CSB346 Lecture 7 Review Notes

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Cell and Systems Biology
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John Peever

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CSB346 Lecture 7 Summary – Peripheral and Central Oxygen Sensing Oxygen sensing - Main O2 sensor is the carotid body (CB) that adjusts ventilation - Oxygenated blood is pumped from the lungs to the brain via the carotid arteries - CB are situated at the bifurcation of the common carotid arteries that sense O2 in the blood o Changes in O2  chemoreceptor afferents  NTS  VRG  initiate respiratory reflexes Regulation of breathing by hypoxia (e.g., hypoxic ventilatory response) 1. HVR is different in neonatal mammals than in adults o In neonates, the HVR is biphasic because hypoxia suppresses metabolism (e.g., O2 consumption is low and CO2 production is low), so there is a reduced drive to breathe  Phase 1 = increase in ventilation is attributable to increase in frequency and tidal volume  Phase 2 = decrease in ventilation due to suppressed metabolism o In adults, hypoxia does not suppress metabolism and therefore, the biphasic response is nullified  The magnitude of ventilation increases and stays elevated 2. HVR is time-dependent and CO2/pH-dependent o HVR does not remain constant o Depends on developmental stage, length of hypoxic exposure, pattern of hypoxia, and species o Sensitization of HVR over time  Breathing rate is increasing (or decreasing) at a constant hypoxic condition o Desensitization of HVR over time (e.g., hypoxic adaptation)  Low altitude resident  ↓ arterial O2 = ↑ ventilation  High altitude resident  ↓ arterial O2 = less ↑ ventilation  High altitude native  ↓ arterial O2 = no change in ventilation 3. HVR is sensitive to the pattern of hypoxia o Intermittent periods (e.g., short) of hypoxia o Sustained periods (e.g., long) of hypoxia - The different HVR is explained by the fact that hypoxia acts both peripherally and centrally (e.g., hypoxia is sensed by the CB and the CNS) Peripheral vs. central hypoxia - Central O2-sensitive sites that manipulate breathing include thalamus, hypothalamus, pons, and medulla o THMP - Central hypoxia in animals o C-fos expression after exposure to hypoxia (↓ O2)  C-fos-positive neurons in medulla (e.g., NTS, raphé nucleus, rostral VLM) and pons (e.g., LC)  Therefore, these brain areas are activated by hypoxia o HVR during sustained hypoxia in vitro  Use a slice preparation of the medulla that contains the respiratory network  Sustained hypoxia = respiratory depression (↓ frequency and ↓ amplitude) in fetus/neonates  HVR decline is due to o Reduced metabolism o Reduced neuronal excitability o Activation of a central inhibitory network (e.g., group of cells inhibited by O2) o Pre-botC responds to changes in O2 levels in vivo  Microinjection of NaCN in pre-BotC = local hypoxia = ↑ breathing in anesthetized adult cats  ↑ phrenic nerve activity = ↑ inspiratory amplitude + ↑ respiratory frequency  NaCN blocks correct oxygen usage by cells  Inhibitor of cellular respiration  Acting on mitochondrial cytochrome oxidase  Blocking electron transport  Decreased oxidative metabolism and oxygen utilization (e.g., anaerobic metabolism)  Lactic acidosis - Peripheral hypoxia (and central hypercapnia) in humans o Humans do not respond to central hypoxia, only peripheral hypoxia in vivo  BR (bilateral CB surgical removal)  Hypoxia = no ventilatory response  Hypercapnia = ↑ ventilation  UR (unilateral CB surgical removal)  Hypoxia = mild ↑ ventilation  Hypercapnia = ↑ ventilation  C (control CB)  Hypoxia = ↑ ventilation  Hypercapnia = ↑ ventilation o The central chemoreceptors are still intact because the CNS responds to central hypercapnia Mechanism for sensing hypoxia - Hypoxia can act on both the CNS and the PNS to affect breathing - Need to consider if the hypoxic exposure is acute, sustained, chronic, or intermittent - Neuronal responses to hypoxia likely reflect changes inthe function of ion channels, oxygen sensors, signalling pathways, neuromodulators, and genomic processes o Membrane hypothesis  role of ion channels that either directly sense O2 or its conductance is regulated by a membrane-bound protein  O2 sensors on the membrane directly sense O2 and regulate the conductance of ion channels o A number of ion channels (e.g., K+, Ca2+, Na+ channels) are modulated by hypoxia in ways that can result in depolarization and increased excitability of cells - Central O2
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