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. 2019 Feb 27;5(2):eaav5447.
doi: 10.1126/sciadv.aav5447. eCollection 2019 Feb.

Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

Lauren M Hablitz  1 , Hanna S Vinitsky  1 , Qian Sun  1 , Frederik Filip Stæger  2 , Björn Sigurdsson  2 , Kristian N Mortensen  2 , Tuomas O Lilius  2   3 , Maiken Nedergaard  1   2
Affiliations

Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

Lauren M Hablitz et al. Sci Adv. .

Abstract

The glymphatic system is responsible for brain-wide delivery of nutrients and clearance of waste via influx of cerebrospinal fluid (CSF) alongside perivascular spaces and through the brain. Glymphatic system activity increases during sleep or ketamine/xylazine (K/X) anesthesia, yet the mechanism(s) facilitating CSF influx are poorly understood. Here, we correlated influx of a CSF tracer into the brain with electroencephalogram (EEG) power, heart rate, blood pressure, and respiratory rate in wild-type mice under six different anesthesia regimens. We found that glymphatic CSF tracer influx was highest under K/X followed by isoflurane (ISO) supplemented with dexmedetomidine and pentobarbital. Mice anesthetized with α-chloralose, Avertin, or ISO exhibited low CSF tracer influx. This is the first study to show that glymphatic influx correlates positively with cortical delta power in EEG recordings and negatively with beta power and heart rate.

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Figures

Fig. 1
Fig. 1. Anesthetic regimen effects CSF tracer distribution at the dorsal and ventral brain surfaces.
(A) Population-based average of tracer distribution at the dorsal (top) and ventral (bottom) brain surfaces with anatomical references. (B) Comparison of average tracer distribution at the dorsal (top) and ventral (bottom) brain surfaces in the six groups of anesthetized mice. (C) Boxplots comparing dorsal (top) and ventral (bottom) tracer distributions for the six different anesthetic agents or combinations (whiskers, minimum and maximum; box, quartiles; and line, median). Kruskal-Wallis test followed by Bonferroni correction, *P < 0.05, **P < 0.01, ***P < 0.001. K/X, n = 35 animals; ISO supplemented with dex (ISO/dex), n = 14 animals; pentobarbital (Pentobar), n = 27 animals; α-chloralose (α-chlor), n = 20 animals; tribromoethanol (Avertin), n = 27 animals; and ISO, n = 20 animals. ACA, anterior cerebral artery; BA, basilar artery; C. Willis, circle of Willis; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; RCS, rostral confluence of sinuses; SS, sigmoid sinus; SSS, superior sagittal sinus; and TS, transverse sinus. a.u., arbitrary units.
Fig. 2
Fig. 2. Anesthetic agents differentially alter CSF tracer distribution in coronal brain sections.
(A) Population-based median tracer distribution within the most posterior slice position in the six groups of anesthetized mice. (B) Boxplot displaying average tracer distribution across all brain slices (each dot represents the average of one brain) in the six groups of anesthetized mice (whiskers, minimum and maximum; box, quartiles; and line, median). Kruskal-Wallis test followed by Bonferroni correction, *P < 0.05, ***P < 0.001. (C and D) Correlation between CSF tracer distribution in coronal slices (slice MPI) and tracer distribution at the (C) ventral and (D) dorsal surfaces. K/X, n = 36 animals; ISO supplemented with dex, n = 14 animals; pentobarbital, n = 27 animals; α-chloralose, n = 20 animals; tribromoethanol, n = 27 animals; and ISO, n = 22 animals.
Fig. 3
Fig. 3. Glymphatic tracer influx correlates with the prevalence of slow delta waves.
(A) Representative normalized EEG power spectra for each anesthetic regimen. (B to E) Scatterplots depicting the correlation between MPI in coronal slices and the prevalence of delta (B), beta (C), theta (D), and alpha (E) EEG band power. Each dot represents the group mean (whiskers, SD). Correlations were calculated using group means; P values and R2 values are displayed for each correlation. K/X, n = 36 animals for influx and 8 animals for EEG; ISO supplemented with dex, n = 14 animals for influx and 7 animals for EEG; pentobarbital, n = 27 animals for influx and 8 animals for EEG; α-chloralose, n = 20 animals for influx and 8 animals for EEG; tribromoethanol, n = 27 animals for influx and 5 animals for EEG; and ISO, n = 23 animals for influx and 6 animals for EEG.
Fig. 4
Fig. 4. Glymphatic tracer influx is inversely correlated with heart rate.
(A) Representative traces of electrocardiogram and respiratory measurements for the six anesthetic regimens. (B to D) Scatterplots showing the correlation between MPI in coronal slices and heart rate (B), respiratory rate (C), and systolic blood pressure (BP) (D) across all anesthetic groups. Each dot represents the group mean (whiskers, SD). Correlations were calculated using group means; P values and R2 values are displayed for each correlation. K/X, n = 36 animals for influx and 9 animals for cardiopulmonary measurements; ISO supplemented with dex, n = 14 animals for influx and 7 animals for cardiopulmonary measurements (CPMs); pentobarbital, n = 27 animals for influx and 8 animals for CPMs; tribromoethanol, n = 27 animals for influx and 5 animals for CPMs; α-chloralose, n = 20 animals for influx and 8 animals for CPMs; and ISO, n = 23 animals for influx and 7 animals for CPMs.
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References

    1. Iliff J. J., Wang M., Liao Y., Plogg B. A., Peng W., Gundersen G. A., Benveniste H., Vates G. E., Deane R., Goldman S. A., Nagelhus E. A., Nedergaard M., A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012). - PMC - PubMed
    1. Jessen N. A., Munk A. S., Lundgaard I., Nedergaard M., The glymphatic system: A beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015). - PMC - PubMed
    1. Mestre H., Hablitz L. M., Xavier A. L. R., Feng W., Zou W., Pu T., Monai H., Murlidharan G., Castellanos Rivera R. M., Simon M. J., Pike M. M., Plá V., Du T., Kress B. T., Wang X., Plog B. A., Thrane A. S., Lundgaard I., Abe Y., Yasui M., Thomas J. H., Xiao M., Hirase H., Asokan A., Iliff J. J., Nedergaard M., Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, e40070 (2018). - PMC - PubMed
    1. Plog B. A., Nedergaard M., The glymphatic system in central nervous system health and disease: Past, present, and future. Annu. Rev. Pathol. 13, 379–394 (2018). - PMC - PubMed
    1. Xie L., Kang H., Xu Q., Chen M. J., Liao Y., Thiyagarajan M., O’Donnell J., Christensen D. J., Nicholson C., Iliff J. J., Takano T., Deane R., Nedergaard M., Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013). - PMC - PubMed

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