Biology subjects

Moradi, K.

Publications and source records attributed to Moradi, K..

7 recordsLinked to original sources

bioRxiv2024

Dendritome Mapping Unveils Spatial Organization of Striatal D1/D2-Neuron Morphology

Morphology is a cardinal feature of a neuron and mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide profiling of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstructed and reference-atlas mapped striatal D1- and D2-medium spiny neurons (MSNs). Integrative morphometric analyses reveal distinct impacts of D1/D2 and anatomical locations on MSN morphology. To analyze striatal regional features of MSN dendrites without prior anatomical constraints, we assigned MSNs to a lattice of cubic boxes in the reference brain atlas, and summarized morphometric representation ("eigen-morph") for each box and clustered boxes with shared morphometry. This analysis reveals 6 modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found aging confers robust and concordant dendritic length and branching defects in D1/D2-MSNs, while Huntingtons disease (HD) mice exhibit MSN-subtype and striatal regional specific pathology. Together, our study demonstrates a systems-biology approach to profile dendritic morphology of genetically-defined single-neurons; and defines novel striatal D1/D2-MSN morphological territories and aging- or HD-associated pathologies.

neuroscience↗

bioRxiv2024

Gossamer: Scaling Image Processing and Reconstruction to Whole Brains

Neuronal reconstruction-a process that transforms image volumes into 3D geometries and skeletons of cells- bottlenecks the study of brain function, connectomics and pathology. Domain scientists need exact and complete segmentations to study subtle topological differences. Existing methods are diskbound, dense-access, coupled, single-threaded, algorithmically unscalable and require manual cropping of small windows and proofreading of skeletons due to low topological accuracy. Designing a data-intensive parallel solution suited to a neurons shape, topology and far-ranging connectivity is particularly challenging due to I/O and load-balance, yet by abstracting these vision tasks into strategically ordered specializations of search, we progressively lower memory by 4 orders of magnitude. This enables 1 mouse brain to be fully processed in-memory on a single server, at 67x the scale with 870x less memory while having 78% higher automated yield than APP2, the previous state of the art in performant reconstruction.

neuroscience↗

bioRxiv2024

HB-EGF and EGF infusion following CNS demyelination mitigates age-related decline in regeneration of oligodendrocytes from neural precursor cells originating in the ventricular-subventricular zone

In multiple sclerosis (MS), chronic demyelination initiated by immune-mediated destruction of myelin, leads to axonal damage and neuronal cell death, resulting in a progressive decline in neurological function. The development of interventions that potentiate remyelination could hold promise as a novel treatment strategy for MS. To this end, our group has demonstrated that neural precursor cells (NPCs) residing in the ventricular-subventricular zone (V-SVZ) of the adult mouse brain contribute significantly to remyelination in response to central nervous system (CNS) demyelination and can regenerate myelin of normal thickness. However, aging takes its toll on the regenerative potential of NPCs and reduces their contribution to remyelination. In this study, we investigated how aging influences the contribution of NPCs to oligodendrogenesis during the remyelination process and whether the delivery of growth factors into the brains of aged mice could potentiate the oligodendrogenic potential of NPCs. To enable us to map the fate of NPCs in response to demyelination induced at different postnatal ages, Nestin-CreERT2; Rosa26-LSL-eYFP mice were gavaged with tamoxifen at either 8 weeks, 30 weeks or one year of age before being challenged with cuprizone for a period of six weeks. Using osmotic minipumps, we infused heparin-binding EGF-like growth factor (HB-EGF), and/or epidermal growth factor (EGF) into the cisterna magna for a period of two weeks beginning at the peak of cuprizone-induced demyelination (n=6-8 mice per group). Control mice received artificial cerebrospinal fluid (vehicle) alone. Mice were perfused six weeks after cuprizone withdrawal and the contribution of NPCs to oligodendrocyte regeneration in the corpus callosum was assessed. Our data reveal that although NPC-derived oligodendrocyte generation declined dramatically with age, this decline was partially reversed by growth factor infusion. Notably, co-infusion of EGF and HB-EGF increased oligodendrocyte regeneration twofold in some regions of the corpus callosum. Our results shed light on the beneficial effects of EGF and HB-EGF for increasing the contribution of NPCs to remyelination and indicate their therapeutic potential to combat the negative effects of aging upon remyelination efficacy.

neuroscience↗

bioRxiv2021

Quantification of neuron types in the rodent hippocampal formation by data mining and numerical optimization

Quantifying the population sizes of distinct neuron types in different anatomical regions is an essential step towards establishing a brain cell census. Although estimates exist for the total neuronal populations in different species, the number and definition of each specific neuron type are still intensively investigated. Hippocampome.org is an open-source knowledge base with morphological, physiological, and molecular information for 122 neuron types in the rodent hippocampal formation. While such framework identifies all known neuron types in this system, their relative abundances remain largely unknown. This work quantitatively estimates the counts of all Hippocampome.org neuron types by literature mining and numerical optimization. We report the number of neurons in each type identified by main neurotransmitter (glutamate or GABA) and axonal-dendritic patterns throughout 26 subregions and layers of the dentate gyrus, Ammons horn, subiculum, and entorhinal cortex. We produce by sensitivity analysis reliable numerical ranges for each type and summarize the amounts across broad neuronal families defined by biomarkers expression and firing dynamics. Study of density distributions indicates that the number of dendritic-targeting interneurons, but not of other neuronal classes, is independent of anatomical volumes. All extracted values, experimental evidence, and related software code are released on Hippocampome.org.

neuroscience↗

bioRxiv2021

A Novel Pharmacogenetic Model for Highly Efficient Ablation of Oligodendrocyte Progenitor Cells in the Adult Mouse CNS

Approaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent central nervous system have been limited by methodological challenges resulting in only partial and transient OPC depletion. We have developed a novel pharmacogenetic model of conditional OPC ablation, eliminating 98.6% of all OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+ NG2+ cells with the capacity to migrate and proliferate extensively throughout the dorsal anterior forebrain. Further application of this novel approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.

neuroscience↗

bioRxiv2019

A comprehensive knowledge base of synaptic electrophysiology in the rodent hippocampal formation

The cellular and synaptic architecture of the rodent hippocampus has been described in thousands of peer-reviewed publications. However, no human- or machine-readable public catalog of synaptic electrophysiology data exists for this or any other neural system. Harnessing state of the art information technology, we have developed a cloud-based toolset for identifying empirical evidence from the scientific literature pertaining to synaptic electrophysiology, for extracting the experimental data of interest, and for linking each entry to relevant text or figure excerpts. Mining more than 1,200 published journal articles, we have identified eight different signal modalities quantified by 68 different methods to measure synaptic amplitude, kinetics, and plasticity in hippocampal neurons. We have designed a data structure that both reflects these variabilities and maintains the existing relations among experimental modalities. Moreover, we mapped every annotated experiment to identified \"synapse types,\" i.e. specific pairs of presynaptic and postsynaptic neuron types. To this aim, we leveraged Hippocampome.org, an open-access knowledge base of morphologically, electrophysiologically, and molecularly characterized neuron types in the rodent hippocampal formation. Specifically, we have implemented a computational pipeline to systematically translate neuron type properties into formal queries in order to find all compatible synapse types. With this system, we have collected nearly 40,000 synaptic data entities covering 88% of the 3,120 potential connections in Hippocampome.org. Correcting membrane potentials with respect to liquid junction potentials significantly reduced the difference between theoretical and experimental reversal potentials, thereby enabling the accurate conversion of all synaptic amplitudes to conductance. This dataset allows for large-scale hypothesis testing of the general rules governing synaptic signals. To illustrate these applications, we confirmed several expected correlations between synaptic measurements and their covariates while suggesting previously unreported ones. We release all data open source at Hippocampome.org in order to further research across disciplines.

neuroscience↗

bioRxiv2017

Extended "Constant Field" equations: an electrodiffusion model of NMDA receptors

Ion channels are experimentally divided into Ohmic and non-Ohmic channels. Similarly, a theoretical dichotomy exists in the flux equations of these channels. The \"constant field\" or \"Goldman-Hodgkin and Katz\" current equation is a commonly accepted analytic model of electrodiffusion in channels. This equation, however, seems to have some shortcomings, such as the inability to explain the nonlinear relation between the single channel current and the membrane potential in non-Ohmic channels. In this study, we introduce the \"general\" and \"extended\" versions of this equation that are applicable to both Ohmic and non-Ohmic channels. Our results showed the ability of these equations to simulate the NMDA receptor current, as a non-Ohmic channel, not only in the symmetric \"uni-ionic\" solutions but also in the asymmetric \"bi-ionic\" solutions of sodium and calcium ions. Our equations reveal for the first time that sodium ions like calcium ions are able to block the NMDA receptors current. It seems that the previously identified cation binding-sites have a prominent role in changing the diffusion coefficient inside the channel. We also propose the concentration-dependent change in the asymmetry of diffusion coefficient as a remarkably effective mechanism for shaping the channels I-V curve.

neuroscience↗