| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
 |
ABSTRACT |
|---|
 TopAbstract IntroductionMethodsResultsDiscussionReferences |
|---|
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The pattern of training has a profound effect on the formation and retention of memories. For example, episodic or spaced training trials are generally more effective in long-lasting memory formation than sustained or massed training trials (Carew et al. 1972; Tully et al. 1994; Yin et al. 1994; Mauelshagen et al. 1998). The cellular mechanisms that impart pattern specificity to memory formation are not well understood.
Long-term facilitation (LTF) of respiratory motor output is a time-dependent memory of the respiratory network following repetitive episodes of carotid chemoafferent activation by electrical stimulation of the carotid sinus nerve (Millhorn et al. 1980a,b; Hayashi et al. 1993) or hypoxia (Hayashi et al. 1993; Bach & Mitchell, 1996; Kinkead & Mitchell, 1999). LTF is serotonin dependent (Millhorn et al. 1980b) and requires the activation of 5-HT2 receptors during (Kinkead & Mitchell, 1999), but not following episodic hypoxia (Fuller et al. 2000b). LTF is primarily a central neural mechanism since LTF is elicited by carotid sinus nerve stimulation (Millhorn et al. 1980a,b; Hayashi et al. 1993), thus bypassing mechanisms of carotid chemosensory transduction.
There is evidence suggesting that LTF is a unique property of intermittent hypoxia. In awake goats, episodic but not sustained hypoxia elicits a long-lasting increase in breathing frequency and tidal volume (viz. Dwinell et al. 1997; Turner & Mitchell, 1997). However, the magnitude of facilitation in awake goats is modest (approximately 20-30% at 40 min) and degrades to baseline relatively quickly (between 40 and 60 min). Thus, long-term facilitation following sustained hypoxia might not be revealed given the small capacity for facilitation in awake goats. On the other hand, anaesthetized, vagotomized rats exhibit considerable facilitation of phrenic motor output 60 min post-episodic hypoxia (approximately 75%), an effect that appears to increase in a time-dependent manner (Bach & Mitchell, 1996). The objective of this study was to investigate the dependence of phrenic LTF on the pattern of hypoxia in anaesthetized, vagotomized rats, a preparation that exhibits robust LTF of phrenic motor output.
|
METHODS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Experiments were conducted on 19 adult male Harlan Sprague-Dawley rats (colony 236), weighing between 280 and 430 g. The Animal Care and Use Committee at the University of Wisconsin-Madison approved all experimental procedures.
Experimental procedures have been described in detail previously (Bach & Mitchell, 1996; Kinkead et al. 1998; Kinkead & Mitchell, 1999). Briefly, rats were anaesthetized initially with isoflurane (2.5%) in 50% O2 (balance N2), then slowly converted to urethane anaesthesia (1.6 g kg-1, I.V.). The adequacy of anaesthesia was assessed periodically by testing blood pressure responses to toe pinch; supplemental doses of urethane were given as necessary. One hour after the beginning of surgery, an intravenous infusion of a 1:4 solution of sodium bicarbonate and lactated Ringer solution was initiated to maintain acid-base balance (5 ml kg-1 h-1).
Rats were vagotomized, paralysed with pancuronium bromide (2.5 mg kg-1) and pump ventilated (VT = 2-2.5 ml, Rodent Respirator, model 683; Harvard Apparatus, South Natick, MA, USA). Phrenic and hypoglossal nerves were dissected, cut distally and desheathed unilaterally using a left dorsal approach. The nerves were submerged in mineral oil and placed on bipolar silver recording electrodes. Nerve activity was amplified (gain = 10K, A-M systems, Everett, WA, USA), band-pass filtered (100 Hz to 10 kHz) and integrated (Paynter filter, CWE 821, Ardmore, PA, USA; time constant, 100 ms). The signal was then digitized, recorded and analysed using the WINDAQ data acquisition system (DATAQ Instruments, Akron, OH, USA).
Following surgery, at least 1.5 h were allowed for electroneurograms and blood pressure to stabilize. Baseline nerve activity was established in hyperoxic and normocapnic conditions (FI,O2= 0.5; arterial PO2 (Pa,O2) > 120 mmHg; arterial PCO2 (Pa,CO2) ~2-3 mmHg above the CO2 apnoeic threshold). End-tidal CO2 was monitored throughout the protocol with a flow-through capnograph (Novametrix; Wallingford, CT, USA), with sufficient response time to measure end-tidal CO2 in rats. Inspired CO2 or ventilator frequency was adjusted as necessary to maintain isocapnia. Blood gases and arterial pressure were monitored and corrected as necessary to ensure that post-hypoxia values were maintained near baseline levels. Experiments were included in the analysis only if: (1) Pa,O2 during hypoxia was between 35 and 45 mmHg, (2) Pa,O2 during the hyperoxic baseline and recovery periods was > 120 mmHg, (3) Pa,CO2 remained within 1.5 mmHg of baseline throughout the protocol, and (4) blood pressure remained within 20 mmHg of its baseline value.
| Baseline | 15 min | 30 min | 60 min | |
| 3 X 3 min | 43.4 ± 1.7 | 43.6 ± 2.0 | 43.4 ± 2.1 | 43.8 ± 1.8 |
| 9 min | 45.1 ± 1.0 | 44.9 ± 1.2 | 45.0 ± 0.9 | 44.8 ± 1.1 |
| 20 min | 43.5 ± 1.1 | 44.9 ± 0.9 | 43.9 ± 1.5 | 43.5 ± 1.1 |
Peak integrated phrenic and hypoglossal amplitudes (Phr and XII) were measured following 3 X 3 min episodes of hypoxia (FI,O2 = 0.11) separated by 5 min isocapnic hyperoxia (FI,O2 = 0.5; n = 6), and 9 (n = 6) and 20 min (n = 7) of continuous hypoxia. The durations of sustained hypoxia were chosen to correspond with the cumulative duration of hypoxic exposure (3 X 3 min = 9 min) or total stimulation protocol time (3 X 3 min episodes plus 2 X 5 min interval = 19 min) in episodic hypoxia. At the end of the final hypoxic exposure, rats were returned to baseline hyperoxic levels. Phrenic and hypoglossal nerve activity were monitored for 1 h post-hypoxia. At the end of the protocol, maximal phrenic and hypoglossal discharges were measured by elevating inspired CO2 concentration until nerve activity failed to increase with further increases in CO2 (approximately 12% CO2). Blood samples (0.3 ml in a heparinized syringe) were drawn before, during, and 15, 30 and 60 min following hypoxia to ensure blood gases met the criteria outlined above; phrenic and hypoglossal measurements corresponding to these time points were used in the analysis. At the conclusion of all experiments, rats were killed with an overdose of urethane (I.V.).
 |
View larger version [in this window] [in a new window] |
|
|
Integrated phrenic discharge during baseline, hypoxia, and 15, 30 and 60 min post-hypoxia. Only episodic hypoxia elicits LTF.
| ||
Peak amplitudes and frequency (bursts min-1) of phrenic and hypoglossal nerve activity were averaged in 1 min bins at each recorded data point (baseline and 15, 30 and 60 min post-hypoxia). Changes in amplitude data were normalized in two ways: (1) as a percentage of the baseline value, and (2) as a percentage of the CO2-stimulated maximal nerve activity. All data are reported as percentage change from baseline, but comparable results were obtained when analysed as a percentage of maximal activity (data not shown). Burst frequency (bursts min-1) is reported as an absolute change from baseline. Statistical analyses were conducted using a two-way ANOVA with a repeated measures design, and individual comparisons were made using the Student-Neuman-Keuls post hoc test. Differences were considered significant if P < 0.05. All values are expressed as means ± S.E.M.
|
RESULTS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Table 1 lists Pa,CO2 values obtained before and after hypoxia. There were no significant changes in any group at any time point. Thus, attempts to maintain arterial isocapnia were successful.
Episodic hypoxia
As previously reported, episodic hypoxia elicited a sustained increase in phrenic burst amplitude (i.e. LTF; Hayashi et al. 1993; Bach & Mitchell, 1996; Kinkead et al. 1998; Kinkead & Mitchell, 1999). Phrenic burst amplitude was significantly above baseline levels at all post-hypoxia time points tested (P < 0.05; Figs 1 and 2). When expressed as a percentage increase from baseline, mean phrenic burst amplitude was increased by 78 ± 15% 60 min post-hypoxia. Phrenic LTF was significantly greater at 60 min than 15 min post-episodic hypoxia (78 ± 15 vs. 34.6 ± 6.6%, respectively; P < 0.05), indicating that hypoxia-induced LTF progressively increases for at least 1 h post-episodic hypoxia. Peak integrated hypoglossal amplitude showed no significant LTF following episodic hypoxia (17.8 ± 11.7% 60 min post-hypoxia; Fig. 2). Previous data from our laboratory suggest that hypoglossal LTF is rat sub-strain dependent (Fuller et al. 2000a). In a subsequent blind study (D. F. Fuller, T. L. Baker, M. Behan & G. S. Mitchell, unpublished observations), we found that Harlan Sprague-Dawley rats (colony 236) do not show significant hypoglossal LTF (< 20%), whereas Sasco Sprague-Dawley rats (colony K62) exhibit significant hypoglossal LTF (approximately 50-70%). The mechanism underlying this difference in the capacity to elicit hypoglossal LTF between rat sub-strains is not understood.
 |
View larger version [in this window] [in a new window] |
|
|
Mean integrated phrenic amplitude (± S.E.M.) at 15, 30 and 60 min following episodic (
| ||
Episodic hypoxia also elicited a sustained increase in nerve burst frequency at all post-hypoxia time points (P < 0.05, Fig. 3). At 60 min post-hypoxia, mean frequency had increased by 11 ± 2.1 bursts min-1 above baseline levels.
Continuous hypoxia
In contrast to episodic hypoxia, 9 or 20 min of continuous hypoxia failed to elicit LTF of phrenic burst amplitude (4.7 ± 5.1 and 10.1 ± 10.2% 60 min following 9 and 20 min hypoxia, respectively; P > 0.05; Figs 1 and 2). Continuous hypoxia also failed to elicit hypoglossal LTF (-11.1 ± 5.6 and 19.3 ± 12.2% 60 min following 9 and 20 min hypoxia, respectively; P > 0.05; Fig. 2). Phrenic burst amplitude following episodic hypoxia was significantly greater than values following 9 or 20 min continuous hypoxia at all time points (P < 0.05). Significant LTF of burst frequency was not observed following 9 or 20 min continuous hypoxia (+4.6 ± 1.3 and +5.1 ± 2 bursts min-1 60 min following 9 and 20 min hypoxia, respectively; P > 0.05; Fig. 3). The increase in burst frequency following episodic hypoxia was significantly greater than that following 9 min of continuous hypoxia at all time points (P < 0.05), or that following 20 min continuous hypoxia at 30 and 60 min post-hypoxia (P < 0.05). Thus, LTF of phrenic burst amplitude and frequency is a unique property of episodic hypoxia.
 |
View larger version [in this window] [in a new window] |
|
|
Mean change in phrenic frequency from baseline (± S.E.M.) at 15, 30 and 60 min following episodic (
| ||
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Long-term facilitation of phrenic motor output has a profound dependence on the pattern of hypoxic exposure in anaesthetized rats. Episodic hypoxia elicits LTF of phrenic amplitude and frequency, whereas continuous hypoxia of an equal cumulative duration does not. These results are consistent with previous reports in awake goats from different investigators, in which episodic, but not continuous hypoxia elicited LTF (Dwinell et al. 1997; Turner & Mitchell, 1997). Other lines of evidence suggest that continuous and episodic hypoxia have differential impact on ventilatory control. Chronic sustained (continuous) hypoxia elicits ventilatory acclimatization, a process thought to be primarily mediated by effects on the carotid body (Bisgard & Neubauer, 1995; Powell et al. 1998). Similarly, continuous, but not episodic hypoxia increases phosphorylation of the cyclic AMP response element binding protein in the carotid body (Wang et al. 2000). Thus, continuous hypoxia may initiate a cascade of cell signalling and gene expression events in the carotid body that enhances carotid body sensitivity, thus giving rise to ventilatory acclimatization. In contrast, episodic hypoxia elicits LTF, which is believed to be a central neural mechanism that arises from serotonin-dependent effects on the respiratory network. Our working hypothesis is that episodic hypoxia elicits repetitive serotonin release and subsequent 5-HT2A receptor activation on respiratory motoneurons, initiating long-lasting effects on phrenic burst amplitude. However, given that episodic hypoxia also elicits LTF in respiratory frequency (albeit smaller than amplitude effects), it is possible that a component of LTF involves facilitation at the level of medullary respiratory neurons associated with rhythm generation. Collectively, available evidence suggests that the pattern of carotid body stimulation is important in determining the type of plasticity elicited, although the detailed cellular mechanisms distinguishing episodic and sustained hypoxia in the CNS and carotid body chemoreceptors remain to be elucidated.
We previously reported that one 5 min hypoxic episode is not sufficient to elicit LTF in anaesthetized rats (Bach et al. 1999). On the other hand, an earlier report suggested that one episode (10 min) of hypoxia is sufficient to elicit LTF in anaesthetized cats (Millhorn et al. 1980a). This earlier report is based on observations from only one cat and may not represent the response of a population of cats. Furthermore, the authors did not measure blood gases or pH before, during or after hypoxia, leaving open the possibility that inadequate control of blood gases or pH could account for the apparent LTF in this case. Alternatively, cats may be different from rats or goats and exhibit LTF following continuous hypoxia.
There are numerous accounts in the neurobiology literature concerning the importance of stimulation pattern in eliciting plasticity. For example, in Aplysia, both episodic and prolonged continuous (> 1 h) serotonin application elicit LTF (Montarolo et al. 1986; Clark & Kandel, 1993; Emptage & Carew, 1993; Ghirardi et al. 1995; Zhang et al. 1997). However, brief (25 min) continuous serotonin applications are less likely to elicit long-term facilitation (Mauelshagen et al. 1998). Intracellular signalling pathways thought to mediate synaptic facilitation in Aplysia are also sensitive to the pattern of serotonin application (Müller & Carew, 1998; Yanow et al. 1998). Episodic serotonin (4-5 pulses, 5 min duration) elicits sustained activation of protein kinase A at intermediate (1 h) and long (20 h) time intervals, whereas continuous (90 min) serotonin application induces persistent protein kinase A activation only at long time intervals (Müller & Carew, 1998). Furthermore, episodic (5 X 5 min episodes) but not continuous serotonin (90 min) increases translational protein synthesis 2 h following stimulation in the isolated pleural ganglia of Aplysia (Yanow et al. 1998). Another example of pattern sensitive neuroplasticity is odour avoidance learning in Drosophila (Yin et al. 1994, 1995; Tully, 1994); spaced training trials give rise to a protein synthesis-dependent long-term memory, whereas continuous training does not (Tully et al. 1994). Thus, the pattern dependence of hypoxia-induced respiratory LTF in rats provides another example of neuroplasticity elicited by episodic, but not continuous stimuli. Respiratory LTF elicited by episodic hypoxia may represent a highly useful and generalizable model for in vivo studies of central neural plasticity. Given the clear physiological significance of long-lasting changes in respiratory motor output, this model of plasticity may have inherent advantages not often found in other frequently investigated models of plasticity.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
| BACH K. B., KINKEAD, R. & MITCHELL, G. S. (1999). Post-hypoxia frequency decline in rats: sensitivity to repeated hypoxia and alpha2-adrenoreceptor antagonism. Brain Research 817, 25-33 | [Medline] |
| BACH K. B. & MITCHELL, G. S. (1996). Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respiration Physiology 104, 251-260 | [Medline] |
| BISGARD G. E. & NEUBAUER, J. A. (1995). Peripheral and central effects of hypoxia. In Regulation of Breathing, ed. DEMPSEY, J. A. & PACK, A. I., pp. 617-618. Marcel Dekker, New York | |
| CAREW T. J., PINSKER, H. M. & KANDEL, E. R. (1972). Long-term habituation of a defensive withdrawal reflex in Aplysia. Science 175, 451-454. | |
| CLARK G. A. & KANDEL, E. R. (1993). Induction of long-term facilitation in Aplysia sensory neurons by local application of serotonin to remote synapses. Proceedings of the National Academy of Sciences of the USA 90, 11411-11415 | [Medline] |
| DWINELL M. R., JANSSEN, P. L. & BISGARD, G. E. (1997). Lack of long-term facilitation of ventilation after exposure to hypoxia in goats. Respiration Physiology 108, 1-9. | [Medline] |
| EMPTAGE N. J. & CAREW, T. J. (1993). Long-term facilitation in the absence of short-term facilitation in Aplysia neurons. Science 262, 253-256 | [Medline] |
| FULLER D. D., BACH, K. B., BAKER, T. L., KINKEAD, R. & MITCHELL, G. S. (2000a). Long term facilitation of phrenic motor output. Respiration Physiology 121, 135-146 | [Medline] |
| FULLER D. D., ZABKA, A. G., BAKER, T. L., FREGOSI, R. F. & MITCHELL, G. S. (2000b). Phrenic long-term facilitation requires 5-HT2 receptor activation during but not following episodic hypoxia. Society for Neuroscience Abstracts 26, 556 | |
| GHIRARDI M., MONTAROLO, P. G. & KANDEL, E. R. (1995). A novel intermediate stage in the transition between short- and long-term facilitation in the sensory to motor neuron synapse of Aplysia. Neuron 14, 413-420 | [Medline] |
| HAYASHI F., COLES, S. K., BACH, K. B., MITCHELL, G. S. & MCCRIMMON, D. R. (1993). Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats. American Journal of Physiology 265, R811-819 | |
| KINKEAD R. & MITCHELL, G. S. (1999). Time-dependent hypoxic ventilatory responses in rats: effects of ketanserin and 5-carboxyamidotryptamine. American Journal of Physiology 277, R658-666 | [Medline] |
| KINKEAD R., ZHAN, W. Z., PRAKASH, Y. S., BACH, K. B., SIECK, G. C. & MITCHELL, G. S. (1998). Cervical dorsal rhizotomy enhances serotonergic innervation of phrenic motoneurons and serotonin-dependent long-term facilitation of respiratory motor output in rats. Journal of Neuroscience 18, 8436-8443 | [Medline] |
| MAUELSHAGEN J., SHERFF, C. M. & CAREW, T. J. (1998). Differential induction of long-term synaptic facilitation by spaced and massed applications of serotonin at sensory neuron synapses of Aplysia californica. Learning and Memory 5, 246-256 | [Medline] |
| MILLHORN D. E., ELDRIDGE, F. L. & WALDROP, T. G. (1980a). Prolonged stimulation of respiration by a new central neural mechanism. Respiration Physiology 42, 87-103 | [Medline] |
| MILLHORN D. E., ELDRIDGE, F. L. & WALDROP, T. G. (1980b). Prolonged stimulation of respiration by endogenous central serotonin. Respiration Physiology 41, 171-188. | |
| MONTAROLO P. G., GOELET, P., CASTELLUCCI, V. G., MORGAN, J. & KANDEL, E. R. (1986). A critical period for macromolecule synthesis in long-term heterosynaptic facilitation in Aplysia. Science 234, 1249-1254. | [Medline] |
| M¬ULLER U. & CAREW, T. J. (1998). Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21, 1423-1434 | [Medline] |
| POWELL F. L., MILSOM, W. K. & MITCHELL, G. S. (1998). Time domains of the hypoxic ventilatory response. Respiration Physiology 112, 123-134 | [Medline] |
| TULLY T., PREAT, T., BOYNTON, S. C. & DEL VECCHIO, M. (1994). Genetic dissection of consolidated memory in Drosophila. Cell 79, 35-47 | [Medline] |
| TURNER D. L. & MITCHELL, G. S. (1997). Long-term facilitation of ventilation following repeated hypoxic episodes in awake goats. Journal of Physiology 499, 543-550. | [Medline] |
| WANG Z. Y., BAKER, T. L., KEITH, I. M., MITCHELL, G. S. & BISGARD, G. E. (2000). Continuous but not episodic hypoxia induces CREB phosphorylation in rat carotid body. Advances in Experimental Medicine and Biology 475, 631-635 | [Medline] |
| YANOW S. K., MANSEAU, F., HISLOP, J., CASTELLUCCI, V. F. & SOSSIN, W. S. (1998). Biochemical pathways by which serotonin regulates translation in the nervous system of Aplysia. Journal of Neurochemistry 70, 572-583 | [Medline] |
| YIN J. C., DELVECCHIO, M., ZHOU, H. & TULLY, T. (1995). CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81, 107-115 | [Medline] |
| YIN J. C., WALLACH, J. S., DEL VECCHIO, M., WILDER, E. L., ZHOU, H., QUINN, W. G. & TULLY, T. (1994). Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49-58 | [Medline] |
| ZHANG F., ENDO, S., CLEARY, L. J., ESKIN, A. & BYRNE, J. H. (1997). Role of transforming growth factor-beta in long-term synaptic facilitation in Aplysia. Science 275, 1318-1320 | [Medline] |
Acknowledgements
These experiments were supported by NIH grants HL 53319 and HL 36780. Tracy Baker was supported by NIH Training Grant HL 07654.
Corresponding author
T. L. Baker: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive West, Madison, WI 53706, USA.
Email: bakert{at}svm.vetmed.wisc.edu
This article has been cited by other articles:
|
|
 |
|
  H. Wadhwa, C. Gradinaru, G. J. Gates, M. S. Badr, and J. H. Mateika Impact of intermittent hypoxia on long-term facilitation of minute ventilation and heart rate variability in men and women: do sex differences exist? J Appl Physiol, June 1, 2008; 104(6): 1625 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mahamed and G. S. Mitchell Simulated apnoeas induce serotonin-dependent respiratory long-term facilitation in rats J. Physiol., April 15, 2008; 586(8): 2171 - 2181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. R. Wilkerson, I. Satriotomo, T. L. Baker-Herman, J. J. Watters, and G. S. Mitchell Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia J. Neurosci., March 12, 2008; 28(11): 2949 - 2958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Hsieh, T. E. Dick, and R. E. Siegel Adaptation to hypobaric hypoxia involves GABAA receptors in the pons Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2008; 294(2): R549 - R557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tadjalli, J. Duffin, Y. M. Li, H. Hong, and J. Peever Inspiratory activation is not required for episodic hypoxia-induced respiratory long-term facilitation in postnatal rats J. Physiol., December 1, 2007; 585(2): 593 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Berner, Y. Shvarev, H. Lagercrantz, A. Bilkei-Gorzo, T. Hokfelt, and R. Wickstrom Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene J Appl Physiol, August 1, 2007; 103(2): 552 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. V. Neverova, S. A. Saywell, L. J. Nashold, G. S. Mitchell, and J. L. Feldman Episodic Stimulation of {alpha}1-Adrenoreceptors Induces Protein Kinase C-Dependent Persistent Changes in Motoneuronal Excitability J. Neurosci., April 18, 2007; 27(16): 4435 - 4442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. S. Griffioen, H. W. Kamendi, C. J. Gorini, E. Bouairi, and D. Mendelowitz Reactive Oxygen Species Mediate Central Cardiorespiratory Network Responses to Acute Intermittent Hypoxia J Neurophysiol, March 1, 2007; 97(3): 2059 - 2066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Day and R. J. A. Wilson Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation J. Physiol., February 1, 2007; 578(3): 843 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mahamed and G. S. Mitchell Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol, January 1, 2007; 92(1): 27 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Zabka, G. S. Mitchell, and M. Behan Conversion from testosterone to oestradiol is required to modulate respiratory long-term facilitation in male rats J. Physiol., November 1, 2006; 576(3): 903 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Braga, R. N. Soriano, and B. H. Machado Sympathoexcitatory response to peripheral chemoreflex activation is enhanced in juvenile rats exposed to chronic intermittent hypoxia Exp Physiol, November 1, 2006; 91(6): 1025 - 1031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Harris, A. Balasubramaniam, M. S. Badr, and J. H. Mateika Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1111 - R1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire, Y. Zhang, D. P. White, and L. Ling Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats J. Physiol., September 1, 2005; 567(2): 599 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Day and R. J. A. Wilson Specific carotid body chemostimulation is sufficient to elicit phrenic poststimulus frequency decline in a novel in situ dual-perfused rat preparation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R532 - R544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Golder and G. S. Mitchell Spinal Synaptic Enhancement with Acute Intermittent Hypoxia Improves Respiratory Function after Chronic Cervical Spinal Cord Injury J. Neurosci., March 16, 2005; 25(11): 2925 - 2932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Morelli, M. S. Badr, and J. H. Mateika Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women J Appl Physiol, November 1, 2004; 97(5): 1673 - 1680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rey, R. Del Rio, J. Alcayaga, and R. Iturriaga Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia J. Physiol., October 15, 2004; 560(2): 577 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Reeves and D. Gozal Platelet-activating factor receptor modulates respiratory adaptation to long-term intermittent hypoxia in mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R369 - R374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Bocchiaro and J. L. Feldman From The Cover: Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons PNAS, March 23, 2004; 101(12): 4292 - 4295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Mateika, C. Mendello, D. Obeid, and M. S. Badr Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans J Appl Physiol, March 1, 2004; 96(3): 1197 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Neubauer and J. Sunderram Oxygen-sensing neurons in the central nervous system J Appl Physiol, January 1, 2004; 96(1): 367 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire, Y. Zhang, D. P. White, and L. Ling Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats J Appl Physiol, October 1, 2003; 95(4): 1499 - 1508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Peng and N. R. Prabhakar Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia J Appl Physiol, June 1, 2003; 94(6): 2342 - 2349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gozal, S. R. Reeves, B. W. Row, J. J. Neville, S. Z. Guo, and A. J. Lipton Respiratory Effects of Gestational Intermittent Hypoxia in the Developing Rat Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1540 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Mitchell and S. M. Johnson Plasticity in Respiratory Motor Control: Invited Review: Neuroplasticity in respiratory motor control J Appl Physiol, January 1, 2003; 94(1): 358 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Babcock, M. Shkoukani, S. E. Aboubakr, and M. S. Badr Determinants of long-term facilitation in humans during NREM sleep J Appl Physiol, January 1, 2003; 94(1): 53 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Bavis and G. S. Mitchell Plasticity in Respiratory Motor Control: Selected Contribution: Intermittent hypoxia induces phrenic long-term facilitation in carotid-denervated rats J Appl Physiol, January 1, 2003; 94(1): 399 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire, Y. Zhang, D. P. White, and L. Ling Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats J Appl Physiol, December 1, 2002; 93(6): 2155 - 2161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Blitz and J.-M. Ramirez Long-Term Modulation of Respiratory Network Activity Following Anoxia In Vitro J Neurophysiol, June 1, 2002; 87(6): 2964 - 2971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Prabhakar, R. D. Fields, T. Baker, and E. C. Fletcher Intermittent hypoxia: cell to system Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L524 - L528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Olson Jr., C. J. Bohne, M. R. Dwinell, A. Podolsky, E. H. Vidruk, D. D. Fuller, F. L. Powell, and G. S. Mitchel Ventilatory long-term facilitation in unanesthetized rats J Appl Physiol, August 1, 2001; 91(2): 709 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ling, D. D. Fuller, K. B. Bach, R. Kinkead, E. B. Olson Jr, and G. S. Mitchell Chronic Intermittent Hypoxia Elicits Serotonin-Dependent Plasticity in the Central Neural Control of Breathing J. Neurosci., July 15, 2001; 21(14): 5381 - 5388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Gozal and D. Gozal Physiological and Genomic Consequences of Intermittent Hypoxia: Invited Review: Respiratory plasticity following intermittent hypoxia: developmental interactions J Appl Physiol, May 1, 2001; 90(5): 1995 - 1999. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
), and 9 min (
) and 20 min (
) continuous hypoxia expressed as a percentage increase from pre-stimulation (baseline) levels. Episodic hypoxia elicited significant phrenic LTF at all time points. In contrast, 9 and 20 min continuous hypoxia did not elicit phrenic LTF. Neither episodic nor continuous hypoxia elicited significant hypoglossal LTF. *Significantly different from pre-stimulus baseline (P < 0.05); significantly different from 3 X 3 min episodic hypoxia.