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Biomedical subjects

M Meredith

Publications and source records attributed to M Meredith.

At least 19 recordsLinked to original sources
PubMed1995

Separation of sequence requirements for HSV-1 Vmw110 multimerisation and interaction with a 135-kDa cellular protein.

Herpes simplex virus type 1 immediate-early polypeptide Vmw110 (ICP0) is a general transactivator of gene expression in transfection assays and is required for the fully efficient onset of viral lytic replication. It has also been implicated in the process of viral reactivation from latency. Its mechanism of action is unknown, but any involvement in latency requires interactions between viral and host factors. We have previously shown that Vmw110 binds to a 135-kDa cellular protein. In this paper we define a short region towards the C-terminal end of Vmw110 that is required for the 135-kDa protein interaction in virus-infected cells and in vitro. We also confirm that the C-terminal region of Vmw110 contains residues that are responsible for the multimerisation of the protein; these sequences are at least partially distinct from those involved in 135-kDa binding. Both multimerisation and 135-kDa protein interaction are required for full viral infectivity, and elimination of these functions affects the normal interactions between Vmw110 and cellular nuclear structures that contain the PML protein.

Animals↗
PubMed1995

Cytosolic biosynthesis of GTP and ATP in normal rat pancreatic islets.

GTP and ATP are necessary for glucose-induced insulin secretion; however, the biosynthetic pathways of purine nucleotides have not been studied in pancreatic islets. The present work examines the cytosolic pathways of purine nucleotide synthesis using intact rat islets cultured overnight in RPMI 1640 medium containing either [14C]glycine (to label the de novo pathway) or [3H]hypoxanthine (to mark the salvage pathway), with or without mycophenolic acid or L-alanosine (selective inhibitors of cytosolic GTP and ATP synthesis, respectively). Addition of mycophenolic acid decreased total GTP content (mass) by 73-81%; although the incorporation of labeled hypoxanthine into GTP also fell by 87%, the incorporation of glycine did not change. Similarly, L-alanosine decreased ATP mass by 26-33% in the presence of either label; whereas the incorporation of hypoxanthine into ATP fell 59%, the incorporation of glycine was again not significantly decreased. Thus, both the de novo and salvage purine nucleotide biosynthetic pathways are present in rat islets; however, the salvage pathway appears to be quantitatively the more important source of nucleotides. This conclusion was supported by additional studies of the effects on nucleotide content and insulin secretion of various site-specific inhibitors of purine synthesis. These findings have potential relevance to the processes of mitogenesis, cell proliferation and differentiation of islet cells, as well as for the control of insulin secretion.

Adenosine Triphosphate↗
PubMed1995

Nervus terminalis ganglion of the bonnethead shark (Sphyrna tiburo): evidence for cholinergic and catecholaminergic influence on two cell types distinguished by peptide immunocytochemistry.

The nervus terminalis is a ganglionated vertebrate cranial nerve of unknown function that connects the brain and the peripheral nasal structures. To investigate its function, we have studied nervus terminalis ganglion morphology and physiology in the bonnethead shark (Sphyrna tiburo), where the nerve is particularly prominent. Immunocytochemistry for gonadotropin-releasing hormone (GnRH) and Leu-Pro-Leu-Arg-Phe-NH2 (LPLRFamide) revealed two distinct populations of cells. Both were acetylcholinesterase positive, but LPLR-Famide-immunoreactive cells consistently stained more darkly for acetylcholinesterase activity. Tyrosine hydroxylase immunocytochemistry revealed fibers and terminal-like puncta in the ganglion, primarily in areas containing GnRH-immunoreactive cells. Consistent with the anatomy, in vitro electrophysiological recordings provided evidence for cholinergic and catecholaminergic actions. In extracellular recordings, acetylcholine had a variable effect on baseline ganglion cell activity, whereas norepinephrine consistently reduced activity. Electrical stimulation of the nerve trunks suppressed ganglion activity, as did impulses from the brain in vivo. During electrical suppression, acetylcholine consistently increased activity, and norepinephrine decreased activity. Muscarinic and, to a lesser extent, alpha-adrenergic antagonists both increased activity during the electrical suppression, suggesting involvement of both systems. Intracellular recordings revealed two types of ganglion cells that were distinguishable pharmacologically and physiologically. Some cells were hyperpolarized by cholinergic agonists and unaffected by norepinephrine; these cells did not depolarize with peripheral nerve trunk stimulation. Another group of cells did depolarize with peripheral trunk stimulation; a representative of this group was depolarized by carbachol and hyperpolarized by norepinephrine. These and other data suggest that the bonnethead nervus terminalis ganglion contains at least two cell populations that respond differently to acetylcholine and norepinephrine. The bonnethead nervus terminalis ganglion appears to differ fundamentally from sensory and autonomic ganglia but does share some features with the neural circuits of forebrain GnRH systems.

Acetylcholinesterase↗
PubMed1995

Facilitation of mating behavior in male hamsters by LHRH and AcLHRH5-10: interaction with the vomeronasal system.

An intact vomeronasal organ is important for the reproductive physiology and behavior of many species. Vomeronasal sensory input is known to influence hormone levels especially LH, presumably by prior modulation of LHRH. LHRH has been shown independently to facilitate mating behavior in rodents of both sexes. In this study intracerebroventricular LHRH at a dose of 50 ng substantially relieved mating behavior deficits caused by prepubertal removal of vomeronasal organs from inexperienced male hamsters. Intranasal LHRH at a higher dose did not have this effect. Behavioral responses were recorded 30 mins after peptide or saline injection. The LHRH analog, AcLHRH5-10 which we demonstrate does not induce LH release, did facilitate mating behavior in these tests, suggesting that LHRH peptides may facilitate male mating behavior via an extra-pituitary mode of action.

Animals↗
PubMed1995

Evidence of a role for GTP in the potentiation of Ca(2+)-induced insulin secretion by glucose in intact rat islets.

Glucose initiates insulin secretion by closing K(+)-ATP channels, leading to Ca2+ influx (E1); it also potentiates Ca(2+)-induced secretion (E2) when the K(+)-ATP channel is kept open using diazoxide and depolarizing concentrations of K+ are provided. To examine the roles of purine nucleotides in E2, we compared the effects of glucose to those of the mitochondrial fuel monomethylsuccinate. Either agonist could induce E2 accompanied by significant increases in ATP, ATP/ADP ratio, and GTP/GDP ratio; GTP increased significantly only with glucose. Mycophenolic acid (MPA), an inhibitor of cytosolic GTP synthesis, markedly inhibited glucose-induced E2 (either in perifusions or in static incubations) and decreased GTP and the GTP/GDP ratio, but did not alter the ATP/ADP ratio. Provision of guanine (but not adenine) reversed these changes pari passu. In contrast, MPA had no effect on succinate-induced E2, despite generally similar changes in nucleotides. A similar lack of effect of MPA on E2 was seen with a second mitochondrial fuel, alpha-ketoisocaproic acid (KIC). However, in the absence of diazoxide and K+, MPA blunted the secretory effects of either glucose, succinate, or KIC. These studies suggest that GTP plays a role in both glucose and succinate or KIC-induced insulin secretion at a step dependent on mitochondrial metabolism and the K(+)-ATP channel. In addition to mitochondrial effects, glucose appears to have extramitochondrial effects important to its potentiation of Ca(2+)-induced insulin secretion that are also dependent on GTP.

ATP-Binding Cassette Transporters↗
PubMed1992

Intracerebroventricular LHRH relieves behavioral deficits due to vomeronasal organ removal.

Contact between the sexes in many species is known to produce hormonal changes in the male [increases in serum luteinizing hormone (LH) and/or testosterone] that can be interpreted as due to an intracerebral release of LH-releasing hormone (LHRH). In some circumstances, these hormonal changes appear to depend on an intact vomeronasal sensory system. Exogenous LHRH is also known to facilitate mating behavior in several species. We show here that LHRH delivered into the cerebral ventricles can restore some mating behavior lost when the vomeronasal organs are removed from sexually inexperienced male hamsters. The results are consistent with our working hypothesis that intracerebral LHRH release is an intermediate in the facilitation of mating behavior by vomeronasal sensory input.

Animals↗
PubMed1992

Neural circuit computation: complex patterns in the olfactory bulb.

The olfactory bulb principal neurons show complex responses during olfactory stimulation that are characterized by periods of profound suppression, temporal patterns of activity, and nonmonotonic intensity response functions. The model presented here suggests that these features may arise from changing spatial patterns of activity across the bulbar surface due to restricted (chemotopic) activation in bulbar glomeruli. The model is based on a simplified version of the bulbar neural circuit as it is presently known from anatomical and physiological investigations and provides explanations for several anomalous bulbar response patterns.

Axons↗
PubMed1991

Sensory processing in the main and accessory olfactory systems: comparisons and contrasts.

The vomeronasal organ (VNO) and accessory olfactory system (AOS) are present in most terrestrial vertebrates except birds and higher primates. The receptor neurons of the AOS are sequestered inside the VNO, away from the main airflow to the main olfactory receptor neurons. Mechanisms of stimulus access to the sensory neurons vary across species but in most cases there is a system for delivering stimuli faster than would be possible by diffusion. Vomeronasal (VN) receptor neurons typically lack cilia, the site of most of the transduction apparatus in the main olfactory receptors. The VN receptor neurons have a restricted but privileged pathway to the areas of the brain concerned with reproduction and social behavior. In contrast, the main olfactory neurons have a broad pathway to wide areas of the brain, including the neocortex. Experiments where the VNOs or other parts of the accessory olfactory pathway were ablated indicate that the system is important in many behavioral and physiological responses to pheromones (chemical signals carrying information about gender or reproductive or dominance status), some of which may be proteins. VN sensory neurons respond to both volatile and non-volatile stimuli. There is no evidence in the vertebrate AOS for the extreme sensitivity or selectivity characteristic of insect pheromone detectors, but this has not been adequately tested. There is some evidence for learning, possibly by synaptic modification at the second-order neuron level. Social and reproductive cues stimulating the AOS often elicit an intracerebral release of LHRH--which may act at receptors different from those of the pituitary to facilitate behavior. Whether the LHRH release is necessary for AOS-mediated behavioral response is not yet clear.

Amygdala↗
PubMed1987

The nervus terminalis of the shark: the effect of efferent impulses on ganglion cell activity.

Tonic activity was recorded extracellularly in the nervus terminalis of the bonnethead shark. Cutting or cooling the nerve central to its ganglion eliminated these spikes, and was followed by an increase in multi-unit activity which appeared to arise from the ganglion. After cutting centrally, electrical stimulation of the distal stump of the nerve suppressed this multi-unit activity. The data suggest that efferent impulses may normally suppress ganglion cell activity.

Action Potentials↗
PubMed1987

Convergence of main and accessory olfactory pathways onto single neurons in the hamster amygdala.

Chemoreceptor pathways from the vomeronasal organ (VNO), and main olfactory system are known to be separate as they pass into the brain, at least until the level of the amygdala. In the amygdala, vomeronasal pathways project to the posteromedial cortical nucleus (PMCN), and medial nucleus (MN). The main olfactory pathways have terminations in the posterolateral cortical nucleus (PLCN), and anterior cortical nucleus (ACN), both of which project to the PMCN and MN. The anatomy thus suggests that the PMCN and MN are sites for convergence of input from the main and accessory olfactory pathways. We have recorded single units in the amygdala and found that electrical stimulation of either the main olfactory bulbs or the VNO could drive some of the same units in the PMCN. Units were also found that were driven by one system but not the other, and units in which activity driven by one system was suppressed by stimulation of the other system.

Action Potentials↗
PubMed1986

Vomeronasal organ removal before sexual experience impairs male hamster mating behavior.

Removal of vomeronasal chemoreceptors before sexual experience in male hamsters resulted in complete failure to mate in some animals but removal of these receptors after sexual experience had no effect. Animals were tested for mating behavior with intact behaviorally receptive females and also with anesthetized males scented with vaginal fluid. The two tests produced essentially the same result. Histological analysis of the lesions and radioimmunoassay of androgen levels showed no group differences, other than vomeronasal organ removal, that could account for the results. The behavioral data suggest that the vomeronasal system may be concerned with the production of preprogrammed behavior.

Androgens↗
PubMed1986

Patterned response to odor in mammalian olfactory bulb: the influence of intensity.

Responses of single neurons in the olfactory bulb of anesthetized hamsters were recorded extracellularly while odors of defined concentration and time course were delivered to the olfactory system at constant flow. Responses could be either excitatory or suppressive, as judged by the first distinguishable change in firing rate during odor delivery. However, when the time course of the response was examined in more detail, approximately one-third of all tests and one-half of the tests at high concentration resulted in complex temporal patterns of firing rate that involved both increases and decreases with respect to spontaneous activity. Approximately two-thirds of all tests produced responses where increased firing rate preceded any distinguishable suppression. Excitatory and suppressive responses were each classified into four groups according to their temporal patterns. Different patterns were not equally represented in the data and the proportions of patterns elicited by the same odor changed with stimulus intensity. Complex responses, where temporal patterns included periods of firing rate above and below spontaneous rate, were increasingly common and intensity was increased. Magnitude of response is difficult to define when a single response includes both increases and decreases of firing rate but more than half of the neurons that responded to more than one stimulus concentration clearly had nonmonotonic intensity-response functions. Forty-one out of 101 neurons were classified as output cells because they could be driven at short constant latency by lateral olfactory tract stimulation. Their responses were not clearly different from the remaining cells that could not be classified as output cells. The contribution of the inhibitory circuits of the olfactory bulb to the generation of patterned response and to changes in pattern with intensity are discussed. The lateral inhibitory circuits of the bulb appear to be sufficient to explain the data presented here.

Action Potentials↗
PubMed1984

Effects of volatile and nonvolatile chemical signals on male sex behaviors mediated by the main and accessory olfactory systems.

Estrous hamster vaginal discharge (HVD) contains both volatile and nonvolatile chemical signals which collectively elicit both male attraction to females and male mating behavior. These two aspects of normal sexual behavior are differentially affected by lesions involving afferents of the main and the accessory olfactory systems. The results of lesions that involve the main olfactory system suggest that it provides information primarily concerning those volatile components of HVD that normally signal the presence of a female. Lesions restricted to the accessory olfactory system do not impair a male's interest in or relative preference for HVD but do significantly interfere with subsequent stages of sexual behavior by reducing the amount of mating obtained upon exposure to HVD. Stimulation of the accessory olfactory system by nonvolatile components of HVD has thus been implicated in the production of mating behavior. In these experiments, male hamsters were attracted to female odor and engaged in significant amounts of mating behavior with surrogate females when only the volatile components of HVD were available to them. These behaviors were further enhanced when both volatile and nonvolatile components of HVD were provided. Lesion studies of the afferents involved reinforce the hypothesis that the main olfactory system is preferentially involved with processing those volatile chemical signals in HVD that denote female attractiveness whereas the accessory olfactory system is preferentially involved with processing those chemical signals, both volatile and nonvolatile, that evoke subsequent steps in male sexual behavior.

Animals↗