Central Rhythm Generation and Spinal Integration
1990; Elsevier BV; Volume: 97; Issue: 3 Linguagem: Inglês
10.1378/chest.97.3_supplement.45s-a
ISSN1931-3543
Autores Tópico(s)Sleep and Wakefulness Research
ResumoOver the last decade there have been several comprehensive reviews concerning the neural mechanism of breathing, and the reader is referred to these 1 Wyman RJ. Neural generation of the breathing rhythm. Ann Rev Physiol. 1977; 39: 417-448 Crossref PubMed Scopus (64) Google Scholar , 2 Cohen MI. Neurogenesis of respiratory rhythm in the mammal. Physiol Rev. 1979; 69: 1105-1173 Google Scholar , 3 Long SE Duffin J. The medullary respiratory neurones: a review. Can J Physiol Pharmacol. 1984; 62: 161-187 Crossref PubMed Scopus (31) Google Scholar , 4 von Euler C. Brain stem mechanisms for generation and control of breathing pattern. in: Cherniak N Widdicombe JG. Handbook of physiology. 2. American Physiological Society, Bethesda1986: 463-524 Google Scholar , 5 Feldman JL. Neurophysiology of respiration in mammals. in: Bloom FE Handbook of physiology, vol 4. The nervous system. 4. American Physiological Society, Bethesda1986: 463-524 Google Scholar for details of recent advances in respiratory neurophysiology utilizing electrophysiologic, biophysical, anatomic, pharmacologic, and histochemical techniques. For those with a major interest in other aspects of respiratory physiology and medicine, the vast amount of information concerning the generation of the respiratory rhythm presents a bewildering array of facts, in which are embedded difficult if not obscure concepts whose roots lie in more remote aspects of neuroscience. In this lecture I propose only to discuss these concepts in a very general way. It is still not known how the mammalian respiratory rhythm is generated; I also believe that hypotheses of how it might be generated should be regarded as complementary, rather than exclusive, each serving to illuminate certain aspects of mechanism and control but not accounting for all. Indeed, that has been the problem created by those who believe they could define and localize a "respiratory center" that does everything of this nature. Commencing with the work of LeGallois 6 Legallois CJJ. Experiences sur le principe de la vie, notamment sur celui des mouvements du coeur, et sur le siege de ce principe. D'Hautel, Paris1812 Google Scholar at the turn of the last century, the investigation of the nervous mechanism of breathing has the longest history of all with regard to research on the neural origin of rhythmic movements. In research on vertebrates, such movements include all aspects of locomotion (eg, walking, running, swimming, flight, mastication, scratching, etc), while that on invertebrates includes, for example, the nervous control of flight (insect), heartbeat (leech), the pyloric rhythm for propelling and filtering food (lobster), and escape swimming activity (Tritonia). It is from the relatively simple central nervous systems of invertebrates, in which each ganglion often contains only 100-200 neurons, that the deepest insights have been obtained about the basis of neuronal rhythmicity in relation to motor behavior. Even in these systems, such as those of Tritonia, where the minimal neural circuitry necessary to sustain the swimming rhythm consists of as few as 12 interneurons, the possible number of monosynaptic connections alone among them is 132, of which apparently 79 have been identified 7 Getting PA. Comparative analysis of invertebrate central pattern generators. in: Cohen AH Rossignol S Grillner S. Neural control of rhythmic movements in vertebrates. John Wiley & Sons, New York1988: 101-127 Google Scholar Again, it was research on invertebrate systems that led to the introduction of the term "central pattern generator" (CPG) to describe the central nervous mechanism(s) responsible for a given pattern of rhythmic motor behavior. As this description also has been adopted by many workers in the field of vertebrate respiratory neurophysiology, indeed displacing the controversial but historic use of the term "respiratory center," which traditionally includes the process of rhythm generation, some discussion of its origins is necessary. As defined by Getting, 7 Getting PA. Comparative analysis of invertebrate central pattern generators. in: Cohen AH Rossignol S Grillner S. Neural control of rhythmic movements in vertebrates. John Wiley & Sons, New York1988: 101-127 Google Scholar "a central pattern generator is viewed as an assembly of neurones which, by virtue of their intrinsic properties and synaptic interactions is capable of generating and controlling the spatial and temporal activity of motor neurones." Work in the early 1960s had shown that stimulation of a single (command) neuron in the nerve cord of the crayfish could elicit a completely coordinated behavior, 8 Wiersma CAG Ikeda K. Interneurones commanding swimmeret movements in the crayfish, Procambarus clarkii (Girard). Comp Biochem Physiol. 1964; 12: 509-525 Crossref PubMed Scopus (77) Google Scholar the behavior itself being governed by the motor network, ie, a CPG. 9 Kennedy P. Control of motor output. in: Stein RB Pearson KG Smith RS Redford JB. Control of posture and locomotion. 7. Plenum Press, New York1973: 429-436 Google Scholar Subsequent research has been preoccupied with identifying the membrane properties of single neurons and their inhibitory and excitatory connections, both within and between individual ganglia. In this way, it has been established that neurons within a small number of ganglia (2–4) generally provide the minimal neural substrate for rhythm generation. Interestingly, related research on locomotion in lower vertebrates has shown that as few as 5 consecutive segments of the completely isolated lamprey spinal cord can generate patterned motor discharges (fictive swimming) corresponding to the natural swimming movements of lateral body undulation, 10 Cohen AH Wallen P. The neuronal correlate of locomotion in fish. "Fictive swimming" induced in an in-vitro preparation of the lamprey spinal cord. Exp Brain Res. 1980; 41: 11-18 Crossref PubMed Scopus (262) Google Scholar while in the tadpole analogous coordinated rhythmic motor discharges can persist in the isolated and longitudinally divided spinal cord. 11 Roberts A Soffe SR Dale N. Spinal interneurones and swimming in frog embryos. in: Grillner S Stein PSG Stuart DG Forssberg H Herman RM. Neurobiology of vertebrate locomotion. Macmillan, London1986: 279-306 Google Scholar In these studies on the notionally simpler nervous systems of invertebrates, the experimental approach has sought either (1), to define "pacemaker" neurons whose discharge timing might account for the rhythm of the motor behavior of the system as a whole, this being the case for the "burster" interneurons of the stomatogastric ganglia that control lobster feeding movements but which nevertheless work cooperatively with a network; 12 Silverston AI Miller JP Wadepuhl M. Cooperative mechanisms for the production of rhythmic movements. in: Roberts A Roberts BL. Neural origin of rhythmic movements. Cambridge University Press, Cambridge1983: 55-88 Google Scholar or (2) to define a network of neurons whose intrinsic membrane properties and connectivity collectively provide the phase shifts and feedback necessary to sustain rhythm generation, as occurs in Tritonia. 7 Getting PA. Comparative analysis of invertebrate central pattern generators. in: Cohen AH Rossignol S Grillner S. Neural control of rhythmic movements in vertebrates. John Wiley & Sons, New York1988: 101-127 Google Scholar There, three groups of interneurons have been identified and designated premotor, none of which alone can generate bursting activity but each of which is essential to the generation of the rhythmic patterned motor output. In this usage "premotor" signifies a group of interneurons that both generates the rhythm and feeds this as an input to the motoneurons. However, as discussed later, in the respiratory literature "premotor" has come to signify as providing the input to motoneurons, but not one of participation in the process of rhythm generation itself. Proof of such a distinction is extremely difficult to provide in the mammalian CNS. 3 Long SE Duffin J. The medullary respiratory neurones: a review. Can J Physiol Pharmacol. 1984; 62: 161-187 Crossref PubMed Scopus (31) Google Scholar However, further important advances can be expected from the use of the isolated brain-stem-spinal cord preparations that exhibit stable neuronal bursts of motor activity corresponding to the respiratory rhythm. 13 Suzue T. Respiratory rhythm generation in the in-vitro brain stem-spinal cord preparation of the neonatal rat. J Physiol (Lond). 1984; 354: 173-183 Crossref Scopus (438) Google Scholar Indeed, Onimaru, Arata, and Homma 14 Onimaru H Arata A Homma I. Primary respiratory rhythm generator in the medulla of brainstem-spinal cord preparation from newborn rat. Brain Res. 1988; 445: 314-324 Crossref PubMed Scopus (140) Google Scholar have recently shown that the preinspiratory neurons (pre-1), whose phasic discharge precedes that of the C4 (phrenic) discharge, play an essential role in rhythm generation in these preparations; and such activity persists when both Cl-dependent (inhibitory) synaptic inputs are blocked 15 Onimaru H Arata A Homma I. Inhibitory synaptic inputs to respiratory rhythm generator in medulla isolated from newborn rats. J Physiol Soc Jpn. 1988; 50: 584 Google Scholar and in solutions of low Ca2+ and high Hg2+ when all chemically mediated synaptic actions are blocked. These authors conclude that, in the newborn rat, respiratory rhythm generation is probably due to a chemical synapse-based neuronal network that functions through endogenous preinspiratory pacemaker (burster) neurons. 16 Onimaru H Arata A Homma I. Firing properties of respiratory rhythm generating neurons in the absence of synaptic transmission in rat medulla in vitro. Exp Brain Res. 1989; 76: 530-536 Crossref PubMed Scopus (121) Google Scholar This result provides the first clear evidence for the possible essential role of "pacemaker" neurons in the generation of the respiratory rhythm, although the bursting "decrescendo" pattern instead of the more usual augmenting one of the motor output, as illustrated by Feldman and collaborators, 17 Feldman JL Smith JC McCrimmon DR Ellenberger HH Speck DF. Generation of respiratory pattern in mammals. in: Cohen AH Rossignol S Grillner S. Neural control of rhythmic movements in vertebrates. John Wiley & Sons, New York1988: 73-100 Google Scholar for example, will doubtless excite much discussion over the normality of rhythm generation in these reduced but important preparations. An important aspect of most of the invertebrate systems studied is the presence of reciprocal inhibition between 2 groups of neurons, although this property alone does not provide the basis for continuous rhythm generation. Nevertheless, it is worth noting here that reciprocally phased inhibition of particular categories of interneuron (e-I and p-I) forms an essential feature of the neural mechanism proposed for respiratory rhythm generation in the mammal by Richter and his colleagues. 18 Richter DW. Generation and maintenance of the respiratory rhythm. J Exp Biol. 1982; 100: 93-107 Crossref PubMed Google Scholar ,19 Richter DW Ballantyne D Remmers JE. How is the respiratory rhythm generated? A model. NIPS. 1986; 1: 109-112 Google Scholar This model, drawing as it does on the measured intrinsic membrane properties of different categories of interneurons, the nature of the synaptic modulation of membrane potential, as well as the firing patterns of the putative neuronal elements of the rhythm-generating machinery in intact preparations, provides the most penetrating insight thus far on how the mammalian respiratory rhythm might be generated. Before giving a summary of Richter's position, it is necessary to discuss the different kind of model, hybrid in nature, formulated by von Euler and collaborators, which embodies concepts that relate to various aspects of the control of the respiratory CPG (respiratory rate, inspiratory time, expiratory time, reflex control, etc) and a global scheme of interaction between 3 hypothetical sets of neurons whose serial connectivity and proposed functional operation determine rhythm generation. 4 von Euler C. Brain stem mechanisms for generation and control of breathing pattern. in: Cherniak N Widdicombe JG. Handbook of physiology. 2. American Physiological Society, Bethesda1986: 463-524 Google Scholar ,20 Bradley GW von Euler C Martilla I Roos B. A model of the central and reflex inhibition of inspiration in the cat. Biol Cybern. 1975; 19: 105-116 Crossref PubMed Scopus (147) Google Scholar ,21 von Euler C. On the central pattern generator for the basic breathing rhythmicity. J Appl Physiol Respirat Environ Exercise Physiol. 1983; 55: 1647-1659 PubMed Google Scholar
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