Hyperthermia Modulates Respiratory Pacemaker Bursting Properties

2004 ◽  
Vol 92 (5) ◽  
pp. 2844-2852 ◽  
Author(s):  
Andrew K. Tryba ◽  
Jan-Marino Ramirez
Keyword(s):  
Network Effects ◽  
Elevated Temperatures ◽  
Heat Stroke ◽  
Network Activity ◽  
Respiratory Neurons ◽  
Population Activity ◽  
Normal Body Temperature ◽  
Respiratory Network ◽  
Hyperthermic Response

Most mammals modulate respiratory frequency (RF) to dissipate heat (e.g., panting) and avoid heat stroke during hyperthermic conditions. Respiratory neural network activity recorded in an isolated brain stem-slice preparation of mice exhibits a similar RF modulation in response to hyperthermia; fictive eupneic frequency increases while inspiratory network activity amplitude and duration are significantly reduced. Here, we study the effects of hyperthermia on the activity of synaptically isolated respiratory pacemakers to examine the possibility that these changes may account for the hyperthermic RF modulation of the respiratory network. During heating, modulation of the bursting frequency of synaptically isolated pacemakers paralleled that of population bursting recorded from the intact network, whereas nonpacemaker neurons were unaffected, suggesting that pacemaker bursting may account for the temperature-enhanced RF observed at the network level. Some respiratory neurons that were tonically active at hypothermic conditions exhibited pacemaker properties at approximately the normal body temperature of eutherian mammals (36.81 ± 1.17°C; mean ± SD) and continued to burst at 40°C. At elevated temperatures (40°C), there was an enhancement of the depolarizing drive potential in synaptically isolated pacemakers, while the amplitude of integrated population activity declined. Isolated pacemaker bursting ceased at 41–42°C ( n = 5), which corresponds to temperatures at which hyperthermic-apnea typically occurs in vivo. We conclude that pacemaker properties may play an important role in the hyperthermic frequency modulation and apnea, while network effects may play important roles in generating other aspects of the hyperthermic response, such as the decreased amplitude of ventral respiratory group activity during hyperthermia.

scholarly journals Reconfiguration of the Pontomedullary Respiratory Network: A Computational Modeling Study With Coordinated In Vivo Experiments

2008 ◽  
Vol 100 (4) ◽  
pp. 1770-1799 ◽  
Author(s):  
I. A. Rybak ◽  
R. O'Connor ◽  
A. Ross ◽  
N. A. Shevtsova ◽  
S. C. Nuding ◽  
...  
Keyword(s):  
Computational Models ◽  
Ad Hoc ◽  
Large Body ◽  
Network Activity ◽  
Respiratory Pattern ◽  
Respiratory Neurons ◽  
Phase Switching ◽  
In Vivo Experiments ◽  
Respiratory Network

A large body of data suggests that the pontine respiratory group (PRG) is involved in respiratory phase-switching and the reconfiguration of the brain stem respiratory network. However, connectivity between the PRG and ventral respiratory column (VRC) in computational models has been largely ad hoc. We developed a network model with PRG-VRC connectivity inferred from coordinated in vivo experiments. Neurons were modeled in the “integrate-and-fire” style; some neurons had pacemaker properties derived from the model of Breen et al. We recapitulated earlier modeling results, including reproduction of activity profiles of different respiratory neurons and motor outputs, and their changes under different conditions (vagotomy, pontine lesions, etc.). The model also reproduced characteristic changes in neuronal and motor patterns observed in vivo during fictive cough and during hypoxia in non-rapid eye movement sleep. Our simulations suggested possible mechanisms for respiratory pattern reorganization during these behaviors. The model predicted that network- and pacemaker-generated rhythms could be co-expressed during the transition from gasping to eupnea, producing a combined “burst-ramp” pattern of phrenic discharges. To test this prediction, phrenic activity and multiple single neuron spike trains were monitored in vagotomized, decerebrate, immobilized, thoracotomized, and artificially ventilated cats during hypoxia and recovery. In most experiments, phrenic discharge patterns during recovery from hypoxia were similar to those predicted by the model. We conclude that under certain conditions, e.g., during recovery from severe brain hypoxia, components of a distributed network activity present during eupnea can be co-expressed with gasp patterns generated by a distinct, functionally “simplified” mechanism.

scholarly journals Imaging of respiratory-related population activity with single-cell resolution

2007 ◽  
Vol 292 (1) ◽  
pp. C508-C516 ◽  
Author(s):  
Frank Funke ◽  
Mathias Dutschmann ◽  
Michael Müller
Keyword(s):  
Single Cell ◽  
Neuronal Activity ◽  
Single Cells ◽  
Activity Patterns ◽  
Respiratory Rhythm ◽  
Network Activity ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Population Activity ◽  
Respiratory Network

The pre-Bötzinger complex (PBC) in the rostral ventrolateral medulla contains a kernel involved in respiratory rhythm generation. So far, its respiratory activity has been analyzed predominantly by electrophysiological approaches. Recent advances in fluorescence imaging now allow for the visualization of neuronal population activity in rhythmogenic networks. In the respiratory network, voltage-sensitive dyes have been used mainly, so far, but their low sensitivity prevents an analysis of activity patterns of single neurons during rhythmogenesis. We now have succeeded in using more sensitive Ca2+ imaging to study respiratory neurons in rhythmically active brain stem slices of neonatal rats. For the visualization of neuronal activity, fluo-3 was suited best in terms of neuronal specificity, minimized background fluorescence, and response magnitude. The tissue penetration of fluo-3 was improved by hyperosmolar treatment (100 mM mannitol) during dye loading. Rhythmic population activity was imaged with single-cell resolution using a sensitive charge-coupled device camera and a ×20 objective, and it was correlated with extracellularly recorded mass activity of the contralateral PBC. Correlated optical neuronal activity was obvious online in 29% of slices. Rhythmic neurons located deeper became detectable during offline image processing. Based on their activity patterns, 74% of rhythmic neurons were classified as inspiratory and 26% as expiratory neurons. Our approach is well suited to visualize and correlate the activity of several single cells with respiratory network activity. We demonstrate that neuronal synchronization and possibly even network configurations can be analyzed in a noninvasive approach with single-cell resolution and at frame rates currently not reached by most scanning-based imaging techniques.

Response of the Respiratory Network of Mice to Hyperthermia

2003 ◽  
Vol 89 (6) ◽  
pp. 2975-2983 ◽  
Author(s):  
Andrew K. Tryba ◽  
Jan-Marino Ramirez
Keyword(s):  
Neural Network ◽  
Heat Stroke ◽  
Brain Structures ◽  
Bath Temperature ◽  
Motor Nucleus ◽  
Temperature Modulation ◽  
Population Activity ◽  
Temperature Changes ◽  
Respiratory Network ◽  
Burst Amplitude

Most mammals modulate respiratory frequency (RF) to dissipate heat (i.e., panting) and avoid heat stroke during hyperthermic conditions. During hyperthermia, the RF of intact mammals increases and then declines or ceases (apnea). It has been proposed that this RF modulation depends on the presence of higher brain structures such as the hypothalamus. However, the direct effects of hyperthermia on the respiratory neural network have not been examined. To address this issue, the respiratory neural network [i.e., ventral respiratory group (VRG)] was isolated in a brain stem preparation taken from the medulla of mice (P0 –P6). Integrated population activity, predominated by inspiratory neurons, was recorded extracellularly from VRG neurons. The bath temperature was then heated from 30 to 40°C, resulting in a biphasic frequency response in VRG activity. Following an initial six- to sevenfold increase and subsequent decline, fictive RF was maintained at a frequency that was higher than baseline frequency; at 40°C, the RF was maintained at about two to four times that at 30°C. The inspiratory burst amplitude and duration were significantly reduced during hyperthermic conditions. An increase in RF and decrease in VRG burst amplitude and duration also occurred when heating from 37 to 40°C. Fictive apnea typically occurred during cooling to the control temperature. Furthermore, changes in hypoglossal motor nucleus activity paralleled those of the VRG, suggesting that temperature modulation of the VRG is likely to have a behaviorally relevant impact on respiration. We conclude that the VRG activity itself is modulated during hyperthermia and the respiratory network is particularly sensitive to temperature changes.

Functional Imaging Reveals Respiratory Network Activity During Hypoxic and Opioid Challenge in the Neonate Rat Tilted Sagittal Slab Preparation

2007 ◽  
Vol 97 (3) ◽  
pp. 2283-2292 ◽  
Author(s):  
Benjamin J. Barnes ◽  
Chi-Minh Tuong ◽  
Nicholas M. Mellen
Keyword(s):  
Functional Imaging ◽  
Respiratory Rhythm ◽  
Network Activity ◽  
Respiratory Neurons ◽  
Respiratory Network ◽  
Burst Amplitude ◽  
Single Unit Recordings ◽  
Parafacial Respiratory Group ◽  
Neonate Rat ◽  
Respiratory Networks

In mammals, respiration-modulated networks are distributed rostrocaudally in the ventrolateral quadrant of the medulla. Recent studies have established that in neonate rodents, two spatially separate networks along this column—the parafacial respiratory group (pFRG) and the pre-Bötzinger complex (preBötC)—are hypothesized to be sufficient for respiratory rhythm generation, but little is known about the connectivity within or between these networks. To be able to observe how these networks interact, we have developed a neonate rat medullary tilted sagittal slab, which exposes one column of respiration-modulated neurons on its surface, permitting functional imaging with cellular resolution. Here we examined how respiratory networks responded to hypoxic challenge and opioid-induced depression. At the systems level, the sagittal slab was congruent with more intact preparations: hypoxic challenge led to a significant increase in respiratory period and inspiratory burst amplitude, consistent with gasping. At opioid concentrations sufficient to slow respiration, we observed periods at integer multiples of control, matching quantal slowing. Consistent with single-unit recordings in more intact preparations, respiratory networks were distributed bimodally along the rostrocaudal axis, with respiratory neurons concentrated at the caudal pole of the facial nucleus, and 350 microns caudally, at the level of the pFRG and the preBötC, respectively. Within these regions neurons active during hypoxia- and/or opioid-induced depression were ubiquitous and interdigitated. In particular, contrary to earlier reports, opiate-insensitive neurons were found at the level of the preBötC.

Identification of Two Types of Inspiratory Pacemaker Neurons in the Isolated Respiratory Neural Network of Mice

2001 ◽  
Vol 86 (1) ◽  
pp. 104-112 ◽  
Author(s):  
Muriel Thoby-Brisson ◽  
Jan-Marino Ramirez
Keyword(s):  
Neural Network ◽  
Respiratory Rhythm ◽  
Network Activity ◽  
Pacemaker Activity ◽  
Patch Clamp Technique ◽  
Population Activity ◽  
Pacemaker Neurons ◽  
Whole Cell Patch Clamp ◽  
Respiratory Network ◽  
Bursting Activity

In the respiratory network of mice, we characterized with the whole cell patch-clamp technique pacemaker properties in neurons discharging in phase with inspiration. The respiratory network was isolated in a transverse brain stem slice containing the pre-Bötzinger complex (PBC), the presumed site for respiratory rhythm generation. After blockade of respiratory network activity with 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX), 18 of 52 inspiratory neurons exhibited endogenous pacemaker activity, which was voltage dependent, could be reset by brief current injections and could be entrained by repetitive stimuli. In the pacemaker group ( n = 18), eight neurons generated brief bursts (0.43 ± 0.03 s) at a relatively high frequency (1.05 ± 0.12 Hz) in CNQX. These bursts resembled the bursts that these neurons generated in the intact network during the interval between two inspiratory bursts. Cadmium (200 μM) altered but did not eliminate this bursting activity, while 0.5 μM tetrodotoxin suppressed bursting activity. Another set of pacemaker neurons (10 of 18) generated in CNQX longer bursts (1.57 ± 0.07 s) at a lower frequency (0.35 ± 0.01 Hz). These bursts resembled the inspiratory bursts generated in the intact network in phase with the population activity. This bursting activity was blocked by 50–100 μM cadmium or 0.5 μM tetrodotoxin. We conclude that the respiratory neural network contains pacemaker neurons with two types of bursting properties. The two types of pacemaker activities might have different functions within the respiratory network.

scholarly journals Inspiratory Off-Switch Mediated by Optogenetic Activation of Inhibitory Neurons in the preBötzinger Complex In Vivo

2021 ◽  
Vol 22 (4) ◽  
pp. 2019
Author(s):  
Swen Hülsmann ◽  
Liya Hagos ◽  
Volker Eulenburg ◽  
Johannes Hirrlinger
Keyword(s):  
Respiratory Rate ◽  
Respiratory Rhythm ◽  
Inhibitory Neurons ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Transgenic Mouse Line ◽  
Respiratory Network ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

The role of inhibitory neurons in the respiratory network is a matter of ongoing debate. Conflicting and contradicting results are manifold and the question whether inhibitory neurons are essential for the generation of the respiratory rhythm as such is controversial. Inhibitory neurons are required in pulmonary reflexes for adapting the activity of the central respiratory network to the status of the lung and it is hypothesized that glycinergic neurons mediate the inspiratory off-switch. Over the years, optogenetic tools have been developed that allow for cell-specific activation of subsets of neurons in vitro and in vivo. In this study, we aimed to identify the effect of activation of inhibitory neurons in vivo. Here, we used a conditional transgenic mouse line that expresses Channelrhodopsin 2 in inhibitory neurons. A 200 µm multimode optical fiber ferrule was implanted in adult mice using stereotaxic surgery, allowing us to stimulate inhibitory, respiratory neurons within the core excitatory network in the preBötzinger complex of the ventrolateral medulla. We show that, in anesthetized mice, activation of inhibitory neurons by blue light (470 nm) continuously or with stimulation frequencies above 10 Hz results in a significant reduction of the respiratory rate, in some cases leading to complete cessation of breathing. However, a lower stimulation frequency (4–5 Hz) could induce a significant increase in the respiratory rate. This phenomenon can be explained by the resetting of the respiratory cycle, since stimulation during inspiration shortened the associated breath and thereby increased the respiratory rate, while stimulation during the expiratory interval reduced the respiratory rate. Taken together, these results support the concept that activation of inhibitory neurons mediates phase-switching by inhibiting excitatory rhythmogenic neurons in the preBötzinger complex.

Tolfenamic Acid Prevents Amyloid β-induced Olfactory Bulb Dysfunction In Vivo

2018 ◽  
Vol 15 (8) ◽  
pp. 731-742 ◽  
Author(s):  
José M. Cornejo-Montes-de-Oca ◽  
Rebeca Hernández-Soto ◽  
Arturo G. Isla ◽  
Carlos E. Morado-Urbina ◽  
Fernando Peña-Ortega
Keyword(s):  
Olfactory Bulb ◽  
Amyloid Beta ◽  
Amyloid Β ◽  
Tolfenamic Acid ◽  
Network Activity ◽  
Protective Effects ◽  
Population Activity ◽  
Activity Inhibition

Background: Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. Objective: To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3β activity. Method: The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3β activation was evaluated with Western-blot. Results: Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3β activation and the protection against amyloid beta-induced olfactory dysfunction. Conclusion: Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

scholarly journals Robustness of respiratory rhythm generation across dynamic regimes

2019 ◽  
Author(s):  
Jonathan E. Rubin ◽  
Jeffrey C. Smith
Keyword(s):  
Central Pattern Generator ◽  
Dynamic Range ◽  
Computational Study ◽  
Dynamic Properties ◽  
Pattern Generator ◽  
Network Activity ◽  
Respiratory Neurons ◽  
Modeling Framework ◽  
Respiratory Network ◽  
Respiratory Central Pattern Generator

AbstractA central issue in the study of the neural generation of respiratory rhythms is the role of the intrinsic pacemaking capabilities that some respiratory neurons exhibit. The debate on this issue has occurred in parallel to investigations of interactions among respiratory network neurons and how these contribute to respiratory behavior. In this computational study, we demonstrate how these two issues are inextricably linked. We use simulations and dynamical systems analysis to show that once a conditional respiratory pacemaker, which can be tuned across oscillatory and non-oscillatory dynamic regimes in isolation, is embedded into a respiratory network, its dynamics become masked: the network exhibits similar dynamic properties regardless of the conditional pacemaker node’s tuning, and that node’s outputs are dominated by network influences. Furthermore, the outputs of the respiratory central pattern generator as a whole are invariant to these changes of dynamical properties, which ensures flexible and robust performance over a wide dynamic range.Author summaryBreathing movements in mammals are generated by brainstem respiratory central pattern generator (CPG) networks, which incorporate an excitatory oscillator located in the pre-Bötzinger Complex (preBötC) that can exhibit autorhythmic behavior. To understand how these autorhythmic properties impact CPG network dynamical performance, we performed computational studies with an established modeling framework to systematically analyze network behavior when the preBötC excitatory neurons’ intrinsic dynamics are tuned to operate in autorhythmic versus non-autorhythmic regimes. Both of these regimes enable rhythmic activity of the CPG network, and we show that the rhythm and its responses to various manipulations are preserved across the tunings of intrinsic properties of the preBötC component. Correspondingly, the emergence of behaviorally appropriate rhythmic patterns of network activity is maintained across preBötC regimes, accompanied by an expansion of the ranges of network output frequencies and amplitudes beyond those attainable with either preBötC regime alone. These results lead to the novel conclusion and concept that the dynamical operation of the CPG is functionally highly robust with respect to the rhythmogenic state of the preBötC excitatory circuits, which could represent a key property for preserved respiratory function across varying conditions and demands on network performance.

scholarly journals Network instability dynamics drive a transient bursting period in the developing hippocampus in vivo

2021 ◽  
Author(s):  
Jürgen Graf ◽  
Vahid Rahmati ◽  
Myrtill Majoros ◽  
Otto W. Witte ◽  
Christian Geis ◽  
...  
Keyword(s):  
Developmental Trajectories ◽  
Local Population ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Functional Coupling ◽  
Population Activity ◽  
Neuronal Synchrony ◽  
Underlying Network ◽  
Experimental Findings

Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying neuronal synchrony in the intact developing brain are largely unknown. Here, we use two-photon Ca2+ imaging to comprehensively map the developmental trajectories of spontaneous network activity in hippocampal area CA1 in vivo. We unexpectedly find that synchronized activity peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network synchrony reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for the emergence of neuronal synchrony. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration.

scholarly journals VIP+ interneurons control neocortical activity across brain states

2016 ◽  
Vol 115 (6) ◽  
pp. 3008-3017 ◽  
Author(s):  
Jesse Jackson ◽  
Inbal Ayzenshtat ◽  
Mahesh M. Karnani ◽  
Rafael Yuste
Keyword(s):  
Neural Activity ◽  
Visual Stimulation ◽  
Network Activity ◽  
Local Network ◽  
Population Activity ◽  
Cell Class ◽  
Brain States ◽  
The Mean ◽  
Mouse Visual Cortex

GABAergic interneurons are positioned to powerfully influence the dynamics of neural activity, yet the interneuron-mediated circuit mechanisms that control spontaneous and evoked neocortical activity remains elusive. Vasoactive intestinal peptide (VIP+) interneurons are a specialized cell class which synapse specifically on other interneurons, potentially serving to facilitate increases in cortical activity. In this study, using in vivo Ca2+ imaging, we describe the interaction between local network activity and VIP+ cells and determine their role in modulating neocortical activity in mouse visual cortex. VIP+ cells were active across brain states including locomotion, nonlocomotion, visual stimulation, and under anesthesia. VIP+ activity correlated most clearly with the mean level of population activity of nearby excitatory neurons during all brain states, suggesting VIP+ cells enable high-excitability states in the cortex. The pharmacogenetic blockade of VIP+ cell output reduced network activity during locomotion, nonlocomotion, anesthesia, and visual stimulation, suggesting VIP+ cells exert a state-independent facilitation of neural activity in the cortex. Collectively, our findings demonstrate that VIP+ neurons have a causal role in the generation of high-activity regimes during spontaneous and stimulus evoked neocortical activity.

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