Neural regulation of respiration
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Neural regulation of respiration
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Neural regulation of respiration
- 2. Overview • Introduction • Phases of respiration and neural correlates • Rhythm generation Pre-Botzinger complex Lateral parafacial area Post inspiratory complex • Inspiratory/expiratory phase transition • Conceptual Model • Applied aspects
- 3. Muscles of respiration Alison McConnell, Respiratory Muscle Training; Theory and Practice. 2013 Muscles of inspiration Accessory Sternocleidomastoid Scalenes Anterior Middle posterior Principal External intercostals Diaphragm Muscles of expiration Quiet Breathing Expiration results from passive recoil of lungs and rib cage Active breathing Internal intercostals Rectus abdominis External oblique Internal oblique
- 4. D.W. Richter. Compr Human Physiol. 1996 Neural phases of respiration
- 5. Functional domains of Respiratory CPG
- 6. Thomas Lumsden J Physiol. 1923 Time tracing at 5 sec. intervals. Observation of respiratory centers in cats
- 7. Observation of respiratory centers in cats Gasping center Apneustic center Pneumotaxic center Thomas Lumsden J Physiol. 1923
- 8. Effect of Transections at different levels of brainstem Hlastala and Berger. Physiology of respiration.1996
- 9. Respiratory cell groups in rat brainstem Alheid & McCrimmon. Respiratory physiology & neurobiology.2008
- 10. Types of respiratory related neurons in brainstem Kazuhisa Ezure. Progress in Neurobiology. 1990
- 11. Smith et al. Trends Neurosci. 2013 Types of respiratory related neurons in brainstem
- 12. Different types of Neurotransmitters Alheid et al., Respir Physiol Neurobiol;2008
- 13. Defining the Neuronal Elements of a Rhythm-Generating Network Criteria: 1. Neuron or group of neurons must be active in phase with the rhythm 2. Neuron(s) need to reset the rhythm in a characteristic phase- dependent manner in response to a brief stimulus. Jan-Marino Ramirez and Nathan Baertsch. Physiology 2018
- 15. Prebotzinger complex- site for rhythmogenesis Smith et al. Science. 1991Integrated phrenic motneuron discharge rostral caudal Invitro neonatal rat brainstem preparation
- 16. Gray et al. Science. 1999 Neurokinin-1 receptor expressing neurons define the preBötC NK1R immunohistochemical expression Invitro rat medullary slice preparation
- 17. Discharge pattern of Pre-BotC NK1R neurons Guyenet and Wang. J Neurophysio. 2001 Model: anesthetized adult rats
- 18. Vann et al. eNeuro. 2018 PhotoInhibition PhotoStimulation Dbx1 neurons of prebotzinger complex Model: transgenic adult mice
- 19. Prebotzinger Complex in humans Schwarzacher et al. Brain. 2011
- 20. Parasagittal section of the brain stem after rostral to caudal serial transections Smith et al. J Neurophysiol. 2007 Model: insitu brainstem-spinal cord preparation, juvenile rats
- 21. Julian Paton. J of Neurosci Methods. 1996
- 22. Activity patterns of efferent nerves recorded after rostral to caudal serial transections of brainstem Smith et al. J Neurophysiol. 2007
- 23. Activity patterns of efferent nerves recorded after rostral to caudal serial transections of brainstem Smith et al. J Neurophysiol. 2007
- 24. Activity patterns of efferent nerves recorded after rostral to caudal serial transections of brainstem Smith et al. J Neurophysiol. 2007
- 25. Microcircuits with associated patterns of respiration Smith et al. J Neurophysiol. 2007
- 26. One-phase rhythm was abolished by blockade of persistent sodium current (INaP) Smith et al. J Neurophysiol. 2007
- 27. Distinct rhythm generator for expiration Janczewski and Feldman. J Physiol. 2006 control Fentanyl (30 µg/kg) Model: juvenile rats, postnatal day 7-13
- 28. Transection rostral & caudal to the facial nucleus Janczewski and Feldman. J Physiol. 2006 Rostral transection Caudal transection
- 29. Retrotrapezoid nucleus/parafacial respiratory group photostimulation Pagliardini et al. The Journal of Neuroscience. 2011 Model: adult rats
- 30. The post-inspiratory complex (PICO) area and neuronal activity Anderson et al. Nature 2016 Model: horizontal slice preparation, postnatal day P5–10 mice
- 31. Light stimulation of cholinergic cells evokes post-inspiratory activity Anderson et al. Nature 2016
- 32. Dutschmann & Herbert. European Journal of Neuroscience 2006 Inspiratory/expiratory phase transition (Inspiratory off-switch)
- 33. Dutschmann & Herbert. European Journal of Neuroscience 2006 Excitation or inhibition of Koliker-Fuse nucleus Model: juvenile rats, postnatal days 21-26
- 34. Dutschmann & Herbert. European Journal of Neuroscience 2006 Excitation or inhibition of Kolliker-Fuse nucleus
- 35. Dutschmann & Herbert. European Journal of Neuroscience 2006 Different types of respiratory neurons in dorsolateral pons
- 36. Pre-I/IEarly-I Early-I aug-I IE Post-I Post-I Late-I Inspiratory motoneurons Expiratory motoneurons aug-E Early-I Aug-E BotC Pre-BotC rVRG cVRG Morschel and Dutschmann Phil. Trans. R. Soc. B. 2009 Pontine respiratory group Medullary respiratory group Pontine-mediated IE phase transition
- 37. Emotional state and sleep wake cycle Prefrontal cortex Ant cingulate cortex Infralimbic cortex Hypothalamus Amygdala Periaquaductal gray Locus ceroleus Respiratory behaviours Vocalising, coughing Sighing, sniffing Non Respiratory behaviours Swallowing Emesis Dutschmann and Dick. Compr Physiol. 2012 Pons: center for integration of sensory inputs to modulate respiratory rhythm
- 38. 1) Swallow initiation in specific phases of the respiratory cycle 2) Arrest of respiratory airflow during swallow: “swallow–apnea” 3) Expiration and phase resetting following swallow Co-ordination of breathing and swallowing in humans Hardemark Cedborg et al. Exp Physiol. 2009
- 39. Production of pharyngeal swallowing and swallow-related breathing changes Bautista et al. Progress in Brain Research Vol. 212, 2014
- 40. Bautista and Dutschmann. J Physiol. 2014 KF nucleus contributes to inhibitory gating of spontaneous swallowing
- 41. Reduction in NK1R neurons of preBotzinger complex in multiple system atrophy patients Translational perspective
- 42. • Congenital central hypoventilation syndrome - Phox2b gene mutation that deletes neurons expressing this transcription factor in the RTN/pFRG • Rett syndrome - Swallowing/breathing dis-coordination due to synaptic imbalance along the nucleus of the solitary tract (NTS)–KF axis. Translational perspective
- 43. Jan-Marino Ramirez and Nathan Baertsch. Physiology 2018 Triple oscillators motor Premotor rVRG Premotor cVRG Inspiration ActiveExpiration Rhythm Pattern motor NTS RTN PRG
- 44. Thank you
Editor's Notes
- Cat. Tracings of various types of respiration in the cat. (a) normal, (b) after vagotomy, (c) prolonged inspiratory tonus (apneusis) and gasps after section of caudal pons (d) gasping. Time tracing at 5 sec. intervals. Inspiration upwards. Tracings from left to right. We have seen that after section above the striae acoustics the respiration consists essentially of a series of prolonged inspirations. It is convenient to have a term for these, and I speak of them as apneuses (a holding of the breath). Since apneuses do not occur when the extreme upper part of the pons is intact, there is in this region a centre which inhibits the activity of the apneustic centre and produces normal breathing. This may be called the pneumotaxic centre.
- Discharge patterns of representative types of VRC respiratory neurons in the rat, depicted over three breaths. The abbreviations, glu, gly, and GABA identify the excitatory or inhibitory fast amino acid transmitters (glutamate, glycine, GABA) used by these cells where they have been experimentally established (see text). In instances where the excitatory or inhibitory nature of a particular cell type has been inferred, but where the transmitter has not been established the cells are marked with + or − signs. In the chart higher action potential frequencies are represented by denser color coding in the temporal firing pattern. Note that most current models account for three phases in the respiratory cycle: Inspiration (I-red), early expiration (E1-light blue), late expiration (E2-dark blue). This is supported by the observation of subsets of expiratory neurons whose active phase of firing only occurs during the early or late phase of expiration under normal relaxed breathing (eupnea). Neuron types include those with decrementing (Dec), constant (Con), or augmenting firing patterns (Aug). Inhibitory E-Dec neurons are included at two levels to reflect the presence of similar inhibitory expiratory neurons rostrally and caudally in the VRC (in the BötC and in the cVRG, respectively). A complete taxonomy of the various neuronal types suggested in different labs, is not encompassed in this single figure, neither have we included alternative terminologies used to designate the neuron types depicted. It is also acknowledged that under various environmental regimens the pattern of firing for individual neuronal types appears to be mutable. Finally, the excitatory and inhibitory nature of the neuronal types depicted represents cells examined in the VRC. While comparable inspiratory and expiratory firing patterns are observed in dorsolateral pontine and NTS neurons, the excitatory and inhibitory transmitters used by these neurons are generally not well defined.
- Traces show integrated phrenic motoneuron population discharge on C4 spinal ventral roots after 75-μm sectioning in the rostral to caudal direction. The steady-state discharge shown is after sections made from the level of caudal facial nucleus through the caudal end of pre-Bötzinger Complex (1 through 11). Sections at the level of pre-Bötzinger Complex (sections 8 to 10) eliminated rhythmic motor output of all spinal and cranial (IX, X, XII) (not shown) respiratory motoneuron populations. (Bottom) A single 75-μm section through the rostral boundary of the preBötzinger Complex caused a reduction in cycle frequency and instabilities of the rhythm (that is, an increase in cycle-to-cycle variation of period). The mean cycle period in the experiment shown was 7.5 ± 0.4 s (n = 15 cycles) after sectioning just rostral to preBötzinger Complex and 11.1 ± 2.9 s after a single transection within this region.
- Discharge pattern of a pre-I neuron. From top to bottom: rectified and integrated phrenic nerve discharge (i-PND, arbitrary units), phrenic nerve discharge (PND; arbitrary units), extracellular single-unit activity, and instantaneous frequency of discharge of the unit. The pre-I latency of this neuron was 125 ms on average
- Using serially sectioned brainstems from 19 normal individuals and patients suffering from neurodegenerative diseases (multiple system atrophy,n = 10;), we have identified a circumscribed area of the ventrolateral medulla that represents the human homologue of the pre-Botzinger complex and have mapped its longitudinal and horizontal extents
- Hypothesized minimal architectures and components of pre-Bötzinger complex (pre-BötC)– Bötzinger complex (BötC) microcircuits with associated patterns of respiratory activity in different states of rhythmic pattern generation. It is postulated that the normal threephase respiratory pattern is generated by interconnected inhibitory (blue) populations forming a mutual inhibitory ring-like structure of early inspiratory (early-I), post-I, and augmenting expiratory (aug-E) neural populations that interacts with the excitatory (red) pre-I/I population within the pre-BötC. The latter consists of synaptically coupled glutamatergic neurons with local and bilateral interconnections. It is hypothesized that the normal operation of these circuits requires excitatory inputs or drives from the more rostral pontine circuits, and from the retrotrapezoid nucleus/parafacial respiratory group (RTN/ pFRG) and raphé nuclei (not shown). The three-phase pattern is depicted by a composite of integrated neuron population activities in BötC, pre-BötC, and rostral ventral respiratory group (rVRG) compartments (the latter is not shown in the schematic) and motor output patterns of phrenic (PN), hypoglossal (HN), and central vagus (cVN) nerves. Recordings depicted were obtained from arterially perfused in situ brainstem–spinal cord preparations from 4-week-old rats that generate a respiratory pattern similar to that in anesthetized juvenile or adult rats in vivo [13]. c,d The three-phase pattern is transformed to a twophase inspiratory–expiratory pattern lacking the post-I phase (d) after removing the pons via ponto–medullary transection (angled dashed line in c). This eliminates pontine excitatory drive required for generation of post-I activity (Box 1). It has been proposed that this two phase pattern involves mutual inhibitory interactions between active pre-BötC inspiratory and BötC expiratory neurons that also interact with pre-BötC excitatory pre-I/I neurons, as illustrated in c. e,f A medullary transection at the rostral pre-BötC boundary transforms the two-phase pattern to one-phase inspiratory oscillations driving all motor outputs. These onephase oscillations arise from intrinsic rhythmogenic mechanisms operating in the mutual excitatory network within the pre-BötC compartment (pre-I/I population; schematic in e), which is sufficient to drive inspiratory activity in the rVRG. This inspiratory activity, as well as the capability of more caudal structures to generate rhythmic motor output, is eliminated by a transection at the pre-BötC–rVRG boundary. Interestingly, the two-phase motor nerve discharges have a square wave-like burst profile (shown in d), whereas the one-phase pattern is strongly decrementing as indicated in f, both of which differ from the augmenting or ramping activity profiles in the normal three-phase pattern (b, bottom two traces). The onephase oscillatory pattern generated by the pre-BötC in situ is remarkably similar to the pattern generated by the pre-BötC isolated in neonatal rodent slices in vitro
- Top three traces, recordings of tidal volume (VT), genioglossus muscle electromyographic (EMGGG) and abdominal muscle electromyographic (EMGABD) activity. Bottom, timing bars indicating occurrence of inspiratory airflow (inspiration) and expiratory motor activity (EMGABD). A, control recording had all normal (I-E) cycles (i.e. cycles with inspiration and expiration). B, onset of quantal breathing as an occasional sequence of inspiration–expiration–expiration, i.e. E-only cycle (cycle without inspiration), is observed at 9 min after an initial dose of fentanyl (20 µg kg−1 S.C.). C, at 4 min after a supplemental dose of fentanyl (10 µg kg−1), there are more E-only cycles. Note split EMGABD bursts in I-E cycles, and single EMGABD burst in E-only cycles.
- A, breathing after transection at the level just rostral to the VII nucleus (dotted line, ‘rostral-t’ in C) in rats that spontaneously recovered from quantal pattern of breathing. B, breathing after transection marked as ‘caudal-t’ in C. Only this most caudal transection completely eliminated EMGABD
- Late expiratory neuron activated by RTN/pFRG photostimulation. A, Brief trains (20 Hz, 10 ms) of photostimulation activate RTN/pFRG neurons and recruits ABDEMG. Note interruption of inspiratory DIAEMG (arrow) on photostimulation with sudden recruitment of ABDEMG and expiratory neuron activity
- a, Two population electrodes were placed at the level of PiCo (black dot and trace) and contralateral preBötC (purple dot and trace) in a Chat-cre;Ai27 horizontal slice. Under spontaneous conditions (no NE), cholinergic neurons expressing channelrhodopsin-2 were light activated with a fiber optic (labeled ‘light’) placed over PiCo ipsilateral to the preBötC electrode. PiCo population bursts were triggered upon the onset of a 1.5 second light pulse while no bursts were light evoked in the preBötC (n=6). Figure shows 10 traces overlaid for each electrode with averaged traces below from a representative experiment. b, Photo-stimulating PiCo in adult anesthetized Chat-cre;Ai27 mice reliably triggers cVN bursts. Figure shows 10 traces overlaid with averages below of cVN and XII activity during a 200 ms light stimulation of PiCo
- (A) Simultaneous recordings from the phrenic nerve (PNA, upper trace) as an index for inspiratory activity and recurrent laryngeal nerve (RLNA, lower trace) as as index for the laryngeal motor outputs. Note the biphasic discharge pattern of the RLNA. The shading highlights the three phases of breathing as we defined and used it for data analysis: dark grey, inspiration (I); light grey, postinspiration (PI); and no shading for the late expiration (E2). (B) PNA and subglottal pressure recordings (SGP). The SGP trace can be used as an index for laryngeal resistance during the respiratory cycle. The shading highlights the three phases as in A. During inspiration, SGP always decreases owing to the activity of laryngeal abductor muscles while during postinspiration, SGP is increased owing to activity of laryngeal adductor muscles. From both traces, we analysed respiratory parameters such as total respiratory cycle length (Ttot), time of inspiration (Ti), time of postinspiration (Tpi), time of late expiration (Te2), and total expiratory duration (Te) including Tpi and Te2.
- Pattern of phrenic (PNA) and recurrent laryngeal nerve activity (RLNA) during the control situation prior to microinjections. Note the ramp-like discharge of PNA and the three-phase pattern of respiration displayed in RLNA, consisting of increasing discharge during inspiration, decreasing discharge in postinspiration, and lack of discharge in late expiration (B) Microinjection of glutamate evoked transient cessation of PNA accompanied by prolonged postinspiratory discharge in the RLN. This effect was defined as transient postinspiratory apnoea. (C) Subsequent injection of isoguvacine in the contralateral site using the same coordinates as for the ipsilateral injection disrupted the eupnoea-like control activity and established an apneustic breathing pattern that was characterized by a further decrease in breathing frequency and a four-fold longer inspiration, as indicated by PNA. The synchronized RLNA was indicative of a virtually abolished postinspiratory discharge of the RLNA
- Excitation or inhibition of postinspiratory laryngeal adductor activity illustrated with subglottal pressure recording. Control activity illustrating the dynamic changes of upper airway patency during the respiratory cycle. Owing to laryngeal abductor activity the upper airway resistance is decreased during the inspiratory phase (indicated by PNA). After inspiration, upper airway resistance was transiently increased due to the activity of laryngeal adductors. During the remaining expiratory phase, SGP levels gradually decreased to baseline level immediately prior to the start of the next inspiration. Effect of glutamate injection into the ipsilateral KF. Note the massive increase of SGP over the prolongation of the expiratory interval following glutamate injection (D) Isoguvacine injection at the contralateral site triggered an apneustic breathing pattern accompanied by absence of any postinspiratory-related upper airway constriction (G) Superimposed traces of the SGP during control (black) and after bilateral isoguvacine injection (red) underlining the absence of laryngeal adductor activity after transient lesion of the KF.
- Intracellular recording of an inspiratory neuron with a decreasing discharge Intracellular recordings of a postinspiratory neuron c) & d) Extracellular recordings of phase-spanning- type neurons. The neuron shown on the left-hand side discharged throughout the late expiratory and inspiratory phase (E-2 ⁄ I) but was consistently inhibited during early expiration. The neuron illustrated on the right-hand side spiked during inspiratory and very early expiratory phase but displayed inhibition during the remaining expiratory interval
- Swallow initiation occurs in the dorsal swallowing group, but it is gated such that swallows occur preferentially at certain points of the respiratory cycle. Parts of the respiratory CPG, including the dorsal respiratory group, may be involved in the latter. The swallow “command” is sent to the ventral swallowing group (VSG), which distributes the message to tongue, pharyngeal, and laryngeal muscles so that they contract/dilate in a sequential manner that propels the ingested material to the esophagus. At the same time, a command is sent to the Bo¨tzinger complex (BOT), specifically BOT E-DEC neurons to inhibit phrenic premotor neurons to minimize diaphragmatic contraction. The swallow command is sent also the dlPRG, which engages the medullary rCPG to restart respiration at expiration following swallow.
- Increased incidence of spontaneous swallows immediately after the second microinjection of isoguvacine into the right KF, bilateral microinjections of isoguvacine into the KF region causes apneusis The sw-CPG required to produce the oropharyngeal stage of swallow is gated under resting conditions in that it requires sensory or cortical commands to trigger swallowing
- Rett syndrome Patients exhibit prolonged breath-holds followed by late swallows upon oral presentation of liquids Disordered breathing and upper airway behaviours (including swallow) in Rett syndrome are closely linked to KF hyper-excitability caused by reduced GABAergic inhibition of KF neurons Aspiration pneumonia common in elderly patients and those with Alzheimer’s disease, Parkinsonism or fronto-temporal dementia