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Biomedical subjects

G Leng

Publications and source records attributed to G Leng.

At least 19 recordsLinked to original sources
PubMed2007

Bistability with hysteresis in the activity of vasopressin cells.

Magnocellular vasopressin neurones generate distinctive 'phasic' patterns of electrical activity during which periods of spiking activity (bursts) alternate with periods of no spikes or occasional spikes. The mechanisms of burst termination in vivo are still not clearly understood. We recorded from single phasic vasopressin cells in vivo and here we show that burst terminations in some phasic cells is preceded by transient increases in activity, consistent with bursts ending as a result of activity-dependent inhibition. We show that extrinsically imposed increases in activity, evoked by brief stimulation of the organum vasculosum of the lamina terminalis, can either trigger bursts if given when a cell is silent, or stop bursts if given when a cell is active. Thus, the magnocellular vasopressin system is a population of independent bistable oscillators. The population as a whole is insensitive to transient changes in input level, whether these are excitatory or inhibitory. The vasopressin cell population thus acts like a 'low-pass filter'; although brief large changes in input rate have little overall effect, the population responds very effectively to small, sustained changes in input rate by evolving a pattern of discharge activity that efficiently maintains secretion. We note that these filtering characteristics are the opposite of the filtering characteristics that are typically associated with neurones.

Action Potentials↗
PubMed2006

Jacques Benoit Lecture. Information processing in the hypothalamus: peptides and analogue computation.

Peptides in the hypothalamus are not like conventional neurotransmitters; their release is not particularly associated with synapses, and their long half-lives mean that they can diffuse to distant targets. Peptides can act on their cells of origin to facilitate the development of patterned electrical activity, they can act on their neighbours to bind the collective activity of a neural population into a coherent signalling entity, and the co-ordinated population output can transmit waves of peptide secretion that act as a patterned hormonal analogue signal within the brain. At their distant targets, peptides can re-programme neural networks, by effects on gene expression, synaptogenesis, and by functionally rewiring connections by priming activity-dependent release.

Animals↗
PubMed2006

Effects of alpha-melanocyte-stimulating hormone on magnocellular oxytocin neurones and their activation at intromission in male rats.

The peptides alpha-melanocyte-stimulating hormone (alpha-MSH) and oxytocin have very similar effects on several behaviours, including male sexual behaviour. Both induce penile erection and enhance copulatory behaviour when given centrally, suggesting that their central actions are not independent. Here, we used intromission as a physiological stimulus to investigate whether some central effects of alpha-MSH during male sexual behaviour are mediated by oxytocin neurones. We used the expression of the immediate-early gene product Fos to investigate oxytocin neurone activation at intromission and after intracerebroventricular (i.c.v.) administration of alpha-MSH (1 microg/5 microl) and studied the effects of i.c.v. administration of a MC4 receptor antagonist on Fos expression and on the latency of male rats to exhibit sexual behaviour in the presence of a receptive female. In rats that showed intromission, Fos was expressed in magnocellular oxytocin neurones in both the paraventricular nucleus (PVN) and the supraoptic nucleus (SON), but there was no significant activation of parvocellular oxytocin neurones of the PVN. Similarly, alpha-MSH increased Fos expression in magnocellular oxytocin neurones but had little or no effect in parvocellular oxytocin neurones. In male rats that achieved intromission, central injection of a MC4 receptor antagonist significantly attenuated the increase in Fos expression in magnocellular oxytocin neurones in both the PVN and the SON and increased mount and intromission latencies compared to vehicle-injected controls. Together, the results indicate that magnocellular oxytocin neurones are involved in the central regulation of male sexual behaviour, and that some of the central effects of alpha-MSH are likely to be mediated by magnocellular oxytocin neurones.

Animals↗
PubMed2005

Modelling the hypothalamic control of growth hormone secretion.

Here, we construct a mathematical model of the hypothalamic systems that control the secretion of growth hormone (GH). The work extends a recent model of the pituitary GH system, adding representations of the hypothalamic GH-releasing hormone (GHRH) and somatostatin neurones, each modelled as a single synchronised unit. An unpatterned stochastic input drives the GHRH neurones generating pulses of GHRH release that trigger GH pulses. Delayed feedback from GH results in increased somatostatin release, which inhibits both GH secretion and GHRH release, producing an overall pattern of 3-h pulses of GH secretion that is very similar to the secretory profile observed in male rats. Rather than directly stimulating somatostatin release, GH feedback triggers a priming effect, increasing releasable stores of somatostatin. Varying this priming effect to reduce the effect of GH can reproduce the less pulsatile form of GH release observed in the female rat. The model behaviour is tested by comparison with experimental observations with a range of different experimental protocols involving GHRH injections and somatostatin and GH infusion.

Animals↗
PubMed2004

Temporal dissociation of the feedback effects of dendritically co-released peptides on rhythmogenesis in vasopressin cells.

Vasopressin neurones fire action potentials in a rhythmic 'phasic' pattern, characterised by alternating periods of activity and silence. Vasopressin and dynorphin are co-packaged in neurosecretory vesicles that are exocytosed from vasopressin cell dendrites and terminals and both have been implicated in the generation of phasic activity patterning through autoregulatory mechanisms. Here, identified supraoptic nucleus vasopressin cells exhibiting spontaneous phasic activity were recorded from urethane-anaesthetised rats administered the V1 vasopressin receptor antagonist, OPC 21268, or the kappa-opioid receptor antagonist, nor-binaltorphimine. OPC 21268 elevated firing rate throughout each burst whereas nor-binaltorphimine excitation emerged over the course of each burst, indicating a progressive activation of kappa-opioid receptor mechanisms during bursts. To determine whether changes in post-spike excitability could account for these effects, we plotted the probability of action potential firing with time after the preceding action potential (hazard function) and found that, similarly to firing rate, this too was elevated by OPC 21268 throughout each burst whilst the excitatory effects of nor-binaltorphimine progressively increased over the course of each burst. Thus, the temporal organisation of the feedback effects of these co-released peptides is different, with vasopressin effectively causing an immediate reduction in overall excitability whilst dynorphin causes a progressive decrease in post-spike excitability over the course of each burst.

Action Potentials↗
PubMed2004

Modelling the pituitary response to luteinizing hormone-releasing hormone.

The pituitary response to luteinizing hormone-releasing hormone (LHRH) is steroid-dependent and varies throughout the reproductive cycle, but the rapid rise in pituitary sensitivity on the day of the ovulation-inducing LH surge is due to a 'self-priming' effect of exposure to LHRH that results in a potentiation of pituitary responsiveness 35-40 min later. The expression of this effect is itself steroid-dependent, and is most marked on pro-oestrus. Here, a model of LHRH-induced LH release was developed to incorporate the changes in pituitary sensitivity observed throughout the reproductive cycle. LH release is based on the Law of Mass Action, and a component related to self-priming is included in the model, incorporating the delay between initial exposure and potentiation of responsiveness and an upper maximum to the achievable level of priming. Where possible, model parameters were obtained from biological values, otherwise they were optimized to fit an experiment performed in vivo. These parameters were then used to test the model against other experimental data obtained both in vivo and in vitro. The model provided a good fit to the in vivo data but the in vitro experimental data required a change in one parameter, the upper limit of priming. We conclude that this model of the pituitary release mechanism can simulate the changes in pituitary responsiveness throughout the reproductive cycle. We suggest that substitution of this model in a previous model of the LHRH pulse generator could allow more appropriate tests of the LHRH pulse generator model.

Animals↗
PubMed2004

Effects of neurotensin on the organization of activity in supraoptic nucleus cells in virgin and lactating rats.

Neurotensin increases the firing rate of supraoptic nucleus oxytocin and vasopressin neurones in vitro and induces Fos protein expression in the supraoptic nucleus in vivo. Here, we used extracellular single-unit electrophysiological recording combined with local microdialysis administration of neurotensin (1 mM at 2 micro l/min) to investigate the effects of locally applied neurotensin on the firing of oxytocin and vasopressin neurones in urethane-anaesthetized virgin and lactating rats. Neurotensin decreased the mean firing rate of oxytocin cells in virgin, but not lactating, rats. In addition, neurotensin increased the index of dispersion (a measure of the variability of firing) in virgin, but not lactating, rats. By contrast to oxytocin cells, neurotensin increased the mean firing rate of vasopressin cells in both virgin and lactating rats, but did not alter the index of dispersion. The increase in firing of phasic vasopressin cells was achieved through an increase in intraburst frequency (rather than an increase in burst duration or decrease in interburst interval), which resulted from a reduction of the spike-frequency adaptation that develops over the course of phasic bursts. Thus, neurotensin has differential effects on activity patterning in oxytocin and vasopressin cells and the effects on oxytocin cells, but not vasopressin cells, depend upon the physiological status of the animal. The increase in the variability of firing of oxytocin cells induced by neurotensin in virgin rats, but not in lactating rats, suggests that neurotensin (or other neurotransmitters/neuromodulators with similar actions) might establish conditions that predispose oxytocin cells to fire in milk-ejection bursts in lactating rats.

Action Potentials↗
PubMed2004

Estimation of parameters for a mathematical model of growth hormone secretion.

Here, we describe partial calibration of a parsimonious mathematical model of growth hormone (GH) secretion. From first principles, we derived a model of the effects on GH secretion from pituitary somatotrophs of stimulation by GH-releasing factor (GRF) or GH secretagogue, and of inhibition by somatostatin. We obtained a concise model by collapsing the many processes of the signal transduction cascade into a single step broadly reflecting the initial binding of GRF to its receptors. In the model, GH secretion is proportional to the rate of binding of GRF to activatable receptors. Desensitization occurs because of reduction of free receptors/available effector units, and resensitization occurs as those lost are replaced. This replacement is speeded up in the presence of somatostatin, which also inhibits GH secretion by reducing the constant of proportionality between the rate of GH secretion and the rate of GRF binding. We derived simple mathematical equations for the rate of GH secretion and cumulative secretion. Using these, we tested the model against data obtained from experiments performed in vitro, and made it quantitative using rigorous statistical approaches to optimize parameter estimates. The behaviour of the calibrated model matches experimental observations closely.

Algorithms↗
PubMed2002

Beta-endorphin cells in the arcuate nucleus: projections to the supraoptic nucleus and changes in expression during pregnancy and parturition.

Supraoptic nucleus oxytocin neurone activity and secretion are inhibited in late pregnancy and parturition by endogenous opioids. Here, we investigated alterations in the projections and gene expression of beta-endorphin/pro-opiomelanocortin neurones in the arcuate nucleus in the pregnant rat. All regions of the arcuate nucleus were found to contain cells immunoreactive for beta-endorphin fluorescent microbeads retrogradely transported from the supraoptic nucleus, and double-labelled neurones (beta-endorphin plus microbeads), showing that beta-endorphin neurones throughout the arcuate nucleus project to the supraoptic nucleus. There was an increase in the number of beta-endorphin-immunoreactive cells in the arcuate nucleus and an increase in the density of beta-endorphin fibres within the supraoptic nucleus and peri-supraoptic region in late pregnancy and parturition, suggesting enhanced expression of beta-endorphin and increased beta-endorphin innervation of the supraoptic nucleus. Pro-opiomelanocortin mRNA expression in the arcuate nucleus increased in late compared to early pregnancy: the number of positive neurones significantly increased in the caudal region. Fos expression (an indicator of neuronal activation) in the arcuate nucleus was colocalized in beta-endorphin neurones in both proestrus and parturient rats, but the number of positive cells did not increase during parturition, suggesting lack of activation of beta-endorphin neurones at birth. Thus, beta-endorphin cells in the arcuate nucleus project to the supraoptic nucleus and increased innervation during pregnancy may explain the enhanced endogenous opioid inhibition of oxytocin neurones.

Animals↗
PubMed2002

The importance of oxytocin mechanisms in the control of mouse parturition.

The role of oxytocin in parturition in mice was investigated. Pup birth profiles, blood samples and brains were collected from parturient mice observed under red light conditions in a reversed light:dark photoperiod. Peripheral administration of an oxytocin antagonist in a dose-dependent manner delayed the birth of subsequent pups, indicating that oxytocin is required for a normal pup birth profile. Oxytocin neurones were activated during birth as shown by both increased immediate early gene ( Fos) expression in oxytocin neurones in the supraoptic nucleus and increased plasma oxytocin concentrations during birth. In addition, the nucleus of the tractus solitarius and the olfactory bulbs, sites that process inputs to oxytocin neurones, become activated during parturition. Exposure to stress during parturition halted subsequent deliveries; at this stage plasma oxytocin concentrations were not higher than those of virgin mice, and birth was restored by administration of oxytocin. Administration of beta-adrenergic antagonist (propranolol) also restored stress-delayed birth, whereas administration of ritrodrine (beta-agonist) delayed birth in non-stressed mice, indicating that adrenergic mechanisms contribute to stress-delayed births in mice. Administration of morphine (mu-opioid agonist) delayed births transiently, but naloxone (opioid antagonist) did not prevent stress-delayed birth, indicating that endogenous opioids do not appear to contribute to neuroendocrine or uterine mechanisms that promote birth in mice. Therefore, despite evidence in oxytocin knockout mice that oxytocin is not essential for parturition in this species, the results of the present study indicate that oxytocin neurone activity and secretion contribute to the birth process in normal mice.

Adrenergic beta-Agonists↗
PubMed2001

Responses of magnocellular neurons to osmotic stimulation involves coactivation of excitatory and inhibitory input: an experimental and theoretical analysis.

How does a neuron, challenged by an increase in synaptic input, display a response that is independent of the initial level of activity? Here we show that both oxytocin and vasopressin cells in the supraoptic nucleus of normal rats respond to intravenous infusions of hypertonic saline with gradual, linear increases in discharge rate. In hyponatremic rats, oxytocin and vasopressin cells also responded linearly to intravenous infusions of hypertonic saline but with much lower slopes. The linearity of response was surprising, given both the expected nonlinearity of neuronal behavior and the nonlinearity of the oxytocin secretory response to such infusions. We show that a simple computational model can reproduce these responses well, but only if it is assumed that hypertonic infusions coactivate excitatory and inhibitory synaptic inputs. This hypothesis was tested first by applying the GABA(A) antagonist bicuculline to the dendritic zone of the supraoptic nucleus by microdialysis. During local blockade of GABA inputs, the response of oxytocin cells to hypertonic infusion was greatly enhanced. We then went on to directly measure GABA release in the supraoptic nucleus during hypertonic infusion, confirming the predicted rise. Together, the results suggest that hypertonic infusions lead to coactivation of excitatory and inhibitory inputs and that this coactivation may confer appropriate characteristics on the output behavior of oxytocin cells. The nonlinearity of oxytocin secretion that accompanies the linear increase in oxytocin cell firing rate reflects frequency-facilitation of stimulus-secretion coupling at the neurohypophysis.

Animals↗
PubMed2001

Effects of the endogenous opioid peptide, endomorphin 1, on supraoptic nucleus oxytocin and vasopressin neurones in vivo and in vitro.

We investigated the actions of the endogenous opioid tetra-peptide endomorphin 1, a selective mu-opioid receptor agonist, on oxytocin and vasopressin cell activity in vivo and in vitro. The activity of antidromically-identified supraoptic nucleus cells were recorded from urethane-anaesthetized female rats. The firing rates of both oxytocin and vasopressin cells were reduced by intracerebroventricular endomorphin 1 (5 - 100 pmol); this inhibition was prevented by intravenous naloxone (5 mg kg(-1)). A second group of rats was infused intracerebroventricularly with endomorphin 1 (27 pmol min(-1)) over 5 days. The firing rates of oxytocin and vasopressin cells in endomorphin 1 pre-treated rats were similar to those of endomorphin 1 naïve rats, indicating tolerance to the inhibitory effects of endomorphin 1. Intravenous naloxone induced similar modest and transient increases in the firing rate of oxytocin cells in endomorphin 1 pre-treated rats and endomorphin 1 naïve rats, indicating that endomorphin 1, unlike the mu-opioid alkaloid agonist, morphine, does not induce mu-opioid dependence in these cells. In vitro, whole-cell current clamp recordings were made from supraoptic nucleus cells in superfused coronal hypothalamic slices from young female rats. Endomorphin 1 (100 nM) inhibited the firing rate of oxytocin cells but had no significant effect on vasopressin cells at up to 10 microM. Inhibition of oxytocin cells was reversed by naloxone, and remained when synaptic transmission was blocked by superfusion with low Ca(2+)/Co(2+)-containing medium. Thus, endomorphin 1 directly inhibits oxytocin cells but inhibits vasopressin cells by indirect actions. Chronic endomorphin 1 administration induces mu-opioid tolerance in oxytocin and vasopressin cells but not mu-opioid dependence in oxytocin cells.

Action Potentials↗
PubMed2001

Uterine contractile activity stimulates supraoptic neurons in term pregnant rats via a noradrenergic pathway.

Oxytocin secretion is important for the normal progress of parturition in the rat. We tested the hypotheses that contractions of the uterus before pup delivery activate oxytocin neurons, and that they do so via a noradrenergic projection. In anesthetized 22-day (term) pregnant rats, i.v. oxytocin pulses enhanced both uterine contractile activity and the firing rate of oxytocin and vasopressin neurons in the supraoptic nucleus, and these were significantly correlated. The same oxytocin treatment also increased the expression of Fos in both the supraoptic nucleus and the nucleus of the tractus solitarius, but not in 21-day pregnant or virgin rats. In five of eight rats on the day of expected parturition, noradrenaline release in the supraoptic nucleus (sampled by microdialysis) exhibited sudden peaks during oxytocin administration, seen in only one of nine rats given vehicle pulses. Noradrenaline release was significantly greater in rats that went into labor or gave birth to a pup than in rats not in labor. In rats infused with the alpha(1)-noradrenergic receptor antagonist, benoxathian, into the supraoptic nucleus before and during iv oxytocin administration, Fos expression in supraoptic neurons was significantly less than that in vehicle controls. Thus, at term pregnancy, uterine contractions activate both oxytocin and vasopressin neurons in the SON, and this activation involves a noradrenergic pathway.

Adrenergic alpha-Antagonists↗
PubMed2001

Central actions of the nonpeptide growth hormone secretagogue GHS-25.

Growth hormone secretagogues (GHSs) increase the activity of hypothalamic arcuate nucleus neurons thought to be involved in controlling the release of growth hormone (GH). The GHS receptor is also found in hypothalamic regions not associated with the release of GH, suggesting that GHSs may influence other hypothalamic systems. This study utilized double-labeling immunocytochemical techniques to examine the hypothalamic actions of a novel nonpeptide GHS, GHS-25. In common with other GHSs, GHS-25 induced significant amounts of Fos immunoreactivity in the arcuate nucleus of conscious male rats. However, unlike other GHSs, GHS-25 also induced Fos immunoreactivity in the supraoptic nucleus. Double labeling revealed that approx 66% of supraoptic nucleus cells that were Fos positive after the administration of GHS-25 were also immunoreactive for oxytocin. Thus, in addition to its actions on the GH axis, GHS-25 may influence the release of neurohypophyseal hormone.

Animals↗
PubMed2000

Nitric oxide and the oxytocin system in pregnancy.

We examined the functional role of the nitric oxide (NO)-producing system in magnocellular neurons and how this changes at the end of pregnancy, using a combination of blood sampling and oxytocin radioimmunoassay, electrophysiology, immunocytochemistry for Fos expression, and in situ hybridization histochemistry. In urethane-anesthetized virgin rats, systemic administration of NO synthase (NOS) inhibitors led to a facilitation of oxytocin release evoked by hyperosmotic stimulation. Direct application of the NO donor sodium nitroprusside to the supraoptic nucleus by in vivo microdialysis inhibited the electrical activity of both oxytocin neurons and vasopressin neurons, whereas direct application of an NOS inhibitor increased electrical activity, indicating that endogenous NO acts within the supraoptic nucleus to inhibit neuronal activity. However, during late pregnancy, the influence of endogenous NO is dramatically downregulated, reflected by a reduced expression of neuronal NOS mRNA in these neurons and a loss of efficacy of NOS inhibitors on stimulus-evoked oxytocin release. This downregulation may cause the oxytocin system to become more excitable at term, resulting in the capacity for greater release of oxytocin during parturition.

Animals↗