins activity. The repressive effect of statins is reversed by mevalonate and 22(R)-hydroxycholesterol, suggesting the involvement of the liver X receptor in the mechanism. The opposite effects of fenofibrate and statins could be consistent with clinical data on homocysteine levels after hypolipidemic drug treatment. Regarding the toxicological aspects, the induction achieved with fenofibric acid, although limited, could increase organophosphate metabolism and may be relevant in certain conditions for protective treatments.

Aryldialkylphosphatase↗

PubMed2002

Presigmoid approach for cavernous angioma in the pons--technical note.

Surgical treatment of brainstem lesions has been encouraged after the development of magnetic resonance imaging. However, direct approaches to intra-axial lesions in the brainstem still carry a high risk of morbidity because the neuronal structures can be injured along the entry routes. We present two patients whose pontine cavernous angiomas were removed via incision of the lateral aspect of the pons with presigmoid approach. The first case, a 41-year-old woman, presented with paresis of the cranial nerves VI, VII, and VIII, and left hemiparesis progressing over 2 weeks caused by a cavernous angioma ventrally located in the lower pons. The second case, a 50-year-old woman, developed dizziness over 2 months due to a large cavernous angioma in the center of the pons. These lesions were totally removed through the presigmoid approach and no additional neurological deficits were observed. An image-guided navigation system was used for the craniotomy and removal of the lesion in the second patient. The presigmoid approach provides a safe route to intra-axial lesions in the pons. A technique for presigmoid craniotomy with one-piece bone flap under the image-guided navigation is also described.

Adult↗

PubMed2005

Functional circuits mediating sensorimotor integration: quantitative comparisons of projections from rodent barrel cortex to primary motor cortex, neostriatum, superior colliculus, and the pons.

Motor performance depends on somatosensory feedback, and consistent with this finding, primary somatosensory (SI) cortex projects to several regions involved in motor control. Although the pathways mediating sensorimotor integration are known, few studies have compared their projection patterns. Therefore, in each animal, we injected two anterograde tracers into SI barrel cortex and compared the relative density and spatial extent of the labeled projections to the primary motor (MI) cortex, neostriatum, superior colliculus, and basal pons. Quantitative analysis revealed that these projections terminated most extensively in the neostriatum, to a lesser extent in MI cortex, and innervated the least amount of neuropil in the superior colliculus and pontine nuclei. Tracer overlap in the pontine nuclei was significantly higher than in the other three brains regions, and was strongly correlated with overlap in the superior colliculus, presumably because some projections to these two brain regions represent collaterals of the same neurons. The density of labeled varicosities was highest in the pons and lowest in MI. As a proportion of total labeling, densely packed clusters of labeled terminals were most prevalent in the pons, less prevalent in neostriatum and superior colliculus, and least prevalent in MI cortex. These results are consistent with physiological evidence indicating strong coherence between SI barrel cortex and the cerebellum during whisking behavior.

Animals↗

PubMed1984

Cortical projections to the paramedian tegmental and basilar pons in the monkey.

The efferent connections of the cerebral cortex to paramedial tegmental and basilar pons were studied in the monkey by using the retrograde and orthograde capabilities of the horseradish peroxidase (HRP) technique. Six capuchin monkeys (Cebus apella) received transcannular pontine HRP gel implants to retrogradely label the cells of origin of corticopontine projections. Four additional capuchin monkeys, one rhesus (Macaca mulatta), and one cynomolgus (Macaca fascicularis) monkey, received HRP gel implants in premotor (area 6), frontal eye field (FEF, area 8), superior (area 5), and inferior (area 7) parietal lobules to orthogradely label the course and termination of corticopontine projections, and thus to confirm the retrograde studies. The brains were processed according to the tetramethylbenzidine (TMB) protocol of Mesulam ('78) and studied with darkfield microscopy. Premotor (area 6) frontal cortex and FEF (area 8) were found to be the main sources of cortical inputs to the ipsilateral paramedian basilar pons, whereas FEF, dorsal prefrontal convexity, and dorsal medial prefrontal (granular frontal association) cortex were the main sources of bilateral projections to the paramedian pontine tegmentum. The medial portion of the nucleus reticularis tegmenti pontis (NRTP), considered to be a tegmental extension of the basilar pontine gray, also received its principal cortical input from the frontal lobe. Parietal cortex, on the other hand, was observed to project to lateral NRTP and lateral basilar pons. Although the possibility exists of convergence of frontal and parietal eye field efferents in the NRTP, the frontal eye field and prefrontal cortex appear to be the principal source of cortical projections to the paramedian pontine tegmentum, which contains the physiologically defined PPRF (paramedian pontine reticular formation), an important preoculomotor center. The results are discussed primarily with regard to their significance for potential cortical influence on the oculomotor system.

Animals↗

PubMed1992

Course of the fiber pathways to pons from parasensory association areas in the rhesus monkey.

The course of the fiber pathways to pons from parasensory association areas in the rhesus monkey was investigated by injection of tritiated amino acids and the technique of autoradiography. Results confirm the projection to pons from parasensory association areas in the temporal, parietal, and occipital lobes and extend these observations to include the posterior parahippocampal gyrus. The findings reveal that the white matter of the posterior limb of the internal capsule above the midpoint of the lateral geniculate nucleus, and at the medial aspect of the lateral geniculate nucleus, comprise common regions through which these corticopontine fibers lead to the basis pontis. The fibers demonstrate a certain degree of topographic organization in the posterior limb of the capsule above the lateral geniculate nucleus and also in the cerebral peduncle. Taken together with previous observations concerning the termination patterns of these associative corticopontine projections, it would appear that the corticopontine system consists of segregated and partially overlapping pathways, which are to some extent distinguishable anatomically at each stage of their trajectory from origin to destination. Furthermore, the existence of a common area through which all parasensory associative input to pons is transmitted suggests that a precisely located lesion in this part of the corticopontocerebellar circuit may disrupt the cerebellar access to higher order information derived from the parasensory associative regions.

Animals↗

PubMed1983

Role and localization of a region in the pons which has a descending inhibitory influence on sympathetically mediated inhibition of the recto-rectal reflex of guinea pigs.

The present study revealed the site of origin and the possible function of a supraspinal descending-inhibitory influence over the lumbar sympathetic component of the recto-rectal reflex of guinea pigs. The recto-rectal reflex contraction was not changed by suprapontine transection. It completely disappeared after subpontine transection, but returned immediately after additional section of the colonic nerves, which contain the sympathetic inhibitory outflow to the rectum, i.e., subpontine transection with the lumbar colonic nerves transected did not suppress the recto-rectal reflex. These results indicate that a descending pathway which can inhibit the lumbar sympathetic component of the reflex may originate in the pons. On stimulation at sites within the pons of animals which had been spinalized at L4 we were able to evoke an increase of rectal motility and an inhibition of the lumbar colonic efferent discharges, thus producing a response which is comparable to the reflex response produced by afferent stimulation of the rectum. The sites from which this effect could be evoked were mainly located in a band running rostrocaudally through the lateral reticular formation of the rostral part of the pons, medial to the sensory nucleus of the trigeminal nerve.

Animals↗

PubMed1985

Medullary respiratory-related neurons with axonal connections to rostral pons and their function in termination of inspiration.

In urethane-anaesthetized, paralyzed and artificially ventilated rabbits, medullary respiration-related neurons (RRU) were classified according to the phase relation of their burst discharge to phrenic nerve activity. Phase-bound inspiratory (I) or expiratory (E) neurons were discriminated from phase-spanning expiratory-inspiratory (EI) or inspiratory-expiratory (IE) units. Mechanisms of termination of inspiration by electrical stimulation of rostral pontine nuclei (Nc. parabrachialis medialis; Lc. coeruleus) were examined firstly to demonstrate whether RRU receive descending excitatory and inhibitory afferents as well as ascending efferents and secondly to analyse the time course of the neuronal pathways involved. Of 120 RRU, 38 neurons were demonstrated to receive pontine afferents. About 33% of all E neurons became orthodromically excited during rostral pons stimulation whereas 18.2% of all I cells became orthodromically inhibited. Some RRU were shown to project up to the rostral pons. 50% of these were of the phase-spanning IE type. The onset of inspiratory inhibition induced by rostral pons stimulation occurred 3.4 ms after the onset of single electrical pulse stimulation. Based on these results a neuronal model for a pontine mechanism terminating inspiration is proposed.

Animals↗

PubMed2005

Alpha(1)-adrenergic and alpha(2)-adrenergic balance in the dorsal pons and gross behavioral activity of mice in a novel environment.

RATIONALE: Central alpha(1)- and alpha(2)-adrenoceptors in a number of different brain regions are known to have opposing actions on gross behavioral activity, with the former stimulating and the latter inhibiting activity. Therefore, blockade of alpha(1)-receptors may induce inactivity by leading to unopposed alpha(2) activity. OBJECTIVE: The aim of this study was to test if central blockade of alpha(2)-receptor function restores behavioral activity in alpha(1)-receptor-blocked mice. METHODS: Dose-response studies were undertaken on the effects of alpha(1)- and alpha(2)-agonists and antagonists microinjected into the dorsal pons on gross behavioral activity in a novel cage test. RESULTS: The behavioral inactivity resulting from blockade of alpha(1)-receptors in the pons with the antagonist, terazosin, was reversed by either a low dose of an alpha(2)-antagonist, atipamezole, or a low dose of an alpha(2)-agonist, dexmedetomidine, but was exacerbated by a high dose of the alpha(2)-agonist. CONCLUSION: The results support the hypothesis that blockade of alpha(1)-receptors in the dorsal pons of mice produces inactivity by causing unopposed activity of alpha(2)-receptors. This condition may be relevant to inactive states seen after stress or during depressive illness.

Adrenergic alpha-Agonists↗

PubMed2005

Effects of electrical stimulation of the posterior part of the hypothalamus on the spike activity of neurons in the oral nucleus of the pons.

Chronic experiments were performed on four cats to study evoked spike activity in neurons in the oral nucleus of the pons to electrical stimulation of the posterior hypothalamus in the waking, slow-wave sleep, and paradoxical sleep states. A total of 42% of study neurons were found to respond to stimulation during waking. PS-on and PS-off neurons were identified in the oral nucleus of the pons, along with phasic cells showing bursts of activity during the physical manifestations of paradoxical sleep. Stimulation induced inhibitory responses in PS-on neurons, excitatory responses in PS-off neurons, and excitatory and inhibitory responses in 68% and 32% respectively of phasic neurons. The magnitudes of evoked responses in these neurons changed during the sleep-waking cycle. These data demonstrate the involvement of the posterior hypothalamus in controlling the mechanisms of paradoxical sleep, these mechanisms being located in the oral nucleus of the pons.

Animals↗

PubMed1991

Lesions of the rostral dorsolateral pons have no effect on afferent-evoked inhibition of inspiration.

This study investigated a possible role of the rostral dorsolateral pons (including nucleus parabrachialis medialis and Kölliker-Fuse nucleus) in mediating several inspiratory inhibitions. These inhibitions included the transient inhibition of phrenic inspiratory motor output produced by stimulation of the superior laryngeal nerve (SLN), the intercostal nerve (ICN) or the phrenic nerve (PN), as well as the inspiratory termination produced by trains of stimuli delivered to the SLN or ICN. In decerebrate, paralyzed, and artificially ventilated cats, the inhibitions produced by stimulation of these nerves were observed before and after lesioning (either radiofrequency, n = 8, or electrolytic, n = 9) the dorsolateral pons. Delivery of stimulus trains to the SLN or the ICN continued to elicit inspiratory termination following pontine lesions with no significant change in the threshold. There were no significant effects of bilateral dorsolateral pontine lesions on the threshold, onset latency, or duration of the short-latency, transient inhibitions produced by SLN, ICN or PN stimulation. From these data, we conclude that the rostral dorsolateral pons is not required in the production of any of these inhibitory reflexes.

Animals↗

PubMed1983

Blockade of morphine dependence-related enhancement of secretory protein synthesis in the pons-medulla and striatum-septum by naltrexone.

The effects of several schedules of multiple morphine pellet implantation on body weight and dependence development in rats were studied. One schedule designated 6/7 (total number of pellets implanted per total number of treatment days), consisting of 1 pellet on day 0, 2 pellets on day 2 and 3 pellets on day 4 and a total treatment period of 7 days, produced high levels of dependence without affecting either body weight or rates of protein synthesis in whole brain or liver. The components of this schedule, 1/2 (one pellet on day 0 and a total treatment period of 2 days), 3/4 (one pellet on day 0 and two pellets on day 2 and a total treatment period of 4 days) and 6/7 (see above), produced a linear increase in the degree of dependence as measured by loss of body weight following naloxone-precipitated withdrawal. Hence, they were used to investigate the relationship between the degree of dependence and the rate of translation in vivo on free and membrane-bound polysomes in seven brain regions (cerebrum, cerebellum, mesencephalon, pons-medulla, striatum-septum, hippocampus-amygdala and thalamus-hypothalamus) following a 6 min pulse with a pool expansion dose of [3H]leucine. The rate of translation on free and membrane-bound polysomes was unaffected except on the bound polysomes of the pons-medulla and striatum-septum, where increased rates of translation were found to be closely correlated with degrees of dependence, measured as loss of body weight. Concomitant administration of naltrexone prevented both the stimulation of protein synthesis and the development of dependence, whereas administration of naltrexone alone did not affect translation rates in either polysome compartment of any region. Thus, it is concluded that the mechanisms underlying opiate dependence involve the stimulation of secretory protein synthesis in the pons-medulla and striatum-septum, presumably by the interaction between morphine and opiate receptors.

Animals↗

PubMedDate not supplied

Afferent projections to the self-stimulation regions of the dorsal pons, including the locus coeruleus, in the rat as demonstrated by the horseradish peroxidase technique.

Afferent projections to the dorsal pons of the rat have been studied using the horseradish peroxidase (HRP) technique. HRP injections were made in each of the following regions: the vicinity of the locus coeruleus (LC); the periventricular gray, medial to the LC; the medial parabrachial region, lateral to the LC; the ventral cerebellum, dorsal to the LC; and the pontine reticular formation, ventral to the LC. Because intracranial self-stimulation (ICSS) has been obtained in these regions, the afferents have been discussed in terms of their possible contributions to the behavior. Previous ICSS studies of the dorsal pons have focussed on the LC as playing a central role. Presently identified inputs to the LC include: the dorsal raphe nucleus: the ventrolateral periaqueductal gray: the pontine reticular formation: the areas that contain the pontine and medullary noradrenergic and adrenergic cell groups: the lateral hypothalamic area: the contralateral LC: the deep cerebellar nuclei: the ventrolateral and parafascicular thalamic nuclei: and the parabrachial regions of the pons and midbrain.

Afferent Pathways↗

PubMed2006

Absence of the basilar pons in mice lacking a functional Large glycosyltransferase gene suggests a defect in pontine neuron migration.

Several forms of congenital muscular dystrophy result from mutations in glycosyltransferases that modify alpha-dystroglycan. As pontine hypoplasia has been reported in some clinical cases of congenital muscular dystrophy, we have begun to examine whether these glycosyltransferases are required for the normal development of the basilar pons, one of several precerebellar nuclei of the hindbrain. In veils (Large(vls)) mice, which carry a loss-of-function mutation in the Large glycosyltransferase gene, the basilar pons is absent. Instead, ectopic clusters of pontine neurons are found lateral to their normal site, suggesting that these neurons are unable to migrate to their appropriate site. Two other precerebellar nuclei, the lateral reticular nucleus and the inferior olive, are present in Large(vls) mice. In addition, the basilar pons forms normally in dystrophin-deficient mice. These results demonstrate that the Large glycosyltransferase but not dystrophin is required for normal basilar pontine development.

Animals↗