Spontaneous Discharge Rate Research Articles

Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice.

Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg-1 ·d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg-1 ·d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.

Analysis of clinical treatment of acute respiratory distress syndrome assisted by artificial intelligence

To evaluate the clinical practice of intensive care unit (ICU) physicians at Hebei General Hospital in identifying patients meeting the diagnostic criteria for acute respiratory distress syndrome (ARDS) and the current status of invasive mechanical ventilation management and adjunctive therapy in these patients, and to analyze the incidence and clinical outcomes of ARDS. A retrospective cohort study was conducted. The patients who were hospitalized in the ICU of Hebei General Hospital from April 10, 2017 to June 30, 2022 and met the Berlin definition diagnostic criteria for ARDS were enrolled as study subjects. Artificial intelligence (AI) technology was applied to search the basic information (age, gender, height, body weight, etc.), auxiliary examination, electronic medical record, non-drug doctor's advice, drug doctor's advice, critical report, scoring system, monitoring master table and other data of the above medical records in the electronic medical record system of the hospital. The first set of laboratory indicators sequentially retrieved from the system daily from 05:00 to 10:00 and vital signs and mechanical ventilation-related parameters recorded in the "critical care report" at 06:00 daily were extracted, and outcome indicators of the patients were collected. After screening and analysis, a total of 255 patients who met the ARDS diagnostic criteria were finally enrolled. The overall incidence of ARDS in the ICU accounted for 3.4% (255/7 434) of the total number of ICU patients, of which mild, moderate and severe ARDS accounted for 22.4% (57/255), 49.0% (125/255), and 28.6% (73/255), respectively, while the recognition rates of clinical doctors were 71.9% (41/57), 58.4% (73/125) and 71.2% (52/73), respectively. During the ICU stay, 250 patients (98.0%) received only invasive mechanical ventilation, while 5 patients (2.0%) received both non-invasive and invasive mechanical ventilation. The tidal volume/ideal body weight of ARDS patients was 7.64 (6.49, 9.01) mL/kg, and the positive end-expiratory pressure (PEEP) was 8.0 (5.0, 10.0) cmH2O (1 cmH2O ≈ 0.098 kPa). In addition, during the diagnosis and detection of ARDS, only 7 patients were recorded the platform pressure and 6 patients were recorded the drive pressure. Regarding adjunctive therapies, 137 patients (53.7%) received deep sedation, 26 patients (10.2%) underwent lung recruitment, 55 patients (21.6%) received prone ventilation, 42 patients (16.5%) were treated with high-dose steroids, 19 patients (7.5%) were treated with neuromuscular blockade, and 8 patients (3.1%) were treated with extracorporeal membrane oxygenation (ECMO). Finally, 70 patients (27.5%) were discharged automatically, while 50 patients (19.6%) died in the ICU, of which the ICU mortality of mild, moderate, and severe ARDS patients were 15.8% (9/57), 22.4% (28/125), and 17.8% (13/73), respectively. After follow-up, it was found that all 70 patients discharged automatically died within 28 days after discharge, and the overall ICU mortality adjusted accordingly was 47.1% (120/255). The overall incidence of ARDS in ICU patients at Hebei General Hospital is relatively low, with a high recognition rate by clinical physicians. Despite the high level of compliance and implementation of lung protective ventilation strategies and auxiliary treatment measures, it is still necessary to further improve the level of standardization in the implementation of small tidal volume and respiratory mechanics monitoring. For the implementation of auxiliary measures such as prone ventilation, it is necessary to further improve the enthusiasm of medical staff. The mortality in ICU is relatively low in ARDS patients, while the rate of spontaneous discharge is relatively high.

Changes in vital signs during adrenaline administration for hemostasis in intracordal injection: an observational study with a hypothetical design of endotracheal adrenaline administration in cardiopulmonary arrest

BackgroundThe background is that intravenous adrenaline administration is recommended for advanced cardiovascular life support in adults and endotracheal administration is given low priority. The reason is that the optimal dose of adrenaline in endotracheal administration is unknown, and it is ethically difficult to design studies of endotracheal adrenaline administration with non-cardiopulmonary arrest. We otolaryngologists think so because we administered adrenaline to the vocal folds for hemostasis after intracordal injection under local anesthesia, but have had few cases of vital changes. We hypothesized that examining vital signs before and after adrenaline administration for hemostasis would help determine the optimal dose of endotracheal adrenaline.MethodsWe retrospectively examined the medical records of 79 patients who visited our hospital from January 2018 to December 2020 and received adrenaline in the vocal folds and trachea for hemostasis by intracordal injection under local anesthesia to investigate changes in heart rate and systolic blood pressure before and after the injection.ResultsThe mean heart rates before and after injection were 83.96 ± 18.51 (standard deviation) beats per minute (bpm) and 81.50 ± 15.38 (standard deviation) bpm, respectively. The mean systolic blood pressure before and after the injection were 138.13 ± 25.33 (standard deviation) mmHg and 135.72 ± 22.19 (standard deviation) mmHg, respectively. Heart rate and systolic blood pressure had P-values of 0.136, and 0.450, respectively, indicating no significant differences.ConclusionsAlthough this study was an observational, changes in vital signs were investigated assuming endotracheal adrenaline administration. The current recommended dose of adrenaline in endotracheal administration with cardiopulmonary arrest may not be effective. In some cases of cardiopulmonary arrest, intravenous and intraosseous routes of adrenaline administration may be difficult and the opportunity for resuscitation may be missed. Therefore, it is desirable to have many options for adrenaline administration. Therefore, if the optimal dose and efficacy of endotracheal adrenaline administration can be clarified, early adrenaline administration will be possible, which will improve return of spontaneous circulation (ROSC) and survival discharge rates.

Cyclosporine A Decreases Dryness-Induced Hyperexcitability of Corneal Cold-Sensitive Nerve Terminals.

Cyclosporine A (CsA) is used for the treatment of dry eye (DE) with good clinical results, improving tear secretion and decreasing subjective symptoms. These effects are attributed to the improved tear film dynamics, but there are no data on the effect of CsA on the abnormal sensory nerve activity characteristic in DE. Our purpose was to evaluate the CsA effect on the enhanced activity of corneal cold thermoreceptors in a tear-deficient DE animal model using in vitro extracellular recording of cold thermoreceptors nerve terminal impulses (NTIs) before and in the presence of CsA. NTI shape was also analyzed. Blinking frequency and tearing rate were also measured in awake animals before and after topical CsA. CsA increased the tearing and blinking of treated animals. CsA significantly decreased the peak response to cold of cold thermoreceptors. Neither their spontaneous NTIs discharge rate nor their cooling threshold were modified. CsA also seemed to reverse some of the changes in NTI shape induced by tear deficiency. These data suggest that, at least in part, the beneficial clinical effects of CsA in DE can be attributed to a direct effect on sensory nerve endings, although the precise mechanisms underlying this effect need further studies to be fully clarified.

Differential Activation of Canal and Otolith Afferents by Acoustic Tone Bursts in Rats.

Vestibular evoked myogenic potentials (VEMPs) are routinely used to test otolith function, but which specific vestibular afferent neurons and central circuits are activated by auditory frequency VEMP stimuli remains unclear. To examine this question, we analyzed the sensitivity of individual vestibular afferents in adult Sprague-Dawley rats to tone bursts delivered at 9 frequencies (125-4000Hz) and 3 intensity levels (60, 70, 80dB SL re: acoustic brainstem response (ABR) threshold). Afferent neuron tone sensitivity was quantified by the cumulative probability of evoking a spike (CPE). Based on a threshold CPE of 0.1, acoustic stimuli in the present study evoked responses in 78.2 % (390/499) of otolith afferent neurons vs. 48.4 % (431/891) of canal afferent neurons. Organ-specific vestibular inputs to the central nervous system in response to tone bursts differ based on intensity and frequency content of the stimulus. At frequencies below 500Hz, tone bursts primarily activated both otolith afferents, even at the highest intensity tested (80dB SL re ABR threshold). At 1500Hz, however, tone bursts activated the canal and otolith afferents at the moderate and high intensities tested (70, 80dB SL), but activated only otolith afferents at the low intensity tested (60dB SL). Within an end organ, diversity of sensitivity between individual afferent neurons correlated with spontaneous discharge rate and regularity. Examination of inner ear fluid mechanics in silico suggests that the frequency response and preferential activation of the otolith organs likely arise from inner ear fluid motion trapped near the oval and round windows. These results provide insight into understanding the mechanisms of sound activation of the vestibular system and developing novel discriminative VEMP testing protocols and interpretative guidelines in humans.

Peristimulus Time Responses Predict Adaptation and Spontaneous Firing of Auditory-Nerve Fibers: From Rodents Data to Humans.

Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to predict the adaptation kinetics and spontaneous rate of the ANFs tuned at the PSTR probe frequency. The predictive model derived from gerbils was then validated in female mice and finally applied to humans by recording PSTRs from the auditory nerve in normal-hearing patients who underwent cerebellopontine angle surgeries. A rapid adaptation time constant of ∼3 ms and a mean spontaneous rate of ∼22 spikes/s in the 4 kHz frequency range were found. This study offers a promising diagnostic tool to map the human auditory nerve, thus opening new avenues to better understanding auditory neuropathies, tinnitus, and hyperacusis.SIGNIFICANCE STATEMENT Neural adaptation in auditory nerve fibers corresponds to the reduction in the neuronal activity to prolonged or repeated sound stimulation. For obvious ethical reasons, single-fiber recordings from the auditory nerve are not feasible in humans, creating a critical gap in extending data obtained using animal models to humans. Using electrocochleography in rodents, we inferred adaptation kinetics and spontaneous discharge rates of the auditory nerve fibers in humans. Routinely used in basic and clinical laboratories, this tool will provide a better understanding of auditory disorders such as neuropathies, tinnitus, and hyperacusis, and will help to improve hearing-aid fittings.

THE IMPACT OF TARGETED TRAINING OF MEDICAL INTERNS ON THE SURVIVAL OF CARDIAC ARREST IN THE EMERGENCY ROOM

Introduction:The prognosis of patients with cardiac arrest is closely related to the quality of cardiopulmonary resuscitation (CPR). The aim of this work was to assess the impact of targeted training on CPR, in accordance with the latest international recommendations, on the management of cardiac arrests in SAUV. Methods:This is a prospective study carried out between January 1 and December 31, 2011 at the SAUV of Ibn Sina University Hospital in Rabat, including all adult patients who experienced cardiac arrest after admission. The main primary objective is to evaluate the impact of targeted training of medical interns on the survival of cardiac arrest in the ER expressed by the Hospital Discharge Survival (HDS) rate. Secondary objectives include the rate of recovery of circulatory activity (RCA), 48-hour survival, and quality of CPR performance. Results:342 patients were included, 159 before and 183 after training. There was no significant difference in terms of recovery from spontaneous circulation, 48h survival or discharge rate at home without sequelae. On the other hand, there was a statistically significant improvement in all the quality criteria for performing CPR. Conclusion:This work shows that the introduction of short training courses such improves the quality of CPR. The lack of impact on the improvement of patient survival seems to be related to numerous shortcomings, in particular basic medical training in emergency medicine, organization and protocolization of care, equipment of emergency rooms, supervision of emergency clerkship and the existence of a CA national registry. These are all areas to be developed in order to improve the prognosis of CA in our hospital structure.

Mechanical Versus Manual Chest Compression: A Retrospective-Cohort in Out-of-Hospital Cardiac Arrest

Objective: In cardiac arrest cases, high quality cardiopulmonary resuscitation and effective chest compression are vital issues in improving survival with good neurological outcomes. In this study, we investigated the effect of mechanical chest compression devices on 30- day survival in out-of-hospital cardiac arrest.
 Materials and Methods: This retrospective case-control study was performed on patients who were over 18 years of age and admitted to the emergency department for cardiac arrest between January 1, 2016 and January 15, 2018. Manual chest compression was performed to the patients before January 15, 2017, and mechanical chest compression was performed after this date. Return of spontaneous circulation, hospital discharge, and 30-day survival rates were compared between the groups of patients in terms of chest compression type. In this study, the LUCAS-2 model piston-based mechanical chest compression device was used for mechanical chest compressions.
 Results: The rate of return of spontaneous circulation was significantly lower in the mechanical chest compression group (11.1% vs 33.1%; p < 0.001). The 30-day survival rate was higher in the manual chest compression group (6.8% vs 3.7%); however, this difference was not statistically significant (p = 0.542). Furthermore, 30-day survival was 0% in the trauma group and 0.6% in the patient group who underwent cardiopulmonary resuscitation for over 20 minutes.
 Conclusion: It can be seen that the effect of mechanical chest compression on survival is controversial; studies on this issue should continue and, furthermore, studies on the contribution of mechanical chest compression on labor loss should be conducted.

Long-term effects of hyperpolarization-activated inward current blockade on cardiac parasympathetic activity

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS - UEFISCDI Background The autonomic control of the pacemaker current, If, and the molecular mechanisms underlying parasympathetic If modulation are well understood. Conversely, the effects of chronic If blockade on the parasympathetic nervous system and on the heart rate (HR) response to acute parasympathetic changes are still largely unknown. Such interactions could significantly influence the course of patients undergoing chronic therapy with the If blocker ivabradine. Purpose We aimed to assess the effects of long-term If blockade using ivabradine on cardiac autonomic modulation and on the cardiovascular response to acute in vivo and in vitro parasympathetic stimulation. Methods Radiotelemetry ECG transmitters were implanted in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day); sympathetic and parasympathetic heart rate variability parameters were assessed. At the end of the study, the right atrium was removed and right atrial HCN(1-4) RNA expression levels were analyzed. The HR and systolic blood pressure (SBP) responses to in vivo electrical stimulation of the right vagus nerve (2–20 Hz) and the spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10-9–10-6 mol/L) were assessed in 6 additional Control and 10 IVA rats. Results At the end of the study, mean 24-h HR was significantly lower in the IVA compared with the Control rats (301.3 ± 7.5 bpm vs. 341.5 ± 8.3 bpm; p< 0.01). Ivabradine administration led to a significant increase in vagal tone and shifted the sympatho-vagal balance towards vagal dominance (awake, asleep, and over 24-h; all p< 0.05). In the Control rats, in vivo vagus nerve stimulation induced a progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in the IVA rats, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). Ivabradine-treated rats also presented a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher HCN4 expression (p = 0.02). Conclusion Long-term If blockade using ivabradine caused a significant increase in vagal tone and shifted the autonomic balance towards vagal dominance in rats. Given the highly proarrhythmic effects of vagal activation at the atrial level, these findings could provide an explanation for the increased risk of atrial fibrillation associated with ivabradine use in clinical trials. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in vivo vagal stimulation, and led to significant sinus node HCN4 up-regulation. These data suggest that ivabradine-induced HCN4 and the consequent If up-regulation could render the sinus node less sensitive to acute vagal inputs and could thus protect against excessive bradycardia induced by acute vagal activation.

Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats.

Background: The complex interactions that exist between the pacemaker current, I f, and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the I f blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to in situ and in vitro parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for I f, was also evaluated. Methods: Sympathetic and parasympathetic heart rate variability parameters and right atrial HCN(1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to in situ electrical stimulation of the vagus nerve (2–20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10−9–10−6 mol/L) was also assessed in these later rats. Results: Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, in situ vagus nerve stimulation induced progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher right atrial HCN4 expression (p = 0.02). Conclusion: Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in situ vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term I f blockade may protect against excessive bradycardia induced by acute vagal activation.

The intrinsic plasticity of medial vestibular nucleus neurons during vestibular compensation\u2014a systematic review and meta-analysis

BackgroundVestibular compensation is a homeostatic process that occurs in the central nervous system in response to peripheral vestibular dysfunction. Experimental studies in rodent models have suggested that unilateral peripheral vestibular lesions are correlated with an increase in the intrinsic excitability of central vestibular neurons. This process may be dependent on the intrinsic properties of the neurons themselves. We aimed to conduct a systematic review of the literature to survey the evidence for changes in intrinsic plasticity observed during the acute phase of vestibular compensation.MethodsWe systematically reviewed the literature regarding the electrophysiological effect of experimentally induced unilateral vestibular deafferentation (UVD) on the intrinsic membrane properties of medial vestibular nucleus neurons in animal models. We developed tools to assess the methodological quality (precision, validity and bias) of studies that met pre-determined inclusion and exclusion criteria. We extracted numerical data and performed a meta-analysis of specific quantitative data pooled from these studies.ResultsWe identified 17 studies that satisfied the inclusion criteria. There is moderate quality evidence to suggest a statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, the spontaneous discharge rate increases by 4 spikes/s on average and the sensitivity to current stimuli increases.ConclusionUsing this novel approach, we demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental animal studies with similar aims.

Exposure to blast shock waves via the ear canal induces deficits in vestibular afferent function in rats

The ears are air-filled structures that are directly impacted during blast exposure. In addition to hearing loss and tinnitus, blast victims often complain of vertigo, dizziness and unsteady posture, suggesting that blast exposure induces damage to the vestibular end organs in the inner ear. However, the underlying mechanisms remain to be elucidated. In this report, single vestibular afferent activity and the vestibulo-ocular reflex (VOR) were investigated before and after exposure to blast shock waves (∼20 PSI) delivered into the left external ear canals of anesthetized rats. Single vestibular afferent activity was recorded from the superior branch of the left vestibular nerves of the blast-treated and control rats one day after blast exposure. Blast exposure reduced the spontaneous discharge rates of the otolith and canal afferents. Blast exposure also reduced the sensitivity of irregular canal afferents to sinusoidal head rotation at 0.5–2Hz. Blast exposure, however, resulted in few changes in the VOR responses to sinusoidal head rotation and translation. To the best of our knowledge, this is the first study that reports blast exposure-induced damage to vestibular afferents in an animal model. These results provide insights that may be helpful in developing biomarkers for early diagnosis of blast-induced vestibular deficits in military and civilian populations.

A Distinct Class of Bursting Neurons with Strong Gamma Synchronization and Stimulus Selectivity in Monkey V1

Cortical computation depends on interactions between excitatory and inhibitory neurons. The contributions of distinct neuron types to sensory processing and network synchronization in primate visual cortex remain largely undetermined. We show that in awake monkey V1, there exists a distinct cell type (››30% of neurons) that has narrow-waveform (NW) action potentials and high spontaneous discharge rates and fires in high-frequency bursts. These neurons are more stimulus selective and phase locked to 30- to 80-Hz gamma oscillations than other neuron types. Unlike other neuron types, their gamma-phase locking is highly predictive oforientation tuning. We find evidence for strong rhythmic inhibition in these neurons, suggesting that they interact with interneurons to act as excitatory pacemakers for the V1 gamma rhythm. We did not find a similar class of NW bursting neurons in L2-L4 of mouse V1. Given its properties, this class of NW bursting neurons should be pivotal for the encoding and transmission of stimulus information.

Reduced Sensory-Evoked Locus Coeruleus-Norepinephrine Neural Activity in Female Rats With a History of Dietary-Induced Binge Eating.

Noradrenergic pathways have been implicated in eating pathologies. These experiments sought to examine how dietary-induced binge eating influences the neuronal activity of the locus coeruleus (LC)-norepinephrine (NE) system. Young adult female Sprague Dawley rats (7–8 weeks old) were exposed to a repeated intermittent (twice weekly) cycle of 30-min access to a highly palatable sweetened fat (i.e., vegetable shortening with 10% sucrose) with or without intermittent (24 h) calorie restriction (Restrict Binge or Binge groups, respectively). Age- and weight-matched female control rats were exposed to standard chow feeding (Naive group) or intermittent chow feeding (Restrict group). The Binge and Restrict Binge groups demonstrated an escalation in sweet-fat food intake after 2.5 weeks. On week 3, in vivo single-unit LC electrophysiological activity was recorded under isoflurane anesthesia. Restrict Binge (20 cells from six rats) and Binge (27 cells from six rats) had significantly reduced (approximate 20% and 26%, respectively) evoked LC discharge rates compared with naive rats (22 cells, seven rats). Spontaneous and tonic discharge rates were not different among the groups. Signal-to-noise ratio was reduced in the groups with intermittent sweetened fat exposure. In order to investigate the neuropeptide alterations as a consequence of dietary binge eating, relative gene expression of neuropeptide Y (NPY), glucagon-like peptide 1 receptor (GLP-1r), prodynorphin, and related genes were measured in LC and hypothalamic arcuate (Arc) regions. Glp-1r, Npy2r, and Pdyn in LC region were reduced with repeated intermittent restriction. Npy1r was reduced by approximately 27% in ARC of Restrict compared with Naive group. Such data indicate that dietary-induced binge eating alters the neural response of LC neurons to sensory stimuli and dampens the neural stress response.

Synergistic effect of orexin-glutamate co-administration on spontaneous discharge rate of locus coeruleus neurons in morphine-dependent rats

Various intrinsic and extrinsic factors can increase the spontaneous discharge rate of locus coeruleus (LC) neurons. Among the extrinsic ones, orexinergic neurons of the lateral hypothalamus (LH) send widespread projections to LC region. Accumulating evidence support the involvement of glutamate in mediating the excitatory effect of orexin-A on LC neurons. In addition, both orexinergic and glutamatergic systems have been shown to play critical roles in molecular changes underlying the development of morphine dependence. The present study was designed to investigate the interaction between orexin-A and glutamate in modulating the firing rate of LC neurons. Regarding the role of both orexinergic and glutamatergic systems in morphine dependence, this effect was also investigated in morphine dependent rats. For this purpose, spontaneous discharge rate of LC neurons was recorded using the whole-cell patch clamp recording method in presence of orexin-A, glutamate or orexin-A plus glutamate in acutely prepared brain slices. Results indicated that superfusion of either orexin-A or glutamate enhances the firing rate of LC neurons in both dependent and non-dependent rats. However, co-application of orexin-A and glutamate elicited a significant synergism in enhancement of firing rate only in morphine dependent animals. In conclusion, it seems that development of morphine dependence promotes adaptations in locus coeruleus neurons that potentiate the orexin-glutamate interaction.

Input-output curves of low and high spontaneous rate auditory nerve fibers are exponential near threshold

Input-output (IO) properties of cochlear transduction are frequently determined by analyzing the average discharge rates of auditory nerve fibers (ANFs) in response to relatively long tonal stimulation. The ANFs in cats have spontaneous discharge rates (SRs) that are bimodally distributed, peaking at low (<0.5 spikes/s) and high (∼60 spikes/s) rates, and rate-level characteristics differ depending upon SR. In an effort to assess the instantaneous IO properties of ANFs having different SRs, static IO-curves were constructed from period histograms based on phase-locking of spikes to the stimulus waveform. These curves provide information unavailable in conventional average rate-level curves. We find that all IO curves follow an exponential trajectory. It is argued that the exponential behavior represents the transduction in the IHC and that the difference among ANFs having different SRs is predominantly a difference in gain attributed most likely to synaptic drive. © 2018 The authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Chronic adolescent morphine exposure alters the responses of lateral paragigantocellular neurons to acute morphine administration in adulthood

Accumulating evidence support the growing non-medical use of morphine during adolescence. Despite this concern which has recently been addressed in some studies, cellular mechanisms underlying the long-term neurobiological and behavioral effects of opiate exposure during this critical period have still remained largely unexplored. Several reports have proposed that subtle long-lasting neurobiological alterations might be triggered by exposure to opiate derivatives or drugs of abuse particularly when this occurs during a critical phase of brain maturation such as adolescence. The present study was designed to investigate how chronic adolescent morphine exposure could affect the responsiveness of lateral paragigantocellular (LPGi) neurons to acute morphine administration in adult rats. Male Wistar rats received chronic escalating morphine or saline during adolescence (30–39d) for 10 days. During adulthood (65d), the extracellular unit activities of LPGi neurons were recorded in urethane-anesthetized animals. Results indicated that adolescent morphine treatment enhances the baseline activity of LPGi neurons. In addition, morphine-induced inhibition of spontaneous discharge rate was potentiated in adult rats received morphine during adolescence. However, this pretreatment did not affect the extent of morphine excitatory effect, onset or peak of cellular response and regularity of unit discharge in LPGi neurons. Our study supports the hypothesis that adolescent morphine exposure induces long-lasting neurophysiological alterations in brain regions known to play a role in mediating opiate effects. This finding sheds light on the possible effect of opiate pre-exposure on addiction susceptibility in future.

Are there Sleep-promoting Neurons in the Mouse Parafacial Zone?

Although recent studies have reported that gamma-aminobutyric acid (GABA) neurons in the parafacial zone (PZ) of the rostral medulla are needed for the induction of slow-wave sleep (SWS) and that the PZ is a medullary SWS-promoting center, it remains unknown whether the PZ contains SWS-active or sleep-promoting neurons. In the present study, a total of 125 neurons were recorded, for the first time, in non-anesthetized, head-restrained mice during the complete wake–sleep cycle throughout the PZ of the rostral medulla. The vast majority (87.2%) of the neurons displayed increased activity during both wakefulness (W) and paradoxical (or rapid eye movement) sleep (PS) compared to during SWS (W/PS-active neurons) and a few (8.0%) discharged phasically and selectively during PS (PS-active neurons), but none discharged maximally during SWS (SWS-active neurons) or displayed a higher rate of spontaneous discharge during both SWS and PS than during W (SWS/PS-active neurons). These findings do not support the view that the GABAergic PZ is a medullary SWS-promoting center.

Spatial Gradients in the Size of Inner Hair Cell Ribbons Emerge Before the Onset of Hearing in Rats.

The size and locations of pre-synaptic ribbons and glutamate receptors within and around inner hair cells are correlated with auditory afferent response features such as the spontaneous discharge rate (SR), threshold, and dynamic range of sound intensity representation (the so-called SR-groups). To test if the development of these spatial gradients requires experience with sound intensity, we quantified the size and spatial distribution of synaptic ribbons from the inner hair cells of neonatal rats before and after the onset of hearing (from post-natal day (P) 3 to P33). To quantify ribbon size, we used high resolution fluorescence confocal microscopy and 3-D reconstructions of immunolabeled ribbons. The size, density, and spatial distribution of ribbons changed during development. At P3, ribbons were densely clustered near the basal/modiolar face of the hair cell where low SR-groups preferentially contact adult hair cells. By P12, the disparity in ribbon count was less striking and ribbons were equally likely to occupy both faces. At all ages before P12, ribbons were larger on the modiolar face than on the pillar face. These differences initially grew larger with age but collapsed around the onset of hearing. Between P12 and P33, the spatial gradients remained small and began to re-emerge around P33. Even by P12, we did not find spatial gradients in the size of the post-synaptic glutamate receptors as is found on afferent terminals contacting adult inner hair cells. These results suggest that spatial gradients in ribbon size develop in the absence of sensory experience.

The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex

Metabotropic glutamate receptor 5 (mGluR5) activation in the infralimbic cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals.Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat–evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats.The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.