Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased blood-brain barrier permeability in chronically stressed mice

Lee, Sohee; Kang, Bok-Man; Kim, Jaehwan; Min, Jiwoong; Kim, Hyung Seok; Ryu, Hyunwoo; Park, Hyejin; Bae, Sungjun; Oh, Daehwan; Choi, Myunghwan; Suh, Minah

doi:10.1038/s41598-018-30875-y

Cited by 59 publications

(34 citation statements)

References 79 publications

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“…The WD in our study modulated expression of genes regulating the cell-cell junctions. Among these was down regulation of Claudin 5 (CLDN5) which has been observed to result in increased BBB permeability 42 , suggesting a potential genetic mechanism for WD-associated increased BBB permeability, a hypothesis in agreement with our previously reported work 8 . Another differentially expressed gene was the gene coding for ERK1/2 which has also been linked to impairment of BBB via a neuro-inflammatory response promoting leukocyte infiltration 43 .…”

Section: Discussionsupporting

confidence: 90%

The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

Nuthikattu

Milenković

Rutledge

et al. 2019

Sci Rep

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Hyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.

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Section: Discussionsupporting

confidence: 90%

The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

Nuthikattu

Milenković

Rutledge

et al. 2019

Sci Rep

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“…Numerous research groups have pinpointed a synergistic relationship between BBB disruption and immune cell entry to the brain mediating neuroinflammatory insults and psychiatric disorders such as depression [137]. Claudin-5 has emerged as a potential mediator of these effects with several studies identifying downregulation of claudin-5 in numerous models of depression [138, 139]. Transient knockdown of claudin-5 in the nucleus accumbens is associated with exacerbated depression-like behaviours in the chronic social defeat model of depression [31].…”

Section: Dynamic Tight Junction Remodelling In Diseasementioning

confidence: 99%

Claudin-5: gatekeeper of neurological function

Greene¹,

Hanley²,

Campbell³

2019

Fluids Barriers CNS

370

277

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Tight junction proteins of the blood–brain barrier are vital for maintaining integrity of endothelial cells lining brain blood vessels. The presence of these protein complexes in the space between endothelial cells creates a dynamic, highly regulated and restrictive microenvironment that is vital for neural homeostasis. By limiting paracellular diffusion of material between blood and brain, tight junction proteins provide a protective barrier preventing the passage of unwanted and potentially damaging material. Simultaneously, this protective barrier hinders the therapeutic effectiveness of central nervous system acting drugs with over 95% of small molecule therapeutics unable to bypass the blood–brain barrier. At the blood–brain barrier, claudin-5 is the most enriched tight junction protein and its dysfunction has been implicated in neurodegenerative disorders such as Alzheimer’s disease, neuroinflammatory disorders such as multiple sclerosis as well as psychiatric disorders including depression and schizophrenia. By regulating levels of claudin-5, it is possible to abrogate disease symptoms in many of these disorders. This review will give an overview of the blood–brain barrier and the role of tight junction complexes in maintaining blood–brain barrier integrity before focusing on the role of claudin-5 and its regulation in homeostatic and pathological conditions. We will also summarise therapeutic strategies to restore integrity of cerebral vessels by targeting tight junction protein complexes.

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“…Chronic restraint stress is a well-established protocol that induces anxiety-like behaviors in mice (Buynitsky and Mostofsky, 2009;Lee et al, 2015Lee et al, , 2018. The EPM, which contains both closed and open arms, is used to test the level of anxiety-like behaviors in animal subjects: the longer the time spent in the closed arms, the higher the level of anxiety-like behavior.…”

Section: Validation Of the Mouse Chronic Stress Modelmentioning

confidence: 99%

Neurovascular Coupling under Chronic Stress Is Modified by Altered GABAergic Interneuron Activity

et al. 2019

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Neurovascular coupling (NVC), the interaction between neural activity and vascular response, ensures normal brain function by maintaining brain homeostasis. We previously reported altered cerebrovascular responses during functional hyperemia in chronically stressed animals. However, the underlying neuronal-level changes associated with those hemodynamic changes remained unclear. Here, using in vivo and ex vivo experiments, we investigate the neuronal origins of altered NVC dynamics under chronic stress conditions in adult male mice. Stimulus-evoked hemodynamic and neural responses, especially beta and gamma-band local field potential activity, were significantly lower in chronically stressed animals, and the NVC relationship, itself, had changed. Further, using acute brain slices, we discovered that the underlying cause of this change was dysfunction of neuronal nitric oxide synthase (nNOS)-mediated vascular responses. Using FISH to check the mRNA expression of several GABAergic subtypes, we confirmed that only nNOS mRNA was significantly decreased in chronically stressed mice. Ultimately, chronic stress impairs NVC by diminishing nNOS-mediated vasodilation responses to local neural activity. Overall, these findings provide useful information in understanding NVC dynamics in the healthy brain. More importantly, this study reveals that impaired nNOS-mediated NVC function may be a contributory factor in the progression of stress-related diseases.

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Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased blood-brain barrier permeability in chronically stressed mice

Cited by 59 publications

References 79 publications

The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

Claudin-5: gatekeeper of neurological function

Neurovascular Coupling under Chronic Stress Is Modified by Altered GABAergic Interneuron Activity

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