Afferent Stimulation Research Articles

Inhalation of electronic cigarette aerosol induces reflex bronchoconstriction by activation of vagal bronchopulmonary C-fibers.

The electronic cigarette (e-cig) has been suggested as a safer alternative to tobacco cigarettes. However, the health effects of e-cigs on the airways have not been fully investigated. Nicotine, the primary chemical constituent of the e-cig aerosol, has been shown to stimulate vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit vigorous pulmonary defense reflexes, including airway constriction. In this study, we investigated the bronchomotor response to e-cig inhalation challenge in anesthetized guinea pigs and the mechanisms involved in regulating these responses. Our results showed that delivery of a single puff of e-cig aerosol into the lung triggered immediately a transient bronchoconstriction that sustained for >2 min. The increase in airway resistance was almost completely abolished by a pretreatment with either intravenous injection of atropine or inhalation of aerosolized lidocaine, suggesting that the bronchoconstriction was elicited by cholinergic reflex mechanism and stimulation of airway sensory nerves was probably involved. Indeed, electrophysiological recording further confirmed that inhalation of e-cig aerosol exerted a pronounced stimulatory effect on vagal bronchopulmonary C-fibers. These effects on airway resistance and bronchopulmonary C-fiber activity were absent when the e-cig aerosol containing zero nicotine was inhaled, indicating a critical role of nicotine. Furthermore, a pretreatment with nicotinic acetylcholine receptor antagonists by inhalation completely prevented the airway constriction evoked by e-cig aerosol inhalation. In conclusion, inhalation of a single puff of e-cig aerosol caused a transient bronchoconstriction that was mediated through cholinergic reflex and triggered by a stimulatory effect of nicotine on vagal bronchopulmonary C-fiber afferents.

Infantile Amnesia Is Related to Developmental Immaturity of the Maintenance Mechanisms for Long-Term Potentiation.

Infantile amnesia (IA) refers to the inability of adults to recall episodic memories from infancy or early childhood. While several hypotheses have been proposed to explain the occurrence of IA, the neurobiological and molecular bases for this accelerated forgetting phenomenon remain elusive. Using hippocampus-dependent object-location memory and contextual fear conditioning tasks, we confirmed that infant mice trained at postnatal day 20 (P20) displayed deficits in long-term memory retention compared to adult (P60) mice. The percentage of CA1 pyramidal neurons expressing phosphorylated cAMP-responsive element-binding protein after fear conditioning was significantly lower in P20 than P60 mice. P20 mice exhibited attenuated basal excitatory synaptic transmission and early-phase long-term potentiation (E-LTP) at Schaffer collateral-CA1 synapses compared to P60 mice, but conversely, P20 mice have a greater susceptibility to induce time-dependent reversal of LTP by low-frequency afferent stimulation than P60 mice. The protein levels of GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), protein kinase Mζ (PKMζ), and protein phosphatase 2B (PP2B) in hippocampal CA1 region were significantly higher in P20 than P60 mice. We also found that the levels of calcium/calmodulin-dependent protein kinase II α autophosphorylation at Thr286, GluA1 phosphorylation at Ser831, and PKMζ protein biosynthesis occurred during the ensuing maintenance of E-LTP were significantly lower in P20 than P60 mice. Pharmacological blockade of GluN2B-containing NMDARs or PP2B effectively restored deficits of E-LTP and long-term memory retention observed in P20 mice. Altogether, these findings suggest that developmental immaturity of the maintenance mechanisms for E-LTP is linked to the occurrence of IA.

Short-term Synaptic Depression in the Feedforward Inhibitory Circuit in the Dorsal Lateral Geniculate Nucleus

Synaptic short-term plasticity (STP) regulates synaptic transmission in an activity-dependent manner and thereby has important roles in the signal processing in the brain. In some synapses, a presynaptic train of action potentials elicits post-synaptic potentials that gradually increase during the train (facilitation), but in other synapses, these potentials gradually decrease (depression). We studied STP in neurons in the visual thalamic relay, the dorsal lateral geniculate nucleus (dLGN). The dLGN contains two types of neurons: excitatory thalamocortical (TC) neurons, which transfer signals from retinal afferents to visual cortex, and local inhibitory interneurons, which form an inhibitory feedforward loop that regulates the thalamocortical signal transmission. The overall STP in the retino-thalamic relay is short-term depression, but the distinct kind and characteristics of the plasticity at the different types of synapses are unknown. We studied STP in the excitatory responses of interneurons to stimulation of retinal afferents, in the inhibitory responses of TC neurons to stimulation of afferents from interneurons, and in the disynaptic inhibitory responses of TC neurons to stimulation of retinal afferents. Moreover, we studied STP at the direct excitatory input to TC neurons from retinal afferents. The STP at all types of the synapses showed short-term depression. This depression can accentuate rapid changes in the stream of signals and thereby promote detectability of significant features in the sensory input. In vision, detection of edges and contours is essential for object perception, and the synaptic short-term depression in the early visual pathway provides important contributions to this detection process.

When a White Horse is a Horse: Embracing the (Obvious?) Overlap Between Acupuncture and Neuromodulation.

When a White Horse is a Horse: Embracing the (Obvious?) Overlap Between Acupuncture and Neuromodulation.

Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder.

Reflexes, that involve the spinobulbospinal pathway control both storage and voiding of urine. The periaqueductal gray matter (PAG), a pontine structure is part of the micturition pathway. Alteration in this pathway could lead to micturition disorders and urinary incontinence, such as the overactive bladder symptom complex (OABS). Although different therapeutic options exist for the management of OABS, these are either not effective in all patients. Part of the pathology of OABS is faulty sensory signaling about the filling status of the urinary bladder, which results in aberrant efferent signaling leading to overt detrusor contractions and the sensation of urgency and frequent voiding. In order to identify novel targets for therapy (i.e., structures in the central nervous system) and explore novel treatment modalities such as neuromodulation, we aimed at investigating which areas in the central nervous system are functionally activated upon sensory afferent stimulation of the bladder. Hence, we designed a robust protocol with multiple readout parameters including immunohistological and behavioral parameters during electrical stimulation of the rat urinary bladder. Bladder stimulation induced by electrical stimulation, below the voiding threshold, influences neural activity in: (1) the caudal ventrolateral PAG, close to the aqueduct; (2) the pontine micturition center and locus coeruleus; and (3) the superficial layers of the dorsal horn, sacral parasympathetic nucleus and central canal region of the spinal cord. In stimulated animals, a higher voiding frequency was observed but was not accompanied by increase in anxiety level and locomotor deficits. Taken together, this work establishes a critical role for the vlPAG in the processing of sensory information from the urinary bladder and urges future studies to investigate the potential of neuromodulatory approaches for urological diseases.

Evaluating the methods used for measuring cerebral blood flow at rest and during exercise in humans.

The first accounts of measuring cerebral blood flow (CBF) in humans were made by Angelo Mosso in ~1880, who recorded brain pulsations in patients with skull defects. In 1890, Charles Roy and Charles Sherrington determined in animals that brain pulsations-assessed via a similar method used by Mosso-were altered during a variety of stimuli including sensory nerve stimulation, asphyxia, and pharmacological interventions. Between 1880 and 1944, measurements for CBF were typically relied on skull abnormalities in humans. Thereafter, Kety and Schmidt introduced a new methodological approach in 1945 that involved nitrous oxide dilution combined with serial arterial and jugular venous blood sampling. Less than a decade later (1950's), several research groups employed the Kety-Schmidt technique to assess the effects of exercise on global CBF and metabolism; these studies demonstrated an uncoupling of CBF and metabolism during exercise, which was contrary to early hypotheses. However, there were several limitations to this technique related to low temporal resolution and the inability to measure regional CBF. These limitations were overcome in the 1960's when transcranial Doppler ultrasound (TCD) was developed as a method to measure beat-by-beat cerebral blood velocity. Between 1990 and 2010, TCD further progressed our understanding of CBF regulation and allowed forinsight into other mechanistic factors, independent of local metabolism, involved in regulating CBF during exercise. Recently, it was discovered that TCD may not be accurate under several physiological conditions. Other measures of indexing CBF such as Duplex ultrasound and magnetic resonance imaging, although not without some limitations, may be more applicable for future investigations.

Synaptic Release of Acetylcholine Rapidly Suppresses Cortical Activity by Recruiting Muscarinic Receptors in Layer 4.

Cholinergic afferents from the basal forebrain (BF) can influence cortical activity on rapid time scales, enabling sensory information processing and exploratory behavior. However, our understanding of how synaptically released acetylcholine (ACh) influences cellular targets in distinct cortical layers remains incomplete. Previous studies have shown that rapid changes in cortical dynamics induced by phasic BF activity can be mediated by the activation of nicotinic ACh receptors (nAChRs) expressed in distinct types of GABAergic interneurons. In contrast, muscarinic ACh receptors (mAChRs) are assumed to be involved in slower and more diffuse ACh signaling following sustained increases in afferent activity. Here, we examined the mechanisms underlying fast cholinergic control of cortical circuit dynamics by pairing optical stimulation of cholinergic afferents with evoked activity in somatosensory cortical slices of mice of either sex. ACh release evoked by single stimuli led to a rapid and persistent suppression of cortical activity, mediated by mAChRs expressed in layer 4 and to a lesser extent, by nAChRs in layers 1-3. In agreement, we found that cholinergic inputs to layer 4 evoked short-latency and long-lasting mAChR-dependent inhibition of the large majority of excitatory neurons, whereas inputs to layers 1-3 primarily evoked nAChR-dependent excitation of different classes of interneurons. Our results indicate that the rapid cholinergic control of cortical network dynamics is mediated by both nAChRs and mAChRs-dependent mechanisms, which are expressed in distinct cortical layers and cell types.SIGNIFICANCE STATEMENT Acetylcholine (ACh) release from basal forebrain (BF) afferents to cortex influences a variety of cognitive functions including attention, sensory processing, and learning. Cholinergic control occurs on the time scale of seconds and is mediated by BF neurons that generate action potentials at low rates, indicating that ACh acts as a point-to-point neurotransmitter. Our findings highlight that even brief activation of cholinergic afferents can recruit both nicotinic and muscarinic ACh receptors expressed in several cell types, leading to modulation of cortical activity on distinct time scales. Furthermore, they indicate that the initial stages of cortical sensory processing are under direct cholinergic control.

BS22. Study of autonomic nervous system activity based on gender differences

The autonomic nervous system is an extensive neural network whose main role is to regulate the milieu interieur by controlling homeostasis and visceral functions. Differences in the autonomic system activity may be due to differences in afferent receptor stimulation, in central reflex transmission, in the efferent nervous system and in post synaptic signaling. Gender differences in the autonomic nervous system may be present because of developmental differences or due to the effect of prevailing levels of male or female sex hormones. Although researchers from myriad of disciplines are beginning to appreciate the importance of considering gender differences in the design and interpretation of their studies, this is an area that is full of potential pitfalls. A female’s reproductive status and ovarian cycle have to be taken into account when studying gender differences in health and disease states. The present study was conducted on 200 medical students in the age group of 17–25 years. They were allocated into two groups: Group 1 comprised of young healthy males (n = 100). Group II comprised of young healthy female (n = 100) and this group underwent two phases of examination: First examination was done during late follicular phase between 10th and 13th day (Group IIA) and the second examination was done during mid luteal phase between 17th and 22nd day (Group IIB) of ovarian (menstrual) cycle. Autonomic function testing to assess sympathetic and parasympathetic activity was done. The finding of the present study indicated that there is marked difference in autonomic functions in males and females and these differences vary with the phase of menstrual cycle of females. This study revealed that there is predominant sympathetic activity in males compared to females whereas there is significant parasympathetic activity in females during late follicular phase compared to males. However, parasympathetic activity was reduced while sympathetic activity was increased in females during mid luteal phase. It has been observed with the obtained results that significant gender related differences exist in the autonomic nervous system activity. As these differences vary with the phase of menstrual cycle in females, it is important to compare males with two or more groups of females where the stage of the menstrual (ovarian) cycle is known.

In Memoriam: Alberto Zanchetti (Parma July 27, 1926 - Milan March 24, 2018).

In Memoriam: Alberto Zanchetti (Parma July 27, 1926 - Milan March 24, 2018).

Peripheral ionotropic glutamate receptors contribute to Fos expression increase in the spinal cord through antidromic electrical stimulation of sensory nerves

Previous studies have shown that peripheral ionotropic glutamate receptors are involved in the increase in sensitivity of a cutaneous branch of spinal dorsal ramus (CBDR) through antidromic electrical stimulation (ADES) of another CBDR in the adjacent segment. CBDR in the thoracic segments run parallel to each other and no synaptic contact at the periphery is reported. The present study investigated whether the increased sensitivity of peripheral sensory nerves via ADES of a CBDR induced Fos expression changes in the adjacent segments of the spinal cord. Fos expression increased in the T8 - T12 segments of the spinal cord evoked by ADES of the T10 CBDR in rats. The increased Fos expression in the T11 and T12, but not T8 - T10 spinal cord segments, was significantly blocked by local application of either N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) or non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the receptive field of T11 CBDR. The results suggest that endogenous glutamate released by ADES of sensory nerve may bind to peripheral ionotropic glutamate receptors and activate adjacent sensory nerve endings to increase the sensitivity of the spinal cord. These data reveal the potential mechanisms of neuron activation in the spinal cord evoked by peripheral sensitization.

Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive.

Major Depressive Disorder (MDD) is considered a “circuitopathy”, and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown if stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in lab animals and humans. Here we show molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation - previously well known for the ability to influence learning and memory - for MDD treatment.

Intrarenal High Salt Administration Causes Tonic Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long‐lasting tonic sympatho‐inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro‐humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho‐depressory mechanism.Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10–7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1‐receptor blocker RP67580 (10*10–3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11‐L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec exposure to 4.5 % NaCl or equi‐osmotic 20% mannitol. Results are given in mean±SEM.IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p<0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p<0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1‐blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p<0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p<0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p<0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (−10708.8±3546.5 pA*, from baseline, p<0.05). No responses to mannitol 20%.Increased intrarenal sodium concentrations might induce long‐lasting sympatho‐depression via a neuro‐humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho‐depressory mechanism could be involved in salt sensitive hypertension.Support or Funding InformationDFG Deutsche Forschungsgemeinschaft VE 104/4‐1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

T227. THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 1 REGULATES STRIATAL DOPAMINE RELEASE VIA AN ENDOCANNABINOID-DEPENDENT MECHANISM: IMPLICATIONS FOR THE TREATMENT OF SCHIZOPHRENIA

BackgroundClinical and preclinical studies suggest that selective activators of the muscarinic M4 receptor have exciting potential as a novel approach for treatment of schizophrenia. M4 reduces striatal dopamine (DA) though release of endocannabinoids (eCB), providing a mechanism for local effects on DA signaling in the striatum. M4 signals through Gαi/o and does not couple to Gαq/11 or induce calcium (Ca++) mobilization. This raises the possibility that M4-induced eCB release and inhibition of DA release may require co-activation of another receptor that activates Gαq/11. If so, this receptor could provide a novel target that may be more proximal to inhibition of DA release. Interestingly, the group 1 metabotropic glutamate (mGlu) receptors (mGlu1 and Glu5), couple to Gαq/11 and activate eCB signaling in multiple brain regions.MethodsWe tested the hypothesis that M4-induced reductions in DA release and subsequent antipsychotic-effect requires co-activation of group 1 mGlu receptors. The effect of M4 activation on electrically-evoked DA release in striatal slices was assessed using fast-scan cyclic voltammetry (FSCV) in the absence or presence of selective negative allosteric modulators (NAMs) of group 1 mGlu receptor subtypes. To evaluate the potential role of mGlu1, we determined the effects of a selective mGlu1 positive allosteric modulators (PAMs) on striatal DA release and antipsychotic-like activity in rodent models that are dependent on increased DA transmission. Since reductions in DA signaling, including D1 signaling have been implicated in reduced motivation, we also determined the effects of an mGlu1 PAM, M4 PAM, and the typical antipsychotic haloperidol on motivational responding in a progressive ratio (PR) schedule.ResultsWe now present exciting new data in which we found that activation of mGlu1 through application of exogenous agonists or selective stimulation of thalamostriatal afferents induces a reduction of striatal DA release and that selective mGlu1 PAMs have robust antipsychotic-like effects in rodent models. Interestingly, our studies also suggest that mGlu1 activation is required for M4 PAM-induced inhibition of DA release and antipsychotic-like effects. However, in contrast to available antipsychotic agents, the present results and previous studies suggest that mGlu1 and M4 PAMs reduce DA signaling through local release of an eCB from striatal SPNs and activation of CB2 receptors on neighboring DA terminals to reduce DA release. While these studies suggest that the effects of M4 PAMs on DA release require activation of mGlu1, we have also found that these targets have important differences. Most notably, M4 PAMs also directly inhibits D1 signaling in D1-SPN terminals in the substatnia nigra pars reticulata (SNr). Unlike M4, mGlu1 does not directly inhibit DA D1 receptor signaling and does not induce behavioral changes that could be associated with negative symptoms.DiscussionOur findings are especially interesting in light of recent findings that multiple loss of function single nucleotide polymorphisms (SNPs) in the human gene encoding mGlu1 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu1 as a gene within the “druggable genome” that could be targeted for treatment of schizophrenia. Recent clinical imaging studies suggesting that symptoms in schizophrenia patients are associated with selective increases in striatal DA signaling and while extrastriatal regions display hypo-dopaminergic function; thus, mGlu1 and M4 PAMs may provide a mechanism for selective inhibition of DA release in striatal regions that are important for antipsychotic efficacy, without further disruptions in extrastriatal DA signaling.

Multiple abdominal burst patterns observed during tracheobronchial coughing in anesthetized cats

The cough motor pattern is classically defined as a neuromechanical sequence of inspiration, compression, and expulsion. This definition is most applicable to single coughs. However, humans routinely produce multiple expulsions per each inspiratory effort during single or repetitive coughing. The functional significance of this coughing pattern is not fully understood, but it could represent a mechanism to facilitate the stairstep movement of particulates and mucus up the airway tree against gravity in humans. This repetitive expulsion pattern following single inspiratory cough efforts has not been reported in animal models of coughing. In the anesthetized cat, repetitive coughing can be produced by either mechanical or chemical stimulation of airway afferents. We hypothesized that expulsive cough motor patterns consistent with those seen in humans could be observed in the anesthetized cat. Further, we have previously observed that thoracotomy depresses cough excitability, presumably though a decrease in pulmonary volume‐related feedback. We also hypothesized that thoracotomy would reduce the occurrence of coughs in which multiple expiratory bursts were observed. We investigated the cough patterns of 9 cats pre‐ (n=5) and post‐thoracotomy (n=4) for multiple abdominal bursting patterns during cough. Thoracotomized animals were artificially ventilated at a positive end expiratory pressure of 5 cmH2O. Electromyograms (EMGs) were recorded from the diaphragm, thyroarytenoid, and internal oblique muscles. Repetitive coughing was produced by mechanical stimulation of the intrathoracic airway. The percentage of cough epochs that contained at least one cough with a multiple bursting pattern was similar for closed (CC, 44±18%) and open chested (OC, 42±11%) animals. These patterns consisted of double abdominal bursts (71%), three abdominal bursts (23%) and four bursts (5%). Corresponding abdominal bursts had similar amplitudes in both CC and OC animals. In OC animals, the amplitude of the second abdominal burst (CC − 45±11 to 31±7%, p=n.s.; OC − 43±4 to 28±5, p<0.05) was significantly lower than the first. Thoracotomy prolonged E2 duration for coughs with only 1 expiratory burst (CC 1±0.2s; OC 2±0.4 s, p < 0.05), but not for multiple expiratory bursts (CC 0.6±0.1 s; OC 0.9±0.4 s). The time between multiple abdominal bursts (CC 232±16 msec; OC 233±32 msec) was not different after thoracotomy. In some animals, small amplitude bursts in thyroarytenoid EMGs occurred out of phase with multiple abdominal bursting, consistent with adductor/abdominal oscillations. We conclude that the anesthetized cat is capable of expressing multiple abdominal bursting following a single inspiratory effort during tracheobronchial coughing. Our results support the existence of multiple oscillatory patterns during repetitive tracheobronchial coughing in the cat. This pattern may be analogous to that exhibited by awake humans.Support or Funding InformationSupported by NIH HL 103415 and 1OT20D001983.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

An Optical Neuron-Astrocyte Proximity Assay at Synaptic Distance Scales

Astrocytes are complex bushy cells that serve important functions through close contacts between theirprocesses and synapses. However, the spatial interactions and dynamics of astrocyte processes relative to synapses have proven problematic to study in adult living brain tissue. Here, we report agenetically targeted neuron-astrocyte proximity assay (NAPA) to measure astrocyte-synapse spatial interactions within intact brain preparations and at synaptic distance scales. The method exploits resonance energy transfer between extracellularly displayed fluorescent proteins targeted to synapses and astrocyte processes. We validated the method in the striatal microcircuitry following invivo expression. We determined the proximity of striatal astrocyte processes to distinct neuronal input pathways, to D1 and D2 medium spiny neuron synapses, and we evaluated how astrocyte-to-excitatory synapse proximity changed following cortical afferent stimulation, during ischemia and in a model of Huntington's disease. NAPA provides a simple approach to measure astrocyte-synapse spatial interactions in a variety of experimental scenarios. VIDEO ABSTRACT.

Influence of bone-conducted vibration on simulator sickness in virtual reality.

Use of virtual reality (VR) technology is often accompanied by a series of unwanted symptoms, including nausea and headache, which are characterised as ‘simulator sickness’. Sensory mismatch has been thought to lie at the heart of the problem and recent studies have shown that reducing cue mismatch in VR can have a therapeutic effect. Specifically, electrical stimulation of vestibular afferent nerves (galvanic vestibular stimulation; GVS) can reduce simulator sickness in VR. However, GVS poses a risk to certain populations and can also result in negative symptoms in normal, healthy individuals. Here, we tested whether noisy vestibular stimulation through bone-vibration can also reduce symptoms of simulator sickness. We carried out two experiments in which participants performed a spatial navigation task in VR and completed the Simulator Sickness Questionnaire over a series of trials. Experiment 1 was conducted using a high-end projection-based VR display, whereas Experiment 2 involved the use of a consumer head mounted display. During each trial, vestibular stimulation was either: 1) absent; 2) coupled with large angular accelerations of the projection camera; or 3) applied randomly throughout each trial. In half of the trials, participants actively navigated using a motion controller, and in the other half they were moved passively through the environment along pre-recorded motion trajectories. In both experiments we obtained lower simulator sickness scores when vestibular stimulation was coupled with angular accelerations of the camera. This effect was obtained for both active and passive movement control conditions, which did not differ. The results suggest that noisy vestibular stimulation can reduce simulator sickness, and that this effect appears to generalize across VR conditions. We propose further examination of this stimulation technique.

Decreased prefrontal oxygenation elicited by stimulation of limb mechanosensitive afferents during cycling exercise.

Our laboratory reported using near-infrared spectroscopy that feedback from limb mechanoafferents may decrease prefrontal oxygenated-hemoglobin concentration (Oxy-Hb) during the late period of voluntary and passive cycling. To test the hypothesis that the decreased Oxy-Hb of the prefrontal cortex would be augmented depending on the extent of limb mechanoafferent input, the prefrontal Oxy-Hb response was measured during motor-driven one- and two-legged passive cycling for 1 min at various revolutions of pedal movement in 19 subjects. Furthermore, we examined whether calculated tissue oxygenation index (TOI) decreased during passive cycling as the Oxy-Hb did, simultaneously assessing blood flows of extracranial cutaneous tissue and the common and internal carotid arteries (CCA and ICA) with laser and ultrasound Doppler flowmetry. Minute ventilation and cardiac output increased and peripheral resistance decreased during passive cycling, depending on both revolutions of pedal movement and number of limbs, whereas mean arterial blood pressure did not change. Passive cycling did not change end-tidal CO2, suggesting absence of a hypocapnic change. Prefrontal Oxy-Hb decreased during passive cycling, being in proportion to revolution of pedal movement but not number of cycling limbs. In addition, prefrontal TOI decreased during passive cycling as Oxy-Hb did, whereas blood flows of forehead cutaneous tissue, CCA, and ICA did not change significantly. Thus, a decrease in Oxy-Hb reflected a decrease in tissue blood flow of the intracerebral vasculature but not the extracerebral compartment. It is likely that feedback from mechanoafferents decreased regional cerebral blood flow of the prefrontal cortex in relation to the revolutions of pedal movement.

Facilitation of antagonist motor output through short-latency sensory pathways during postnatal development in the mouse

Reciprocal inhibition of motor neurons via Ia inhibitory interneurons recruited by stimulation of proprioceptive afferents supplying antagonist muscles has been well described. Changes in the efficacy of inhibition, and sometimes even a switch from inhibition to facilitation, have been reported in the literature after disruption of descending pathways. We sought to test whether such facilitation could be expressed in normal animals by evaluating the presence of facilitation in acute preparations from uninjured animals. Using an isolated spinal cord preparation from neonatal mice, changes in the monosynaptic stretch reflex response in knee flexor motor neurons (posterior biceps semitendinosus; PBST) were monitored following conditioning stimulation of proprioceptive sensory afferents in other muscle nerves. As expected for reciprocal inhibition, conditioning by stimulation of quadriceps (knee extensors and PBST antagonists) sensory afferents resulted in inhibition of the stretch reflex response. Facilitation, however, of the stretch reflex response by quadriceps conditioning stimulation was observed when the glycinergic reciprocal inhibitory pathway was blocked by application of strychnine. Facilitation was elicited by low-threshold proprioceptive afferents and occurred at latencies consistent with a disynaptic circuit. The magnitude of facilitation was larger at birth than at one week postnatal. Our results also suggest reciprocal facilitation is restricted to antagonist muscle pairs, as facilitation of PBST responses was not observed when conditioned with the obturator nerve supplying the adductor muscles. Overall, these data suggest the efficacy of facilitation is modulated during the first postnatal week, while the specificity of facilitation is already established by birth.

Cortical stimulation in conscious rats controls joint inflammation

The neuronal control of the immune system is fundamental to the development of new therapeutic strategies for inflammatory disorders. Recent studies reported that afferent vagal stimulation attenuates peripheral inflammation by activating specific sympathetic central and peripheral networks, but only few subcortical brain areas were investigated. In the present study, we report that afferent vagal stimulation also activates specific cortical areas, as the parietal and cingulate cortex. Since these cortical structures innervate sympathetic-related areas, we investigate whether electrical stimulation of parietal cortex can attenuate knee joint inflammation in non-anesthetized rats. Our results show that cortical stimulation in rats increased sympathetic activity and improved joint inflammatory parameters, such as local neutrophil infiltration and pro-inflammatory cytokine levels, without causing behavioral disturbance, brain epileptiform activity or neural damage. In addition, we superposed the areas activated by afferent vagal or cortical stimulation to map common central structures to depict a brain immunological homunculus that can allow novel therapeutic approaches against inflammatory joint diseases, such as rheumatoid arthritis.

The role and relevance of mast cells in urticaria.

This review presents evidence that the skin mast cell, in particular the MCTC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non-lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD2 and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals.