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PubMed1993

Respiratory modulation of the activity in postganglionic neurons supplying skeletal muscle and skin of the rat hindlimb.

1. The respiratory modulation of activity in postganglionic neurons of the lumbar sympathetic outflow to skeletal muscle and hairy skin of the hindlimb was studied in anesthetized rats, either breathing spontaneously or paralyzed and artificially ventilated, using single- and multifiber recordings. The activity of the neurons was analyzed with respect to the phrenic nerve discharges or with respect to the cycle of artificial ventilation under various experimental conditions. 2. In total, 19 single and 62 multiunit preparations supplying skeletal muscle and 42 single and 95 multiunit preparations supplying skin were analyzed. Qualitatively, both populations and single- and multiunit preparations exhibited similar patterns. The majority (187/218 preparations) exhibited a depression of activity during inspiration and a peak of activity during expiration that was mostly accentuated during early expiration. The remainder exhibited a peak of activity at the transition between expiration and inspiration (n = 15) or showed no respiratory modulation (n = 16). 3. Respiratory modulation in the postganglionic neurons was similar in animals breathing spontaneously and in those that were paralyzed and artificially ventilated. 4. Systemic hypercapnia and asphyxia in most cases enhanced both the peak of activity during early expiration and the depression of activity during inspiration. 5. No peripheral (reflex) component mediated by arterial baroreceptors was found in vagotomized animals that was related to the cycle of artificial ventilation using a tidal volume of 1-2 ml and a ventilation frequency of 70 +/- 7 (SD) strokes, min-1. However, a small ventilation-related rhythm of arterial baroreceptor activity recorded from the aortic nerve was found under these conditions. 6. Respiratory modulation of postganglionic activity was similar before and after bilateral vagotomy. 7. It is concluded that respiratory modulation of sympathetic activity in rats is less differentiated than in cats. The observed differences between neurons supplying different targets are only quantitative. Possible mechanisms involved in the generation of respiratory modulation are discussed.

Afferent Pathways↗
PubMed1994

Modulation of gap-junction channel gating at zebrafish retinal electrical synapses.

1. Transmission at electrical synapses is modulated by a variety of physiological signals, and this modulation is a potentially general mechanism for regulating signal integration in neural circuits and networks. In the outer plexiform layer of the retina, modulation of horizontal-cell electrical coupling by dopamine alters the extent of spatial integration in the horizontal-cell network. By analyzing the activity of individual gap-junction channels in low-conductance electrical synapses of zebrafish retinal horizontal cells, we have defined the properties of these synaptic ion channels and characterized the functional changes in them during modulation of horizontal-cell electrical synapses. 2. Zebrafish horizontal-cell gap-junction channels have a unitary conductance of 50-60 pS and exhibit open times of several tens of milliseconds. The kinetic process of channel closure is best described by the sum of two rate constants. 3. Dopamine, and its agonist, (+/-)-6,7-dihydroxy-2-amino-tetralin (ADTN), modulates electrical synaptic transmission between horizontal cells predominantly by affecting channel-gating kinetics. These agents reduced the open probability of gap-junction channels two- to threefold by reducing both the duration and frequency of channel openings. Both time constants for channel open duration were reduced, whereas the duration of shut periods was increased. Similar changes in open-time kinetics were observed in power spectra of higher conductance gap junctions. 4. These results provide a description of rapid electrical synaptic modulation at the single channel level. The description should be useful in understanding the mechanisms of plasticity at these synapses throughout the vertebrate central nervous system.

Animals↗
PubMed1996

Serotonin modulates N- and P-type calcium currents in neocortical pyramidal neurons via a membrane-delimited pathway.

1. The effects of serotonin (5HT) on neocortical pyramidal neurons were studied using whole cell and ON-cell patch-clamp recordings from acutely dissociated neurons. 2. 5HT decreased high voltage-activated calcium channel currents in a dose-dependent and reversible manner in acutely dissociated neocortical pyramidal neurons. The maximum block was 30% of the peak whole cell current (at -10 mV). 3. The 5HT modulation was mimicked by 5HT1A agonists and was reduced by 5HT1A antagonists. 5HT2 antagonists had no effect on the modulation. These data suggest that the 5HT effects were mediated by 5HT1A receptors. 4. The 5HT1A modulation was reduced in the presence of the specific N-type blocker omega-conotoxin GVIA (CgTx) and by the P-type channel blocker omega-agatoxin IVA (AgTx), but not by the L-type blocker nifedipine. 5HT did not modulate the slowed tail currents in the presence of the dihydropyridine agonist Bay K 8644. These data suggest that N- and P-type channels (but not L-type channels) were targeted by 5HT. 5. The modulation involved G proteins and utilized a membrane-delimited pathway. The modulation was rapid in onset (tau approximately 600 ms) and offset. About 50% of the reduction in current by 5HT1A agonists was overcome by prepulses to 120 mV. 6. Slowing of current onset kinetics in response to 5HT1A agonists was seen rarely in neocortical pyramidal neurons (11% of cases). The presence of slowing depended on agonist concentration, being evident only with high micromolar doses.

Animals↗
PubMed1996

Tachykinin-mediated modulation of sensory neurons, interneurons, and synaptic transmission in the lamprey spinal cord.

1. Tachykinin-like immunoreactivity is found in the dorsal roots, dorsal horn, and dorsal column of the lamprey. The effect of tachykinins on sensory processing was examined by recording intracellularly from primary sensory dorsal cells and second-order spinobulbar giant interneurons. Modulation of synaptic transmission was examined by making paired recordings from dorsal cells and giant interneurons, or by eliciting compound depolarizations in the giant interneurons by stimulating the dorsal root or dorsal column. 2. Bath application of tachykinins depolarized the dorsal cells. This effect was mimicked by stimulation of the dorsal root, suggesting that dorsal root afferents may be a source of endogenous tachykinin input to the spinal cord. The depolarization was reduced by removal of sodium or calcium from the Ringer, or when potassium conductances were blocked, and was not associated with a measurable change in input resistance. Dorsal root stimulation also caused a depolarization in the dorsal cells, and this effect and that of bath-applied substance P, was blocked by the tachykinin antagonist spantide. 3. The tachykinin substance P could reduce inward and outward rectification in the dorsal cells, the effect on outward rectification only being seen when potassium conductances were blocked by tetraethylammonium (TEA). 4. Substance P increased the excitability of the dorsal cells and giant interneurons, shown by the increased spiking in response to depolarizing current pulses. The increased excitability was blocked by the tachykinin antagonist spantide. 5. Substance P modulated the dorsal cell action potential, by increasing the spike duration and reducing the amplitude of the afterhyperpolarization. The spike amplitude was not consistently affected. 6. Stimulation of the dorsal column resulted in either depolarizing or hyperpolarizing potentials in the giant interneurons. The amplitude of the depolarization was increased by substance P, whereas the amplitude of the hyperpolarization was reduced. These effects occurred independently of a measurable change in postsynaptic input resistance, suggesting that the modulation occurred presynaptically. Paired recordings from dorsal cells and giant interneurons failed to reveal an effect of substance P on dorsal cell-evoked excitatory postsynaptic potentials (EPSPs), suggesting that the potentiation of the dorsal column-evoked depolarization was due to an effect on other axons in the dorsal column. Dorsal root-evoked potentials could also be increased in the presence of substance P, although this effect was less consistent than the effect on dorsal column stimulation. 7. These results suggest that tachykinins modulate sensory input to the lamprey spinal cord by increasing the excitability of primary afferents and second-order giant interneurons, and also by modulating synaptic transmission. Tachykinins may result in potentiation of local spinal reflexes and also modulation of descending reticulospinal inputs to the spinal locomotor network as a result of potentiation of spinobulbar inputs.

Action Potentials↗
PubMed1997

Medial olivocochlear efferent system in humans studied with amplitude-modulated tones.

Evoked otoacoustic emissions (EOAEs) are assumed to be generated by outer hair cells (OHCs). It is now generally accepted that EOAEs represent a means of functional exploration of the active micromechanical properties of OHCs. Efferent fibers of the medial olivocochlear system (MOCS) are connected along the sides and the bases of OHCs. Some studies have shown that a suppression effect on EOAE amplitude is induced by the MOCS neurons during contralateral stimulation, presumably by modification of OHC motility. The contralateral acoustic stimuli used in experiments on the EOAE suppression effect have consisted mainly of sounds without a slow temporal fluctuation in their envelopes (broad-band noise, narrow-band noise, pure tones, or clicks). To elucidate further the parameters of MOCS activation, in the present study we looked at the contralateral suppression effect of amplitude-modulated (AM) tones. The results showed that EOAE amplitude was reduced with AM tones compared with no contralateral acoustic stimulation. The suppression effect mainly depended on three parameters. 1) Contralateral stimulation intensity: EOAE suppression occurred only with intensities > or = 40 dB SL. 2) The greater the modulation depth, the greater the suppression effect: statistical analysis showed a significant effect for 75 and 100% modulation depth. 3) The 100- and 140-Hz modulation frequencies gave the greatest suppression effect for 100 and 75% modulation depths. The suppression effect was frequency specific. The greatest decreases were observed when the carrier frequency of the contralateral AM tone was close to the frequency of the EOAE under study, i.e., 1 and 2 kHz. Acoustic cross talk and middle ear effects, which cannot be completely excluded, are discussed. However, the demonstrated frequency specificity of the EOAE suppression effect, together with observed presence of contralateral EOAE suppression in patients without stapedial reflex and the very weak intensities used (i.e., below acoustic reflex threshold), suggested that it was unlikely that the observed effects were due merely to middle ear reflexes. Our results confirm further the contralateral suppression effect on human cochlea mechanisms and show that the suppression effect can be influenced by amplitude modulations of the suppressor, characteristic of sounds in the environment.

Acoustic Stimulation↗
PubMed2000

On the origin of the soleus H-reflex modulation pattern during human walking and its task-dependent differences.

Recently, Brooke and colleagues have suggested "that the strong inhibition arising from passive movement about the knee and hip joints, lays down the base for the soleus H-reflex gain modulation seen during human gait." In particular stretch-evoked afferent activity from the quadriceps muscle was emphasized as the most important source of movement-induced inhibition of the H-reflex. To test this hypothesis we examined the kinematics and electromyographic (EMG) activity of the leg during human walking and correlated these with the modulation pattern of the soleus H-reflex. To further test the possible contribution of stretch-evoked quadriceps afferent activity to the soleus H-reflex modulation pattern during walking different walking gaits were studied. In one condition subjects were asked to walk with their knee locked in full extension by a rigid knee brace. In a second condition subjects were asked to walk backwards. During normal walking, the soleus H-reflex modulation pattern is strongly correlated with the EMG events of the soleus and tibialis anterior (TA), but not with hip, knee, or ankle angular displacement or velocity. When subjects walked with the knee locked in full extension, the amplitude of the H-reflex, its modulation pattern, and the task-dependent changes of its amplitude were the same as during normal walking. During backward walking, the H-reflex increases in late swing before activity of the soleus has begun and while the knee is flexing, an observation that highlights central control of the H-reflex amplitude. The effects of imposed flexion of the knee in passive subjects were also reexamined. The knee flexion imposed by the experimenter followed the same trajectory as that which occurred during the swing phase of the subject's step cycle. It was found that imposed knee flexions elicited a burst of TA EMG activity with an average latency of 81.6 ms (SD = 21 ms) in six out of eight subjects. Inhibition of the H-reflex, when it occurred, was associated with the occurrence of this burst. When subjects voluntarily flexed their right knee from an initial quiet standing posture, the inhibition of the soleus H-reflex began before flexion of the knee or that of any other leg segment. Once again the onset of inhibition was closely associated with the onset of activity in the TA. In the discussion section the present observations are examined in light of the predictions made by the movement-induced inhibition hypothesis of Brooke et al. It will be concluded that none of the predictions of this hypothesis were corroborated by present tests done during human walking. In consequence, we suggest that the modulation pattern of the H-reflex observed during normal human walking is centrally determined, as are the task-dependent differences of its amplitude (e.g., standing versus the stance phase of human walking).

Adult↗
PubMed2000

Anabolic steroids induce region- and subunit-specific rapid modulation of GABA(A) receptor-mediated currents in the rat forebrain.

Anabolic-androgenic steroids (AAS) have become significant drugs of abuse in recent years with the highest increase reported in adolescent girls. In spite of the increased use of AAS, the CNS effects of these steroids are poorly understood. We report that in prepubertal female rats, three commonly abused AAS, 17alpha-methyltestosterone, stanozolol, and nandrolone, induced rapid and reversible modulation of GABAergic currents in neurons of two brain regions known to be critical for the expression of reproductive behaviors: the ventromedial nucleus of the hypothalamus (VMN) and the medial preoptic area (mPOA). All three AAS significantly enhanced peak synaptic current amplitudes and prolonged synaptic current decays in neurons of the VMN. Conversely all three AAS significantly diminished peak current amplitudes of synaptic currents from neurons of the mPOA. The endogenous neuroactive steroids, 3alpha-hydroxy-5alpha-pregnan-20-one and 5alpha-androstane-3alpha,17beta-diol, potentiated currents in the VMN as did the AAS. In contrast to the negative modulation induced by AAS in the mPOA, the endogenous steroids potentiated responses in this region. To determine the concentration response relationships, modulation by the AAS, 17alpha-methyltestosterone (17alpha-meT), was assessed for currents evoked by ultrafast perfusion of brief pulses of GABA to acutely isolated neurons. Half-maximal effects on currents elicited by 1 mM GABA were elicited by submicromolar concentrations of AAS for neurons from both brain regions. In addition, the efficacy of 10(-5) to 10(-2) M GABA was significantly increased by 1 microM 17alpha-meT. Previous studies have demonstrated a striking dichotomy in receptor composition between the VMN and the mPOA with regard to gamma subunit expression. To determine if the preferential expression of gamma(2) subunit-containing receptors in the VMN and of gamma(1) subunit-containing receptors in the mPOA could account for the region-specific effects of AAS in the two regions, responses elicited by ultrafast perfusion of GABA to human embryonic kidney 293 cells transfected with alpha(2), beta(3), and gamma(2) or alpha(2), beta(3), and gamma(1) subunit cDNAs were analyzed. As with native VMN neurons, positive modulation of GABA responses was elicited for alpha(2)beta(3)gamma(2) recombinant receptors, while negative modulation was induced at alpha(2)beta(3)gamma(1) receptors as in the mPOA. Our data demonstrate that AAS in doses believed to occur in steroid abusers can induce significant modulation of GABAergic transmission in brain regions essential for neuroendocrine function. In addition, the effects of these steroids can vary significantly between brain regions in a manner that appears to depend on the subunit composition of GABA(A) receptors expressed.

Anabolic Agents↗
PubMed2000

Auditory temporal processing: responses to sinusoidally amplitude-modulated tones in the inferior colliculus.

Time-varying envelopes are a common feature of acoustic communication signals like human speech and induce a variety of percepts in human listeners. We studied the responses of 109 single neurons in the inferior colliculus (IC) of the anesthetized Mongolian gerbil to contralaterally presented sinusoidally amplitude-modulated (SAM) tones with a wide range of parameters. Modulation transfer functions (MTFs) based on average spike rate (rMTFs) showed regions of enhancement and suppression, where spike rates increased or decreased respectively as stimulus modulation depth increased. Specifically, almost all IC rMTFs could be described by some combination of a primary and a secondary region of enhancement and an intervening region of suppression, with these regions present to varying degrees in individual rMTFs. rMTF characteristics of most neurons were dependent on sound pressure level (SPL). rMTFs in most neurons with "onset" or "onset-sustained" peri-stimulus time histograms (PSTHs) in response to brief pure tones showed only a peaked primary region of enhancement. The region of suppression tended to occur in neurons with "sustained" or "pauser" PSTHs, and usually emerged at higher SPLs. The secondary region of enhancement was only found in eight neurons. The lowest modulation frequency at which the spike rate reached a clear peak ("best modulation frequency" or BMF) was measured. All but two mean BMFs lay between 0 and 100 Hz. Fifty percent of the 49 neurons tested over at least a 20-dB range of SPLs showed a BMF variation larger than 66% of their mean BMF. MTFs based on vector strength (tMTFs) showed a variety of patterns; although mostly similar to those reported from the cochlear nucleus, tMTFs of IC neurons showed higher maximum values, smaller dynamic range with depth, and a lower high-frequency limit for significant phase locking. Systematic and large increases in phase-lead commonly occurred as SPL increased. rMTFs measured at multiple carrier frequencies (F(c)s) showed that the suppressive region was not the result of sideband inhibition. There was no systematic relationship between BMF and F(c) of stimulation in the cells studied, even at low carrier frequencies. The results suggest various possible mechanisms that could create IC MTFs, and strongly support the idea that inhibitory inputs shape the rMTF by sharpening regions of enhancement and creating a suppressive region. The paucity of BMFs above 100 Hz argues against simple rate-coding schemes for pitch. Finally, any labeled line or topographic representation of modulation frequency is unlikely to be independent of SPL.

Acoustic Stimulation↗
PubMed2001

Dynamic modulation of mossy fiber system throughput by inferior olive synchrony: a multielectrode study of cerebellar cortex activated by motor cortex.

We investigated the effects of climbing fiber synchrony on the temporal dynamics of mossy fiber system throughput in populations of cerebellar Purkinje cells (PCs). A multielectrode technique was used in ketamine-anesthetized rats that allowed both complex and simple spikes (CSs and SSs) to be recorded from multiple PCs simultaneously in lobule crus IIa. Stimulation of the tongue area of the primary motor cortex (TM1) was used to evoke cerebro-cerebellar interaction. At the single PC level, robust short-term interactions of CSs and SSs were observed after TM1 stimulation that typically consisted of an immediate depression and subsequent enhancement of SS firing after the occurrence of a CS. Such modulations of SS rate in a given PC were as robustly correlated to the CSs of simultaneously recorded PCs as they were to the CS on its own membrane-and did not require a CS on its own membrane-indicating a network basis for the interaction. Analyses of simultaneously recorded PCs using the normalized joint perievent time histogram demonstrated that CS and SS firing were dynamically correlated after TM1 stimulation in a manner that indicated strong control of mossy fiber system throughput by CS synchrony. For < or =300 ms after TM1 stimulation, most PCs showed episodic modulations in SS rate that appeared to be entrained by the population rhythm of climbing fiber synchrony. SS rhythmicity also was modulated dynamically by CSs, such that it was depressed by CSs and facilitated by their absence. Like the modulations in SS rate, a given PC's modulation in SS rhythmicity did not require it to fire a CS but was, on those instances, equally correlated to the synchronous CSs of other PCs. The data indicate that the climbing fiber system controls the temporal dynamics of SS firing in populations of PCs by using synchrony to engage intracerebellar circuitry and modulate mossy fiber system throughput.

Action Potentials↗
PubMed2002

Effects of excitatory modulation on intrinsic properties of turtle motoneurons.

The purpose of this study was to quantify the effects of excitatory modulation on the intrinsic properties of motoneurons (MNs) in slices of spinal cord taken from the adult turtle. Responses were noted following application of an excitatory modulator: serotonin (5-HT), muscarine, trans-1-amino-1,3-cyclopentane dicarboxylic acid (tACPD), or all three combined. A sample of 44 MNs was divided into 2 groups, on the basis of whether MNs did (28/44) or did not (16/44) demonstrate a nifedipine-sensitive acceleration of discharge during a 2-s, intracellularly injected stimulus pulse. Such acceleration indicates the development of a plateau potential (PP). Excitatory modulation lowered the MNs' resting potential, increased input resistance, decreased rheobase, reduced several afterhyperpolarization values, and shifted the conventional, one-phase stimulus current-spike frequency (I-f) relation to the left. For both MN groups, the relative efficacy of excitatory modulation on both non-PP and PP MNs was generally in the following order: combined application > 5-HT approximately muscarine > tACPD. In many instances, the effects of modulation differed significantly for non-PP versus PP MNs, the most pronounced being in their I-f relation. To describe this difference, it was necessary to measure a two-phase relation. In PP MNs, excitatory modulation considerably increased the slope of the first (initial) phase and flattened the second (later) phase of this relation. The latter result bore similarities to that obtained in a previous study, which addressed MN firing behavior during fictive locomotion of the high-decerebrate cat.

Animals↗
PubMed2000

Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease.

Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer's disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common approaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhib- its AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients' level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine's modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine's sustained efficacy.

Alzheimer Disease↗
PubMed2001

Enhanced affective startle modulation in salt-sensitive subjects.

Salt-sensitive normotensive men exhibit an enhanced pressor response to mental stress. Although an enhanced pressor response is associated with higher affective startle modulation in men, an association between salt sensitivity of blood pressure and affective startle modulation has not been studied so far. We studied reactivity to mental stress and startle modulation in 14 salt-sensitive healthy white male students and 14 salt-resistant control subjects, who were well matched for age, body mass index, physical fitness, and family history of hypertension. Subjects performed a computerized information-processing task under time pressure (manometer test), while heart rate and blood pressure were continuously registered. In a separate session, subjects viewed a series of 42 pictures of the International Affective Picture System (IAPS), varying in pleasure and arousal, while acoustic startle probes were administered randomly, and electromyogram activity of the orbicular eye muscle was continuously recorded. Startle modulation was calculated as the difference between startle responses under negative and positive affective stimuli. In contrast to salt-resistant subjects, salt-sensitive subjects showed significantly enhanced startle amplitudes under negative stimuli and diminished amplitudes under positive stimuli. Thus, salt-sensitive subjects displayed a significantly higher startle modulation than did salt-resistant subjects (P<0.05). Subjective ratings of the presented IAPS pictures did not differ between the groups. The increased startle modulation of salt-sensitive subjects suggests an enhanced activity of the central nucleus of the amygdala. This enhanced central nervous responsiveness may contribute to higher sympathetic pressor reactivity and, thus, to the later development of hypertension in salt-sensitive individuals.

Adult↗
PubMed2003

Processing tonal modulations: an ERP study.

A common stylistic element of Western tonal music is the change of key within a musical sequence (known as modulation in musical terms). The aim of the present study was to investigate neural correlates of the cognitive processing of modulations with event-related brain potentials. Participants listened to sequences of chords that were infrequently modulating. Modulating chords elicited distinct effects in the event-related brain potentials: an early right anterior negativity reflecting the processing of a violation of musical regularities and a late frontal negativity taken to reflect processes of harmonic integration. Additionally, modulations elicited a tonic negative potential suggested to reflect cognitive processes characteristic for the processing of tonal modulations, namely, the restructuring of the "hierarchy of harmonic stability" (which specifies musical expectations), presumably entailing working memory operations. Participants were "nonmusicians"; results thus support the hypothesis that nonmusicians have a sophisticated (implicit) knowledge about musical regularities.

Acoustic Stimulation↗
PubMed2005

The effect of NMDA receptors on gain modulation.

The ability of individual neurons to modulate the gain of their input-output function is important for information processing in the brain. In a recent study, shunting inhibition was found to modulate the gain of cerebellar granule cells subjected to simulated currents through AMPA receptor synapses. Here we investigate the effect on gain modulation resulting from adding the currents mediated by NMDA receptors to a compartmental model of the granule cell. With only AMPA receptors, the changes in gain induced by shunting inhibition decreased gradually with the average firing rate of the afferent mossy fibers. With NMDA receptors present, this decrease was more rapid, therefore narrowing the bandwidth of mossy fiber firing rates available for gain modulation. The deterioration of gain modulation was accompanied by a reduced variability of the input current and saturation of NMDA receptors. However, when the output of the granule cell was plotted as a function of the average input current instead of the input firing frequency, both models showed very similar response curves and comparable gain modulation. We conclude that NMDA receptors do not directly impair gain control by shunting inhibition, but the effective bandwidth decreases as a consequence of the increased total charge transfer.

Animals↗
PubMed2002

Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection.

The epsilon isoform of protein kinase C (PKCepsilon) is a member of the PKC family of serine/threonine kinases and plays a critical role in protection against ischemic injury in multiple organs. Functional proteomic analyses of PKCepsilon signaling show that this isozyme forms multiprotein complexes in the heart; however, the precise signaling mechanisms whereby PKCepsilon orchestrates cardioprotection are poorly understood. Here we report that Lck, a member of the Src family of tyrosine kinases, forms a functional signaling module with PKCepsilon. In cardiac cells, PKCepsilon interacts with, phosphorylates, and activates Lck. In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCepsilon or by ischemic preconditioning enhances the formation of PKCepsilon-Lck modules. Disruption of these modules, via ablation of the Lck gene, abrogated the infarct-sparing effects of these two forms of cardioprotection, indicating that the formation of PKCepsilon-Lck signaling modules is required for the manifestation of a cardioprotective phenotype. These findings demonstrate, for the first time to our knowledge, that the assembly of a module (PKCepsilon-Lck) is an obligatory step in the signal transduction that results in a specific phenotype. Thus, PKCepsilon-Lck modules may serve as novel therapeutic targets for the prevention of ischemic injury.

Animals↗
PubMed1997

Validation of the Panic Outcomes Module.

This article discusses the validation of a module designed to evaluate the outcomes of clinical care for panic disorder. The research utilized a longitudinal design to examine cross-sectional relationships and change over time within and between subjects. Baseline, follow-up, and test-retest data were collected on 73 patients. The initial field test indicates that the Panic Outcomes Module measures outcomes and case-mix characteristics with acceptable levels of measurement error for group data. The module's measure of change in panic severity demonstrated encouraging agreement with the structured interviewer's judgement of change. This module, completed in approximately 20 minutes, is short enough to incorporate into outpatient mental health settings. We recommend that providers and administrators interested in monitoring the outcomes of specialty care for panic disorder seek assistance from health services researchers to use the Panic outcomes module. Further research is needed to validate this module for use in primary care populations.

Adult↗
PubMed2004

Evaluating student paediatric advanced nurse practitioners' experiences of a paediatric pharmacology module: in the context of reflective learning.

An evaluation of the first paediatric pharmacology module at Master's level was undertaken. The broad aims were: to ascertain whether the participants had achieved the modular learning outcomes; how their pharmacological knowledge base had altered as a result of the module; and whether their professional practice had been influenced subsequent to undertaking the module. The findings of the 12 participants who registered on the module are reported. Three tools were utilized to generate the data for this broadly qualitative study. The findings indicated that reflective thinking at the evaluative level enabled the participants to monitor their professional and personal performance and that their critical thinking skills and confidence had increased. The questionnaire survey had some limitations, but was seen as the only feasible method of achieving a representation as to whether the module had subsequently influenced the professional practice of the participants. The data presented convincing evidence of the relevance of study of a paediatric pharmacology module at Master's level for the professional and personal development of practitioners.

Child↗
PubMed2003

The TROVE module: a common element in Telomerase, Ro and Vault ribonucleoproteins.

BACKGROUND: Ribonucleoproteins carry out a variety of important tasks in the cell. In this study we show that a number of these contain a novel module, that we speculate mediates RNA-binding. RESULTS: The TROVE module--Telomerase, Ro and Vault module--is found in TEP1 and Ro60 the protein components of three ribonucleoprotein particles. This novel module, consisting of one or more domains, may be involved in binding the RNA components of the three RNPs, which are telomerase RNA, Y RNA and vault RNA. A second conserved region in these proteins is shown to be a member of the vWA domain family. The vWA domain in TEP1 is closely related to the previously recognised vWA domain in VPARP a second component of the vault particle. This vWA domain may mediate interactions between these vault components or bind as yet unidentified components of the RNPs. CONCLUSIONS: This work suggests that a number of ribonucleoprotein components use a common RNA-binding module. The TROVE module is also found in bacterial ribonucleoproteins suggesting an ancient origin for these ribonucleoproteins.

Amino Acid Motifs↗