Psychoacoustic tests: effects of atropine]

The efferent pathways exert a control action on the function of the cochlear nucleus and hair cells. Acetylcholine is the neurotransmitter of the centrifugal system and its action can be blocked by atropine. In order to give a contribution to the knowledge of the function of the efferent bundle and of the cochlea efficiency we examined 10 young normal subjects before and after infusion of 1 mg of atropine i.v. a battery of three psychoacoustical tests (Remote Masking, Critical Ratio and Brief Tone Audiometry). After infusion of atropine we have shown an increase of 0.25 Hz hearing threshold, an increase of RC values and a decrease of RM values. It can be concluded that the pharmacological block of the olivo-cochlear bundle determines a stiffness of outer hair cells and basilar membrane; this finding means that the atropine can inhibit the facilitating activity of the efferent system on the cochlear performance.     

Latency, threshold and frequency selectivity of the crossed medial cochlear efferent pathways

The efferent innervation of guinea pig cochleas was sectioned medially, at the level of the floor of the fourth ventricle, to study the effects of the crossed part of the medial efferent pathway on the compound action potential (CAP) masking phenomenon. Sectioning reduced CAP masking for a masker level varying with the frequency of the masker and the time elapsed between the masker onset and the probe onset. Functional properties of the crossed part of the medial efferent tracts: latency, thresholds and frequency selectivity, could be deduced from these data. This intensification of the masking phenomenon permitting the improvement of the signal to noise ratio, may thus be attributed to the crossed part of the medial efferent bundle which innervates the outer hair cells.     

Physiological studies of small mediastinal ganglia in the cardiopulmonary nerves of dogs

Stimulation of the cranial end of a decentralized canine cardiopulmonary nerve results in the generation of a compound action potential which can be recorded at the caudal end. A region has been identified which, on stimulation, produces a compound action potential with complex configuration which is different from simpler wave forms obtained by stimulating 1 mm or more in either the rostral or caudal direction. Histological examination reveals that clusters of neuronal cell bodies are localized to this region of the nerve, whereas none is found to either side. Characteristics of the different wave forms evoked by changing the site of stimulation and reversing the stimulation and recording electrodes provide evidence for the existence of both afferent and efferent synaptic pathways. The compound action potential evoked by the most rostral stimulations and presumed to contain synaptic components was not altered by intravenously administered cholinergic and adrenergic pharmacological blocking agents (hexamethonium, atropine, phentolamine, or propranolol). It was, however, depressed by local injections of chymotrypsin or manganese into the functionally identified transitional region. It is concluded that synapses, which can be activated at relatively high frequencies (1-10 Hz) and may be important for rapidly changing local neural regulation of the heart and lungs, appear to exist within the course of cardiopulmonary nerves.     

Direct measurement of the action of acetylcholine on isolated outer hair cells of the guinea pig cochlea.

Acetylcholine has long been thought to be the neurotransmitter of the cochlear efferent system in mammals although the evidence is largely indirect. By using whole-cell recordings from isolated outer hair cells, we show that acetylcholine activates a large rapidly desensitizing outward potassium current. This corresponds to hyperpolarization of the membrane potential from rest. The half maximal dose for acetylcholine was 13.5 microM with a cooperativity of 2. The response was not due to a conventional muscarinic action of acetylcholine for it was not blocked by 0.1 microM atropine and muscarinic antagonists but it could be blocked by 0.1 microM curare, suggesting that it shared many properties of a nicotinic receptor. It was, however, inhibited by 10 microM strychnine. The potassium current activated by acetylcholine required external calcium and was characterized by a significant delay at room temperature. This points to the involvement of a second messenger system, possibly calcium itself.     

Time delay of vagally mediated cardiac baroreflex response varies with autonomic cardiovascular control.

To examine whether changes in autonomic activity have an effect on the latency of the vagally mediated cardiac baroreflex response in humans, we investigated the effects of neck suction fluctuating sinusoidally at 0.2 Hz on R-R intervals (known to be mediated mainly by vagal activity) in the supine position, during 15 degrees head-down tilt and 60 degrees head-up tilt, and during vagotonic (2 microg/kg) and vagolytic (10 microg/kg) doses of atropine while the subjects breathed at 0.25 Hz. The phase shift between fluctuations in neck chamber pressure and in R-R interval was calculated by complex transfer function analysis and was used as a measure of the time delay between carotid baroreceptor stimulation and cardiac effector response. Cardiac baroreflex responsiveness increased significantly during low-dose atropine and decreased during head-up tilt or 10 microg/kg atropine. With increasing tilt angle, the time delay between cyclic baroreceptor stimulation and oscillations in R-R interval increased from 0.32 +/- 0.27 s (head down), to 0.59 +/- 0.25 s (supine position, P < 0.05 vs. head down), and to 0.86 +/- 0.27 s (head up, P < 0.01 vs. supine). Low-dose atropine had a similar effect to head-down tilt on baroreflex latency, whereas 10 microg/kg atropine increased the time delay markedly to 1.24 +/- 0.30 s. Our results demonstrate that changes in autonomic activity, generated either by gravitational stimulus or by atropine, not only affect baroreflex responsiveness but also have a major influence on the latency of the vagally mediated carotid baroreceptor-heart rate reflex. The prolonged baroreflex latency during decreased parasympathetic function may contribute to an unstable regulation of heart rate in patients with cardiac disease.     

Retention of a spatial task after intraperitoneal, subcutaneous or intravenous injections of equal doses of atropine

The retention of a well-learned spatial task was assessed in rats after equal doses of atropine sulfate (30 mg/kg) were administered by intraperitoneal, subcutaneous or intravenous injection. Atropine sulfate disrupted first choice accuracy and escape latency measures of spatial retention. Intravenous and intraperitoneal atropine sulfate produced significant impairments in choice accuracy. However, only intravenous atropine sulfate produced a significant impairment in escape latency. Atropine sulfate administered subcutaneously never produced a significant impairment in spatial retention compared to the intravenous saline control. One would predict from the present findings that a centrally active drug might produce a highly variable effect on a specific behavior as a function of the parenteral route of administration.     

Localization of the calcium channel subunits Cav1.2 (alpha1C) and Cav2.3 (alpha1E) in the mouse organ of Corti

Voltage-activated Ca2+ channels play an important role in synaptic transmission, signal processing and development. The immunohistochemical localization of Cav1.2 (alpha1C) and Cav2.3 (alpha1E) Ca2+ channels was studied in the developing and adult mouse organ of Corti using subunit-specific antibodies and fluorescent secondary antibodies with cochlear cryosections. Cav1.2 immunoreactivity has been detected from postnatal day 14 (P14) onwards at the synapses between cholinergic medial efferents and outer hair cells as revealed by co-staining with anti-synaptophysin and anti-choline acetyltransferase. Most likely the Cav1.2 immunoreactivity was located presynaptically at the site of contact of the efferent bouton with the outer hair cell which suggests a role for class C L-type Ca2+ channels in synaptic transmission of the medial efferent system. The localization of the second Ca2+ channel tested, Cav2.3, showed a pronounced change during cochlear development. From P2 until P10, Cav2.3 immunoreactivity was found in the outer spiral bundle followed by the inner spiral bundle, efferent endings and by medial efferent fibers. Around P14, Cav2.3 immunoreactivity disappeared from these structures and from P19 onwards it was observed in the basal poles of the outer hair cell membranes.     

ARL4C might serve as a prognostic factor and a novel therapeutic target for gastric cancer: bioinformatics analyses and biological experiments

The ADP-ribosylation factor-like proteins (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive. In this study, we systematically investigate the expression status, interactive relations, potential pathways, genetic variations and clinical values of ARLs in GC. We find that ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant clinical indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that ARL4C is highly correlated with TGF-β1 signalling. Correspondingly, TGF-β1 treatment dramatically increases ARL4C expression and ARL4C knockdown inhibits the phosphorylation level of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients. Our work comprehensively demonstrates the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.     

Auditory cortex basal activity modulates cochlear responses in chinchillas

Background

The auditory efferent system has unique neuroanatomical pathways that connect the cerebral cortex with sensory receptor cells. Pyramidal neurons located in layers V and VI of the primary auditory cortex constitute descending projections to the thalamus, inferior colliculus, and even directly to the superior olivary complex and to the cochlear nucleus. Efferent pathways are connected to the cochlear receptor by the olivocochlear system, which innervates outer hair cells and auditory nerve fibers. The functional role of the cortico-olivocochlear efferent system remains debated. We hypothesized that auditory cortex basal activity modulates cochlear and auditory-nerve afferent responses through the efferent system.

Methodology/Principal Findings

Cochlear microphonics (CM), auditory-nerve compound action potentials (CAP) and auditory cortex evoked potentials (ACEP) were recorded in twenty anesthetized chinchillas, before, during and after auditory cortex deactivation by two methods: lidocaine microinjections or cortical cooling with cryoloops. Auditory cortex deactivation induced a transient reduction in ACEP amplitudes in fifteen animals (deactivation experiments) and a permanent reduction in five chinchillas (lesion experiments). We found significant changes in the amplitude of CM in both types of experiments, being the most common effect a CM decrease found in fifteen animals. Concomitantly to CM amplitude changes, we found CAP increases in seven chinchillas and CAP reductions in thirteen animals. Although ACEP amplitudes were completely recovered after ninety minutes in deactivation experiments, only partial recovery was observed in the magnitudes of cochlear responses.

Conclusions/Significance

These results show that blocking ongoing auditory cortex activity modulates CM and CAP responses, demonstrating that cortico-olivocochlear circuits regulate auditory nerve and cochlear responses through a basal efferent tone. The diversity of the obtained effects suggests that there are at least two functional pathways from the auditory cortex to the cochlea.     

Propranolol blocks the tachycardia induced by galanin (1-15) but not by galanin (1-29)

The efferent pathways involved in the tachycardia induced by intracisternal injections of the N-terminal galanin fragment (1-15) (GAL (1-15)) and galanin (GAL (1-29)) has been evaluated in rats pretreated with the cholinergic antagonist atropine or the beta-antagonist propranolol. The pretreatment with propranolol significantly blocked the tachycardic and vasopressor effect produced by intracisternal injection of GAL (1-15) (p<0.05), but the pretreatment with atropine did not modify these cardiovascular effects. However, the cardiovascular response elicited by GAL (1-29) is modified by the pretreatment with atropine (p<0.05) but not by propranolol. These findings demonstrate that the central cardiovascular action of GAL (1-15), but not GAL (1-29), is mediated by beta-receptor stimulation and this suggests the existence of a different pathway involved in the cardiovascular response produced by the N-terminal galanin fragment as compared with the parent molecule GAL (1-29).     

Inhibition and efferent facilitation of sensory activity in the isolated labyrinth of the frog

The functioning modalities of the efferent system were analysed in the isolated frog labyrinth. The efferent synapses of the posterior canal were activated via an axon reflex by antidromic electrical shocks (10-200 Hz) applied for increasing times (250 ms-10 s) to the anterior-horizontal nerves. Either decrease (inhibition) or increase (facilitation) in the resting discharge rate were observed in the majority of the units examined. Inhibition and facilitation, however, are peculiar to any given unit since inhibition does not reverse to facilitation or vice-versa. This fact as well as the long response latency (not less than 10 ms) and the linear dependence of both effects on the stimulation frequency suggest that inhibition and facilitation are due to the repetitive activation of two different types of efferent fibres synapsing on the hair cells. The drastic modifications in the afferent synaptic discharge produced by full activation of the efferent system indicate that the static properties (response asymmetry) as well as the dynamic properties (response adaptation) of the mechanically driven afferent response can be substantially controlled by the central nervous system at the receptor level.     

Validation of surface recordings of the diaphragm response to transcranial magnetic stimulation in humans.

The integrity of the central efferent motor pathways to the diaphragm can be assessed by using transcranial magnetic stimulation to measure the latency of the corresponding motor evoked potentials with surface electrodes. Because transcranial magnetic stimulation does not activate the diaphragm alone, signal contamination is a potential problem. To evaluate this issue, surface diaphragmatic motor-evoked potential latencies were compared with latencies recorded from diaphragm needle in 9 healthy volunteers. Surface latencies of muscles likely to contaminate the diaphragm signals (serratus anterior, pectoralis major, and tranversus abdominis) were also recorded. The latencies in response to nonfocal transcranial stimulation from surface electrodes were not significantly different from the needle ones (17 +/- 1.3 vs. 17.2 +/- 1.1 ms, respectively) but were significantly different from the latencies of the other muscles. In two cases, signal contamination appeared likely (serratus anterior in 1 case, abdominal muscles in 1 case). It is possible to reliably measure the latency of the diaphragm response to transcranial magnetic stimulation with adequately positioned surface electrodes.     

Clinical relevance of phase of steady-state VEPs to P100 latency of transient VEPs

Pattern visual evoked potentials (VEPs) to transient and steady-state stimulation were recorded in 10 normal subjects at 4 levels of luminance (180, 57, 22 and 11 cd/m²). VEPs were also recorded in 5 patients with optic neuropathy at a fixed luminance (180 cd/m²). The relationship between P100 latency of transient VEPs (T-VEPs) and the phase of steady-state VEPs (S-VEPs) was analyzed. As luminance decreased in normal subjects, P100 latency was prolonged and the phase lag increased. A significant linear relationship between the P100 latency and phase was found. Patients showed both the prolonged P100 latency and the delayed phase. The simple linear regression line of the phase-P100 latency function of normal subjects closely matched the patients' values. These results suggest that changes in the phase may be equivalent to changes in the P100 latency. S-VEPs, therefore, may be clinically useful in assessing visual function.     

Biphasic effects of atropine on sensory-evoked hippocampal rhythmical slow activity in urethane-anaesthetized rats

This study investigated the response of hippocampal RSA, recorded from electrodes in CA1 and the contralateral dentate gyrus of urethane-anaesthetized rats, to atropine sulphate administered at 15 min intervals in a cumulative dose-response schedule (1, 3, 10, 50 and 50 mg x kg(-1) i.p.). The power of CA1 and dentate gyrus RSA in the 3-7 Hz band was increased after administering the first 3 doses of atropine (1, 3 and 10 mg x kg(-1) cumulatively) in rats held in the stereotaxic frame or removed from the frame and given electrical sensory stimulation to the base of the tail. This increase in RSA was dependent on sensory input, since it was not seen in animals outside the frame unless sensory stimulation was given, and it was abolished by increasing the dose of atropine (an additional 50 and 50 mg x kg(-1) cumulatively). Methylatropine (6 mg x kg(-1) i.p.) did not increase RSA power. The biphasic effect of atropine on sensory-evoked hippocampal RSA activity may be explained by differential effects at pre- and post-synaptic sites e.g. in the septo-hippocampal system or on pathways processing sensory information.     

Experimentally induced ulcers and gastric sensory-motor function in rats

Prior studies have demonstrated that inflammation can sensitize visceral afferent neurons, contributing to the development of hyperalgesia. We hypothesized that both afferent and efferent pathways are affected, resulting in changes in motor and sensory function. Kissing ulcers (KU) were induced in the distal stomach by injecting 60% acetic acid for 45 s into a clamped area of the stomach. In controls, saline was injected into the stomach. A balloon catheter was surgically placed into the stomach, and electromyographic responses to gastric distension were recorded from the acromiotrapezius muscle at various times after ulcer induction. The accommodation reflex was assessed by slowly infusing saline into the distally occluded stomach. Gastric pressure changes in response to vagal stimulation were measured in anesthetized rats. Contractile function of circular muscle strips was examined in vitro using force-displacement transducers. KU caused gastric hypersensitivity that persisted for at least 14 days. Fluid distension of the stomach led to a rapid pressure increase in KU but not in control animals, consistent with an impaired accommodation reflex. Gastric ulcers enhanced the contractile response to vagal stimulation, whereas the effect of cholinergic stimulation on smooth muscle in vitro was not changed. These data suggest that inflammation directly alters gastric sensory and motor function. Increased activation of afferents will trigger vagovagal reflexes, thereby further changing motility and indirectly activating sensory neurons. Thus afferent and efferent pathways both contribute to the development of dyspeptic symptoms.     

The Electrical Response of the Planarian Ocellus

The planarian ocellar potential (OP), an action potential evoked from the planarian ocellus by a light flash, was recorded with microelectrodes. OP amplitude, latency, and peak delay varied as a function of stimulus intensity and state of adaptation in a manner similar to the responses of other photoreceptors. Changes in the OP that occurred with different directions of incident light are described and attributed to screening effects of the ocellar pigment cells. The temperature coefficient (Q₁₀) of OP latency was 1.5; latency decreased continuously as temperature was increased to destructive levels. The energy of activation of the rate of OP formation was calculated to approximate 10 kcal. These findings suggest dependence of OP latency on ionic diffusion and of OP formation on a biocatalytic process.     

Somatostatin and GABA correlate with cervical autonomic nerve activity

The mode of inhibitory action of centrally administered SRIF on the efferent activity of autonomic nerves was investigated in the rat by assessing the SRIF-induced change in the activity of the superior laryngeal nerve with or without pretreatment with various drugs. After picrotoxin or bicuculline treatment, the inhibition of nerve activity by SRIF was abolished while reserpine and atropine failed to abolish the SRIF effect. The centrally administered GABA inhibited the activity of the superior laryngeal nerve and the cervical sympathetic trunk. However, SRIF did not affect the sympathetic trunk. Arterial blood pressure was increased by SRIF while GABA produced hypotension.

These data provide evidence for a GABAergic system as the mediator of SRIF action in the brain and for the selectivity of SRIF action on the particular intermediary GABAergic neurones.     

A novel cholinergic receptor mediates inhibition of chick cochlear hair cells.

The central nervous system provides feedback regulation at several points within the peripheral auditory apparatus. One component of that feedback is inhibition of cochlear hair cells by release of acetylcholine (ACh) from efferent brainstem neurons. The mechanism of hair cell inhibition, and the character of the presumed cholinergic receptor, however, have eluded understanding. Both nicotinic and muscarinic, as well as some non-cholinergic ligands can affect the efferent action. We have made whole-cell, tight-seal recordings from short (outer) hair cells isolated from the chick's cochlea. These are the principal targets of cochlear efferents in birds. ACh hyperpolarizes short hair cells by opening a cation channel through which Ca2+ enters the cell and subsequently activates Ca(2+)-dependent K+ current (Fuchs & Murrow 1991, 1992). Both curare and atropine are effective-antagonists of cholinergic inhibition at 3 microM, whereas trimethaphan camsylate and strychnine block at 1 microM. The normally irreversible nicotinic antagonist, alpha-bungarotoxin, reversibly blocked the hair cell response, as did kappa-bungarotoxin. The half-blocking concentration for alpha-bungarotoxin was 26 nM. It is proposed that the hair cell AChR is a ligand-gated cation channel related to the nicotinic receptor of nerve and muscle.     

连续全遮盖法治疗双眼屈光参差性弱视的有效性与安全性分析

目的:探讨连续q全遮盖法治疗双眼屈光参差性弱视的有效性与安全性。方法:选择2014年2月到2016年9月在我院诊治的126例双眼屈光参差性弱视患儿作为研究对象,根据治疗方法的不同分为阿托品组60例与遮盖组66例,遮盖组采用连续全遮盖法治疗,阿托品组给予阿托品治疗,两组都治疗观察3个月。比较两组治疗期间不良反应的发生情况、治疗后的总有效率、最佳矫正视力、电位潜伏期、波幅。结果:两组治疗期间都无严重不良反应发生。治疗后,遮盖组与阿托品组的总有效率分别为98.5%和88.3%,遮盖组的总有效率明显高于阿托品组(P0.05)。两组治疗后的最佳矫正视力都高于治疗前,且遮盖组治疗后的最佳矫正视力也明显高于阿托品组(P0.05)。两组治疗后的电位潜伏期都较治疗前明显缩短,而波幅明显增强(P0.05),且遮盖组治疗后的潜伏期明显短于阿托品组,而波幅显著强于阿托品组(P0.05)。结论:连续全遮盖法治疗双眼屈光参差性弱视具有很好的安全性,能提高患儿的治疗效果,改善视力,促进神经元的兴奋性。     

Contralateral Noise Stimulation Delays P300 Latency in School-Aged Children

Background and Objective

The auditory cortex modulates auditory afferents through the olivocochlear system, which innervates the outer hair cells and the afferent neurons under the inner hair cells in the cochlea. Most of the studies that investigated the efferent activity in humans focused on evaluating the suppression of the otoacoustic emissions by stimulating the contralateral ear with noise, which assesses the activation of the medial olivocochlear bundle. The neurophysiology and the mechanisms involving efferent activity on higher regions of the auditory pathway, however, are still unknown. Also, the lack of studies investigating the effects of noise on human auditory cortex, especially in peadiatric population, points to the need for recording the late auditory potentials in noise conditions. Assessing the auditory efferents in schoolaged children is highly important due to some of its attributed functions such as selective attention and signal detection in noise, which are important abilities related to the development of language and academic skills. For this reason, the aim of the present study was to evaluate the effects of noise on P300 responses of children with normal hearing.

Methods

P300 was recorded in 27 children aged from 8 to 14 years with normal hearing in two conditions: with and whitout contralateral white noise stimulation.

Results

P300 latencies were significantly longer at the presence of contralateral noise. No significant changes were observed for the amplitude values.

Conclusion

Contralateral white noise stimulation delayed P300 latency in a group of school-aged children with normal hearing. These results suggest a possible influence of the medial olivocochlear activation on P300 responses under noise condition.