Modulation of the synaptic drive to respiratory premotor and motor neurons1

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Abstract

The characteristics of GABAergic inhibitory modulation of respiratory bulbospinal neuronal activity and short-term potentiation (STP) of phrenic motoneuronal activity were studied. Extracellular unit recording and picoejection techniques in anesthetized dogs showed that both the spontaneous rhythmic and reflexly induced discharge patterns of inspiratory (I) and expiratory (E) premotor neurons were proportionately amplified by the localized application of picomole amounts of bicuculline (Bic), a competitive GABAA antagonist. Intracellular recording and paired-pulse stimulation techniques in anesthetized rats demonstrated an STP of phrenic motor output that appears to be mediated by NMDA receptors and is associated with facilitation of EPSPs and prolonged depolarization of individual phrenic motoneurons. We speculate that both GABAergic gain modulation of premotor neuronal activity and NMDA-mediated STP of phrenic activity may be neural substrates which are involved with the optimization of respiratory and non-respiratory behaviors, via adaptive and/or differential control of breathing.

Introduction

Recently, there has been increasing recognition that many forms of physiological regulation cannot be explained solely on the basis of simple feedback or feedforward reflex control. During exercise-induced hyperpnea, for example, there is little change in PaCO2 from resting values. Even when a small increment in respiratory dead space increases the respiratory challenge during exercise, the exercise ventilatory response increases proportionately in goats and humans, thereby maintaining PaCO2 regulation with respect to its resting level (Mitchell, 1990, Poon et al., 1992).

The ability of the respiratory controller to adapt to various physiological conditions can be mimicked by models incorporating a process of self-tuning adaptive control, in which the respiratory controller adaptively adjusts the controller gain in order to minimize the energy and chemical homeostasis costs of breathing (Poon, 1996a). Since several types of ventilatory adaptation occur with minimal change in respiratory frequency, Mitchell et al. (1984) proposed that respiratory motoneurons could have a central role in this adaptive response. Increases in the excitability of spinal respiratory motoneurons, together with gain changes at the level of the bulbospinal premotor neurons, could result in greater motor output and ventilatory effort for a given stimulus.

The studies outlined in this report provide evidence for the existence of modulation of the excitability of bulbospinal inspiratory (I) and expiratory (E) neurons, as well as the short term potentiation of synaptic responses in motoneurons. Specifically, a potent GABAergic gain control mechanism regulates the excitability of bulbospinal neurons in a manner that multiplicatively modulates their discharge rate. In addition, activation of NMDA receptors on phrenic motoneurons increases their excitability and may contribute to STP of phrenic motor output.

Section snippets

General

Experiments were performed on mongrel dogs (8–15 kg). Halothane anesthesia (1.0–1.4% end-tidal concentration) was used during the surgical preparation, while thiopental sodium was used for induction of anesthesia (15 mg/kg i.v.) and during the experimental protocol (8–12 mg/kg/h i.v.). Animals were monitored for signs of inadequate anesthesia, including salivation, lacrimation, and/or increases in blood pressure or heart rate. The anesthetic depth was increased if such signs were present. Dogs

Respiratory premotor neurons in dogs: Gain modulation

Gain modulation is defined as a multiplicative process whereby the output discharge frequency of a neuron, Fo(t), is the product of its underlying neuronal discharge frequency, Fi(t) (i.e. the discharge frequency in the absence of the modulatory input), and a modulation coefficient, (1−α). In the general case where the modulatory input tonically inhibits the underlying discharge of the neuron, gain modulation will produce an output that is an attenuated, proportional replica of the underlying

Discussion

Earlier views held that motor neurons and their immediate premotor drives were essentially follower neurons, able to integrate a variety of motor and afferent inputs but exhibiting little ability for modifying their excitability and hence current-response relationships. However, recent work has shown that both respiratory (c.f. Berger and Bellingham, 1995) and nonrespiratory motoneurons (e.g. Hounsgaard and Kiehn, 1989, Berger and Takahashi, 1990) are capable of considerable modulation of their

Acknowledgements

The authors express their appreciation to Jack Tomlinson for his excellent technical assistance. This work was supported by NIH grant HL40336, The Department of Veterans Affairs Medical Research Funds and the Department of Anesthesiology of the Medical College of Wisconsin, Milwaukee.

References (30)

  • P.K. Gill et al.

    Properties of phrenic motoneurones

    J. Appl. Physiol.

    (1963)
  • A. Haji et al.

    Evidence that glycine and GABA mediate postsynaptic inhibition of bulbar respiratory neurons in the cat

    J. Appl. Physiol.

    (1992)
  • F. Hayashi et al.

    Time-dependent phrenic nerve responses to carotid afferent activation: Intact vs. decerebellate rats

    Am. J. Physiol.

    (1993)
  • E.J. Heyer et al.

    Bicuculline: A convulsant with synaptic and nonsynaptic actions

    Neurology

    (1981)
  • Hille, B., 1984. Potassium channels and chloride channels. In: Ionic Channels of Excitable Membranes. Sinauer...
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