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UID:20251219T215805EST-3250pSUvCw@132.216.98.100
DTSTAMP:20251220T025805Z
DESCRIPTION:Speaker: Clifford. B. Saper\n\nDepartment of Neurology\, Progra
 m in Neuroscience\, Beth Israel Deaconess Medical Center and Harvard Medic
 al School\, USA\n\nRegistration available here. \n\nAbstract: Sleep apnea 
 is caused by relaxation of the airway dilator muscles during sleep that ca
 uses the airway to become occluded. During the apnea\, there is a rise in 
 CO2\, fall in O2\, and increased negative airway pressure as the individua
 l tries to breathe. These stimuli eventually cause arousal with wakening a
 s well as sudden increase in muscle tone\, opening the airway. The patient
  then falls asleep again\, only to have this recur a few minutes later. We
  have traced the neural pathways taken by hypoxic\, hypercarbic\, and airw
 ay mechanoreceptors into the brain\, and found that all of these converge 
 on neurons in the ventrolateral part of the parabrachial nucleus (PB) in t
 he pons. The PB neurons that are activated by hypoxia or hypercarbia are g
 lutamatergic\, and we found that deleting the vesicular glutamate transpor
 ter 2 gene from them prevents arousals to these stimuli. In a molecular di
 ssection of the PB\, we found that the neurons activated by hypercarbia th
 at project to the forebrain express calcitonin gene-related peptide (CGRP)
 . Optogenetic inhibition of just the CGRP neurons in the PB or their targe
 ts in the forebrain caused loss of awakening to CO2\, although stimulation
  of respiration remained intact\, suggesting that the respiratory and arou
 sal components of CO2 response are mediated by different neurons.\n\nOther
  work had suggested that the serotonin system is also required for CO2 res
 ponse. We found that the serotonin input to the CGRP neurons comes from th
 e dorsal raphe nucleus. Optogenetic inhibition of the dorsal raphe seroton
 in neurons or their terminals in the PB prevented arousal to CO2\, but not
  respiratory response. PB CGRP neurons were found to express 5HT2a recepto
 rs for serotonin\, and when animals were given a 5HT2a agonist\, inhibitio
 n of the dorsal raphe no longer prevented arousal to CO2. Thus the effect 
 of the serotonin system on CO2 arousal is due to dorsal raphe inputs to th
 e PB CGRP cells. However\, this pathway has little effect on the respirato
 ry response to CO2.\n\nWe next looked for genetic markers that define the 
 PB neurons that contribute to the respiratory response to CO2. We found th
 at neurons that express the FoxP2 transcription factor send efferents to t
 he respiratory control centers in the medulla\, and show increased activit
 y with fiber photometry during CO2 exposure. Optogenetic activation of the
 se neurons selectively increases respiration\, while photoinhibition cause
 s a reduction in CO2 stimulated ventilation\, but not in awakening to CO2.
 \n\nWe are currently studying single cell expression profiling in the PB t
 o determine which genetically defined classes of cells contribute to the w
 akening and ventilatory responses to CO2\, and whether differences in rece
 ptor expression may permit differential reduction in awakening and increas
 ed respiratory response in patients with sleep apnea\, thus limiting sleep
  fragmentation and periods of hypoxia.\n\n\nSupported by the generosity of
  the Killam Trusts \, The Neuro’s Killam Seminar series hosts outstanding 
 guest speakers whose research is of interest to the scientific community a
 t The Neuro and 91Ë¿¹ÏÊÓƵ.\n
DTSTART:20211005T200000Z
DTEND:20211005T210000Z
SUMMARY:Killam Seminar Series: 'Brain Circuitry for Arousal from Sleep Apne
 a'
URL:/neuro/channels/event/killam-seminar-series-brain-
 circuitry-arousal-sleep-apnea-333598
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