Inflammatory pain is thought to arise from increased transmission from nociceptors and recruitment of 'silent' afferents. To evaluate inflammation-induced changes, mice expressing GCaMP3 in cutaneous sensory neurons were generated and neuronal responses to mechanical stimulation in vivo before and after subcutaneous infusion of an 'inflammatory soup' (IS) were imaged in an unanesthetized preparation. Infusion of IS rapidly altered mechanical responsiveness in the majority of neurons. Surprisingly, more cells lost, rather than gained, sensitivity and 'silent' afferents that were mechanically insensitive and gained mechanosensitivity after IS exposure were rare. However, the number of formerly silent afferents that became mechanosensitive was increased 5-fold when the skin was heated briefly prior to infusion of IS. These findings suggest that pain arising from inflamed skin reflects a dramatic shift in the balance of sensory input, where gains and losses in neuronal populations results in novel output that is ultimately interpreted by the CNS as pain.
- Brian M Davis
- Jennifer J DeBerry
- Jeffery C Woodbury
- Jeffery C Woodbury
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All studies were performed in accordance within guidelines of the Institutional Animal Care and Use Committees at the Universities of Pittsburgh and Wyoming and the National Institutes of Health guidelines for the Care and Use of Laboratory Animals. Approved animal protocol numbers include Univ. of Wyoming IACUC protocol #20131206JW00049-03 (for in vivo studies), # p20131203JW00048-3-03 (for ex vivo studies) and University of Pittsburgh IACUC protocol # 15106942 (for calcium imaging studies).
- David D Ginty, Howard Hughes Medical Institute, Harvard Medical School, United States
© 2016, Smith-Edwards 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.