Biology subjects

Ramezani, M.

Publications and source records attributed to Ramezani, M..

8 recordsLinked to original sources

bioRxiv2026

Flexible 3D multimodal organoid interface reveals functional subnetworks and coordinated circuit activity in cortical organoids

The balance between excitatory and inhibitory (E/I) neurons is fundamental to cortical function, and its disruption underlies a wide range of neurological disorders, including epilepsy, Alzheimers disease and autism spectrum disorder. Cortical organoids offer a promising model to study this balance, as they recapitulate key features of brain development, including the emergence of E/I circuitry. However, no existing technology can simultaneously resolve neuronal identity, spatial organization, and dynamic network activity within intact organoids, limiting precise interrogation of E/I circuit function. Here, we report INFORM, an INtegrated Flexible Organoid Recording Multimodal neural interface that conformally wraps organoids of any size and shape, enabling long-term recordings over 371 days with above 90% of channels detecting spikes. INFORM interface combines four distinct modalities; electrophysiology, two-photon calcium imaging, targeted electrical microstimulation, and chemical intervention to monitor and modulate neural activity across multiple spatial and temporal scales spanning from action potentials from single neurons to synchronized bursts from large-scale populations. Such high-resolution interrogation enables probing of emergence of functional connectivity in fusing assembloids and resolves spatially discrete functional subnetworks that can be selectively recruited and modulated by INFORM. Neurotransmission blockade confirms that stimulus-evoked suppression of neuronal spiking is mediated by GABAergic inputs providing direct functional evidence of the presence of inhibitory signaling in organoids. This work allows single-cell dissection of functional networks in brain organoids, providing a powerful platform for modelling and studying cortical development, neurological diseases, and the E/I imbalances underlying circuit dysfunction.

neuroscience↗

bioRxiv2025

Ancient DNA indicates 3,000 years of genetic continuity in the Northern Iranian Plateau, from the Copper Age to the Sassanid Empire

In this study, we present new ancient DNA data from prehistoric and historic populations of the Iranian Plateau. By analysing 50 samples from nine archaeological sites across Iran, we report 23 newly sequenced mitogenomes and 13 nuclear genomes, spanning 4700 BCE to 1300 CE. We integrate an extensive reference sample set of previously published ancient DNA datasets from Western and South-Central Asia, enhancing our understanding of genetic continuity and diversity within ancient Iranian populations. A new Early Chalcolithic sample, predating all other Chalcolithic genomes from Iran, demonstrates mostly Early Neolithic Iranian genetic ancestry. This finding reflects long-term cultural and biological continuity in and around the Zagros area, alongside evidence of some western genetic influence. Our sample selection prioritizes northern Iran, with a particular focus on the Achaemenid, Parthian, and Sassanid periods (355 BCE-460 CE). The genetic profiles of historical samples from this region position them as intermediates on an east-west genetic cline across the Persian Plateau. They also exhibit strong connections to local and South-Central Asian Bronze Age populations, underscoring enduring genetic connections across these regions. Diachronic analyses of uniparental lineages on the Iranian Plateau further highlight population stability from prehistoric to modern times.

genomics↗

bioRxiv2023

Cellular Calcium Activity at Depth Predicted from Surface Potential Recordings using Ultra-high Density Transparent Graphene Arrays

Recording brain activity with high spatial and high temporal resolution across deeper layers of cortex has been a long-sought methodology to study how neural information is coded, stored, and processed by neural circuits and how it leads to cognition and behavior. Electrical and optical neural recording technologies have been the key tools in neurophysiology studies toward a comprehensive understanding of the neural dynamics. The advent of optically transparent neural microelectrodes has facilitated multimodal experiments combining simultaneous electrophysiological recordings from the brain surface with optical imaging and stimulation of neural activity. A remaining challenge is to scale down electrode dimensions to single -cell size and increase the density to record neural activity with high spatial resolution across large areas to capture nonlinear neural dynamics at multiple spatial and temporal scales. Here, we developed microfabrication techniques to create transparent graphene microelectrodes with ultra-small openings and a large, completely transparent recording area. We achieved this by using long graphene microwires without any gold extensions in the field of view. To overcome the quantum capacitance limit of graphene and scale down the microelectrode diameter to 20 m, we used Pt nanoparticles. To prevent open circuit failure due to defects and disconnections in long graphene wires, we employed interlayer doped double layer graphene (id-DLG) and demonstrated cm-scale long transparent graphene wires with microscale width and low resistance. Combining these two advances, we fabricated high-density microelectrode arrays up to 256 channels. We conducted multimodal experiments, combining recordings of cortical potentials with high-density transparent arrays with two-photon calcium imaging from layer 1 (L1) and layer 2/3 (L2/3) of the V1 area of mouse visual cortex. High-density recordings showed that the visual evoked responses are more spatially localized for high-frequency bands, particularly for the multi-unit activity (MUA) band. The MUA power was found to be strongly correlated with the cellular calcium activity. Leveraging this strong correlation, we applied dimensionality reduction techniques and neural networks to demonstrate that single-cell (L2/3) and average (L1 and L2/3) calcium activities can be decoded from surface potentials recorded by high-density transparent graphene arrays. Our high-density transparent graphene electrodes, in combination with multimodal experiments and computational methods, could lead to the development of minimally invasive neural interfaces capable of recording neural activity from deeper layers without requiring depth electrodes that cause damage to the tissue. This could potentially improve brain computer interfaces and enable less invasive treatments for neurological disorders.

neuroscience↗

bioRxiv2023

A genome-wide atlas of human cell morphology

A key challenge of the modern genomics era is developing data-driven representations of gene function. Here, we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-scale genotype-phenotype maps comprising >20,000 single-gene CRISPR-Cas9-based knockout experiments in >30 million cells. Our optical pooled cell profiling approach (PERISCOPE) combines a de-stainable high-dimensional phenotyping panel (based on Cell Painting1,2) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This approach provides high-dimensional phenotypic profiles of individual cells, while simultaneously enabling interrogation of subcellular processes. Our atlas reconstructs known pathways and protein-protein interaction networks, identifies culture media-specific responses to gene knockout, and clusters thousands of human genes by phenotypic similarity. Using this atlas, we identify the poorly-characterized disease-associated transmembrane protein TMEM251/LYSET as a Golgi-resident protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes, showing the power of these representations. In sum, our atlas and screening technology represent a rich and accessible resource for connecting genes to cellular functions at scale.

genomics↗

bioRxiv2023

Alpha Synuclein Modulates Mitochondrial Ca2+ Uptake from ER During Cell Stimulation and Under Stress Conditions

Alpha synuclein (a-syn) is an intrinsically disordered protein prevalent in neurons, and aggregated forms are associated with synucleinopathies including Parkinson disease (PD). Despite the biomedical importance and extensive studies, the physiological role of a-syn and its participation in etiology of PD remain uncertain. We showed previously in model RBL cells that a-syn colocalizes with mitochondrial membranes, depending on formation of N-terminal helices and increasing with mitochondrial stress.1 We have now characterized this colocalization and functional correlates in RBL, HEK293, and N2a cells. We find that expression of a-syn enhances stimulated mitochondrial uptake of Ca2+ from the ER, depending on formation of its N-terminal helices but not on its disordered C-terminal tail. Our results are consistent with a-syn acting as a tether between mitochondria and ER, and we show increased contacts between these two organelles using structured illumination microscopy. We tested mitochondrial stress caused by toxins related to PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and found that a-syn prevents recovery of stimulated mitochondrial Ca2+ uptake. The C-terminal tail, and not N-terminal helices, is involved in this inhibitory activity, which is abrogated when phosphorylation site serine-129 is mutated (S129A). Correspondingly, we find that MPTP/MPP+ and CCCP stress is accompanied by both phosphorylation (pS129) and aggregation of a-syn. Overall, our results indicate that a-syn can participate as a tethering protein to modulate Ca2+ flux between ER and mitochondria, with potential physiological significance. A-syn can also prevent cellular recovery from toxin-induced mitochondrial dysfunction, which may represent a pathological role of a-syn in the etiology of PD.

cell biology↗

bioRxiv2021

E-Cannula reveals anatomical diversity in sharp-wave ripples as a driver for the recruitment of distinct hippocampal assemblies

The hippocampus plays a critical role in spatial navigation and episodic memory. However, research on in vivo hippocampal activity dynamics has mostly relied on single modalities such as electrical recordings or optical imaging, with respectively limited spatial and temporal resolution. This technical difficulty greatly impedes multi-level investigations into network state-related changes in cellular activity. To overcome these limitations, we developed the E-Cannula integrating fully transparent graphene microelectrodes with imaging-cannula. The E-Cannula enables the simultaneous electrical recording and two-photon calcium imaging from the exact same population of neurons across an anatomically extended region of the mouse hippocampal CA1 stably across several days. These large-scale simultaneous optical and electrical recordings showed that local hippocampal sharp wave ripples (SWRs) are associated with synchronous calcium events involving large neural populations in CA1. We show that SWRs exhibit spatiotemporal wave patterns along multiple axes in 2D space with different spatial extents (local or global) and temporal propagation modes (stationary or travelling). Notably, distinct SWR wave patterns were associated with, and decoded from, the selective recruitment of orthogonal CA1 cell assemblies. These results suggest that the diversity in the anatomical progression of SWRs may serve as a mechanism for the selective activation of the unique hippocampal cell assemblies extensively implicated in the encoding of distinct memories. Through these results we demonstrate the utility of the E-Cannula as a versatile neurotechnology with the potential for future integration with other optical components such as green lenses, fibers or prisms enabling the multi-modal investigation of cross-time scale population-level neural dynamics across brain regions.

neuroscience↗

bioRxiv2021

Decoding of cortex-wide brain activity from local recordings of neural potentials

ObjectiveElectrical recordings of neural activity from brain surface have been widely employed in basic neuroscience research and clinical practice for investigations of neural circuit functions, brain-computer interfaces, and treatments for neurological disorders. Traditionally, these surface potentials have been believed to mainly reflect local neural activity. It is not known how informative the locally recorded surface potentials are for the neural activities across multiple cortical regions. ApproachTo investigate that, we perform simultaneous local electrical recording and wide-field calcium imaging in awake head-fixed mice. Using a recurrent neural network model, we try to decode the calcium fluorescence activity of multiple cortical regions from local electrical recordings. Main resultsThe mean activity of different cortical regions could be decoded from locally recorded surface potentials. Also, each frequency band of surface potentials differentially encodes activities from multiple cortical regions so that including all the frequency bands in the decoding model gives the highest decoding performance. Despite the close spacing between recording channels, surface potentials from different channels provide complementary information about the large-scale cortical activity and the decoding performance continues to improve as more channels are included. Finally, we demonstrate the successful decoding of whole dorsal cortex activity at pixel-level using locally recorded surface potentials. SignificanceThese results show that the locally recorded surface potentials indeed contain rich information of the large-scale neural activities, which could be further demixed to recover the neural activity across individual cortical regions. In the future, our cross-modality inference approach could be adapted to virtually reconstruct cortex-wide brain activity, greatly expanding the spatial reach of surface electrical recordings without increasing invasiveness. Furthermore, it could be used to facilitate imaging neural activity across the whole cortex in freely moving animals, without requirement of head-fixed microscopy configurations.

neuroscience↗

bioRxiv2018

Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model

We characterized phenotypes in RBL-2H3 mast cells transfected with human alpha synuclein (a-syn) using stimulated exocytosis of recycling endosomes as a proxy for similar activities of synaptic vesicles in neurons. We found that low expression of a-syn inhibits stimulated exocytosis and that higher expression causes slight enhancement. NMR measurements of membrane interactions correlate with these functional effects: they are eliminated differentially by mutants that perturb helical structure in the helix 1 (A30P) or NAC/helix-2 (V70P) regions of membrane-bound a-syn, but not by other PD-associated mutants or C-terminal truncation. We further found that a-syn (but not A30P or V70P mutants) associates weakly with mitochondria, but this association increases markedly under conditions of cellular stress. These results highlight the importance of specific structural features of a-syn in regulating vesicle release, and point to a potential role for a-syn in perturbing mitochondrial function under pathological conditions.

cell biology↗