Critical Role of Plasma Corticosteroid-Binding-Globulin During Stress to Promote Glucocorticoid Delivery to the Brain: Impact on Memory Retrieval

Previous investigations on the antipyretic properties of arginine vasopressin have used bacterial endotoxins or pyrogens to induce fever. Because these experimental models of fever fail to mimic all aspects of the responses to infection, we felt it was important to examine the role of endogenously released vasopressin as a neuromodulator in febrile thermoregulation during infection. Therefore the present study examines the effects of chronic infusion of a V1-receptor antagonist or saline (via osmotic minipumps into the ventral septal area of the brain) on a fever induced by injection of live bacteria. Telemetry was used for continuous measurement of body temperature in the awake unhandled rat. Animals infused with the V1-antagonist exhibited fevers that were greater in duration compared with those of saline-infused animals. These results support the hypothesis that vasopressin functions as an antipyretic agent or fever-reducing agent in brain. Importantly, they suggest that endogenously released vasopressin may play a role as a neuromodulator in natural fever.

Download Full-text

Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain

Steroids ◽

10.1016/j.steroids.2013.10.013 ◽

2014 ◽

Vol 81 ◽

pp. 109-115 ◽

Cited By ~ 22

Author(s):

M.P. Moisan ◽

A.M. Minni ◽

G. Dominguez ◽

J.C. Helbling ◽

A. Foury ◽

...

Keyword(s):

Corticosteroid Binding Globulin ◽

The Brain

Download Full-text

Syk and Hrs Regulate TLR3-Mediated Antiviral Response in Murine Astrocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6927380 ◽

2019 ◽

Vol 2019 ◽

pp. 1-21 ◽

Cited By ~ 2

Author(s):

Matylda B. Mielcarska ◽

Magdalena Bossowska-Nowicka ◽

Karolina P. Gregorczyk-Zboroch ◽

Zbigniew Wyżewski ◽

Lidia Szulc-Dąbrowska ◽

...

Keyword(s):

Immune Responses ◽

Signaling Pathway ◽

Critical Role ◽

Antiviral Response ◽

Proteolytic Processing ◽

Viral Dsrna ◽

Kinase Substrate ◽

Tlr3 Signaling ◽

The Brain

Toll-like receptors (TLRs) sense the presence of pathogen-associated molecular patterns. Nevertheless, the mechanisms modulating TLR-triggered innate immune responses are not yet fully understood. Complex regulatory systems exist to appropriately direct immune responses against foreign or self-nucleic acids, and a critical role of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), endosomal sorting complex required for transportation-0 (ESCRT-0) subunit, has recently been implicated in the endolysosomal transportation of TLR7 and TLR9. We investigated the involvement of Syk, Hrs, and STAM in the regulation of the TLR3 signaling pathway in a murine astrocyte cell line C8-D1A following cell stimulation with a viral dsRNA mimetic. Our data uncover a relationship between TLR3 and ESCRT-0, point out Syk as dsRNA-activated kinase, and suggest the role for Syk in mediating TLR3 signaling in murine astrocytes. We show molecular events that occur shortly after dsRNA stimulation of astrocytes and result in Syk Tyr-342 phosphorylation. Further, TLR3 undergoes proteolytic processing; the resulting TLR3 N-terminal form interacts with Hrs. The knockdown of Syk and Hrs enhances TLR3-mediated antiviral response in the form of IFN-β, IL-6, and CXCL8 secretion. Understanding the role of Syk and Hrs in TLR3 immune responses is of high importance since activation and precise execution of the TLR3 signaling pathway in the brain seem to be particularly significant in mounting an effective antiviral defense. Infection of the brain with herpes simplex type 1 virus may increase the secretion of amyloid-β by neurons and astrocytes and be a causal factor in degenerative diseases such as Alzheimer’s disease. Errors in TLR3 signaling, especially related to the precise regulation of the receptor transportation and degradation, need careful observation as they may disclose foundations to identify novel or sustain known therapeutic targets.

Download Full-text

Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits

Human Molecular Genetics ◽

10.1093/hmg/ddaa198 ◽

2020 ◽

Vol 29 (18) ◽

pp. 3054-3063

Author(s):

Congyao Zha ◽

Carole A Farah ◽

Richard J Holt ◽

Fabiola Ceroni ◽

Lama Al-Abdi ◽

...

Keyword(s):

Optic Lobe ◽

Critical Role ◽

Genetic Diagnosis ◽

Compound Heterozygous ◽

Clinical Genetic ◽

Eye Disorders ◽

Neurodevelopmental Deficits ◽

Independent Families ◽

The Brain

Abstract Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.

Download Full-text

Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

10.1101/2021.05.21.21257099 ◽

2021 ◽

Author(s):

Niklas Schwarz ◽

Simone Seiffert ◽

Manuela Pendziwiat ◽

Annika Rademacher ◽

Tobias Bruenger ◽

...

Keyword(s):

Functional Analysis ◽

De Novo ◽

Critical Role ◽

Specific Response ◽

Loss Of Function ◽

Causative Gene ◽

Characteristic Functional ◽

Research Collaborations ◽

The Brain

Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid. Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

Download Full-text

Role of astroglial Connexin 43 in pneumolysin cytotoxicity and during pneumococcal meningitis

PLoS Pathogens ◽

10.1371/journal.ppat.1009152 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1009152

Author(s):

Chakir Bello ◽

Yasmine Smail ◽

Vincent Sainte-Rose ◽

Isabelle Podglajen ◽

Alice Gilbert ◽

...

Keyword(s):

Plasma Membrane ◽

Connexin 43 ◽

Critical Role ◽

Neurovascular Unit ◽

Brain Slices ◽

Host Cells ◽

Intermediate Filament Protein ◽

Young Infants ◽

The Brain

Streptococcus pneumoniae or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people worldwide. The mechanism underlying PN crossing of the blood brain barrier (BBB) and specifically, the role of non-endothelial cells of the neurovascular unit that control the BBB function, remains poorly understood. Here, we show that the astroglial connexin 43 (aCx43), a major gap junctional component expressed in astrocytes, plays a predominant role during PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. Immunofluorescence analysis of brain slices indicated that PN induces the aCx43–dependent destruction of the network of glial fibrillary acid protein (GFAP), an intermediate filament protein specifically expressed in astrocytes and up-regulated in response to brain injury. PN also induced nuclear shrinkage in astrocytes associated with the loss of BBB integrity, bacterial translocation across endothelial vessels and replication in the brain cortex. We found that aCx4-dependent astrocyte damages could be recapitulated using in vitro cultured cells upon challenge with wild-type PN but not with a ply mutant deficient for the pore-forming toxin pneumolysin (Ply). Consistently, we showed that purified Ply requires Cx43 to promote host cell plasma membrane permeabilization in a process involving the Cx43-dependent release of extracellular ATP and prolonged increase of cytosolic Ca2+ in host cells. These results point to a critical role for astrocytes during PN meningitis and suggest that the cytolytic activity of the major virulence factor Ply at concentrations relevant to bacterial infection requires co-opting of connexin plasma membrane channels.

Download Full-text

Glymphatics: A Transformative Development in Medical Neuroscience Relevant to Injuries in Military Central Nervous System

Military Medicine ◽

10.1093/milmed/usab344 ◽

2021 ◽

Author(s):

James Meyerhoff ◽

Nabarun Chakraborty ◽

Rasha Hammamieh

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Sleep Deprivation ◽

Brain Edema ◽

Critical Role ◽

Spatial Relationship ◽

Military Operations ◽

Glymphatic System ◽

The Brain

ABSTRACT Introduction The glia-operated glymphatic system, analogous to but separate from the lymphatics in the periphery, is unique to brain and retina, where it is very closely aligned with the arteriolar system. This intimate relationship leads to a “blood vessel like” distribution pattern of glymphatic vessels in the brain. The spatial relationship of glymphatics, including their essential component aquaporin-4 with vascular pericytes of brain arterioles is critical to functionality and is termed “polarization”. Materials and Methods We review the available literature on the factors affecting the resting state of glymphatics under normal conditions, including the important role of sleep in supporting normal glymphatic function (including waste removal) as well as the critical role of “polarization” under normal conditions. We then examine the effects of traumatic brain injury (TBI) or seizures on the glymphatic system and its state of “polarization”. Results Injury, such as TBI, can disrupt polarization resulting in “depolarization” leading to brain edema. Conclusion Damage to the glymphatic system might explain the brain edema so often seen following TBI or other insult. Moreover, similar damage should be expected in response to seizures, which can often be associated with chemical exposures as well as with TBI. Military operations, whether night operations or continuous operations, quite often impose limitations on sleep. As glymphatic function is sleep-dependent, sleep deprivation alone could compromise glymphatic function, as well, and might in addition, explain some of the well-known performance deficits associated with sleep deprivation. Possible effects of submarine and diving operations, chemical agents (including seizures), as well as high altitude exposure and other threats should be considered. In addition to the brain, the retina is also served and protected by the glymphatic system. Accordingly, the effect of military-related risks (e.g., exposure to laser or other threats) to retinal glymphatic function should also be considered. An intact glymphatic system is absolutely essential to support normal central nervous system functionality, including cognition. This effects a broad range of military threats on brain and retinal glymphatics should be explored. Possible preventive and therapeutic measures should be proposed and evaluated, as well.

Download Full-text

Cathelicidin Protects the Brain from Mitochondrial DNA Damage in Health, but not Following Septic Shock

10.21203/rs.3.rs-514325/v1 ◽

2021 ◽

Author(s):

Denise Frediani barbeiro ◽

Suely Kubo Ariga ◽

Hermes Vieira Barbeiro ◽

Nadja C Souza-Pinto ◽

Fabiano Pinheiro da Silva

Keyword(s):

Septic Shock ◽

Dna Damage ◽

Mitochondrial Dna ◽

Critical Role ◽

Innate Immune ◽

Experimental Sepsis ◽

Mitochondrial Dna Damage ◽

Innate Immune Signaling ◽

The Brain

Abstract Recent discoveries have demonstrated that mitochondria play a critical role in innate immune signaling. By the other hand, immune responses may lead to mitochondrial deregulation. Cathelicidins play a critical role in innate immunity, promoting poorly understood cellular responses that may enhance or inhibit several signaling pathways, depending on the health conditions and subjacent microenvironment.Here, we investigated the role of CRAMP, the murine cathelicidin, in healthy mice and following experimental sepsis. We found that sepsis induces significant mitochondrial DNA damage in the prefrontal cortex and that cathelicidin protects the brain from this kind of damage in healthy animals, but not following septic shock.

Download Full-text

Context Retrieval as a Critical Component in Selective Memory Retrieval

Current Directions in Psychological Science ◽

10.1177/0963721419827520 ◽

2019 ◽

Vol 28 (2) ◽

pp. 177-182 ◽

Cited By ~ 2

Author(s):

Karl-Heinz T. Bäuml

Keyword(s):

Memory Retrieval ◽

Critical Role ◽

Temporal Context ◽

Critical Component ◽

Memory Research ◽

Item Repetition ◽

Induced Forgetting

Selective retrieval often impairs recall of nonretrieved items, a finding referred to as retrieval-induced forgetting. In this article, I review recent research showing that selective retrieval can also improve recall of other items. This research points to a critical role of context retrieval in selective memory retrieval. The concept of context retrieval, which has played a prominent role in other lines of memory research, suggests that selective retrieval can reactivate the retrieved items’ temporal context during study, facilitating recall of other items that had a similar context at study. Such facilitatory effects on recall can arise both when selective item repetition occurs via retrieval and when it occurs via restudy, which suggests a link to the reminding literature. The findings offer new perspectives for investigating and understanding the effects of selective memory retrieval.

Download Full-text

Age and Dietary Vitamin C Intake Affect Brain Physiology in Genetically Modified Mice Expressing Human Lipoprotein(A) and Unable to Synthesize Vitamin C

Current Aging Science ◽

10.2174/1874609814666210706170326 ◽

2021 ◽

Vol 14 ◽

Author(s):

Lei Shi ◽

Aleksandra Niedzwiecki ◽

Matthias Rath

Keyword(s):

Vitamin C ◽

Oxidative Damage ◽

Critical Role ◽

Cholesterol Homeostasis ◽

Dietary Vitamin ◽

Brain Health ◽

Lipoprotein A ◽

Vitamin C Deficiency ◽

The Brain

Aims: Lipoprotein (a) deposition in coronary vascular plaques and cerebral vessels is a recognized risk factor for cardiovascular disease, and research supports its role as a “repair factor” in vascular walls weakened by vitamin C deficiency. Background: Humans depend on dietary vitamin C as an important antioxidant, and as a cofactor in collagen synthesis, yet are prone to vitamin C deficiency. The brain is the one with the highest vitamin C content, due to its high oxygen consumption and oxidative stress. It has been shown that brain aging is accompanied by accumulated oxidative damage, which can lead to memory decline and neurological diseases. Objective: Our transgenic mouse, Gulo (-/-); Lp(a)+, presents a unique model for the study of key aspects of human metabolism with respect to a lack of internal vitamin C synthesis and the production of human Lipoprotein(a). Method: This mouse model was used in our study to investigate the effects of prolonged intake of low and high levels of vitamin C, at different ages, on oxidative damage, cholesterol levels and Lipoprotein(a) deposition in the brain. Result: The results show that a long-term high vitamin C intake is important in maintaining brain cholesterol homeostasis and preventing oxidative damage in Gulo(-/-);Lp(a)+ mice as they age. Moreover, we observed that the formation of brain Lipoprotein(a) deposits was negatively correlated with brain level of vitamin C, thereby confirming its role as a stability factor for an impaired extracellular matrix. Conclusion: Our study emphasizes the critical role of vitamin C in protecting brain health as we age. Other: Our findings show that optimal vitamin C intake from early life to old age is important in brain health to prevent oxidative stress damage and to maintain cholesterol homeostasis in the brain. More importantly, negative correlation between brain ascorbic levels and the formation of Lp(a) deposit on the choroid plexus further emphasizes the critical role of vitamin C in protecting brain health throughout the normal aging process.

Download Full-text