The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose— opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem's breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.
Summary data generated in this study are included as a supplemental supporting file. All Matlab code and an example data are posted on Github: https://github.com/YackleLab/Opioids-depress-breathing-through-two-small-brainstem-sites
- Kevin Yackle
- Kevin Yackle
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Ronald L Calabrese, Emory University, United States
© 2020, Bachmutsky 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.
During deep anesthesia, the electroencephalographic (EEG) signal of the brain alternates between bursts of activity and periods of relative silence (suppressions). The origin of burst-suppression and its distribution across the brain remain matters of debate. In this work, we used functional magnetic resonance imaging (fMRI) to map the brain areas involved in anesthesia-induced burst-suppression across four mammalian species: humans, long-tailed macaques, common marmosets, and rats. At first, we determined the fMRI signatures of burst-suppression in human EEG-fMRI data. Applying this method to animal fMRI datasets, we found distinct burst-suppression signatures in all species. The burst-suppression maps revealed a marked inter-species difference: in rats, the entire neocortex engaged in burst-suppression, while in primates most sensory areas were excluded—predominantly the primary visual cortex. We anticipate that the identified species-specific fMRI signatures and whole-brain maps will guide future targeted studies investigating the cellular and molecular mechanisms of burst-suppression in unconscious states.
In humans, ageing is characterized by decreased brain signal variability and increased behavioral variability. To understand how reduced brain variability segregates with increased behavioral variability, we investigated the association between reaction time variability, evoked brain responses and ongoing brain signal dynamics, in young (N=36) and older adults (N=39). We studied the electroencephalogram (EEG) and pupil size fluctuations to characterize the cortical and arousal responses elicited by a cued go/no-go task. Evoked responses were strongly modulated by slow (<2 Hz) fluctuations of the ongoing signals, which presented reduced power in the older participants. Although variability of the evoked responses was lower in the older participants, once we adjusted for the effect of the ongoing signal fluctuations, evoked responses were equally variable in both groups. Moreover, the modulation of the evoked responses caused by the ongoing signal fluctuations had no impact on reaction time, thereby explaining why although ongoing brain signal variability is decreased in older individuals, behavioral variability is not. Finally, we showed that adjusting for the effect of the ongoing signal was critical to unmask the link between neural responses and behavior as well as the link between task-related evoked EEG and pupil responses.