67 results found
Real R, Peter M, Trabalza A, et al., 2018, In vivo modeling of human neuron dynamics and Down syndrome., Science, Vol: 362
Harnessing the potential of human stem cells for modeling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. We show that human induced pluripotent stem cell (iPSC)-derived cortical neurons transplanted into the adult mouse cortex consistently organized into large (up to ~100 mm3) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Lastly, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modeling of cortical development, physiology, and pathogenesis.
Bloomfield PS, Bonsall D, Wells L, et al., 2018, The effects of haloperidol on microglial morphology and translocator protein levels: An in vivo study in rats using an automated cell evaluation pipeline., J Psychopharmacol, Pages: 269881118788830-269881118788830
BACKGROUND: Altered microglial markers and morphology have been demonstrated in patients with schizophrenia in post-mortem and in vivo studies. However, it is unclear if changes are due to antipsychotic treatment. AIMS: Here we aimed to determine whether antipsychotic medication affects microglia in vivo. METHODS: To investigate this we administered two clinically relevant doses (0.05 mg n=12 and 2.5 mg n=7 slow-release pellets, placebo n=20) of haloperidol, over 2 weeks, to male Sprague Dawley rats to determine the effect on microglial cell density and morphology (area occupied by processes and microglial cell area). We developed an analysis pipeline for the automated assessment of microglial cells and used lipopolysaccharide (LPS) treatment ( n=13) as a positive control for analysis. We also investigated the effects of haloperidol ( n=9) or placebo ( n=10) on the expression of the translocator protein 18 kDa (TSPO) using autoradiography with [3H]PBR28, a TSPO ligand used in human positron emission tomography (PET) studies. RESULTS: Here we demonstrated that haloperidol at either dose does not alter microglial measures compared with placebo control animals ( p > 0.05). Similarly there was no difference in [3H]PBR28 binding between placebo and haloperidol tissue ( p > 0.05). In contrast, LPS was associated with greater cell density ( p = 0.04) and larger cell size ( p = 0.01). CONCLUSION: These findings suggest that haloperidol does not affect microglial cell density, morphology or TSPO expression, indicating that clinical study alterations are likely not the consequence of antipsychotic treatment. The automated cell evaluation pipeline was able to detect changes in microglial morphology induced by LPS and is made freely available for future use.
Canty A, Jackson J, Huang L, et al., 2018, Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex
Despite the widespread occurrence of axon degeneration in the injured and diseased nervous system, the mechanisms of the degenerative process remain incompletely understood. In particular, the factors that regulate how individual axons degenerate within their native environment in the mammalian brain are unknown. Longitudinal imaging of >120 individually injured cortical axons revealed a threshold length below which injured axons undergo a rapid-onset form of Wallerian degeneration (ROWD). ROWD consistently starts 10 times earlier and is executed 4 times slower than classic Wallerian degeneration (WD). ROWD is dependent on synaptic density, unlike WD, but is independent of axon complexity. Finally, we provide both pharmacological and genetic evidence that a Nicotinamide Adenine Dinucleotide (NAD + )-dependent pathway controls cortical axon ROWD independent of transcription in the damaged neurons. Thus, our data redefine the therapeutic window for intervention to maintain neurological function in injured cortical neurons, and support the use of in vivo optical imaging to gain unique insights into the mechanisms of axon degeneration in the brain.
Cali C, Wawrzyniak M, Becker C, et al., 2018, The effects of aging on neuropil structure in mouse somatosensory cortex-A 3D electron microscopy analysis of layer 1, PLOS ONE, Vol: 13, ISSN: 1932-6203
Bass C, Helkkula P, De Paola V, et al., 2017, Detection of axonal synapses in 3D two-photon images, PLOS ONE, Vol: 12, ISSN: 1932-6203
Gorlitz F, Kelly DJ, Warren SC, et al., 2017, Open Source High Content Analysis Utilizing Automated Fluorescence Lifetime Imaging Microscopy, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
Krusche B, Ottone C, clements MP, et al., 2016, EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells, ELIFE, Vol: 5, ISSN: 2050-084X
Song S, Grillo FW, Xi J, et al., 2016, EPBscore: a Novel Method for Computer-Assisted Analysis of Axonal Structure and Dynamics, NEUROINFORMATICS, Vol: 14, Pages: 121-127, ISSN: 1539-2791
Bloomfield PS, Selvaraj S, Veronese M, et al., 2016, Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [C-11]PBR28 PET Brain Imaging Study, AMERICAN JOURNAL OF PSYCHIATRY, Vol: 173, Pages: 44-52, ISSN: 0002-953X
Grillo F, Canty AJ, Bloomfield P, et al., 2015, 2015, In vivo visualization of single axons and synaptic remodeling in normal and pathological conditions, Publisher: Axons and Brain Architecture, Elsevier 2015, ISBN: 9780128013939
Selvaraj S, Bloomfield P, Veronese M, et al., 2015, Imaging Translocator Protein (TSPO) in Subjects at High Risk of Psychosis and in Schizophrenia: An [11C] PBR28 Pet Brain Imaging Study, 54th Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP), Publisher: NATURE PUBLISHING GROUP, Pages: S559-S560, ISSN: 0893-133X
Jackson J, Canty AJ, Huang L, et al., 2015, Laser-Mediated Microlesions in Mouse Neocortex to Investigate Neuronal Degeneration and Regeneration., Curr Protoc Neurosci, Vol: 73, Pages: 2.24.1-2.2417
In vivo two-photon (2P) imaging enables neural circuitry to be repeatedly visualized in both normal conditions and following trauma. This protocol describes how laser-mediated neuronal microlesions can be created in the cerebral cortex using an ultrafast laser without causing a significant inflammatory reaction or compromising the blood-brain barrier. Furthermore, directives are provided for the acute and chronic in vivo imaging of the lesion site, as well as for post-hoc analysis of the lesion site in fixed tissue, which can be correlated with the live imaging phase.
Pienaar IS, Gartside SE, Sharma P, et al., 2015, Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease, MOLECULAR NEURODEGENERATION, Vol: 10, ISSN: 1750-1326
Grillo FW, West L, De Paola V, 2015, Removing synaptic brakes on learning, NATURE NEUROSCIENCE, Vol: 18, Pages: 1062-1064, ISSN: 1097-6256
Bloomfield P, Selvaraj S, Bonoldi I, et al., 2015, Translational investigation of microglia and antipsychotic medication, GLIA, Vol: 63, Pages: E315-E315, ISSN: 0894-1491
Jackson J, Canty AJ, Huang L, et al., 2015, 2015, Laser mediated microlesions in the mouse neocortex to investigate neuronal degeneration and regeneration, Current Protocols in Neuroscience, ISSN: 1934-8584
Selvaraj S, Bloomfield P, Veronese M, et al., 2015, Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study, BIOLOGICAL PSYCHIATRY, Vol: 77, ISSN: 0006-3223
Selvaraj S, Bonoldi I, Veronese M, et al., 2015, Microglia, psychosis and medication; a translational investigation. (De Paola and Howes, Co-Senior authors), BAP 2015 Summer Meeting (Selected for oral presentation)
Bloomfield P, Howes OD, De Paola V, 2015, THE EFFECTS OF ANTIPSYCHOTIC TREATMENT ON BRAIN VOLUME, INFLAMMATION AND GLUTAMATE SIGNALING GENES., SCHIZOPHRENIA BULLETIN, Vol: 41, Pages: S1-S1, ISSN: 0586-7614
Johnson MR, Behmoaras J, Bottolo L, et al., 2015, Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Bloomfield PS, West L, Howes OD, et al., 2014, The effects of antipsychotic medication on cortical and peripheral inflammation. (*joint senior authors and corresponding authors), European Neuropsychopharmacology, Vol: 24, Pages: s516-s516, ISSN: 1873-7862
Pienaar IS, Sharma P, Elson JL, et al., 2014, A DREADD approach for acute stimulation of cholinergic neurons of the pedunculopontine nucleus reverses Parkinsonism in the lactacystin model of Parkinson's disease, MOVEMENT DISORDERS, Vol: 29, Pages: S145-S146, ISSN: 0885-3185
Zhilun Y, Qian W, Ge G, et al., 2014, A Semi-automated Program for Axonal Reconstructions from Time-lapse 2-Photon Images, Frontiers in Neuroinformatics, Vol: 8
Allegra Mascaro AL, Cesare P, Sacconi L, et al., 2013, In vivo two-photon imaging of climbing fibers plasticity after laser axotomy, Neurophotonics, Microscopy of the Brain, ISSN: 1605-7422
In the adult nervous system, different neuronal classes show different regenerative behavior. Although previous studies demonstrated that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Here we describe the approach followed to characterize the reactive plasticity after injury. © 2013 OSA-SPIE.
Mascaro ALA, Cesare P, Sacconi L, et al., 2013, In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 10824-10829, ISSN: 0027-8424
Canty AJ, Teles-Grilo Ruivo LM, Nesarajah C, et al., 2013, Synaptic elimination and protection after minimal injury depend on cell type and their prelesion structural dynamics in the adult cerebral cortex., J Neurosci, Vol: 33, Pages: 10374-10383
The axonal and synaptic mechanisms underlying dysfunction and repair of the injured CNS are poorly understood. Unresolved issues include to what degree, when, and how the surviving neurons degenerate and the extent of synaptic remodeling both along the severed axon and in the nearby area. One of the main reasons is the lack of tools to study the complex asynchronous and dynamic features of individual lesioned axon responses in the intact brain. To address these issues, we combined two-photon microscopy and laser microsurgery to image the real-time reorganization of cortical circuitry at synaptic resolution for periods of up to 1 year in the brain of living mice. Injured cortical axons were eliminated proximally through a two-phase retraction process, which continued for at least 3 months postlesion and was independent of the presence of scar tissue. Remarkably, axons which later attempt to regenerate in both the mature and juvenile brain retracted less, raising the possibility that targeting retraction may improve the chances of axon regrowth after axotomy. Comparing prelesion and postlesion dynamics on the same axons over several days and weeks revealed that, although synapse formation rates were unaffected, boutons on injured axons were either rapidly and persistently lost, or extremely resistant, depending on cell-type and their prelesion structural dynamics. Our data suggest a lasting deficiency in synaptic output on surviving injured cortical axons and a surprising difference in the vulnerability of synaptic boutons after axotomy, which depend on cell-type and their recent history.
Allegra Mascaro AL, Cesare P, Sacconi L, et al., 2013, In vivo reactive neural plasticity investigation by means of correlative two photon: Electron microscopy, Progress in Biomedical Optics and Imaging - Proceedings of SPIE, Vol: 8588, ISSN: 1605-7422
In the adult nervous system, different populations of neurons correspond to different regenerative behavior. Although previous works showed that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury1, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Time lapse two-photon imaging has been combined to laser nanosurgery2, 3 to define a temporal pattern of the degenerative event and to follow the structural rearrangement after injury. To characterize the damage and to elucidate the possible formation of new synaptic contacts on the sprouted branches of the lesioned CF, we combined two-photon in vivo imaging with block face scanning electron microscopy (FIB-SEM). Here we describe the approach followed to characterize the reactive plasticity after injury. © 2013 SPIE.
Canty AJ, Huang L, Jackson JS, et al., 2013, In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits, NATURE COMMUNICATIONS, Vol: 4, ISSN: 2041-1723
Grillo FW, Song S, Ruivo LMT-G, et al., 2013, Increased axonal bouton dynamics in the aging mouse cortex, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: E1514-E1523, ISSN: 0027-8424
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