For more than a decade, we have been interested in the control of breathing and in ventilatory abnormalities in the young and in the mature adult subject. In particular, we have focussed on the study of mechanisms that can potentially lead to apnea and hypoventilation as well as on their consequences in early life and with maturation. Investigations from our laboratory and others have indicated that there are a number of central neuromodulators that are involved in producing apnea and hypoventilation or are release during hypoxia thus altering ventilation. Examples are the opioid and adenosine systems. Although the effect of these systems on ventilation has been studied at the system level, little data are available about the specific cellular mechanisms underlying their action. We have recently developed an in-vitro brain slice preparation to study the electrophysiological properties of neurons in the ventral region of the Nucleus Tractus solitarius (v-NTS) and in the ventral respiratory group (VRG) in a rat model. Specifically we intend to 1) examine the postnatal maturation of the cellular and membrane properties of neurons in the v-NTS and VRG, 2) study the postnatal development in the response of neurons within these areas to neuromodulators (opioids and adenosine) and 3) study the ionic mechanisms underlying the inherent cellular properties of these neurons before and after exposure to opioids and adenosine agonists and antagonists in the newborn and with maturation. The methods used are based on intracellular recording and staining as well as current and voltage clamp techniques. We will also use pharmacologic tools including extracellular channel blockers (e.g. cobalt, TEA, 4-AP) or intracellular chelating agents (e.g. EGTA). To identify bulbospinal neurons, a retrogradely transported dye will be injected into the phrenic motor nucleus prior to the preparation of the in-vitro brain slice. Neurons studied in the slice will be labelled with Lucifer yellow or carboxyfluorescin. Double labelled cells would indicate a characterized bulbospinal neuron. It is out belief that it is with more fundamental understanding of respiratory control phenomena that effective pharmacologic approaches can be designed for the treatment of respiratory and cardiovascular instabilities in early life.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (SRC (29))
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Yale University
Schools of Medicine
New Haven
United States
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Xia, Y; Haddad, G G (2001) Major difference in the expression of delta- and mu-opioid receptors between turtle and rat brain. J Comp Neurol 436:202-10
Zhang, J; Haddad, G G; Xia, Y (2000) delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury. Brain Res 885:143-53
Xia, Y; Fung, M L; O'Reilly, J P et al. (2000) Increased neuronal excitability after long-term O(2) deprivation is mediated mainly by sodium channels. Brain Res Mol Brain Res 76:211-9
Xia, Y; Haddad, G G (1999) Effect of prolonged O2 deprivation on Na+ channels: differential regulation in adult versus fetal rat brain. Neuroscience 94:1231-43
Friedman, J E; Chow, E J; Haddad, G G (1998) State of actin filaments is changed by anoxia in cultured rat neocortical neurons. Neuroscience 82:421-7
Croning, M D; Haddad, G G (1998) Comparison of brain slice chamber designs for investigations of oxygen deprivation in vitro. J Neurosci Methods 81:103-11
Xia, Y; Warshaw, J B; Haddad, G G (1997) Effect of chronic hypoxia on glucose transporters in heart and skeletal muscle of immature and adult rats. Am J Physiol 273:R1734-41
Marks, J D; Friedman, J E; Haddad, G G (1996) Vulnerability of CA1 neurons to glutamate is developmentally regulated. Brain Res Dev Brain Res 97:194-206
O'Reilly, J P; Haddad, G G (1996) Chronic hypoxia in vivo renders neocortical neurons more vulnerable to subsequent acute hypoxic stress. Brain Res 711:203-10
Xia, Y; Warshaw, J B; Haddad, G G (1995) Chronic hypoxia causes opposite effects on glucose transporter 1 mRNA in mature versus immature rat brain. Brain Res 675:224-30

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