Abstract
Chronic hypoxia increases the hypoxic ventilatory response (HVR) in awake humans and animals [1] and we have shown that this involves changes in the gain of the The ventilatory or phrenic nerve response to pharmacological stimulation of carotid bodies or electrical stimulation of the carotid sinus nerve is significantly increased in awake and anesthetized rats, respectively, after 2–7 days at PIO2 = 74 Torr [2]. We hypothesize that changes in neurotransmitters and their receptors along the HVR reflex pathway, and specifically in the nucleus tractus solitarius (NTS), increase the CNS gain of the HVR during chronic hypoxia. Previously we found that dramatic time-dependent changes in dopaminergic neurotransmission occur in the NTS during chronic hypoxia but they cannot explain the changes in the HVR [2]. Now we are testing the hypothesis that NMDA receptors in the NTS are necessary for the increased CNS gain of the HVR during chronic hypoxia. We previously reported no significant changes in mRNA for NMDA-R1 receptors during 7 days of hypoxia [3] but further experiments are planned to quantify changes in actual receptor protein. In awake unrestrained rats held in normoxic conditions (n = 6), chronic administration of a non-competitive NMDA receptor antagonist to the caudal NTS (25 μL/hr of MK-801 for 7 days via an Alzet miniosmotic pump) did not significantly change the HVR measured with barometric pressure plethysmography after 2 or 7 days of treatment. This is in contrast to the decrease in the HVR observed by other laboratories performing acute microinjections of MK-801 to the NTS [4]. However, acute systemic injections of MK-801 (3 mg/kg ip.) decreased the HVR in our laboratory (n = 8) in agreement with published results [5]. These results suggest time-dependent changes in glutamate neurotransmission with chronic blockade of NMDA receptors and we are testing this by repeating experiments using acute microinjections of MK-801. Experiments with acute or chronic blockade of NMDA receptors after chronic hypoxia will be compared with the former results to determine the independent effects of hypoxia versus NMDA receptor activation on the CNS gain of the HVR. Future experiments will investigate the role of GABA in determining the CNS gain of the HVR. Chronic hypoxia changes mRNA levels for GABA-R1α [3] and GABA is reported to modulate the gain of preinspiratory bulbospinal neuron responsiveness to other neural inputs [6]. This change in gain instead of set point is similar to that observed for the HVR during chronic hypoxia.
Highlights
To be effective, inspiratory muscles on the left and right sides must contract together
We have found that a prominent gap in the column of ventral respiratory group (VRG) The nucleus tractus solitarii (NTS) relays information from primary related parvalbumin cells [2] likely corresponds to the pBc since visceral receptors to the central nervous system and is critically parvalbumin cells are rare in this zone and never co-localize with involved in the reflex control of autonomic functions
The specific protein(s) necessary for longterm facilitation (LTF) is unknown, we recently found that episodic hypoxia and LTF are associated with elevations in ventral spinal concentrations of brain derived neurotrophic factor (BDNF)
Summary
Inspiratory muscles on the left and right sides must contract together. The left and right halves of the diaphragm are synchronised because a bilateral population of medullary premotor neurones [1] simultaneously excites left and right phrenic motoneurones. Transection studies demonstrate that each side of the brainstem is capable of generating respiratory rhythm independently [2], so that left and right medullary inspiratory neurones must themselves be synchronised. The interconnections and common excitation that accomplish such synchronisation are unknown in rats. The respiratory rhythm of hypoglossal (XII) nerve discharge in transverse medullary slice preparations from neonatal rats is thought to originate in the region of the ventral respiratory group (VRG); generated there by a combination of “pacemaker” neurones [1] and their interactions with other respiratory neurones. Our goal was to discover interconnections between left and right VRG neurones as well as their connections to XII motoneurones
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