Publications
28 results found
Radulescu CI, Doostdar N, Zabouri N, et al., 2023, Age-related dysregulation of homeostatic control in neuronal microcircuits, Nature Neuroscience, Vol: 26, Pages: 2158-2170, ISSN: 1097-6256
Neuronal homeostasis prevents hyperactivity and hypoactivity. Age-related hyperactivity suggests homeostasis may be dysregulated in later life. However, plasticity mechanisms preventing age-related hyperactivity and their efficacy in later life are unclear. We identify the adult cortical plasticity response to elevated activity driven by sensory overstimulation, then test how plasticity changes with age. We use in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduce cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also find overstimulation disrupts cognition in older but not younger animals. We propose that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance.
Rueda-Carrasco J, Sokolova D, Lee S-E, et al., 2023, Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models, EMBO JOURNAL, Vol: 42, ISSN: 0261-4189
Nutma E, Fancy N, Weinert M, et al., 2023, Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases, Nature Communications, Vol: 14, Pages: 1-25, ISSN: 2041-1723
Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.
Melgosa-Ecenarro L, Doostdar N, Radulescu CI, et al., 2023, Pinpointing the locus of GABAergic vulnerability in Alzheimer?s disease, SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, Vol: 139, Pages: 35-54, ISSN: 1084-9521
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- Citations: 3
Barnes SJ, Keller GB, Keck T, 2022, Homeostatic regulation through strengthening of neuronal network-correlated synaptic inputs, ELIFE, Vol: 11, ISSN: 2050-084X
Dehghan A, Pinto RC, Karaman I, et al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424
Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.
Morten MJ, Sirvio L, Rupawala H, et al., 2022, Quantitative super-resolution imaging of pathological aggregates reveals distinct toxicity profiles in different synucleinopathies., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424
Protein aggregation is a hallmark of major neurodegenerative disorders. Increasing data suggest that smaller aggregates cause higher toxic response than filamentous aggregates (fibrils). However, the size of small aggregates has challenged their detection within biologically relevant environments. Here, we report approaches to quantitatively super-resolve aggregates in live cells and ex vivo brain tissues. We show that Amytracker 630 (AT630), a commercial aggregate-activated fluorophore, has outstanding photophysical properties that enable super-resolution imaging of α-synuclein, tau, and amyloid-β aggregates, achieving ∼4 nm precision. Applying AT630 to AppNL-G-F mouse brain tissues or aggregates extracted from a Parkinson's disease donor, we demonstrate excellent agreement with antibodies specific for amyloid-β or α-synuclein, respectively, confirming the specificity of AT630. Subsequently, we use AT630 to reveal a linear relationship between α-synuclein aggregate size and cellular toxicity and discovered that aggregates smaller than 450 ± 60 nm (aggregate450nm) readily penetrated the plasma membrane. We determine aggregate450nm concentrations in six Parkinson's disease and dementia with Lewy bodies donor samples and show that aggregates in different synucleinopathies demonstrate distinct potency in toxicity. We further show that cell-penetrating aggregates are surrounded by proteasomes, which assemble into foci to gradually process aggregates. Our results suggest that the plasma membrane effectively filters out fibrils but is vulnerable to penetration by aggregates of 450 ± 60 nm. Together, our findings present an exciting strategy to determine specificity of aggregate toxicity within heterogeneous samples. Our approach to quantitatively measure these toxic aggregates in biological environments opens possibilities to molecular examinations of disease mechanisms under physiological conditions.
Radulescu CI, Barnes SJ, 2021, Learning and memory: Scaling new areas, CURRENT BIOLOGY, Vol: 31, Pages: R721-R723, ISSN: 0960-9822
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- Citations: 1
Davis N, Mota BC, Stead L, et al., 2021, Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer's disease, Journal of Neuroinflammation, Vol: 18, ISSN: 1742-2094
BackgroundAstrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear.MethodsTo explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h.ResultsTreatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reducti
Radulescu CI, Cerar V, Haslehurst P, et al., 2021, The aging mouse brain: cognition, connectivity and calcium, Cell Calcium, Vol: 94, Pages: 1-19, ISSN: 0143-4160
Aging is a complex process that differentially impacts multiple cognitive, sensory, neuronal and molecular processes. Technological innovations now allow for parallel investigation of neuronal circuit function, structure and molecular composition in the brain of awake behaving adult mice. Thus, mice have become a critical tool to better understand how aging impacts the brain. However, a more granular systems-based approach, which considers the impact of age on key features relating to neural processing, is required. Here, we review evidence probing the impact of age on the mouse brain. We focus on a range of processes relating to neuronal function, including cognitive abilities, sensory systems, synaptic plasticity and calcium regulation. Across many systems, we find evidence for prominent age-related dysregulation even before 12 months of age, suggesting that emerging age-related alterations can manifest by late adulthood. However, we also find reports suggesting that some processes are remarkably resilient to aging. The evidence suggests that aging does not drive a parallel, linear dysregulation of all systems, but instead impacts some processes earlier, and more severely, than others. We propose that capturing the more fine-scale emerging features of age-related vulnerability and resilience may provide better opportunities for the rejuvenation of the aged brain.
Doostdar N, Airey J, Radulescu CI, et al., 2021, Multi-scale network imaging in a mouse model of amyloidosis, Cell Calcium, Pages: 102365-102365, ISSN: 0143-4160
Davis N, Mota B, Stead L, et al., 2020, Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease, Publisher: BioMed Central
Knopfel T, Sweeney Y, Radulescu CI, et al., 2019, Audio-visual experience strengthens multisensory assemblies in adult mouse visual cortex, Nature Communications, Vol: 10, ISSN: 2041-1723
We experience the world through multiple senses simultaneously. To better understand mechanisms of multisensory processing we ask whether inputs from two senses (auditory and visual) can interact and drive plasticity in neural-circuits of the primary visual cortex (V1). Using genetically-encoded voltage and calcium indicators, we find coincident audio-visual experience modifies both the supra and subthreshold response properties of neurons in L2/3 of mouse V1. Specifically, we find that after audio-visual pairing, a subset of multimodal neurons develops enhanced auditory responses to the paired auditory stimulus. This cross-modal plasticity persists over days and is reflected in the strengthening of small functional networks of L2/3 neurons. We find V1 processes coincident auditory and visual events by strengthening functional associations between feature specific assemblies of multimodal neurons during bouts of sensory driven co-activity, leaving a trace of multisensory experience in the cortical network.
Real R, Peter M, Trabalza A, et al., 2018, In vivo modeling of human neuron dynamics and Down syndrome, Science, Vol: 362, ISSN: 0036-8075
INTRODUCTIONScientists are building detailed maps of the cellular composition in the human brain to learn about its development. In the human cortex, the largest area of the mammalian brain, neural circuits are formed through anatomical refinement, including axon and synaptic pruning, and the emergence of complex patterns of network activity during early fetal development. Cellular analyses in the human brain are restricted to postmortem material, which cannot reveal the process of development. Model organisms are, therefore, commonly used for studies of brain physiology, development, and pathogenesis, but the results from model organisms do not always translate to humans.RATIONALESystems to model human neuron dynamics and their dysfunction in vivo are needed. While biopsy specimens and the generation of neurons from induced pluripotent stem cells (iPSCs) could provide the necessary human genetic background, two- and three-dimensional cultures lack factors that normally support neuronal development, including blood vessels, immune cells, and interaction with innervating neurons from other brain areas. On the basis of previous stem cell transplantation studies in mice, we reasoned that the physiological microenvironment of the adult mouse brain could support the growth of human cortical tissue grafts that had been generated from iPSC-derived neuronal progenitors. With human neurons implanted into the mouse brain, high-resolution, real-time in vivo monitoring of human neuron dynamics for periods of time spanning the range from subseconds to several months becomes feasible.RESULTSWe found that transplanted human iPSC–derived neuronal progenitors consistently assembled into vascularized territories with complex cytoarchitecture, mimicking key features of the human fetal cortex, such as its large size and cell diversification. Single-cell-resolution intravital microscopy showed that human neuronal arbors were refined via branch-specific retraction, rather than dege
Barnes S, 2018, In vivo modelling of human neuron dynamics and Down syndrome, Science, ISSN: 0036-8075
Sweeney Y, Barnes S, Clopath C, 2018, Diverse homeostatic responses to visual deprivation by uncovering recurrent subnetworks, Publisher: bioRxiv
Multiple homeostatic plasticity mechanisms are thought to be critical for the prevention of excessively high or aberrantly low neural activity in the adult cortex. In L2/3 of adult mouse visual cortex the interplay between disinhibition and local functional interactions may support homeostatic recovery following visual deprivation. Despite blanket disinhibition only a subset of L2/3 excitatory neurons are observed to exhibit homeostatic recovery. Recovering neurons tend to be correlated with each other, forming functional networks prior to deprivation. How homeostatic recovery occurs in this way is therefore unclear, particularly in conditions of global disinhibition. Here, we employ a computational modelling approach to investigate the origin of diverse homeostatic responses in the cortex. This model finds network size to be a critical determinant of the diverse homeostatic activity profiles observed following visual deprivation, as neurons which belong to larger networks exhibit a stronger homeostatic response. Our simulations provide mechanistic insights into the emergence of diverse homeostatic responses, and predict that neurons with a high proportion of enduring functional associations will exhibit the strongest homeostatic recovery. We test and confirm these predictions experimentally.
Sammons RP, Clopath C, Barnes SJ, 2018, Size-dependent axonal bouton dynamics following visual deprivation in vivo, Cell Reports, Vol: 22, Pages: 576-584, ISSN: 2211-1247
Persistent synapses are thought to underpin the storage of sensory experience. Yet, little is known about their structural plasticity in vivo. We investigated how persistent presynaptic structures respond to the loss of primary sensory input. Using in vivo two-photon (2-P) imaging we measured fluctuations in the size of excitatory axonal boutons in L2/3 of adult mouse visual cortex after monocular enucleation. The average size of boutons did not change after deprivation, but the range of bouton sizes was reduced. Large boutons decreased and small boutons increased. Reduced bouton variance was accompanied by a reduced range of correlated calcium mediated neural activity in L2/3 of awake animals. Network simulations predicted that size-dependent plasticity may promote conditions of greater bidirectional plasticity. These predictions were supported by electrophysiological measures of short and long-term plasticity. We propose size-dependent dynamics facilitate cortical reorganization by maximising the potential for bidirectional plasticity.
Barnes, Franzoni E, Jacobsen RI, et al., 2017, Deprivation-induced homeostatic spine scaling in vivo is localized to dendritic branches that have undergone recent spine loss, Neuron, Vol: 96, Pages: 871-882.e5, ISSN: 0896-6273
Synaptic scaling is a key homeostatic plasticity mechanism and is thought to be involved in the regulation of cortical activity levels. Here we investigated the spatial scale of homeostatic changes in spine size following sensory deprivation in a subset of inhibitory (layer 2/3 GAD65-positive) and excitatory (layer 5 Thy1-positive) neurons in mouse visual cortex. Using repeated in vivo two-photon imaging, we find that increases in spine size are tumor necrosis factor alpha (TNF-α) dependent and thus are likely associated with synaptic scaling. Rather than occurring at all spines, the observed increases in spine size are spatially localized to a subset of dendritic branches and are correlated with the degree of recent local spine loss within that branch. Using simulations, we show that such a compartmentalized form of synaptic scaling has computational benefits over cell-wide scaling for information processing within the cell.
Song C, Barnes S, Knopfel T, 2017, Mammalian cortical voltage imaging using genetically encoded voltage indicators: a review honoring professor Amiram Grinvald, NEUROPHOTONICS, Vol: 4, ISSN: 2329-423X
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- Citations: 9
Quicke P, Barnes SJ, Knöpfel T, 2017, Imaging of Brain Slices with a Genetically Encoded Voltage Indicator., Methods Mol Biol, Vol: 1563, Pages: 73-84
Functional fluorescence microscopy of brain slices using voltage sensitive fluorescent proteins (VSFPs) allows large scale electrophysiological monitoring of neuronal excitation and inhibition. We describe the equipment and techniques needed to successfully record functional responses optical voltage signals from cells expressing a voltage indicator such as VSFP Butterfly 1.2. We also discuss the advantages of voltage imaging and the challenges it presents.
Barnes S, Song C, Knoepfel T, 2017, Functional Cortical Connectomics through Co-Expression of Genetically Expressed Voltage and Calcium Indicators, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 340A-341A, ISSN: 0006-3495
Barnes SJ, Cheetham CE, Liu Y, et al., 2015, Delayed and Temporally Imprecise Neurotransmission in Reorganizing Cortical Microcircuits, JOURNAL OF NEUROSCIENCE, Vol: 35, Pages: 9024-9037, ISSN: 0270-6474
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- Citations: 14
Barnes SJ, Sammons RP, Jacobsen RI, et al., 2015, Subnetwork-specific homeostatic plasticity in mouse visual cortex in vivo, Neuron, Vol: 86, Pages: 1290-1303, ISSN: 0896-6273
Homeostatic regulation has been shown to restore cortical activity in vivo following sensory deprivation, but it is unclear whether this recovery is uniform across all cells or specific to a subset of the network. To address this issue, we used chronic calcium imaging in behaving adult mice to examine the activity of individual excitatory and inhibitory neurons in the same region of the layer 2/3 monocular visual cortex following enucleation. We found that only a fraction of excitatory neurons homeostatically recover activity after deprivation and inhibitory neurons show no recovery. Prior to deprivation, excitatory cells that did recover were more likely to have significantly correlated activity with other recovering excitatory neurons, thus forming a subnetwork of recovering neurons. These network level changes are accompanied by a reduction in synaptic inhibition onto all excitatory neurons, suggesting that both synaptic mechanisms and subnetwork activity are important for homeostatic recovery of activity after deprivation.
Lyamzin DR, Barnes SJ, Donato R, et al., 2015, Nonlinear Transfer of Signal and Noise Correlations in Cortical Networks, JOURNAL OF NEUROSCIENCE, Vol: 35, Pages: 8065-8080, ISSN: 0270-6474
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- Citations: 14
Barnes SJ, Cheetham CEJ, 2014, A Role for Short-Lived Synapses in Adult Cortex?, JOURNAL OF NEUROSCIENCE, Vol: 34, Pages: 7044-7046, ISSN: 0270-6474
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- Citations: 6
Albieri G, Barnes SJ, de Celis Alonso B, et al., 2014, Rapid bidirectional reorganization of cortical microcircuits., Cereb Cortex, ISSN: 1047-3211
Mature neocortex adapts to altered sensory input by changing neural activity in cortical circuits. The underlying cellular mechanisms remain unclear. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to show reorganization in somatosensory cortex elicited by altered whisker sensory input. We found that there was rapid expansion followed by retraction of whisker cortical maps. The cellular basis for the reorganization in primary somatosensory cortex was investigated with paired electrophysiological recordings in the periphery of the expanded whisker representation. During map expansion, the chance of finding a monosynaptic connection between pairs of pyramidal neurons increased 3-fold. Despite the rapid increase in local excitatory connectivity, the average strength and synaptic dynamics did not change, which suggests that new excitatory connections rapidly acquire the properties of established excitatory connections. During map retraction, entire excitatory connections between pyramidal neurons were lost. In contrast, connectivity between pyramidal neurons and fast spiking interneurons was unchanged. Hence, the changes in local excitatory connectivity did not occur in all circuits involving pyramidal neurons. Our data show that pyramidal neurons are recruited to and eliminated from local excitatory networks over days. These findings suggest that the local excitatory connectome is dynamic in mature neocortex.
Cheetham CEJ, Barnes SJ, Albieri G, et al., 2014, Pansynaptic enlargement at adult cortical connections strengthened by experience, Cerebral Cortex, Vol: 24, Pages: 521-531, ISSN: 1047-3211
Behavioral experience alters the strength of neuronal connections in adult neocortex. These changes in synaptic strength are thought to be central to experience-dependent plasticity, learning, and memory. However, it is not known how changes in synaptic transmission between neurons become persistent, thereby enabling the storage of previous experience. A long-standing hypothesis is that altered synaptic strength is maintained by structural modifications to synapses. However, the extent of synaptic modifications and the changes in neurotransmission that the modifications support remain unclear. To address these questions, we recorded from pairs of synaptically connected layer 2/3 pyramidal neurons in the barrel cortex and imaged their contacts with high-resolution confocal microscopy after altering sensory experience by whisker trimming. Excitatory connections strengthened by experience exhibited larger axonal varicosities, dendritic spines, and interposed contact zones. Electron microscopy showed that contact zone size was strongly correlated with postsynaptic density area. Therefore, our findings indicate that whole synapses are larger at strengthened connections. Synaptic transmission was both stronger and more reliable following experience-dependent synapse enlargement. Hence, sensory experience modified both presynaptic and postsynaptic function. Our findings suggest that the enlargement of synaptic contacts is an integral part of long-lasting strengthening of cortical connections and, hence, of information storage in the neocortex.
Barnes SJ, Finnerty GT, 2010, Sensory Experience and Cortical Rewiring, NEUROSCIENTIST, Vol: 16, Pages: 186-198, ISSN: 1073-8584
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- Citations: 71
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