Biomedical subjects

Jasna Saponjic

Publications and source records attributed to Jasna Saponjic.

7 recordsLinked to original sources

PubMed2006

Effects of intertrigeminal region NMDA and non-NMDA receptors on respiratory responses in rats.

Respiratory disturbance, including apnea, can be induced by microinjection of glutamate into the intertrigeminal region (ITR) of the lateral pons, a region that is anatomically coupled to both the dorsal and ventral respiratory groups of the medulla. We showed that the ITR plays a functional role in regulating both vagal reflex apnea and spontaneous sleep-related apnea in rats, but the mechanisms have not been determined. This study shows that functional NMDA receptors are expressed in the ITR since the blockade of these receptors by AP5, a specific NMDA receptor antagonist, was fully effective in blocking apnea induced by glutamate injection within this region. Selective blockade of ITR NMDA receptors had no effect on the immediate apnea evoked by an intravenous 5-HT bolus, whereas the nonspecific glutamate receptor antagonist kynurenic acid significantly increased the duration of this vagal reflex apnea. These findings are of interest because pontine NMDA receptors participate in inspiratory off-switch mechanisms and have been implicated in various short- and long-term potentiation and depression phenomena. These data support the involvement of ITR non-NMDA receptors in modulation of reflex apnea per se, whereas NMDA receptors play a role in damping respiratory responses to transient disturbances.

2-Amino-5-phosphonovalerate↗

PubMed2006

Modulation of respiratory pattern and upper airway muscle activity by the pedunculopontine tegmentum: role of NMDA receptors.

The pedunculopontine tegmental nucleus (PPT) is postulated to have important functions relevant to the regulation of rapid eye movement (REM) sleep and arousal, and various motor control systems including respiration. We have recently shown that pharmacologic activation of a neuronal subpopulation within the PPT, induced by micropipette injection of glutamate in nanoliter volumes, can produce respiratory rhythm disturbances and changes in genioglossus muscle activity in anesthetized rats. The aim of this study was to determine whether the respiratory pattern disturbance and increased genioglossus muscle tone induced by glutamate injection within the PPT are mediated by activation of N-methyl-D-aspartate (NMDA) receptors within the PPT. Experiments were performed in eight adult male spontaneously breathing Sprague-Dawley rats anesthetized using nembutal. Respiratory movements were monitored by piezoelectric strain gauge. Three-barrel glass pipettes were used to pressure inject glutamate (as a probe for respiratory modulating sites), ketamine (an NMDA channel blocker), and oil-red dye (to aid in histological verification of the injection sites) within the PPT. Electroencephalograms were recorded from the sensorimotor cortex, the hippocampus, and the pons, contralateral to the injection site. Electromyograms (EMGs) were recorded from the genioglossus muscle. The typical response to glutamate injection within the PPT respiratory-modulating region was immediate apnea followed by tachypnea and increased genioglossal tonic activity. The noncompetitive NMDA receptor channel-antagonist ketamine, injected at the same site and in the same volume as glutamate (5 nl), blocked respiratory dysrhythmia and genioglossal EMG responses to subsequent glutamate injections. For the first time, the present results suggest that respiratory rhythm and upper airway muscle tone are controlled by the activation of pedunculopontine tegmental nucleus NMDA receptors.

Animals↗

PubMed2005

Injection of glutamate into the pedunculopontine tegmental nuclei of anesthetized rat causes respiratory dysrhythmia and alters EEG and EMG power.

The pedunculopontine tegmental nucleus (PPT) has been shown to have important functions relevant to the regulation of behavioral states and various motor control systems, including breathing control. Our previous work has shown that the activation of neurons within the PPT, a structure that is typically active during rapid eye movement (REM) sleep, can produce respiratory disturbances in freely moving and anesthetized rats. The aim of this study was to test the hypothesis that respiratory modulation by the PPT in anesthetized rats can be evoked in the absence of other signs of an REM-sleep-like state. We characterized electroencephalogram (EEG) and electromyogram (EMG) changes during respiratory disturbances induced by glutamatergic stimulation of the PPT in spontaneously breathing, adult male Sprague-Dawley rats anesthetized with a ketamine/xylazine combination or with nembutal. Respiratory movements were monitored by a piezoelectric strain gauge. Two-barrel glass pipettes were used to pressure inject glutamate, to probe for respiratory effective sites within the PPT, and to inject oil red dye at the end of the experiments for histological verification of the injection sites. The EEGs were recorded from the sensorimotor cortex, hippocampus, and from the pons contralateral from the injection site. The EMGs were recorded from the genioglossus muscle. The initial response to glutamate injection into the respiratory modulating region of the PPT was always a respiratory pattern disturbance. Subsequent activation of EMG and EEG often occurred in ketamine/xylazine-anesthetized rats, but REM-sleep-like patterns were not observed. Respiratory pattern and EMG power changes in nembutal-anesthetized rats were similar, but EEG activation was never observed. Thus, we conclude that respiratory suppression produced by the local activation of PPT neurons may not necessarily be accompanied by an REM-sleep-like cortical state in this anesthetized model.

Anesthesia↗

PubMed2005

Serotonin and noradrenaline modulate respiratory pattern disturbances evoked by glutamate injection into the pedunculopontine tegmentum of anesthetized rats.

STUDY OBJECTIVES: We hypothesized that 2 important neurotransmitters related to behavioral state control, serotonin and noradrenaline, could also be modulators of pedunculopontine tegmental nucleus (PPT)-induced respiratory dysrhythmia. DESIGN: We examined the impact of serotonin and noradrenaline at respiratory control sites in the PPT functionally identified by immediate apnea of 2.5- to 10-second duration, followed by increased variability of breath time (CVT(T)) (P < .04) after locally injecting glutamate in anesthetized rats. SETTING: Basic sleep and respiratory neurobiology laboratory. PARTICIPANTS: Sixteen adult, male Sprague-Dawley rats. MEASUREMENTS AND RESULTS: Glutamate-induced respiratory responses, including increases of total apnea duration and CVT(T), were not different between groups of rats in which we further tested monoaminergic modulatory effects (for CVT(T) P = .98, and for total apnea duration, P = .80). Serotonin or noradrenaline injected at the same sites as glutamate had equal impact on CVT(T) (P = .34) and on mean total apnea duration (P = .80), but pretreatment of PPT sites with serotonin blocked (remained equal to preinjection; P = .11), whereas pretreatment with noradrenaline potentiated (P = .04) the increment of respiratory-timing variability induced by glutamate. The serotonergic-blocking effect on glutamate-induced respiratory dysrhythmia was specific to the PPT: the respiratory responses induced by glutamate injection outside the PPT were not modulated by serotonin (for CVT(T), P = .46, and for mean apnea duration, P = .99). CONCLUSIONS: The opposed impact of serotonin and noradrenaline on PPT-induced respiratory dysrhythmia, in contrast to their convergent regulatory role in behavioral state control, suggests a functionally distinct role for the PPT in respiratory-pattern control independent of rapid eye movement sleep control.

Anesthesia↗

PubMed2004

Modulation of reflex and sleep related apnea by pedunculopontine tegmental and intertrigeminal neurons.

We describe and summarize here our recent findings about the role in respiration of two pontine structures that are not classically included in the pontine respiratory group: the pedunculopontine tegmental nucleus (PPT) and the intertrigeminal region (ITR). We also discuss significant contributions of other workers in the field, especially, S. Datta [Cell. Mol. Neurobiol. 17: 341-365, 1997], R. Lydic and H. Baghdoyan [Sleep, 25: 617-622, 2002], and N. Chamberlin and C. Saper [J. Neurosci. 18: 6048-6056, 1998], who postulated a role for the ITR in modulating reflex apnea. In anesthetized and freely moving rats we have consistently documented that PPT and ITR have a role in respiration. Neurochemical manipulations of each area affected the brainstem respiratory pattern generator and respiratory pattern variability,observed as spontaneous disturbances during sleep or as induced reflex apnea. Although the exact central mechanisms of apnea cannot be determined from our studies to date, we postulate that reflex and sleep-related apneas in rats share some common brainstem pathways, which may include PPT and ITR.

Animals↗

PubMed2003

Respiratory pattern modulation by the pedunculopontine tegmental nucleus.

This study demonstrates respiratory modulation caused by stimulation of the pedunculopontine tegmental nucleus (PPT), a structure not classically included in the pontine respiratory neuronal network. The long-lasting increase in variability of respiratory parameters following glutamate microinjection into PPT in anesthetized, spontaneously breathing Sprague Dawley rats was more pronounced under ketamine than nembutal anesthesia. The induced respiratory perturbations were characterized by intermittent apneas and increased variability of expiratory (TE) and total (TT) breath durations in all animals. Although the baseline spontaneous breathing patterns (mean values of all respiratory parameters and their variabilities) were equivalent under ketamine and nembutal anesthesia, different anesthetic agents did affect respiratory responses to PPT stimulation by glutamate in terms of latency, duration, and structure. We conclude that glutamatergic stimulation of PPT has a significant impact on the brainstem respiratory pattern generator.

Analysis of Variance↗

PubMed2003

Intertrigeminal region attenuates reflex apnea and stabilizes respiratory pattern in rats.

The goal of the present study was to determine whether the newly described anatomical pathway involving the pontine intertrigeminal region (ITR), (Chamberlin and Saper, 1998), has a physiological role in mediating or modulating vagally-induced reflex apnea. We explored the ITR impact on vagal reflex apnea elicited by intravenuously injected 5-HT in ten anesthetized rats. The animals had a catheter inserted into the femoral vein for administration of 5-HT (0.00375 mg) and respiration was recorded by piezo-electric crystal. Multibarrel pipettes were used to pressure inject glutamate (5-10 nl, 10 mM), kynurenic acid (10 nl, 50 mM, a glutamate receptor antagonist), and red dye into the ITR, unilaterally and bilaterally. Intravenous administration of 5-HT produced an immediate 3-s apnea. Microinjections of glutamate into the ITR produced apneas, while microinjections of kynurenic acid blocked the glutamate effect. Following glutamate antagonism, subsequent administration of 5-HT produced apneas of much longer duration (8 s). Acute ponto-medullary transection in two animals yielded even greater prolongation of 5-HT-induced apnea. We conclude that a physiological role for the ITR in respiration is to attenuate vagally-induced reflex apneas. This finding is in agreement with the general modulatory role of pontine structures in autonomic activities including respiration, heart rate and regulation of blood pressure. In addition, our data indicate that medullary circuits, independent of pontine structures, are sufficient to produce 5-HT induced reflex apnea.

Animals↗