Initial Inhibitory Response Research Articles

Motor cortical plasticity in adolescents with early onset schizophrenia: A TMS-EMG study assessing the perturbation effect of intermittent and continuous theta burst stimulation.

Neuroplasticity in adolescents is distinct from that of adults. Literature pertaining to neuroplasticity in schizophrenia is limited to adult populations. We aimed to assess baseline (or resting) cortical excitability and cortical plasticity in adolescents with schizophrenia using the transcranial magnetic stimulation-electromyography (TMS-EMG) protocol. Twenty adolescent cases with schizophrenia and 20 age and gender matched healthy controls were studied using a crossover design. Single pulse TMS elicited resting motor threshold (RMT) and motor evoked potentials (MEPs) were assessed. Cortical plasticity was determined by tracking MEPs after a single session continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) up to 120 min at 12 intervals. Baseline (or resting) cortical excitability was found to be significantly lower in cases compared with controls. Response patterns to cTBS and iTBS were similar between the crossover. While cTBS led to inhibitory response, iTBS had an excitatory effect in both the groups. In the cases, while cTBS led to significantly greater initial inhibitory response, iTBS led to significantly lower excitatory response, compared with controls. The time taken to return to baseline excitability was significantly longer after receiving cTBS for cases, compared with controls. iTBS and cTBS lead to excitatory and inhibitory response, representing classical long-term depression and long-term potentiation effects, respectively, in both cases and controls. We conclude that adolescents with schizophrenia have significantly lower baseline (resting) cortical excitability as well as significantly greater inhibitory plasticity; excitatory plasticity is significantly lower.

The functional role of protease-activated receptors on contractile responses by activation of Ca2+ sensitization pathways in simian colonic muscles.

It has been known that activation of protease-activated receptors (PARs) affects gastrointestinal motility. In this study, we tested the effects of PAR agonists on electrical and contractile responses and Ca2+ sensitization pathways in simian colonic muscles. The Simian colonic muscle was initially hyperpolarized by PAR agonists. After the transient hyperpolarization, simian colonic muscle repolarized to the control resting membrane potential (RMP) without a delayed depolarization. Apamin significantly reduced the initial hyperpolarization, suggesting that activation of small conductance Ca2+-activated K+ (SK) channels is involved in the initial hyperpolarization. In contractile experiments, PAR agonists caused an initial relaxation followed by an increase in contractions. These delayed contractile responses were not matched with the electrical responses that showed no after depolarization of the RMP. To investigate the possible involvement of Rho-associated protein kinase 2 (ROCK) pathways in the PAR effects, muscle strips were treated with ROCK inhibitors, which significantly reduced the PAR agonist-induced contractions. Furthermore, PAR agonists increased MYPT1 phosphorylation, and ROCK inhibitors completely blocked MYPT1 phosphorylation. PAR agonists alone had no effect on CPI-17 phosphorylation. In the presence of apamin, PAR agonists significantly increased CPI-17 phosphorylation, which was blocked by protein kinase C (PKC) inhibitors suggesting that Ca2+ influx is increased by apamin and is activating PKC. In conclusion, these studies show that PAR activators induce biphasic responses in simian colonic muscles. The initial inhibitory responses by PAR agonists are mainly mediated by activation of SK channels and delayed contractile responses are mainly mediated by the CPI-17 and ROCK Ca2+ sensitization pathways in simian colonic muscles. NEW & NOTEWORTHY In the present study, we found that the contractile responses of simian colonic muscles to protease-activated receptor (PAR) agonists are different from the previously reported contractile responses of murine colonic muscles. Ca2+ sensitization pathways mediate the contractile responses of simian colonic muscles to PAR agonists without affecting the membrane potential. These findings emphasize novel mechanisms of PAR agonist-induced contractions possibly related to colonic dysmotility in inflammatory bowel disease.

Responses to flooding of plant water relations and leaf gas exchange in tropical tolerant trees of a black-water wetland.

This review summarizes the research on physiological responses to flooding of trees in the seasonal black-water wetland of the Mapire River in Venezuela. Inter-annual variability was found during 8 years of sampling, in spite of which a general picture emerged of increased stomatal conductance (gs) and photosynthetic rate (PN) during the flooded period to values as high as or higher than in plants in drained wet soil. Models explaining the initial inhibitory responses and the acclimation to flooding are proposed. In the inhibitory phase of flooding, hypoxia generated by flooding causes a decrease in root water absorption and stomatal closure. An increase with flooding in xylem water potential (ψ) suggests that flooding does not cause water deficit. The PN decreases due to changes in relative stomatal and non-stomatal limitations to photosynthesis; an increase in the latter is due to reduced chlorophyll and total soluble protein content. Total non-structural carbohydrates (TNC) accumulate in leaves but their content begins to decrease during the acclimatized phase at full flooding, coinciding with the resumption of high gs and PN. The reversal of the diminution in gs is associated, in some but not all species, to the growth of adventitious roots. The occurrence of morpho-anatomical and biochemical adaptations which improve oxygen supply would cause the acclimation, including increased water absorption by the roots, increased rubisco and chlorophyll contents and ultimately increased PN. Therefore, trees would perform as if flooding did not signify a stress to their physiology.

Voluntary and involuntary ventilation do not alter the human inspiratory muscle loading reflex

The reflex mechanism of the short-latency inhibitory reflex to transient loading of human inspiratory muscles is unresolved. Muscle afferents mediate this reflex, but they may act via pontomedullary inspiratory centers, other bulbar networks, or spinal circuits. We hypothesized that altered chemical drive to breathe would alter the initial inhibitory reflex if the neural pathways involve inspiratory medullary centers. Inspiration was transiently loaded in 11 subjects during spontaneous hypercapnic hyperpnea and matched voluntary hyperventilation. Electromyographic activity was recorded bilaterally from scalene muscles with surface electrodes. The latencies of the initial inhibitory response (IR) onset (32 +/- 0.7 and 38 +/- 1 ms for spontaneous and voluntary conditions respectively, P < 0.001) and subsequent excitatory response (ER) onset (80 +/- 2.9 and 78 +/- 2.6 ms, respectively, P = 0.46) and the normalized sizes of IR (65 +/- 2 and 67 +/- 3%, respectively, P = 0.50) and ER (51 +/- 8 and 69 +/- 6%, respectively, P = 0.005) were measured. Mean end-tidal Pco(2) was 43 +/- 1.5 Torr with dead space ventilation and was 14 +/- 0.6 Torr with matched voluntary hyperventilation (P < 0.001). A mean minute volume >30 liters was achieved in both conditions. The absence of significant difference in the size of the IR suggested that the IR reflex arc does not transit the brain stem inspiratory centers and that the reflex may be integrated at a spinal level. In voluntary hyperventilation, an initial excitation occurred more frequently and, consequently, the IR onset latency was significantly longer. The size of the later ER was also greater during voluntary hyperventilation, which is consistent with it being mediated via longer, presumably cortical, pathways, which are influenced by voluntary drive.

Gonadotropin‐releasing hormone modulates voltage‐activated sodium current and odor responses in Necturus maculosus olfactory sensory neurons

The terminal nerve (nervus terminalis) extends from the basal forebrain to the nasal cavity and has been shown to contain gonadotropin-releasing hormone (GnRH). The specific function of the terminal nerve is unknown, but it has been hypothesized that it modulates the function of olfactory neurons. To examine the effects of GnRH on isolated Necturus maculosus olfactory sensory neurons (OSNs), we used the perforated configuration of the patch clamp technique to record current responses. GnRH had no effect on the membrane current at any holding potential but did modulate voltage-activated TTX-sensitive sodium current (INa). Within 1 min of applying GnRH, approximately 60% of the OSNs showed a decrease in the magnitude of INa. Initial responses to GnRH were inhibitory, although in one group of cells the initial inhibitory response was followed by a potentiation of INa with continual application (approximately 5 min). The time course of the GnRH response suggested that a second messenger pathway mediated the response. Inhibitors of PKC, tyrosine kinase, and PI3K were all able to inhibit the INa, but none of them could prevent the GnRH response. Application of a cAMP analog mimicked the effects of GnRH, and only inhibitors of PKA and PKG could prevent GnRH-induced inhibition of INa. This suggests that the modulation of voltage-activated sodium currents by GnRH involve a cyclic nucleotide pathway. In addition, GnRH modulated the odor responses of OSNs. Our data suggest the release of GnRH, presumably from the terminal nerve, can serve to modulate olfactory sensory neurons.

Identification, Distribution and Physiological Activity of Three Novel Neuropeptides of Lymnaea: FLRlamide and pQFYRlamide Encoded by the FMRFamide Gene, and a Related Peptide

We are interested in analysing the detailed modulation of defined neuronal systems by multiple neuropeptides encoded in the FMRFamide locus of the snail Lymnaea. Cloning of the FMRFamide gene has predicted the existence of two novel peptides previously unknown from biochemical analysis, the pentapeptides EFLRlamide and QFYRlamide. These peptides may form part of a new family of peptides sharing the sequence motif -FXRlamide. In this paper we adopt a novel approach to first identify and characterize -FXRlamide-like peptides in extracts from the central nervous system of Lymnaea. By a combination of high-performance liquid chromatography (HPLC) and continuous-flow fast atom bombardment mass spectrometry, we identify three novel peptides: EFLRlamide, pQFYRlamide and pQFLRlamide. The first two are those predicted in exon II of the FMRFamide locus whereas the last is, interestingly, a product which cannot be derived from post-translational modification of the predicted peptides but must be encoded by as yet unidentified nucleotide sequences. A specific antibody raised to EFLRlamide, and immunoreactive to all three peptides, revealed EFLRlamide-like expression throughout the central nervous system in the same cells where exon II is transcribed and the peptide SEEPLY (a post-translational product of exon II) was localized. Additional cells, however, were also identified. Immunoreactivity was mapped in a number of identified neurons in the central nervous system, including two heart cardioexcitatory motoneurons, the Ehe cells (E heart excitors of the visceral ganglion) and penial motoneurons in the right cerebral ganglion. The peripheral tissues (heart and penial complex) that these respective classes of neurons innervate also exhibited EFLRlamide immunoreactivity. The central and peripheral localization of EFLRlamide-like immunoreactivity suggested that EFLRlamide/pQFYRlamide may have an important physiological role in both these peripheral systems as well as in the central nervous system. This was confirmed by physiological experiments that showed that EFLRlamide and pQFYRlamide inhibited many central neurons and in particular the Bgp neurons in the right parietal ganglion. EFLRlamide had complex biphasic effects on the frequency of heart-beat: an initial inhibitory response was followed by a long-lasting increase in the rate of beating. Taken together with earlier work, this study now completes the analysis and localization of the full set of post-translational products of the FMRFamide precursor in Lymnaea and supplies further evidence towards the characterization of the physiological systems which such peptides may modulate in concert.

Swallowing and urine flow responses of ovine fetuses to 24 h of hypoxia

The aim of this study was to determine the effects of 24 h of hypoxia on fetal swallowing and urine flow rates. The study design included successive 24-h control, hypoxia, and recovery periods. To induce hypoxia, we infused nitrogen into the trachea of late-gestation pregnant sheep. During hypoxia, there were decreases in fetal arterial oxygen saturation [from 62.7 +/- 2.2 to 30.9 +/- 2.9% (SE)] and PO2 (from 21.1 +/- 1.0 to 14.1 +/- 0.9 mmHg) (n = 7). Fetal arterial pH decreased maximally by 0.04 +/- 0.01 at 6 h and returned to control thereafter. Fetal swallowing decreased from 13.4 +/- 2.1 to 0.6 +/- 0.2 ml.h-1.kg fetal wt-1 with the onset of hypoxia and gradually increased, but only to one-half control levels, during the last 12 h of hypoxia. Fetal urine flow gradually decreased from 9.6 +/- 1.6 ml.h-1.kg-1 to a minimum of 5.3 +/- 0.5 ml.h-1.kg-1 at 2-3 h of hypoxia and returned to control thereafter. During the first hour of the recovery period, fetal swallowing transiently increased to twice control levels before returning to control. This was followed by a delayed, transient increase in urine flow to 63% above control levels at 2-6 h after hypoxia. We conclude that the fetal swallowing and urine flow responses to prolonged hypoxia in the absence of acidemia are distinctly different from the initial inhibitory responses, in that swallowing partially and urine flow fully recovers from the initial suppression.

Effects of caudate nucleus stimulation on substantia nigra cell activity in monkey.

The present study provides evidence that the saccadic signals in the caudate nucleus (caudate) are transmitted to the substantia nigra pars reticulata (SNr). We inserted two microelectrodes into the caudate and SNr of monkeys trained to perform saccade tasks. After identifying the functional characteristics of a SNr neuron recorded, we stimulated the caudate (single pulse, < 100 microA) to see whether its discharge rate changed. Among 138 SNr cells tested, 60 showed responses to stimulation of the caudate: inhibition only (n = 21), inhibition-excitation (n = 17), excitation only (n = 9), and excitation-inhibition (n = 13). The latencies were 9.0-32.5 ms (mean 16.7 ms) for the initial inhibitory responses and 6.5-35.0 ms (mean 16.7 ms) for the initial excitatory responses. Pars compacta cells (n = 10) were unresponsive. The effect of caudate stimulation was selective in terms of (1) functional type of SNr cells, (2) location of SNr cells, and (3) stimulation site within the caudate. Functional type of SNr cells: saccadic, visual, expectation-related cells were more responsive than auditory, mouth/hand/arm movement-related, and reward-related cells. Many of the cells whose functional characteristics were unidentified responded to the caudate stimulation. The preferential effects were seen among the functional subtypes: cells related to memory-guided saccades, not visually guided saccades; cells with conditioned visual responses, not simple visual responses. Location of SNr cells: the stimulus effects were seen preferentially in cells in the central part of the SNr, not in the dorsal part. Stimulus site: stronger effects, whether inhibition or excitation, were obtained when the stimulation was applied to the head-body transitional zone where visuooculomotor cells were clustered. Behaviorally contingent correlation of spike activity was found between the caudate-nigral pair of cells. For example when a SNr cell with memory-contingent saccadic activity was inhibited by the caudate stimulation, a caudate cell at or close to the stimulation site may show memory-contingent saccadic activity with a similar movement field.

Effect of catecholaminergic transmission deficiency upon neuronal responses of the ventrolateral thalamic nucleus evoked by stimulation of cerebellar and pallidal inputs

Neuronal responses of the ventrolateral thalamic nucleus (VL) to the afferent stimulation were studied in chronic experiments on cats before and after injection of haloperidol and droperidol in cataleptic doses. As distinct from the reactions of intact animals, after injection of neuroleptics the initial excitative VL neuronal responses to the cerebellar stimulation were characterized by the irregularity of manifestation and the variability of the latent period, the responses in the form of burst discharges appeared. During pallidal stimulation a statistically significant increase in the number of initial inhibitory responses consisting of two periods of the background activity suppression with an excitation phase separating them was observed, while monophase inhibitory reactions prevailed (68%) in intact animals. Under neuroleptics the reactions with rhythmic alternation of excitative and inhibitory periods of the impulsive activity with frequency 3-5/s. occurred. It is suggested that revealed peculiarities of the neuronal reactions result from the hyperpolarizing state of the VL neurons because of the augmented external inhibitory actions due to a blockade of dopamine receptors of the nigrostriatal system or because of the reduced depolarizing influences under the break of the central alpha-adrenergic transmission.

Modulation of the afferent input to the septal neurons by cholinergic drugs

The effects of cholinergic drugs upon the evoked activity of extracellularly recorded neurons of the medial septal nucleus-nucleus of the diagonal band (MS-DB complex) were tested in unanesthetized rabbits. Electrical stimulation of MFB resulted in entrainment of the background θ-cycles in the neurons with strong rhythmic discharge (types I and II). Phase-locking of the background θ-cycles to the stimulus occurred ‘by the burst’, or ‘by the pause’ within the θ-range of frequencies (3–12 Hz). Single-spike responses, following up to 30 Hz and more, were also evoked by MFB stimulation, especially in the cells with weak θ-modulation (type III) or without it (type IV). Injection of physostigmine increased background θ-modulation of neuronal activity and simultaneously blocked or diminished responses to repetitive MFB stimulation in 82% of the MS-DB units, independent of their type of response. Driving of θ-cycles both ‘by the burst’ and ‘by the pause’ was ineffective or drastically reduced. Single spike responses disappeared or became unstable, though their minimal latencies did not change. Initial inhibitory responses were blocked or became significantly shorter. Antimuscarinic drugs, scopolamine and atropine, which abolished θ-modulation in many MS-DB units, restored responses and sometimes enhanced them. Repetitive stimulation of the MFB in this condition was effective up to the high frequencies, well beyond the θ-range. Thus, the majority of the MS-DB units did not respond to the afferent stimuli during prominent θ-activity evoked by physostigmine. The role of the septal cholinergic system in gating of afferent input during the θ-state and its importance for learning and memory is suggested.

Rapid and transient excitation of respiration mediated by central chemoreceptor.

We evaluated rapid and transient changes in phrenic nerve (PN) and internal intercostal (IIC) activities when 0.2-0.5 ml of saline saturated with 100% CO2 was injected into the vertebral artery during various respiratory phases in decerebrated spontaneously breathing cats. The injections evoked an initial transient inhibition of ongoing PN or IIC activity with a mean onset latency of 0.17 s, followed by excitation of subsequent respiratory activities with an onset latency ranging from 0.4 to 2.7 s; the average onset latency of expiratory excitation (1.49 s) was significantly longer than that of inspiratory facilitation (0.89 s). The initial inhibitory responses were analogous to reflex effects of injections of phenyl biguanide, indicating that the initial inhibition was due to activation of vascular nociceptors and the subsequent excitation was due to stimulation of the central chemoreceptors. In addition, CO2-saline injections during hypocapnic apnea developed a quick reappearance of respiratory rhythm, and the first facilitatory effect appeared in tonic IIC activity, which became more active before rhythm started. In summary, the present study, by use of a technique of vertebral arterial injections of 100% CO2-saline, revealed dynamic properties of respiratory control system mediated by central chemoreceptors and vascular nociceptors.

Motoneurones of the submucous plexus regulate electrical activity of the circular muscle of canine proximal colon.

The hypothesis that the circular muscle of the canine proximal colon receives motor input from neurones in the submucous plexus was tested. Circular muscle cells were impaled with micro-electrodes and submucous plexus neurones were stimulated by electrical field stimulation and microejection of acetylcholine (ACh). In the presence of atropine to block the direct muscarinic effects, microejection of ACh onto the submucosa where intact submucous ganglia were suspended evoked: (i) an inhibitory junction potential (i.j.p.) that reduced the amplitude, duration and rate of rise of the subsequent slow wave; (ii) a slow wave of increased duration following the initial inhibitory response. These responses were enhanced by increasing the volume of ACh administered. Responses to ACh were blocked by hexamethonium, 10(-4) M; d-tubocurarine, 10(-4) M; or tetrodotoxin (TTX), 10(-6) M, suggesting they were neural in origin. Both inhibitory and excitatory responses were the result of non-cholinergic and non-adrenergic nerves. The transmitters mediating these effects are unknown. Removal of the longitudinal muscle, myenteric plexus, and the serosal portion of the circular muscle had no apparent effect on the responses to application of ACh to submucosal ganglia. In these preparations the responses to field stimulation were identical to those produced by ACh. The submucous plexus also provides cholinergic input to the circular muscle. When ACh was discretely applied to the submucosa cholinergic responses were elicited at the muscle cell which were significantly reduced by hexamethonium or TTX. These findings suggest that the cholinergic responses were the result of ACh release by neurones at the effector and not by overflow of the exogenous ACh. Cholinergic responses were also elicited in preparations in which the myenteric plexus had been removed. Slow waves in circular muscle of the proximal colon yield excitation-contraction coupling in the absence of Ca2+ action potentials. Therefore the influence of submucous neurones on electrical slow waves has direct consequences on motor activity. Reduction in the amplitude and duration of slow wave by i.j.p.s. results in reduction in the amplitude and duration of phasic contractions. Excitatory inputs enhance contractions. The data support a new concept: motoneurones emanating from submucous ganglia innervate the circular muscle and provide inhibitory and excitatory inputs to regulate slow wave activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Neocortical evoked responses and spike activity during startling in response to stimulation of the mesencephalic reticular formation.

1. Stimulation of the mesencephalic RF by a single pulse of current (of threshold strength for elicitation of the startle response) evoked a reticulocortical response (RCR) in the cortex (LP 2.5–3 msec) with a focus of maximal activity in the sensomotor cortex. The RCR recorded from the surface of the cortex is polyphasic and consists of early (a negative-positive complex) and late (negative and positive waves) components of the evoked response. RCRs from different regions of the cortex had a similar configuration but differed in the absolute and relative amplitude characteristics of the different phases. 2. Among the sensomotor cortical neurons with an initial response of excitation to stimulation of RF which were investigated (248 cells) two groups were distinguished. Neurons of the first group (136, LP 3–50 msec) showed correlation with the appearance of the various phases of the global surface potential: during development of the early and late negative phases of the RCR neurons in the upper level of the cortex (24.1 and 19.3% of neurons respectively) were involved in the response; the response of 25.5% of neurons in the lower layers correlated with the appearance of the early positive wave of the RCR. For neurons of the second group (112, LP > 50 msec) no correlation was found with waves of the cortical surface potential. Neurons with an initial inhibitory response (66 cells) changed their activity during recording of the early negative component of the RCR (lower level, 40.4% of neurons). During recording of the early positive potential, spike activity in neurons of the upper layers was slowed or ceased (19.7% of cells). 3. The results indicate that the flow of nonspecific impulses to the cortex along oligosynaptic pathways is destined mainly for cells in the upper level of the cortex. 4. It is postulated that the motor component of the unconditioned startle response arising to stimulation of RF may be triggered from subcortical structures.

Inhibition of prostacyclin and platelet thromboxane A2 after low-dose aspirin.

To compare the inhibitory effects of aspirin on prostaglandin synthesized by vessel walls and platelets, we obtained vein segments from five subjects before they were given 150 or 300 mg of aspirin and at various intervals afterward. We then measured prostacyclin (PGI2) synthesis with a radioimmunoassay for its stable metabolite, 6-keto-prostaglandin F1 alpha. Platelet production of thromboxane A2 was measured with a radioimmunoassay for its stable metabolite, thromboxane B2. Two hours after aspirin had been given, 81 to 100 per cent inhibition of PGI2 synthesis was demonstrated; 86 per cent inhibition was still evident in one subject tested eight hours after administration. Simultaneously, platelet production of thromboxane B2 was completely inhibited for more than 24 hours. We conclude that there is little difference between the initial inhibitory response of platelet cyclooxygenase and that of vessel-wall cyclooxygenase to these doses of aspirin. Our results also indicate that in male subjects the prolonged template bleeding time after aspirin is not the consequence of selective inhibition of platelet production of thromboxane.

Effect of sanguinarine, a benzophenanthridine alkaloid, on frog skin potential difference and short circuit current

Sanguinarine, a benzophenanthridine alkaloid, causes an initial stimulation of frog skin short circuit current I sc when present in the mucosal bathing medium at 10 −4 M. The stimulation is accompanied by an increase in spontaneous potential difference (PD) and increase in D.C. resistance. No effects are seen with sanguinarine in the serosal bathing medium. The initial stimulation is followed by a decrease in I se and PD, but a continued increase in resistance. In skins whose initial spontaneous PD is high, no initial stimulation in se and PD is seen; however, clamping these skins to a lower potential does not alter their initial inhibitory response to sanguinarine. Likewise, clamping the lower potential skins to higher potential does not alter their initial stimulatory response. Sanguinarine seems to be acting on the permeability barriers at the outer surface of the frog skin.