The increase in ventilation during acute exposure to hypoxia is termed the hypoxic ventilatory response (HVR) and is the reflex response to hypoxic stimulation of carotid body chemoreceptors. Ventilatory acclimatisation to hypoxia (VAH) includes the time-dependent increase in the HVR that occurs during hours to weeks of hypoxic exposure. Two major mechanisms have been described to explain the increase in the HVR during chronic hypoxia. First, the sensitivity of the carotid body glomus cells, to oxygen, increases during chronic hypoxia. Second there is an increase in the CNS responsiveness to afferent input from the carotid body.
Afferent fibres from the O2-sensing glomus cells of the carotid body report to the brain via the carotid sinus nerve whose afferents project to the nucleus of the solitary tract (NTS). In turn, the NTS contains neurons that project to the phrenic motor nucleus (the phrenic nerve innervates the diaphragm) and premotor neurons that project to the VRG. Several recent studies have indicated an important role for both NMDA and non-NMDA glutamatergic receptors within the NTS, in the regulation of breathing under hypoxic conditions (low inspired O2).
Current Studies
The major focus of my current research is to examine central mechanisms involved in regulating the hypoxic ventilatory response before and after acclimatisation to chronic hypoxia. Currently I am focusing on NMDA and non-NMDA mediated glutamatergic processes in the NTS with future plans to also examine GABAergic processes in both the NTS and VRG. The overall hypothesis of this research is that chronic hypoxia alters amino acid neurotransmission in the NTS and VRG. Currently I am focusing on three studies related to hypoxic changes in NMDA-mediated processes in the NTS.
1. The effects of chronic hypoxia on the hypoxic ventilatory response (HVR) following systemic administration of an NMDA-receptor channel blocker, MK 801.
2. The effects of chronic hypoxia, on the HVR, following direct application of MK 801 (± DNQX, a non-NMDA receptor antagonist) into the caudal NTS via cannula implanted into the brainstem (caudal NTS).
3. The effects, on the HVR, of chronic administration of MK 801 into the NTS (with Alzet brain infusion pumps). This study aims to separate the effects of increased neural activity (i.e. increased glutamatergic neurotransmission) from the direct effects of low O2 (presumably mediated by HIF (hypoxia inducible factor) activated processes).
Chronic hypoxia (10% inspired O2) is induced in a hypobaric chamber that is constantly ventilated with room air and can regulate internal pressure between 225 to 760 mmHg. In awake animals, the HVR is measured using the whole body method of plethysmography comparing acute hypoxic and hyperoxic challenges from the basal level of inspired O2. In anaesthetised preparations the central nervous system (CNS) gain of the HVR is quantified as the change in phrenic nerve output for a given level of stimulation of the carotid sinus nerve. Cannula for both acute and chronic administration of MK801 are placed into the NTS using stereotaxic procedures.
Figure 1 illustrates the effects of acute hypoxia (step change from 30% to 10% inspired O2) on tidal volume (the volume of each breath) in rats exposed to 1 week of chronic hypoxia. This data suggests that MK801 has a greater effect on the HVR following chronic hypoxia and is consistent with the hypothesis that chronic hypoxia causes an up-regulation of glutamatergic neurotransmission in the nucleus of the solitary tract.
Future Studies
Changes in ventilation and the HVR during chronic hypoxia can be viewed as changes in "offset" and "gain", respectively, using a control system approach to ventilatory chemoreflexes. The increase in ventilation in normoxia (or hyperoxia), with minimal afferent input from arterial chemoreceptors, represents an offset in ventilatory drive. The increase in the slope of the HVR (i.e. the increase in ventilation per unit increase in hypoxic stimulation of arterial chemoreceptors) represents an increase in the sensitivity, or gain, of the reflex. Similar changes in offset and gain have been described for respiratory neurons in the medulla. Specifically, glutamate modulates the absolute frequency of action potentials in an additive fashion without changing the sensitivity of discharge frequency to the level of stimulus input (i.e. glutamate modulates the offset of neural activity). In contrast, GABA modulates the sensitivity of discharge frequency to the level of stimulus input in a multiplicative fashion (i.e. GABA modulates the gain of the system) so GABA effects are proportional to the level of stimulus input.
Future studies will address the overall hypothesis that a GABAergic mechanism of gain modulation occurs in the NTS and other respiratory centers such as the VRG, and that changes in GABAergic neurotransmission in the NTS during chronic hypoxia contribute to ventilatory acclimatisation to hypoxia. Studies will focus on changes in GABAergic transmission similar to those outlined above as well as changes in gene expression for different GABA receptor subunits. Ultimately this hypothesis must be tested on single cells from the NTS where membrane potential and cellular currents are measured in response to GABA agonists and antagonists.
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