Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes

Pulido, Robert S.; Munji, Roeben N.; Chan, Tamara; Quirk, Clare R; Weiner, Geoffrey; Weger, Benjamin D.; Rossi, Meghan; Elmsaouri, Sara; Malfavon, Mario; Deng, Aaron; Profaci, Caterina P.; Blanchette, Marie; Qian, Tongcheng; Foreman, Koji L.; Shusta, Eric V.; Gorman, Michael R.; Gachon, Frédéric; Leutgeb, Stefan; Daneman, Richard

doi:10.1016/j.neuron.2020.09.002

Cited by 112 publications

(93 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While an increasing number of statistical methods allow the analysis of rhythmicity from time-series gene expression analysis, algorithms to assess differential rhythmicity across multiple conditions remain scarce ( 25 , 26 ). Previously, we have used harmonic regression and model selection to assess differential rhythmicity between conditions in various settings ( 27 – 33 ). The key idea is that rhythmicity parameters (amplitude and phase) for each condition can be shared across subsets of conditions, leading to a combinatorial set of possible models for each gene ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms

Weger

Gobet

David

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

118

View full text Add to dashboard Cite

The circadian clock and feeding rhythms are both important regulators of rhythmic gene expression in the liver. To further dissect the respective contributions of feeding and the clock, we analyzed differential rhythmicity of liver tissue samples across several conditions. We developed a statistical method tailored to compare rhythmic liver messenger RNA (mRNA) expression in mouse knockout models of multiple clock genes, as well as PARbZip output transcription factors (Hlf/Dbp/Tef). Mice were exposed to ad libitum or night-restricted feeding under regular light–dark cycles. During ad libitum feeding, genetic ablation of the core clock attenuated rhythmic-feeding patterns, which could be restored by the night-restricted feeding regimen. High-amplitude mRNA expression rhythms in wild-type livers were driven by the circadian clock, but rhythmic feeding also contributed to rhythmic gene expression, albeit with significantly lower amplitudes. We observed that Bmal1 and Cry1/2 knockouts differed in their residual rhythmic gene expression. Differences in mean expression levels between wild types and knockouts correlated with rhythmic gene expression in wild type. Surprisingly, in PARbZip knockout mice, the mean expression levels of PARbZip targets were more strongly impacted than their rhythms, potentially due to the rhythmic activity of the D-box–repressor NFIL3. Genes that lost rhythmicity in PARbZip knockouts were identified to be indirect targets. Our findings provide insights into the diurnal transcriptome in mouse liver as we identified the differential contributions of several core clock regulators. In addition, we gained more insights on the specific effects of the feeding–fasting cycle.

show abstract

Section: Resultsmentioning

confidence: 99%

Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms

Weger

Gobet

David

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

118

View full text Add to dashboard Cite

show abstract

“…Sleep quality is controlled by circadian rhythms. Recent papers in rodents ( Hablitz et al, 2020 ; Pulido et al, 2020 ) and Drosophila ( Artiushin et al, 2018 ; Zhang et al, 2018 ) emphasized the circadian regulation of the glymphatic system, lymphatic drainage and BBB permeability. For instance, in mice, glymphatic CSF influx, and solute clearance from the brain, do vary according to circadian rhythms independent of arousal state ( Hablitz et al, 2020 ).…”

Section: Glymphatic System and Periphery: Implications For Cns Disordmentioning

confidence: 99%

“…This is matched by the perivascular polarization of AQP4, which is highest during the rest phase. An intricate relationship has been documented between neuronal activity and the expression of circadian clock genes within brain ECs, which in turn, orchestrate the activity-dependent control of BBB efflux transport ( Pulido et al, 2020 ).…”

Section: Glymphatic System and Periphery: Implications For Cns Disordmentioning

confidence: 99%

Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

et al. 2021

View full text Add to dashboard Cite

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term “glymphatic” (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer’s disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood–brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

show abstract

“…Increased BBB permeability provokes an immediate loss of homeostatic control of ions, ATP, and neurotransmitters levels in the brain, promoting abnormal synaptic transmission or neuronal firing, possibly leading to neurological sequelae ( 6 – 13 ). On the other hand, neuronal activity significantly influences cerebrovascular functions in health and disease conditions ( 14 , 15 ). Diagnostically and because of increased BBB permeability, peripherally injected imaging contrast agents can access the brain parenchyma while a suite of central nervous system (CNS) proteins (see Table 1 ) or nucleic acids [circulating free DNA and microRNA; for a review see ( 44 , 45 )] can exit into the peripheral blood ( Figures 2A–C , 3A–C ).…”

Section: Introduction: From Blood–brain Barrier To Blood–brain Dynamimentioning

confidence: 99%

Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

et al. 2021

View full text Add to dashboard Cite

Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.

show abstract

Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes

Cited by 112 publications

References 107 publications

Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms

Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms

Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

Contact Info

Product

Resources

About