Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe
Abstract
Cerebral blood flow is highly sensitive to changes in CO2/H+ where an increase in CO2/H+ causes vasodilation and increased blood flow. Tissue CO2/H+ also functions as the main stimulus for breathing by activating chemosensitive neurons that control respiratory output. Considering that CO2/H+-induced vasodilation would accelerate removal of CO2/H+ and potentially counteract the drive to breathe, we hypothesize that chemosensitive brain regions have adapted a means of preventing vascular CO2/H+-reactivity. Here, we show in rat that purinergic signaling, possibly through P2Y2/4 receptors, in the retrotrapezoid nucleus (RTN) maintains arteriole tone during high CO2/H+ and disruption of this mechanism decreases the CO2ventilatory response. Our discovery that CO2/H+-dependent regulation of vascular tone in the RTN is the opposite to the rest of the cerebral vascular tree is novel and fundamentally important for understanding how regulation of vascular tone is tailored to support neural function and behavior, in this case the drive to breathe.
Article and author information
Author details
Funding
National Institutes of Health (HL104101)
- Daniel K Mulkey
National Institutes of Health (DK053832)
- Mark T Nelson
National Institutes of Health (HL131181)
- Mark T Nelson
Sao Paulo Research Foundation (2016/22069-0)
- Thiago S Moreira
Sao Paulo Research Foundation (2015/23376-1)
- Thiago S Moreira
Sao Paulo Research Foundation (2014/07698-6)
- Milene R Malheiros-Lima
Conselho Nacional de Desenvolvimento Científico e Tecnológico (471283/2012-6)
- Thiago S Moreira
Conselho Nacional de Desenvolvimento Científico e Tecnológico (301651/2013-2)
- Ana C Takakura
Conselho Nacional de Desenvolvimento Científico e Tecnológico (301904/2015-4)
- Thiago S Moreira
Totman Medical Research Trust
- Mark T Nelson
Fondation Leducq
- Mark T Nelson
EC horizon 2020
- Mark T Nelson
Connecticut department of public health (150263)
- Daniel K Mulkey
Sao Paulo Research Foundation (2014/22406-1)
- Ana C Takakura
Conselho Nacional de Desenvolvimento Científico e Tecnológico (471263/2013-3)
- Ana C Takakura
National Institutes of Health (HL126381)
- Virginia E Hawkins
National Institutes of Health (HL095488)
- Mark T Nelson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All in vitro procedures were performed in accordance with National Institutes of Health and University of Connecticut Animal Care and Use Guidelines (protocol # A16-034). All in vivo procedures were performed in accordance with guidelines approved by the University of São Paulo Animal Care and Use Committee (protocol # 112/2015).
Reviewing Editor
- Jan-Marino Ramirez, Seattle Children's Research Institute and University of Washington, United States
Publication history
- Received: January 18, 2017
- Accepted: April 6, 2017
- Accepted Manuscript published: April 6, 2017 (version 1)
- Accepted Manuscript updated: April 7, 2017 (version 2)
- Version of Record published: May 8, 2017 (version 3)
Copyright
© 2017, Hawkins et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Neuroscience
The response of the brainstem to increased levels of carbon dioxide in the blood is coordinated with the response of the cardiovascular system.
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- Neuroscience
Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are poorly understood. The developmental transition has important functional consequences, as the latter state is thought to allow for more efficient storage, retrieval and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation-inhibition (E-I) ratio towards inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in mice mimicking the etiology of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.