scholarly journals Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Laurence Dion-Albert ◽  
Alice Cadoret ◽  
Ellen Doney ◽  
Fernanda Neutzling Kaufmann ◽  
Katarzyna A. Dudek ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Stress Responses ◽  
Social Stress ◽  
Depressive Disorders ◽  
Brain Regions ◽  
Brain Barrier ◽  
Female Mice ◽  
Blood Brain ◽  
Stressed Female ◽  
Soluble E Selectin

AbstractPrevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.

scholarly journals Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression

2021 ◽  
Author(s):  
Laurence Dion-Albert ◽  
Alice Cadoret ◽  
Ellen Doney ◽  
Fernanda Neutzling Kaufmann ◽  
Katarzyna A. Dudek ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Chronic Stress ◽  
Stress Responses ◽  
Social Stress ◽  
Brain Regions ◽  
Brain Barrier ◽  
Social Avoidance ◽  
Morphological Alterations ◽  
Blood Brain ◽  
Vascular Biomarkers

Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood and postmortem brain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.

Osmotic Blood-Brain Barrier Modification and Combination Chemotherapy: Concurrent Tumor Regression in Areas of Barrier Opening and Progression in Brain Regions Distant to Barrier Opening

Neurosurgery ◽  
1984 ◽  
Vol 15 (3) ◽  
pp. 362-366 ◽  
Author(s):  
Edward A. Neuwelt ◽  
Suellen A. Hill ◽  
Eugene P. Frenkel
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Tumor Regression ◽  
Primary Cns Lymphoma ◽  
Brain Regions ◽  
Metastatic Carcinoma ◽  
Brain Barrier ◽  
Cns Lymphoma ◽  
Blood Brain ◽  
Barrier Opening

Abstract Chemotherapeutic drug delivery can be enhanced by administering drugs into the internal carotid or vertebral artery circulation after osmotic opening of the blood-brain barrier (BBB). As evidence of the clinical implications of this technique, radiographic documentation of central nervous system (CNS) tumor regression was observed in three patients concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic blood-brain barrier opening. These three patients, one with metastatic carcinoma of the breast, one with glioblastoma, and one with primary CNS lymphoma, highlight the importance of drug delivery to CNS malignancies.

scholarly journals Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

2021 ◽  
Vol 22 (18) ◽  
pp. 10045
Author(s):  
Phuong Thao Do ◽  
Chung-Che Wu ◽  
Yung-Hsiao Chiang ◽  
Chaur-Jong Hu ◽  
Kai-Yun Chen
Keyword(s):  
Stem Cells ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Brain Regions ◽  
Brain Barrier ◽  
Therapeutic Effects ◽  
Pathophysiological Mechanism ◽  
Cell Based Therapy ◽  
Blood Brain

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

scholarly journals Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions during Toxoplasma gondii infection

2019 ◽  
Vol 116 (49) ◽  
pp. 24796-24807 ◽  
Author(s):  
Christine A. Schneider ◽  
Dario X. Figueroa Velez ◽  
Ricardo Azevedo ◽  
Evelyn M. Hoover ◽  
Cuong J. Tran ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Light Sheet ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cell Segmentation ◽  
Cns Infection ◽  
Light Sheet Microscopy ◽  
Blood Brain ◽  
The Brain

Brain infection by the parasite Toxoplasma gondii in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling T. gondii. However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2+Ly6Chi) and patrolling (CX3CR1+Ly6Clo) monocytes into the blood and brain during T. gondii infection of C57BL/6J and CCR2RFP/+CX3CR1GFP/+ mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood–brain barrier (BBB) within 2 wk of T. gondii infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact T. gondii-infected brains using iDISCO+ and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of T. gondii and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of T. gondii clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., Nature 445:168–176 (2007)] indicated a consistent pattern of monocyte infiltration during T. gondii infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during T. gondii CNS infection.

Blood-brain barrier permeability to sucrose and dextran after osmotic opening

1984 ◽  
Vol 247 (4) ◽  
pp. R634-R638 ◽  
Author(s):  
Y. Z. Ziylan ◽  
P. J. Robinson ◽  
S. I. Rapoport
Keyword(s):  
Blood Brain Barrier ◽  
Brain Regions ◽  
Brain Barrier ◽  
Differential Rate ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Size Dependent ◽  
Blood Brain ◽  
Permeability Surface ◽  
Brain Barrier Permeability

Regional cerebrovascular permeability-surface area (PA) products were calculated for two nonelectrolyte tracers differing considerably in molecular weight and size [( 14C]sucrose: mol wt 340 daltons, radius 5 A; and [3H]dextran: mol wt approximately 79,000 daltons, radius approximately 65 A) in control (uninfused) rats and in rats 6, 35, and 55 min after the blood-brain barrier was opened by a 30-s infusion of 1.8 molal L(+)-arabinose into a carotid artery. In control brain regions, mean PA for [14C]sucrose was 10(-5) s-1, whereas PA was not measurable for [3H]dextran. Six minutes after arabinose infusion, PA for both substances increased dramatically to 10(-4) s-1 or more; PA then declined at 35 and 55 min after arabinose infusion, but more markedly for [3H]dextran than for [14C]sucrose. The results demonstrate a size-dependent, differential rate of closure of the blood-brain barrier after osmotic opening. This is shown to be consistent with a pore model with bulk flow for blood-brain barrier permeability after osmotic opening.

The impact of depressive disorders and treatment with an antidepressant on the activity of P-glycoprotein at the blood-brain barrier

2010 ◽  
Vol 122 ◽  
pp. S39-S40
Author(s):  
O.L. de Klerk⁎ ◽  
A.T.M. Willemsen ◽  
F.J. Bosker ◽  
P. Meerlo ◽  
R.A. Dierckx ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Depressive Disorders ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Impact

Influence of age on the passage of paraquat through the blood-brain barrier in rats: A distribution and pathological examination

1996 ◽  
Vol 15 (3) ◽  
pp. 231-236 ◽  
Author(s):  
PS Widdowson ◽  
MJ Farnworth ◽  
MG Simpson ◽  
EA Lock
Keyword(s):  
Blood Brain Barrier ◽  
Neuronal Damage ◽  
Lethal Dose ◽  
Age Groups ◽  
Brain Regions ◽  
Adult Brain ◽  
Brain Barrier ◽  
Pathological Examination ◽  
Neonatal Brain ◽  
Blood Brain

Experiments were performed to determine the extent of paraquat entry into the brain of neonatal and elderly rats, as compared with adult rats, which may be dependent on the efficacy of the blood-brain barrier. A single, median lethal dose (20 mg/kg s.c.) of paraquat containing [14C]paraquat was administered to neonatal (10 day old), adult (3 month old) and elderly (18 month old) rats. In contrast to the adult and elderly rats where paraquat levels fell over the 24 h post-dosing period to negligible levels, paraquat concentrations in neonatal brains did not decrease with time between 0.5 and 24 h following dosing. The distribution of [14C]paraquat was measured in selective brain regions using quantitative autoradiogra phy in all three age groups of rats, 30 min and 24 h following dosing. Autoradiography demonstrated that brain paraquat distributions were similar in the rat age groups. Most of the paraquat was confined to regions outside the blood-brain barrier and to brain regions that lack a complete blood-brain barrier e.g. dorsal hypotha lamus, area postrema and the anterior olfactory bulb. Between 0.5 h and 24 h following dosing, paraquat concentrations in deeper brain structures, some distance away from the sites of entry, began to slowly increase in all the rat age groups. By 24 h following dosing, a majority of brain regions examined using quantitative autoradiogra phy revealed significantly higher paraquat concentrations in neonatal brains as compared to brain regions of adult and elderly rats. Despite increased paraquat entry into neonatal brain, we could find no evidence for paraquat- induced neuronal cell damage following a detailed histopathological examination of perfused-fixed brains. In conclusion, impaired blood-brain barrier integrity in neonatal brain thus permitting more paraquat to enter than in adult brain, did not result in neuronal damage.

scholarly journals Transfer Constants for Blood-Brain Barrier Permeation of the Neuroexcitatory Shellfish Toxin, Domoic Acid

1991 ◽  
Vol 18 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Edward Preston ◽  
Ivo Hynie
Keyword(s):  
Blood Brain Barrier ◽  
Domoic Acid ◽  
Carrier Transport ◽  
Polar Compounds ◽  
Brain Regions ◽  
Brain Barrier ◽  
Adult Rats ◽  
Mean Values ◽  
Blood Brain ◽  
The Brain

ABSTRACT:The cause of the toxic mussel poisoning episode in 1987 was traced to a plankton-produced excitotoxin, domoic acid. Experiments were undertaken to quantitate the degree to which blood-borne domoic acid can permeate the microvasculature to enter the brain. Pentobarbital-anesthetized, adult rats received an i.v. injection of 3H-domoic acid which was permitted to circulate for 3-60 min. Transfer constants (Ki) describing blood-to-brain diffusion of tracer were calculated from analysis of the relationship between brain vs plasma radioactivity with time. Mean values (mL.g-1.s-1 x 106) for permeation into 7 brain regions (n = 10 rats) ranged from 1.60 ± 0.13 (SE) to 1.86 ± 0.33 (cortex, ponsmedulla respectively), and carrier transport or regional selectivity in uptake were not evident. Nephrectomy prior to domoic acid injection resulted in the elevation of circulating plasma tracer level and brain uptake. The Ki values are comparable to those for other polar compounds such as sucrose, and indicate that the blood-brain barrier greatly limits the amount of toxin that enters the brain. Together with absorbed dosage, integrity of the cerebrovascular barrier and normal kidney function are important to the outcome of accidentally ingesting domoic acid.

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