Blood Flow: Supplying the sleeping brain
During sleep, the brain experiences large fluctuations in blood volume and altered coupling between neural and vascular signals.
- Department of Psychological and Brain Sciences, Boston University, United States
- Department of Biomedical Engineering, Boston University, United States
The amount of blood the brain receives is tightly regulated to respond to the metabolic needs of neurons. This ‘neurovascular coupling’ allows flexible delivery of energy, with blood rushing in when neurons are active (Iadecola, 2017). Many brain imaging techniques rely on this process. Functional magnetic resonance imaging (or fMRI for short), in particular, uses blood oxygenation signals to pinpoint changes in neural activity. Understanding neurovascular dynamics is therefore essential for neuroscience research and the correct interpretation of fMRI measurements.
Sleep profoundly transforms most aspects of brain physiology, including blood oxygenation signals (Horovitz et al., 2008), but its effects on neurovascular dynamics are not well understood. Now, in eLife, Patrick J. Drew and colleagues from Pennsylvania State University – with Kevin Turner as first author – report an in-depth characterization of how blood volume and neurovascular coupling change across arousal states in mice (Turner et al., 2020; Figure 1).
Figure 1
Large fluctuations in blood volume and altered neurovascular coupling occur during sleep in mice.
Changes in neurovascular dynamics were examined in head-fixed mice (left) which were awake (grey), in non-rapid eye movement sleep (NREM; blue), and rapid eye movement sleep (REM; red). (A) As inferred from changes in cortical hemoglobin levels, total blood volume increases drastically during sleep, especially during REM sleep. (B) Average arteriole dilation during sleep increases above the level found during the awake state. (C) Sleep occurs during eyes-open behavioral rest in head-fixed mice. NREM sleep (38% of rest periods) commonly occurred during behavioral rest. REM sleep was less common but still occurred (5% of rest periods). (D) The strength of coupling between neural signals (multi-unit activity, or MUA) and levels of cortical hemoglobin (HbT) increased during NREM sleep, and the timing of coupling shifted across sleep stages.
Image credit: Mouse illustrations adapted from Luigi Petrucco via SciDraw (CCBY 4.0); Blood cells illustrations adapted from John Chilton via SciDraw (CCBY 4.0); Panel C adapted from Turner et al., 2020 (CCBY 4.0).
To investigate this question, Turner et al. monitored behavioral, neural, and vascular signals while mice were awake or in non-rapid and rapid eye movement sleep (respectively NREM and REM). The heads of the animals were immobilized to allow imaging. However, mice can still sleep with their eyes open under these conditions, prompting Turner et al. to collect detailed behavioral and physiological measurements to determine sleep stages.
First, intrinsic optical signal imaging was used to infer the amount of hemoglobin, which in turn is correlated with the volume of blood in the brain. This method relies on the light reflection changing with the hemoglobin content, and it revealed large variations in the volume of blood in the brain during sleep. When mice entered NREM sleep, the amplitude of oscillations in hemoglobin levels more than doubled compared to the awake state; during REM sleep, they showed a prolonged increase in total hemoglobin that lasted more than 30 seconds. The amount of total hemoglobin changed drastically as mice woke up or fell asleep, highlighting that blood volume dynamics are coupled with arousal state. Together, these results show that blood volume in the brain fluctuates greatly during sleep.
In addition to these large-scale measurements of hemoglobin, Turner et al. tracked the diameter of tiny vessels known as arterioles. During NREM sleep, arteriole diameters fluctuated greatly, and they increased even further (over tens of seconds) when mice entered REM sleep. These measurements helped to unravel how arterioles, capillaries and veins each contribute to the changes in global blood volume measured by intrinsic optical signal imaging.
Next, Turner et al. examined whether the changes in blood volume during sleep were linked to variations in neural activity, which normally drive fluctuations in the diameter of arterioles (Mateo et al., 2017). This revealed that the strength of the neurovascular coupling changed depending on arousal states, increasing substantially during NREM sleep compared to wakefulness. The timing of the coupling was also altered, with the blood volume response being slower during REM sleep than in the awake state.
Many studies that use head-fixed mice do not systemically assess whether the animals are awake, raising the question of how much time they actually spend asleep. Analyzing all 15 seconds rest periods in which mice had their eyes open showed that they were actually sleeping in nearly half of these intervals. In addition, only measuring heart rate or whisker movements could not reliably identify sleeping periods. These findings suggest that head-fixed imaging studies should include measurements of arousal state to detect if the mice are asleep.
Overall, Turner et al. identify a striking transformation of neurovascular dynamics during sleep: blood volume increases and exhibits large oscillations, and coupling to neural activity is altered. Intriguingly, vascular dynamics during sleep, including variations in blood volume, are much larger than those driven by the well-studied stimuli and behaviors found in the awake state. Why is this the case? In addition to changes in neural activity and cognition, sleep also involves increased waste clearance from the brain, which has been linked to vascular oscillations (Xie et al., 2013; Iliff et al., 2013; Mestre et al., 2018; van Veluw et al., 2020). Thus, these results also help identify the consequences of sleep for the brain, and how blood dynamics may contribute to brain health.
References
-
Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brainJournal of Neuroscience 33:18190–18199.https://doi.org/10.1523/JNEUROSCI.1592-13.2013
Article and author information
Author details
Stephanie D Williams
Publication history
- Version of Record published: December 23, 2020 (version 1)
Copyright
© 2020, Williams and Lewis
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,025
- Page views
-
- 251
- Downloads
-
- 3
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Blood Flow: Supplying the sleeping brain
eLife 9:e64597.
https://doi.org/10.7554/eLife.64597
Further reading
-
- Neuroscience
Medial frontal cortical areas are thought to play a critical role in the brain’s ability to flexibly deploy strategies that are effective in complex settings, yet the underlying circuit computations remain unclear. Here, by examining neural ensemble activity in male rats that sample different strategies in a self-guided search for latent task structure, we observe robust tracking during strategy execution of a summary statistic for that strategy in recent behavioral history by the anterior cingulate cortex (ACC), especially by an area homologous to primate area 32D. Using the simplest summary statistic – strategy prevalence in the last 20 choices – we find that its encoding in the ACC during strategy execution is wide-scale, independent of reward delivery, and persists through a substantial ensemble reorganization that accompanies changes in global context. We further demonstrate that the tracking of reward by the ACC ensemble is also strategy-specific, but that reward prevalence is insufficient to explain the observed activity modulation during strategy execution. Our findings argue that ACC ensemble dynamics is structured by a summary statistic of recent behavioral choices, raising the possibility that ACC plays a role in estimating – through statistical learning – which actions promote the occurrence of events in the environment.
-
- Neuroscience
Postsynaptic mitochondria are critical for the development, plasticity, and maintenance of synaptic inputs. However, their relationship to synaptic structure and functional activity is unknown. We examined a correlative dataset from ferret visual cortex with in vivo two-photon calcium imaging of dendritic spines during visual stimulation and electron microscopy reconstructions of spine ultrastructure, investigating mitochondrial abundance near functionally and structurally characterized spines. Surprisingly, we found no correlation to structural measures of synaptic strength. Instead, we found that mitochondria are positioned near spines with orientation preferences that are dissimilar to the somatic preference. Additionally, we found that mitochondria are positioned near groups of spines with heterogeneous orientation preferences. For a subset of spines with a mitochondrion in the head or neck, synapses were larger and exhibited greater selectivity to visual stimuli than those without a mitochondrion. Our data suggest mitochondria are not necessarily positioned to support the energy needs of strong spines, but rather support the structurally and functionally diverse inputs innervating the basal dendrites of cortical neurons.
