Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

AbstractCommunication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.

Download Full-text

Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus

10.1101/515759 ◽

2019 ◽

Cited By ~ 1

Author(s):

Felix C. Nebeling ◽

Stefanie Poll ◽

Lena C. Schmid ◽

Manuel Mittag ◽

Julia Steffen ◽

...

Keyword(s):

Neuronal Activity ◽

Dendritic Spines ◽

Synapse Formation ◽

Brain Parenchyma ◽

Two Photon ◽

Contact Rates ◽

Health And Disease ◽

The Impact ◽

The Brain

AbstractMicroglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

Download Full-text

The role of acetylcholine in hallucinatory perception

Behavioral and Brain Sciences ◽

10.1017/s0140525x05380137 ◽

2005 ◽

Vol 28 (6) ◽

pp. 773-773 ◽

Cited By ~ 2

Author(s):

John Raymond Smythies

Keyword(s):

Virtual Reality ◽

Brain Function ◽

Hallucinatory Experience ◽

Digital Compression ◽

Health And Disease ◽

The Brain

This commentary reviews and extends the target article's treatment of the topic of the role of acetylcholine in hallucinatory experience in health and disease. Particular attention is paid to differentiating muscarinic and nicotinic effects in modulating the use of virtual reality mechanisms by the brain. Then, attention is drawn to the similarities between these aspects of brain function and certain aspects of television digital compression technology.

Download Full-text

A luciferase prosubstrate and a red bioluminescent calcium indicator to image neuronal activity

10.1101/2021.12.06.471018 ◽

2021 ◽

Author(s):

Xiaodong Tian ◽

Yiyu Zhang ◽

Xinyu Li ◽

Ying Xiong ◽

Tianchen Wu ◽

...

Keyword(s):

Neuronal Activity ◽

Nonspecific Esterase ◽

New Paradigm ◽

Fluorescent Indicators ◽

Neuronal Ensembles ◽

Brain Functions ◽

Calcium Indicator ◽

Health And Disease ◽

The Brain

AbstractGenetically encoded fluorescent indicators have been broadly used to monitor neuronal activity in live animals, but invasive surgical procedures are required. This study presents a functional bioluminescence imaging (fBLI) method for recording the activity of neuronal ensembles in the brain in awake mice. We developed a luciferase prosubstrate activatable in vivo by nonspecific esterase to enhance the brain delivery of the luciferin. We further engineered a bright, bioluminescent indicator with robust responsiveness to calcium ions (Ca2+) and appreciable emission above 600 nm. Integration of these advantageous components enabled the imaging of Ca2+ dynamics in awake mice minimally invasively with excellent signal- to-background and subsecond temporal resolution. This study thus establishes a new paradigm for studying brain functions in health and disease.

Download Full-text

Implantable neural interfaces

10.1093/oso/9780199674923.003.0050 ◽

2018 ◽

Author(s):

Stefano Vassanelli

Keyword(s):

Brain Function ◽

Large Scale ◽

Ionic Channels ◽

Patch Clamp Technique ◽

Advantages And Disadvantages ◽

Optogenetic Stimulation ◽

Physical Interfaces ◽

The Brain

Establishing direct communication with the brain through physical interfaces is a fundamental strategy to investigate brain function. Starting with the patch-clamp technique in the seventies, neuroscience has moved from detailed characterization of ionic channels to the analysis of single neurons and, more recently, microcircuits in brain neuronal networks. Development of new biohybrid probes with electrodes for recording and stimulating neurons in the living animal is a natural consequence of this trend. The recent introduction of optogenetic stimulation and advanced high-resolution large-scale electrical recording approaches demonstrates this need. Brain implants for real-time neurophysiology are also opening new avenues for neuroprosthetics to restore brain function after injury or in neurological disorders. This chapter provides an overview on existing and emergent neurophysiology technologies with particular focus on those intended to interface neuronal microcircuits in vivo. Chemical, electrical, and optogenetic-based interfaces are presented, with an analysis of advantages and disadvantages of the different technical approaches.

Download Full-text

Plant-Derived Extracellular Vesicles: Current Findings,Challenges, and Future Applications

Membranes ◽

10.3390/membranes11060411 ◽

2021 ◽

Vol 11 (6) ◽

pp. 411

Author(s):

Nader Kameli ◽

Anya Dragojlovic-Kerkache ◽

Paul Savelkoul ◽

Frank R. Stassen

Keyword(s):

Human Health ◽

Extracellular Vesicles ◽

Preliminary Results ◽

In Vivo Experiments ◽

Health And Disease ◽

Conducting Research ◽

Protocol Standardization ◽

Insight Into

In recent years, plant-derived extracellular vesicles (PDEVs) have gained the interest of many experts in fields such as microbiology and immunology, and research in this field has exponentially increased. These nano-sized particles have provided researchers with a number of interesting findings, making their application in human health and disease very promising. Both in vitro and in vivo experiments have shown that PDEVs can exhibit a multitude of effects, suggesting that these vesicles may have many potential future applications, including therapeutics and nano-delivery of compounds. While the preliminary results are promising, there are still some challenges to face, such as a lack of protocol standardization, as well as knowledge gaps that need to be filled. This review aims to discuss various aspects of PDEV knowledge, including their preliminary findings, challenges, and future uses, giving insight into the complexity of conducting research in this field.

Download Full-text

Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽

10.3390/cells10040767 ◽

2021 ◽

Vol 10 (4) ◽

pp. 767

Author(s):

Courtney Davis ◽

Sean I. Savitz ◽

Nikunj Satani

Keyword(s):

Ischemic Stroke ◽

Extracellular Vesicles ◽

Neurovascular Unit ◽

Culture Conditions ◽

Therapeutic Effects ◽

Stroke Treatment ◽

Inflammatory Molecules ◽

The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

Download Full-text

ChemInform Abstract: Role of Heart-Type Fatty Acid Binding Protein in the Brain Function

ChemInform ◽

10.1002/chin.200926278 ◽

2009 ◽

Vol 40 (26) ◽

Author(s):

Keiju Motohashi ◽

Yui Yamamoto ◽

Norifumi Shioda ◽

Hisatake Kondo ◽

Yuji Owada ◽

...

Keyword(s):

Fatty Acid ◽

Brain Function ◽

Fatty Acid Binding Protein ◽

Binding Protein ◽

Fatty Acid Binding ◽

Acid Binding Protein ◽

The Brain

Download Full-text

The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

Psychopharmacology ◽

10.1007/s00213-021-05808-9 ◽

2021 ◽

Author(s):

Marlaina R. Stocco ◽

Ahmed A. El-Sherbeni ◽

Bin Zhao ◽

Maria Novalen ◽

Rachel F. Tyndale

Keyword(s):

Neurotransmitter Release ◽

Behavioral Sensitization ◽

Serotonin Release ◽

Striatal Dopamine ◽

Irreversible Inhibitor ◽

Drug Concentrations ◽

Metabolite Concentrations ◽

The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

Download Full-text

News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Biomedicines ◽

10.3390/biomedicines9030252 ◽

2021 ◽

Vol 9 (3) ◽

pp. 252

Author(s):

Jacopo Meldolesi

Keyword(s):

Neurodegenerative Diseases ◽

Imaging Techniques ◽

Imaging Biomarkers ◽

Positron Emission ◽

Specific Proteins ◽

Great Relevance ◽

The Brain ◽

Positive Point

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

Download Full-text

DNAJB6b is Downregulated in Synucleinopathies

Journal of Parkinson s Disease ◽

10.3233/jpd-202512 ◽

2021 ◽

pp. 1-13

Author(s):

Jonas Folke ◽

Sertan Arkan ◽

Isak Martinsson ◽

Susana Aznar ◽

Gunnar Gouras ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Substantia Nigra Pars Compacta ◽

Endogenous Protein ◽

Highly Sensitive ◽

Brain Material ◽

Health And Disease ◽

Isoform B

Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.

Download Full-text