scholarly journals In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia

2020 ◽  
Vol 1 (5) ◽  
pp. 385-389
Author(s):  
Sophie V. Morse ◽  
Tamara Boltersdorf ◽  
Tiffany G. Chan ◽  
Felicity N. E. Gavins ◽  
James J. Choi ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Focused Ultrasound ◽  
Imaging Agent ◽  
Targeted Imaging ◽  
Activated Microglia ◽  
The Brain ◽  
In Vivo Delivery

Targeted imaging agent labels activated microglia when delivered into the brain with focused ultrasound and microbubbles – a tool to investigate inflammation in neurological disorders.

scholarly journals Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 566
Author(s):  
Jae-Geun Lee ◽  
Hyun-Ju Cho ◽  
Yun-Mi Jeong ◽  
Jeong-Soo Lee
Keyword(s):  
Neurological Disorders ◽  
Genetic Model ◽  
Molecular Genetic ◽  
Autism Spectrum ◽  
Behavioral Abnormalities ◽  
Bidirectional Signaling ◽  
Intestinal Dysbiosis ◽  
The Central Nervous System ◽  
The Brain

The microbiota–gut–brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota–gut–brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer’s disease.

scholarly journals PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2289
Author(s):  
Naresh Damuka ◽  
Paul Czoty ◽  
Ashley Davis ◽  
Michael Nader ◽  
Susan Nader ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Neurological Disorders ◽  
Healthy Male ◽  
Time Activity ◽  
Positron Emission ◽  
Pet Ct ◽  
Scan Data ◽  
The Brain ◽  
Human Primate

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

scholarly journals Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Alessandro Galgani ◽  
Francesco Lombardo ◽  
Daniele Della Latta ◽  
Nicola Martini ◽  
Ubaldo Bonuccelli ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Neurological Disorders ◽  
Potential Role ◽  
Neurological Diseases ◽  
Mri Findings ◽  
Promising Tool ◽  
Experimental Tool ◽  
Early Biomarker ◽  
The Brain

Abstract Purpose of Review Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and its degeneration is considered to be key in the pathogenesis of neurodegenerative diseases. In the last 15 years,MRI has been used to assess LC in vivo, both in healthy subjects and in patients suffering from neurological disorders. In this review, we summarize the main findings of LC-MRI studies, interpreting them in light of preclinical and histopathological data, and discussing its potential role as diagnostic and experimental tool. Recent findings LC-MRI findings were largely in agreement with neuropathological evidences; LC signal showed to be not significantly affected during normal aging and to correlate with cognitive performances. On the contrary, a marked reduction of LC signal was observed in patients suffering from neurodegenerative disorders, with specific features. Summary LC-MRI is a promising tool, which may be used in the future to explore LC pathophysiology as well as an early biomarker for degenerative diseases.

scholarly journals Sonogenetic stimulation of the brain at a spatiotemporal resolution suitable for vision restoration

2021 ◽  
Author(s):  
Sara Cadoni ◽  
Charlie Demene ◽  
Matthieu Provansal ◽  
Diep Nguyen ◽  
Dasha Nelidova ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Neurological Disorders ◽  
Real Life ◽  
Spatiotemporal Resolution ◽  
Brain Machine Interfaces ◽  
Ultrasound Stimulation ◽  
Wide Range ◽  
The Brain ◽  
Stimulation Of

Remote, precisely controlled activation of the brain is a fundamental challenge in the development of brain machine interfaces providing feasible rehabilitation strategies for neurological disorders. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain, but this approach lacks spatial resolution and cellular selectivity and loads the brain with high levels of acoustic energy. The combination of the expression of ultrasound-sensitive proteins with ultrasound stimulation (sonogenetic stimulation) can provide cellular selectivity and higher sensitivity, but such strategies have been subject to severe limitations in terms of spatiotemporal resolution in vivo, precluding their use for real-life applications. We used the expression of large-conductance mechanosensitive ion channels (MscL) with high-frequency ultrasonic stimulation for a duration of milliseconds to activate neurons selectively at a relatively high spatiotemporal resolution in the rat retina ex vivo and the primary visual cortex of rodents in vivo. This spatiotemporal resolution was achieved at low energy levels associated with negligible tissue heating and far below those leading to complications in ultrasound neuromodulation. We showed, in an associative learning test, that sonogenetic stimulation of the visual cortex generated light perception. Our findings demonstrate that sonogenetic stimulation is compatible with millisecond pattern presentation for visual restoration at the cortical level. They represent a step towards the precise transfer of information over large distances to the cortical and subcortical regions of the brain via an approach less invasive than that associated with current brain machine interfaces and with a wide range of applications in neurological disorders.

scholarly journals Sono-optogenetics facilitated by a circulation-delivered rechargeable light source for minimally invasive optogenetics

2019 ◽  
Vol 116 (52) ◽  
pp. 26332-26342 ◽  
Author(s):  
Xiang Wu ◽  
Xingjun Zhu ◽  
Paul Chong ◽  
Junlang Liu ◽  
Louis N. Andre ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Visible Light ◽  
Optical Fibers ◽  
Focused Ultrasound ◽  
Circulatory System ◽  
Light Sources ◽  
Light Emitters ◽  
Subtype Specificity ◽  
The Brain

Optogenetics, which uses visible light to control the cells genetically modified with light-gated ion channels, is a powerful tool for precise deconstruction of neural circuitry with neuron-subtype specificity. However, due to limited tissue penetration of visible light, invasive craniotomy and intracranial implantation of tethered optical fibers are usually required for in vivo optogenetic modulation. Here we report mechanoluminescent nanoparticles that can act as local light sources in the brain when triggered by brain-penetrant focused ultrasound (FUS) through intact scalp and skull. Mechanoluminescent nanoparticles can be delivered into the blood circulation via i.v. injection, recharged by 400-nm photoexcitation light in superficial blood vessels during circulation, and turned on by FUS to emit 470-nm light repetitively in the intact brain for optogenetic stimulation. Unlike the conventional “outside-in” approaches of optogenetics with fiber implantation, our method provides an “inside-out” approach to deliver nanoscopic light emitters via the intrinsic circulatory system and switch them on and off at any time and location of interest in the brain without extravasation through a minimally invasive ultrasound interface.

scholarly journals A Mixed-Surface Polyamidoamine Dendrimer for In Vitro and In Vivo Delivery of Large Plasmids

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 619
Author(s):  
Bhairavi Srinageshwar ◽  
Maria Florendo ◽  
Brittany Clark ◽  
Kayla Johnson ◽  
Nikolas Munro ◽  
...  
Keyword(s):  
Viral Vectors ◽  
Viral Vector ◽  
Direct Injection ◽  
Gene Therapies ◽  
Large Plasmids ◽  
Surface Modified ◽  
The Brain ◽  
In Vivo Delivery

Drug delivery to the brain is highly hindered by the presence of the blood–brain barrier (BBB), which prevents the entry of many potential drugs/biomolecules into the brain. One of the current strategies to achieve gene therapy for neurodegenerative diseases involves direct injection of a viral vector into the brain. There are various disadvantages of viral vectors, including limitations of cargo size and safety concerns. Nanomolecules, such as dendrimers, serve as an excellent alternative to viral delivery. In this study, as proof-of-concept, we used a surface-modified dendrimer complex and delivered large plasmids to cells in vitro and in vivo in healthy rats via intracranial injection. The dendrimers were biodegradable by chemicals found within cells and toxicity assays revealed that the modified dendrimers were much less toxic than unmodified amine-surface dendrimers. As mentioned in our previous publication, these dendrimers with appropriately modified surfaces are safe, can deliver large plasmids to the brain, and can overcome the cargo size limitations associated with viral vectors. The biocompatibility of this dendritic nanomolecule and the ability to finely tune its surface chemistry provides a gene delivery system that could facilitate future in vivo cellular reprograming and other gene therapies.

scholarly journals Engineering Viral Vectors for Acoustically Targeted Gene Delivery

2021 ◽  
Author(s):  
Hongyi Li ◽  
John E Heath ◽  
James S Trippett ◽  
Mikhail G. Shapiro ◽  
Jerzy O Szablowski
Keyword(s):  
Gene Delivery ◽  
Viral Vectors ◽  
Focused Ultrasound ◽  
Systemic Circulation ◽  
Brain Regions ◽  
Transduction Efficiency ◽  
Site Specific ◽  
Targeted Gene Delivery ◽  
The Brain

Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, limiting their scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency, requires ultrasound parameters close to tissue damage limits, and results in undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

scholarly journals Aberrant Calcium Signals in Reactive Astrocytes: A Key Process in Neurological Disorders

2019 ◽  
Vol 20 (4) ◽  
pp. 996 ◽  
Author(s):  
Eiji Shigetomi ◽  
Kozo Saito ◽  
Fumikazu Sano ◽  
Schuichi Koizumi
Keyword(s):  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Brain Disease ◽  
Reactive Astrocytes ◽  
Brain Functions ◽  
Progression Of Disease ◽  
Brain Insults ◽  
The Brain

Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca2+ signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca2+ signals. We discuss the molecular mechanisms underlying aberrant Ca2+ signals in reactive astrocytes and the functional significance of aberrant Ca2+ signals in neurological disorders.

scholarly journals In Vivo MRI of Functionalized Iron Oxide Nanoparticles for Brain Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Tang Tang ◽  
Anthony Valenzuela ◽  
Fanny Petit ◽  
Sarah Chow ◽  
Kevin Leung ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Scavenger Receptor ◽  
Brain Inflammation ◽  
Necrosis Factor Alpha ◽  
Activated Microglia ◽  
Intracerebral Administration ◽  
Positron Emission ◽  
Imaging Probes ◽  
The Brain

Microglia are intrinsic components of the brain immune system and are activated in many central nervous system disorders. The ability to noninvasively image these cells would provide valuable information for both research and clinical applications. Today, most imaging probes for activated microglia are mainly designed for positron emission tomography (PET) and target translocator proteins that also reside on other cerebral cells. The PET images obtained are not specific for microglia-driven inflammation. Here, we describe a potential PET/MRI multimodal imaging probe that selectively targets the scavenger receptor class A (SR-A) expressed on activated microglia. These sulfated dextran-coated iron oxide (SDIO) nanoparticles are avidly taken up by microglia and appear to be nontoxic when administered intravenously in a mouse model. Intravenous administration of this SDIO demonstrated visualization by T2∗-weighted MRI of microglia activated by intracerebral administration of tumor necrosis factor alpha (TNF-α). The contrast was significantly enhanced by SDIO, whereas there was little to no contrast change in animals treated with nontargeted nanoparticles or untreated controls. Thus, SR-A targeting represents a promising strategy to image activated microglia in the brain.

scholarly journals Ca2+ activity is required for injury-induced migration of microglia

2021 ◽  
Author(s):  
Tian Du ◽  
Xi Zhou ◽  
Robert Duyang Zhang ◽  
Xu-Fei Du
Keyword(s):  
Brain Injury ◽  
In Vivo Model ◽  
Immune Functions ◽  
Injury Site ◽  
Activated Microglia ◽  
Larval Zebrafish ◽  
Microglial Migration ◽  
Local Injury ◽  
The Brain

Objectives: Microglia are the resident immune cells in the brain. Brain injury can activate the microglia and induce its directional migration towards injury sites for exerting immune functions. While extracellular ATP released from the injury site mediates the directionality of activated microglia's migration, what endows activated microglia with migration capability remains largely unexplored. Methods: In the present study, we used the larval zebrafish as an in vivo model to visualize the dynamics of both morphology and Ca2+ activity of microglia during its migration evoked by local brain injury. Results: We found that, in response to local injury, activated microglia exhibited an immediate Ca2+ transient and later elevated Ca2+ bursts frequency during its migration towards the local injury site (P < 0.01). Furthermore, suppression of Ca2+ activities significantly retarded microglial migration (P < 0.05). Conclusion: Thus, our study suggests that intracellular Ca2+ activity is required for activated microglia's migration.

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