Decreased Burst Frequency Research Articles

Sympathoinhibition during cardiopulmonary baroreceptor loading is attenuated in older females.

The purpose of the present study was to clarify the impact of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. Nine older females (mean±SD, 70±6 years) and eleven younger females (20±1 years) completed the study. A passive leg raising (PLR) test was performed wherein the participants were positioned supine (baseline, 0º), and their lower limbs were passively lifted at 10º, 20º, 30º, and 40º (3 min at each angle). Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. The central venous pressure was estimated based on peripheral venous pressure (eCVP), which was monitored using a cannula in the right large antecubital vein. Baseline MSNA was higher in older females compared to younger females. MSNA burst frequency (BF) decreased during the PLR test in both older and younger females, but the magnitude of the decrease in MSNA BF was smaller in older females than in younger females (older, -3.5±1.5 vs. younger, -6.3±1.5 bursts/min at 40º from baseline, P=0.014). The eCVP increased during the PLR in both groups, and there was no difference in the changes in eCVP between the two groups (older, +1.07±0.37 vs. younger, +1.12±0.33 mmHg at 40º from baseline, P=0.941). These results suggest that inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age in females.

Effects of Postural Resonance on Skin Sympathetic Nerve Activity and Blood Pressure: A Pilot Study Evaluating Vascular Tone Baroreflex Stimulation Through Biofeedback.

Heart rate and vascular tension baroreflex exhibit resonance characteristics at approximately 0.1 and 0.03Hz. In this study, we aimed to induce postural resonance (PR) through rhythmic postural adjustments. To assess the viability of this technique, we investigated the acute impacts of postural resonance on blood pressure, sympathetic nerve activity, and mood. Fifteen healthy study participants, consisting of 8 males and 7 females, were selected for this self-controlled study. Skin sympathetic nerve activity was continuously monitored during both the intervention and stress test on the experimental day. After PR intervention, the diastolic blood pressure and mean arterial pressure in the PR group exhibited significant reductions compared to the CON group (P = 0.032, CON = 71.67 ± 2.348, PR = 64.08 ± 2.35; P = 0.041, CON = 75.00 ± 2.17, PR = 81.67 ± 2.17). After PR intervention both left brachial ankle pulse wave velocity and right brachial ankle pulse wave velocity exhibited a significant reduction compared to pre-intervention levels (from 1115.86 ± 150.08 to 1048.43 ± 127.40cm/s, p < 0.001; 1103.86 ± 144.35 to 1060.43 ± 121.35cm/s, p = 0.018). PR intervention also led to a significant decrease in burst frequency and duration (P = 0.049; CON = 8.96 ± 1.17, PR = 5.51 ± 1.17) and a noteworthy decrease in burst amplitude and burst threshold during the cold-pressor test (P = 0.002; P = 0.002). Additionally, VAS scores exhibited a substantial increase following PR (P = 0.035, CON = 28.4 ± 4.49, PR = 42.17 ± 4.10). PR can induce resonance effects within the cardiovascular system, resulting in the effective reduction of blood pressure, skin sympathetic nerve activity and pulse wave velocity, and decreased burst amplitude and burst threshold of the sympathetic nerve during the cold-pressor test.

Disinhibition does not play a role in endomorphin-2-induced changes in inspiratory motoneuron output produced by in vitro neonatal rat preparations

Low level activation of mu-opioid receptors (MORs) in neonatal rat brainstem-spinal cord preparations increases inspiratory burst amplitude recorded on cervical spinal roots. We tested whether: (1) MOR activation with an endogenous ligand, such as endomorphin-2, increases inspiratory burst amplitude, (2) disinhibition of GABAergic or glycinergic inhibitory synaptic transmission is involved, and (3) inflammation alters endomorphin-2 effects. Using neonatal rat (P0-P3) brainstem-spinal cord preparations, bath-applied endomorphin-2 (10–200 nM) increased inspiratory burst amplitude and decreased burst frequency. Blockade of GABAA receptors (picrotoxin), glycine receptors (strychnine), or both (picrotoxin and strychnine) did not abolish endomorphin-2-induced effects. In preparations isolated from neonatal rats injected 3 h previously with lipopolysaccharide (LPS, 0.1 mg/kg), endomorphin-2 continued to decrease burst frequency but abolished the burst amplitude increase. Collectively, these data indicate that disinhibition of inhibitory synaptic transmission is unlikely to play a role in endomorphin-2-induced changes in inspiratory motor output, and that different mechanisms underlie the endomorphin-2-induced increases in inspiratory burst amplitude and decreases in burst frequency.

Revealing the Spectral State Transition of the Clocked Burster, GS 1826-238, with NuSTAR StrayCats

We present the long-term analysis of GS 1826-238, a neutron star X-ray binary known as the Clocked Burster, using data from NuSTAR StrayCats. StrayCats, a catalog of NuSTAR stray light data, contains data from bright, off-axis X-ray sources that have not been focused by the NuSTAR optics. We obtained stray light observations of the source from 2014–2021, reduced and analyzed the data using nustar-gen-utils Python tools, demonstrating the transition of the source from the island atoll state to a banana branch. We also present the light-curve analysis of Type I X-ray bursts from the Clocked Burster and show that the bursts from the banana/soft state are systematically shorter in duration than those from the island/hard state and have a higher burst fluence. From our analysis, we note an increase in the mass accretion rate of the source, and a decrease in burst frequency with the transition.

Mu-opioid receptor-dependent transformation of respiratory motor pattern in neonates in vitro.

Endogenous opioid peptides activating mu-opioid receptors (MORs) are part of an intricate neuromodulatory system that coordinates and optimizes respiratory motor output to maintain blood-gas homeostasis. MOR activation is typically associated with respiratory depression but also has excitatory effects on breathing and respiratory neurons. We hypothesized that low level MOR activation induces excitatory effects on the respiratory motor pattern. Thus, low concentrations of an MOR agonist drug (DAMGO, 10–200 nM) were bath-applied to neonatal rat brainstem-spinal cord preparations while recording inspiratory-related motor output on cervical spinal roots (C4-C5). Bath-applied DAMGO (50–200 nM) increased inspiratory motor burst amplitude by 40–60% during (and shortly following) drug application with decreased burst frequency and minute activity. Reciprocal changes in inspiratory burst amplitude and frequency were balanced such that 20 min after DAMGO (50–200 nM) application, minute activity was unaltered compared to pre-DAMGO levels. The DAMGO-induced inspiratory burst amplitude increase did not require crossed cervical spinal pathways, was expressed on thoracic ventral spinal roots (T4-T8) and remained unaltered by riluzole pretreatment (blocks persistent sodium currents associated with gasping). Split-bath experiments showed that the inspiratory burst amplitude increase was induced only when DAMGO was bath-applied to the brainstem and not the spinal cord. Thus, MOR activation in neonates induces a respiratory burst amplitude increase via brainstem-specific mechanisms. The burst amplitude increase counteracts the expected MOR-dependent frequency depression and may represent a new mechanism by which MOR activation influences respiratory motor output.

Activation of Brainstem mu‐Opioid Receptors (mORs) Increases Respiratory‐Related Motor Burst Amplitude in Neonatal Rat Brainstem‐Spinal Cord Preparations

Mu‐opioid receptors (mORs) located on brainstem respiratory neurons are part of an intricate peptidergic neuromodulatory system that regulates breathing. The endogenous role of mORs in respiratory motor control, however, is poorly understood. To explore this question, very low (nanomolar) concentrations of mOR agonist drugs were bath‐applied to neonatal rat (P1‐P3) brainstem‐spinal cord preparations while measuring respiratory‐related motor output from spinal C4‐C5 rootlets containing phrenic motor neuron axons. When DAMGO (synthetic mOR agonist) or endomorphin‐2 (endogenous mOR ligand) were bath‐applied for 15 min at 20‐100 nM, respiratory motor burst amplitude increased dramatically with a modest decrease in burst frequency. Burst amplitude facilitated by 45 ± 38% and 32 ± 24% (mean ± stdev) above baseline for 50 nM DAMGO (n=8) and 100 nM endomorphin‐2 (n=10), respectively (p&lt;0.001). To test whether respiratory motor output on thoracic ventral roots was altered by mOR activation, brainstem‐spinal cord preparations were isolated to include spinal segments C1‐T8. Bath‐applied DAMGO (50 nM) induced burst amplitude facilitation on thoracic roots T4‐T6 and cervical roots C4‐C5 by 62 ± 19% and 38 ± 36%, respectively (p&lt;0.012). To test whether mOR‐induced burst facilitation is due to brainstem or spinal mechanisms, a split‐bath chamber with a barrier at C1‐C2 was used to separately bathe the brainstem and spinal cord compartments. DAMGO (50 nM) application to the spinal cord (C2‐C8) had little effect on respiratory motor output measured from C4‐C5 rootlets, whereas DAMGO application to the brainstem increased C4‐C5 motor output by 34 ± 19% (p&lt;0.004). These data suggest that mOR activation in the brainstem can transform the respiratory network to produce a motor pattern with decreased frequency balanced by increased amplitude, with relatively little change in overall neural output. Given that mOR‐induced facilitation was observed in both cervical and thoracic motor neuron pools, we hypothesize that burst amplitude facilitation is due to mOR activation on rhythm‐generating neurons or premotor neurons in the brainstem. This study reveals that endogenous mOR activation modulates the neural control of breathing in a manner that is potentially different from respiratory depression, which is more commonly associated with opioids.

The Influence of OSA Treatment on Muscle Sympathetic Nerve Activity: A Systematic Review and Meta‐Analysis

Introduction Obstructive Sleep Apnea (OSA) is commonly treated with Continuous Positive Airway Pressure (CPAP) therapy, which reduces the number of airway obstructions while sleeping. Recently, diet and exercise interventions have been explored as a possible alternative treatment for OSA. Microneurography is a technique used to measure efferent postganglionic muscle sympathetic nerve activity (MSNA) via direct interneural recordings. CPAP therapy and diet and exercise interventions reduce disease severity, but their influence on MSNA is less clear. Purpose The present meta-analysis aims to examine the influence of type and length of treatment for OSA on MSNA. Methods A structured search of electronic databases was performed by a research librarian. Two reviewers independently assessed the titles of abstracts of articles; studies meeting eligibility criteria were selected for full-text review. Two reviewers independently extracted the data and assessed the quality of the studies using Joanna Briggs Institute Critical Appraisal of Evidence Effectiveness tool. Review Manager v5.3 was used to conduct the statistical analyses, and significance was set at P < 0.05. Results Evidence from 10 interventions (n=186) shows CPAP therapy significantly decreases MSNA burst frequency in individuals with OSA (Mean Difference, +12.6 bursts/min; 95% CI, 10.1-15.2 bursts/min; I2 = 39%). The same is shown for burst incidence in 6 studies (n=113) (MD, +21.5 bursts/100 hbs; 95% CI, 18.6-24.5 bursts/100 hbs; I2 = 0%). Reductions in MSNA (burst frequency and burst incidence) were seen for all time points of CPAP therapy: 1, 6, and 12 months. Data from 5 studies shows a significant decrease in burst frequency following diet and exercise intervention (n=68) (MD, +9.86 bursts/min; 95% CI, 5.37-14.35 bursts/min; I2 = 75%). A meta-regression analysis identified a relationship between CPAP therapy length and burst frequency (R2 = 0.329, p = 0.003). Conclusion CPAP therapy decreases MSNA in individuals with OSA, and a relationship exists between length of treatment and sympathetic activity. However, a significant reduction in sympathetic activity was also seen as a result of diet and exercise interventions; although, only burst frequency data was reported. More data is needed to determine optimal treatment type and length.

Isolated adult turtle brainstems exhibit central hypoxic chemosensitivity

During hypoxia, red-eared slider turtles increase ventilation and decrease episodic breathing, but whether these responses are due to central mechanisms is not known. To test this question, isolated adult turtle brainstems were exposed to 240 min of hypoxic solution (bath PO2 = 32.6 ± 1.2 mmHg) and spontaneous respiratory-related motor bursts (respiratory event) were recorded on hypoglossal nerve roots. During hypoxia, burst frequency increased during the first 15 min, and then decreased during the remaining 35–240 min of hypoxia. Burst amplitude was maintained for 120 min, but then decreased during the last 120 min. The number of bursts/respiratory event decreased within 30 min and remained decreased. Pretreatment with either prazosin (α1-adrenergic antagonist) or MDL7222 (5-HT3 antagonist) blocked the hypoxia-induced short-term increase and the longer duration decrease in burst frequency. MDL7222, but not prazosin, blocked the hypoxia-induced decrease in bursts/respiratory event. Thus, during bath hypoxia, isolated turtle brainstems continued to produce respiratory motor output, but the frequency and pattern were altered in a manner that required endogenous α1-adrenergic and serotonin 5-HT3 receptor activation. This is the first example of isolated reptile brainstems exhibiting central hypoxic chemosensitivity similar to other vertebrate species.

Excitatory Modulation of the preBötzinger Complex Inspiratory Rhythm Generating Network by Endogenous Hydrogen Sulfide.

Hydrogen Sulfide (H2S) is one of three gasotransmitters that modulate excitability in the CNS. Global application of H2S donors or inhibitors of H2S synthesis to the respiratory network has suggested that inspiratory rhythm is modulated by exogenous and endogenous H2S. However, effects have been variable, which may reflect that the RTN/pFRG (retrotrapezoid nucleus, parafacial respiratory group) and the preBötzinger Complex (preBötC, critical for inspiratory rhythm generation) are differentially modulated by exogenous H2S. Importantly, site-specific modulation of respiratory nuclei by H2S means that targeted, rather than global, manipulation of respiratory nuclei is required to understand the role of H2S signaling in respiratory control. Thus, our aim was to test whether endogenous H2S, which is produced by cystathionine-β-synthase (CBS) in the CNS, acts specifically within the preBötC to modulate inspiratory activity under basal (in vitro/in vivo) and hypoxic conditions (in vivo). Inhibition of endogenous H2S production by bath application of the CBS inhibitor, aminooxyacetic acid (AOAA, 0.1–1.0 mM) to rhythmic brainstem spinal cord (BSSC) and medullary slice preparations from newborn rats, or local application of AOAA into the preBötC (slices only) caused a dose-dependent decrease in burst frequency. Unilateral injection of AOAA into the preBötC of anesthetized, paralyzed adult rats decreased basal inspiratory burst frequency, amplitude and ventilatory output. AOAA in vivo did not affect the initial hypoxia-induced (10% O2, 5 min) increase in ventilatory output, but enhanced the secondary hypoxic respiratory depression. These data suggest that the preBötC inspiratory network receives tonic excitatory modulation from the CBS-H2S system, and that endogenous H2S attenuates the secondary hypoxic respiratory depression.

Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks.

Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more “natural” locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance.SIGNIFICANCE STATEMENT The sodium pump is ubiquitously expressed and responsible for at least half of total brain energy consumption. The pumps maintain ionic gradients and the resting membrane potential of neurons, but increasing evidence suggests that activity- and state-dependent changes in pump activity also influence neuronal firing. Here we demonstrate that changes in sodium pump activity regulate locomotor output in the spinal cord of neonatal mice. We describe a sodium pump-mediated afterhyperpolarization in spinal neurons, mediated by spike-dependent increases in pump activity, which is affected by dopamine. Understanding how sodium pumps contribute to network regulation and are targeted by neuromodulators, including dopamine, has clinical relevance due to the role of the sodium pump in diseases, including amyotrophic lateral sclerosis, parkinsonism, epilepsy, and hemiplegic migraine.

Developmental Nicotine Exposure Alters The Respiratory Frequency Response to Muscarine

Prenatal nicotine exposure with continued exposure through breast milk over the first week of life (developmental nicotine exposure, DNE) alters development of the brainstem circuits that control breathing. Previous work has shown that DNE desensitizes nicotinic acetylcholine receptors (nAChRs) and alters the respiratory motor response to exogenous nicotine in neonatal rats. In the brainstem‐spinal cord (BSSC) split‐bath preparation, nicotine applied to the medullary compartment increases the frequency of respiratory related bursting recorded from the fourth cervical ventral root (C4VR), but this effect is markedly blunted by DNE. Because ACh is the endogenous ligand for both nAChRs and muscarinic acetylcholine receptors (mAChRs), and mAChRs are expressed on PreBotzinger neurons, we hypothesized that DNE also alters muscarinic modulation of C4VR frequency in this system. In neonatal rats, postnatal day 0‐6, 1 mM muscarine, a mAChR agonist, applied to the medullary compartment in the BSSC split‐bath preparation increased burst frequency recorded from C4VR in 4/4 control animals and, in some cases, the pattern of bursting became irregular. Muscarine applied to the medulla decreased burst frequency in 4/4 DNE animals. These preliminary data show that chronic stimulation of nAChRs also alters the development of muscarinic synaptic transmission by yet to be determined mechanisms.

Related neuropeptides use different balances of unitary mechanisms to modulate the cardiac neuromuscular system in the American lobster, Homarus americanus.

To produce flexible outputs, neural networks controlling rhythmic motor behaviors can be modulated at multiple levels, including the pattern generator itself, sensory feedback, and the response of the muscle to a given pattern of motor output. We examined the role of two related neuropeptides, GYSDRNYLRFamide (GYS) and SGRNFLRFamide (SGRN), in modulating the neurogenic lobster heartbeat, which is controlled by the cardiac ganglion (CG). When perfused though an isolated whole heart at low concentrations, both peptides elicited increases in contraction amplitude and frequency. At higher concentrations, both peptides continued to elicit increases in contraction amplitude, but GYS caused a decrease in contraction frequency, while SGRN did not alter frequency. To determine the sites at which these peptides induce their effects, we examined the effects of the peptides on the periphery and on the isolated CG. When we removed the CG and stimulated the motor nerve with constant bursts of stimuli, both GYS and SGRN increased contraction amplitude, indicating that each peptide modulates the muscle or the neuromuscular junction. When applied to the isolated CG, neither peptide altered burst frequency at low peptide concentrations; at higher concentrations, SGRN decreased burst frequency, whereas GYS continued to have no effect on frequency. Together, these data suggest that the two peptides elicit some of their effects using different mechanisms; in particular, given the known feedback pathways within this system, the importance of the negative (nitric oxide) relative to the positive (stretch) feedback pathways may differ in the presence of the two peptides.

Control of Breathing in In Vitro Brain Stem Preparation from Goldfish (Carassius auratus; Linnaeus)

In vitro brain stem preparations from goldfish (Carassius auratus) were used to first determine whether this species possesses central chemoreceptors able to modulate respiratory activity. Preparations were superfused with an artificial cerebrospinal fluid (aCSF); fictive breathing was recorded extracellularly by placing a suction electrode on cranial nerve VII. Reducing the level of O2 in the gas mixture used to bubble the aCSF from a hyperoxic level (80% or 98.7% O2) to a relative hypoxic level (20% or 40% O2) increased the frequency of the fictive respiratory burst (P = 0.0002). Reducing the pH of the aCSF from 7.9 to 7.4 by increasing CO2 in the superfusate did not affect fictive breathing. Chloride-mediated neurotransmission (GABA/glycine) is a major modulator of respiratory activity; however, its effect on the neural circuits that regulate breathing in teleosts remains unknown. Bath application of GABA (0.5, 5.0 mM) decreased burst frequency but not amplitude; this effect was dose dependent (drug × concentration: P = 0.01). Superfusion of the preparations with aCSF containing 1.25 μM of bicuculline methochloride and 1.50 μM of strychnine hydrochloride (GABAA and glycine receptor antagonists, respectively) increased burst frequency (P = 0.002) and amplitude (P < 0.001). We conclude that respiratory activity produced by the goldfish brain stem is not responsive to the moderate CO2 levels used in this study; it may contain O2 chemoreceptors, but the relatively small response could also reflect nonspecific effects of hypoxia on the central nervous system. Cl(-)-mediated neurotransmission inhibits fictive breathing; this aspect of respiratory regulation is similar to other groups of vertebrates.

Differentiated Baroreflex Modulation of Sympathetic Nerve Activity During Deep Brain Stimulation in Humans

Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting.

Adaptation to visual stimulation modifies the burst firing property of V1 neurons.

The mean firing rate of visual cortical neurons is reduced after prolonged visual stimulation, but the underlying process by which this occurs as well as the biological significance of this phenomenon remains unknown. Computational neuroscience studies indicate that high-frequency bursts in stimulus-driven responses can be transmitted across synapses more reliably than isolated spikes, and thus may carry accurate stimulus-related information. Our research examined whether or not adaptation affects the burst firing property of visual cortical neurons by examining changes in the burst firing changes of V1 neurons during adaptation to the preferred visual stimulus. The results show that adaptation to prolonged visual stimulation significantly decreased burst frequency (bursts/s) and burst length (spikes/burst), but increased burst duration and the interspike interval within bursts. These results suggest that the adaptation of V1 neurons to visual stimulation may result in a decrease of feedforward response gain but an increase of functional activities from lateral and/or feedback connections, which could lead to a reduction in the effectiveness of adapted neurons in transmitting information to its driven neurons.

Site-specific hydrogen sulfide-mediated central regulation of respiratory rhythm in medullary slices of neonatal rats

Hydrogen sulfide (H2S) is involved in central regulation of respiratory rhythm at the level of the medulla oblongata. The present study was carried out to test our hypothesis that H2S exerts site-specific regulatory action on respiratory rhythm in the medulla oblongata of neonatal rats. The rhythmic discharge of hypoglossal rootlets in medullary slices of neonatal rats was recorded. 200μM NaHS (an H2S donor) increased burst frequency (BF) in 900-μm slices containing the pre-Bötzinger complex (preBötC), whereas it caused diphasic responses in 1200-, 1400- and 1800-μm slices containing both the preBötC and part or all of the parafacial respiratory group (pFRG): an initial decrease in BF followed by an increase. The initial decrease in BF was no longer observed after unilateral lesion of the pFRG region in the 1400-μm slices. In addition, BF was increased by a unilateral micro-injection of NaHS into the preBötC region, but was decreased by an injection into the pFRG region. These data support our hypothesis that the regulatory action of H2S on respiratory rhythm in the medulla oblongata is site-specific. The excitatory effect is caused by the preBötC, while the inhibitory effect is from the pFRG.

Characterization of the relationship between inspiratory neural discharges and the micturition reflex in decerebrate and urethane‐anesthetized adult in vivo rat

Previous studies have characterized respiratory neural outputs during the micturition reflex (MR). However, these studies primarily were conducted in cats, and it is not known if the relationship seen in the cat model is maintained in rodent models. To begin to address this issue, we recorded bladder pressure and phrenic (Phr), hypoglossal (XII) and pudendal motor nerve activity in decerebrate or urethane‐anesthetized vagi‐intact adult rats during passive bladder filling and active bladder contraction. Spontaneous MRs were elicited by slow infusion of saline into the bladder. The data show increased Phr post‐inspiratory activity and a transient increase followed by a transient decrease in burst frequency (due to changes in TE). Small XII neural discharges were observed during expiration while the bladder actively contracted. In contrast to cat data, no changes in Phr or XII amplitude were observed. Finally, while severe hypercapnia and hypocapnia affected respiratory patterns, they did not affect the MR. We conclude that, while there are some similarities to the cat model, a different relationship between respiration and micturition occurs in rat. Supported by HL63175

Cannabinoid receptor activation reverses kainate-induced synchronized population burst firing in rat hippocampus

Cannabinoids have been shown to possess anticonvulsant properties in whole animal models of epilepsy. The present investigation sought to examine the effects of cannabinoid receptor activation on kainic acid (KA)-induced epileptiform neuronal excitability. Under urethane anesthesia, acute KA treatment (10 mg kg−1, i.p.) entrained the spiking mode of simultaneously recorded neurons from random firing to synchronous bursting (% change in burst rate). Injection of the high-affinity cannabinoid agonist (-)-11-hydroxy-8-tetrahydrocannabinol-dimethyl-heptyl (HU210, 100 μg kg−1, i.p.) following KA markedly reduced the burst frequency (% decrease in burst frequency) and reversed synchronized firing patterns back to baseline levels. Pre-treatment with the central cannabinoid receptor (CB1) antagonist N-piperidino-5-(4-clorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant, SR141716A 3 mg kg−1, i.p.) completely prevented the actions of HU210. The present results indicate that cannabinoids exert their antiepileptic effects by impeding pathological synchronization of neuronal networks in the hippocampus.

Rhythm generation by the pre-Bötzinger Complex in medullary slice and island preparations: Effects of adenosine A1receptor activation

BackgroundThe pre-Bötzinger complex (preBötC) is a central pattern generator within the ventrolateral medulla oblongata's ventral respiratory group that is important for the generation of respiratory rhythm. Activation of adenosine A1 receptors (A1R) depresses preBötC rhythmogenesis. Although it remains unclear whether A1R activation is important for organisms in a normal metabolic state, A1R activation is important to the response of the preBötC to metabolic stress, such as hypoxia. This study examined mechanisms linking A1R activation to depression of preBötC rhythmogenesis in medullary slice and island preparations from neonatal mice.ResultsConverting medullary slices to islands by cutting away much of the medullary tissue adjacent to the preBötC decreased the amplitude of action potential bursts generated by a population of neurons within the preBötC (recorded with an extracellular electrode, and integrated using a hardware integrator), without noticeably affecting burst frequency. The A1R agonist N6-Cyclopentyladenosine (NCPA) reduced population burst frequency in slices by ca. 33% and in islands by ca. 30%. As in normal (drug-free) artificial cerebrospinal fluid (aCSF), NCPA decreased burst frequency in slices when GABAAergic or GABAAergic and glycinergic transmission were blocked, and in islands when GABAAergic transmission was antagonized. Converting slices to island preparations decreased synaptic input to inspiratory neurons. NCPA further decreased the frequency of synaptic inputs to neurons in island preparations and lowered the input resistance of inspiratory neurons, even when chemical communication between neurons and other cells was impeded.ConclusionTogether these data support the suggestion that depression of preBötC activity by A1R activation involves both decreased neuronal excitability and diminished inter-neuronal communication.

Blockade of GABA and glycine reuptake differentially affects temporal and spectral characteristics of phrenic nerve discharge in arterially‐perfused adult rat

Fast synaptic inhibition plays an essential role in control of the central respiratory network. Recently, we have shown that blockade of GABAA and glycine receptors in an arterially‐perfused adult rat preparation alters the temporal and spectral characteristics of phrenic nerve discharge and markedly reduces inspiratory network complexity. The influence of excess endogenous GABA and glycine on phrenic motor output, however, is not known. Therefore, we examined the effects of blockade of GABA and glycine reuptake using sarcosine (SAR; n=6) and nipecotic acid (NA; n=5), respectively, on phrenic nerve discharge in the same preparation. Perfusion with either reuptake blocker (100 mM) ultimately abolished phrenic nerve discharge; the effects of SAR resulted from a decrease in burst amplitude (P=0.0001) while those of NA resulted from a decrease in burst frequency (P=0.004). SAR and NA slightly enhanced MFO spectral power; however, HFO spectral power was differentially affected (i.e., SAR decreased; NA increased). Inspiratory network complexity (approximate entropy) was unchanged by SAR or NA. These data demonstrate that excess endogenous GABA and glycine differentially modulate the temporal and spectral characteristics of phrenic nerve discharge, providing additional evidence supporting separate and distinct roles for GABA and glycine in central respiratory neural control. Support: NS045321, NS049310