bioRxiv Science⌕ Search

Biology subjects

Hosseini, H.

Publications and source records attributed to Hosseini, H..

11 recordsLinked to original sources
bioRxiv2026

mGluR6 coordinates cone terminal targeting and synaptic layer assembly during human retinal development

The metabotropic glutamate receptor 6 (mGluR6), encoded by GRM6, is a core component of the ON-bipolar signaling cascade in the retina, but its role in human retinal development remains unclear. Here, we used temporally controlled CRISPR-based genetic ablation in human induced pluripotent stem cell-derived retinal organoids to define the developmental functions of mGluR6. Unexpectedly, we found that mGluR6 is expressed not only in depolarizing ON-bipolar cells but also transiently in cone photoreceptors during human retinal development, a pattern not observed in the mouse retina. Early loss of GRM6 prior to synaptogenesis disrupted cone pedicle architecture, leading to mislocalization of synaptic proteins including Bassoon, ELFN2, and TRPM1, and ultimately resulting in widening or duplication of the outer plexiform layer (OPL). In contrast, deletion after synapse formation did not alter OPL synapses or morphology, revealing a temporally restricted requirement for mGluR6 during circuit assembly. These findings uncover a previously unrecognized role for mGluR6 in coordinating cone terminal targeting and synaptic layer assembly during human retinal development and highlight the power of temporally controlled genetic manipulation in organoid systems to reveal species-specific mechanisms of neural circuit formation.

neuroscience↗
bioRxiv2026

Chronic nicotine reduces nigral dopaminergic activity and remodels pedunculopontine cholinergic subpopulations

Chronic nicotine is linked to neuroprotective effects and reduced Parkinsons disease (PD) risk, yet its physiological effects on vulnerable substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons are not fully understood. These populations exhibit specialized properties such as spontaneous pacemaking and elevated dendritic calcium influx that contribute to their selective neurodegeneration in PD. Here, we used whole-cell patch-clamp, two-photon calcium imaging, and morphological reconstruction in acute brain slices from adult mice of both sexes following 8-10 weeks of oral nicotine. Chronic nicotine reduced spontaneous pacemaking, burst propensity, and rebound firing in SNc dopaminergic neurons, while decoupling tonic firing rate from proximal dendritic calcium levels. The changes in the SNc occurred without altering L-type channel contributions, dendritic arborization, or excitatory synaptic drive. In PPN cholinergic neurons, chronic nicotine induced subregion-specific plasticity. Rostral PPN neurons showed depolarized membrane potentials, broadened action potentials, and dendritic pruning, whereas caudal PPN neurons showed reduced spike frequency adaptation and accelerated excitatory postsynaptic current kinetics. These findings reveal potential cellular and circuit mechanisms by which nicotine may contribute to resilience against PD. Significant StatementEpidemiological studies have revealed nicotines surprising protective effect in Parkinsons disease (PD). Interestingly, this protection appears only preventative, as nicotine shows no therapeutic benefits after PD diagnosis. Here, we evaluated the effects of chronic nicotine on two brainstem populations known to selectively degenerate in PD: substantia nigra pars compacta (SNc) dopaminergic neurons and pedunculopontine (PPN) cholinergic neurons. Chronic nicotine decreases activity levels of SNc neurons, depolarizes rostral PPN neurons, and enhances sustained firing capability in caudal PPN neurons. Notably, this is the first study to assess whether chronic nicotine alters the physiology and dendritic morphology of these vulnerable subpopulations. These cellular insights uncover potential mechanisms for promoting neuronal resilience in neurodegenerative diseases.

neuroscience↗
bioRxiv2025

Indirect Deuterium Displacement Exchange Imaging for Non-invasive High-Resolution CSF Production Mapping

Cerebrospinal fluid (CSF) production is central to brain homeostasis, yet existing measurement techniques are invasive, technically demanding, and confounded by intracranial perturbations. Here, we introduce indirect deuterium displacement exchange imaging (CSF-iDDxI), a noninvasive MRI approach for mapping CSF production in vivo. The method leverages intravenously infused deuterium oxide (D2O), which crosses the blood-CSF barrier, replaces existing H2O in CSF, producing concentration-dependent attenuation of proton (1H) signal within CSF spaces. Using high-resolution 3D balanced steady-state free precession MRI in rats, we demonstrate robust and spatially widespread D2O-induced CSF signal loss that is selectively suppressed by acetazolamide, a carbonic anhydrase inhibitor known to suppress CSF production by the choroid plexus. Dynamic imaging during intravenous D2O infusion further revealed that cortical parenchymal signal changes were unaffected by acetazolamide, confirming specificity to CSF production. Exploratory kinetic modeling estimated rapid CSF water turnover (k {approx} 0.09 min-1) under physiological conditions, reduced to k {approx} 0.031 min-1 with acetazolamide suppression, consistent with prior isotope tracer studies. Together, these findings establish CSF-iDDxI as a sensitive, pharmacologically validated tool for quantifying CSF production and turnover.

neuroscience↗
bioRxiv2025

Plastimos: a live cell imaging-based framework to study dynamics of EMT-mediated cellular plasticity in breast cancer

Cancer cell plasticity, primarily mediated by the process of epithelial-mesenchymal transition (EMT), plays a critical role in promoting therapeutic resistance, tumor heterogeneity, and metastasis. EMT-mediated plasticity enables cancer cells to undergo molecular and phenotypic changes, which alter their invasiveness and resistance to treatments. This study aims to develop a quantitative, high-throughput system to assess EMT-mediated plasticity, which can inform therapeutic strategies for metastatic cancers. To accomplish this, we developed Plastimos, a semi-automated imaging analysis pipeline. This framework utilizes time-series images to track live cells through deep learning-based segmentation and employs a greedy algorithm to map cell trajectories, enabling the extraction of cellular phenotypic features. These features are used to study the EMT-mediated plasticity state of cells in response to the well-known EMT-inducing factors EGF and TGF-{beta}1. We selected two breast cancer cell lines, MCF7 and MDA-MB-231, representing classical epithelial-like and mesenchymal-like cell. The pipeline assigns a Plasticity Index based on various parameters, including motility, morphology, and proliferation, thus providing a quantitative estimate for the plasticity of deviating from the epithelial state. Our results indicate that epithelial-like cells respond to EMT-inducing factors at both molecular and phenotypic levels, while mesenchymal-like cells responses are only seen phenotypically. The Plasticity Index classifies cells along the EMT spectrum, converting to a Plasticity Score that reflects mesenchymal proportions. Availability and implementationThe pipeline implementation and the source code of Plastimos can be found at: https://github.com/Durdam/Plastimos.git

bioinformatics↗
bioRxiv2025

Functional connectivity patterns as an early indicator of later very early preterm outcomes

Abnormal functional brain development associated with preterm birth has been widely reported; however, the functional brain architectures of later neurodevelopmental difficulties are not yet fully understood. Here, we applied connectome-based predictive modeling approaches to identify the brain networks associated with later neurocognitive scores at 2-3 years of age in very preterm infants ([&le;]31 weeks gestation, N=79) using resting-state functional magnetic resonance imaging (rs-fMRI). The whole-brain functional connectome soon after birth successfully predicted verbal ability at 3 years of corrected age (r=0.53, = 4.0410!") and motor ability at age 2 (r=0.39, = 0.0004) in very preterm infants. In particular, we found that functional edges between the frontoparietal network and limbic, motor, and medial frontal networks at birth contributed significantly to the prediction of future verbal language ability, while the edges connecting the medial frontal network and motor and basal ganglia networks contributed the most to the prediction of future motor ability. In a separate validation analysis, we demonstrated that the mean connectivity strength among these top brain networks significantly differentiated (average accuracy 76%, p<0.001) poor from normal performers at 2 and 3 years of ages. These findings highlight regional functional connectivity soon after birth as a promising biomarker for identifying risks for later brain disorders, which could inform the targeted development of effective early treatments and interventions.

neuroscience↗
bioRxiv2025

Grin2a Dysfunction Impairs Cognitive Flexibility by Disrupting LC Modulation of mPFC Circuits

Cognitive flexibility, a key executive function, is impaired in psychiatric disorders involving prefrontal cortical dysfunction. The medial prefrontal cortex (mPFC) regulates cognitive flexibility and receives noradrenergic input from the locus coeruleus (LC). Mutations in GRIN2A, encoding GluN2A-containing NMDA receptors, impair cognitive flexibility and psychiatric resilience, yet the circuit mechanisms remain unclear. Optogenetic LC[->]mPFC activation improved reversal learning in wild-type and Grin2a heterozygous (HET) mice but not in knockouts (KO), indicating a loss of noradrenergic modulation. Grin2a mutants displayed disrupted gamma and high-frequency oscillations (HFOs) in the mPFC. Exogenous norepinephrine failed to restore oscillatory activity, implicating 2-adrenoceptors in NE-driven cortical dynamics. Increased LC innervation and norepinephrine transporter (NET) expression in Grin2a mutants suggest excessive noradrenergic input and impaired NE clearance. These findings identify GluN2A as essential for LC-driven prefrontal network synchronization and cognitive flexibility, offering insights into NE dysfunction in psychiatric disorders.

neuroscience↗
bioRxiv2024

Grin2a Ablation Distinctly Reshapes PV+ and SST+ Interneuron circuits in the Medial Prefrontal Cortex to Amplify Gamma Oscillations

Schizophrenia (SCZ) is a debilitating mental health disorder marked by cognitive deficits, especially in executive functions, which are often resistant to treatment. The GRIN2A gene encodes the GluN2A subunit of N-methyl-D-aspartate (NMDA) receptor. Rare coding mutations in GRIN2A, such as protein-truncating variants, increase susceptibility to SCZ by [~]20-fold. However, the effects on network dynamics and the function of GABAergic interneurons (INs) in the medial prefrontal cortex (mPFC) remain unclear. In this study, we use brain slices from Grin2a mutant mice to investigate inhibitory synaptic and oscillatory activity driven by parvalbumin-positive (PV+) and somatostatin-positive (SST+) INs. Our findings reveal significant alterations in synaptic currents and inhibitory modulation arise from GluN2A deficiency. Specifically, both heterozygous and knockout Grin2a mutants exhibit impaired synaptic transmission and release properties of INs inputs, including changes in release probability and evoked quantal events to layer V pyramidal neurons. Genotype-dependent alterations were observed in the frequency, kinetics, and amplitude of excitatory and inhibitory postsynaptic currents. Immunohistochemical analysis showed an increased density of PV+ and SST+ INs in the Grin2a mutants, consistent with an overall increase in inhibitory tone. Additionally, optogenetic stimulation revealed a dynamic shift for inducing gamma-band oscillations through PV+ INs. Overall, our study highlights the essential role of GluN2A-containing NMDA receptors in modulating inhibitory tone and maintaining network stability in the mPFC of adult mice and elucidates a pathophysiological mechanism that might contribute to cognitive deficits often observed in SCZ patients.

neuroscience↗
bioRxiv2023

A versatile synaptotagmin-1 nanobody provides perturbation-free live synaptic imaging and low linkage-error in super-resolution microscopy

Imaging of living synapses has relied for over two decades on the overexpression of synaptic proteins fused to fluorescent reporters. This strategy changes the stoichiometry of synaptic components and ultimately affects synapse physiology. To overcome these limitations, here we introduce a nanobody that binds the calcium sensor synaptotagmin-1 (NbSyt1). This nanobody functions in living neurons as an intrabody (iNbSyt1) and is minimally invasive, leaving synaptic transmission almost unaffected, as demonstrated by the crystal structure of the NbSyt1 bound to synaptotagmin-1 and by our physiological data. Its single-domain nature enables the generation of protein-based fluorescent reporters, as we showcase here by measuring spatially-localized presynaptic Ca2+ with an NbSyt1-jGCaMP8 chimera. Moreover, its small size makes the NbSyt1 ideal for various super-resolution imaging methods. Overall, NbSyt1 is a versatile binder that will enable imaging in cellular and molecular neuroscience at a higher precision than possible in the past, over multiple spatiotemporal scales.

neuroscience↗
bioRxiv2022

Exploring volume mediated bystander-inhibition in a neuron model of the Locus coeruleus

The Locus coeruleus (LC) modulates various neuronal circuits throughout the brain. Its unique architectural organization encompasses a net of axonal innervation that spans the entire brain; while its somatic core is highly compact. Recent research revealed an unexpected cellular input specificity within the nucleus that can give rise to various network states that either broadcast norepinephrine signals throughout the brain or pointedly modulate specific brain areas. Such adaptive input-output functions likely surpass our existing network models that build upon a given synaptic wiring configuration between neurons. As the distances between noradrenergic neurons in the core of the LC are unusually small, neighboring neurons could theoretically impact each other via volume transmission of NE. We therefore set out to investigate if such interaction could be mediated through noradrenergic alpha2-receptors in a spiking neuron model of the LC. We validate our model of LC neurons through comparison with experimental patch-clamp data and identify key variables that impact alpha2-mediated inhibition of neighboring LC neurons. Our simulation confirms a reliable autoinhibition of LC neurons after episodes of high neuronal activity that continue even after neuronal activity subsided. Also, dendro-somatic synapses inhibit spontaneous spiking in the somatic compartment of connected neurons in our model. We determined the exact position of hundreds of LC neurons in the mouse brain stem via a tissue clearing approach and, based on this, further determined that 25 percent of noradrenergic neurons have a neighboring LC neuron within less than a 25-micrometer radius. By modeling NE diffusion, we estimate that more than 15 percent of alpha2-adrenergic receptors fraction can bind NE within such diffusion radius. Our spiking neuron model of LC neurons predicts that repeated or long-lasting episodes of high neuronal activity induce partitioning of the gross LC network, and reduces the spike rate in neighboring neurons at distances smaller than 25 micrometers. As these volume-mediate neighboring effects are challenging to test with the current methodology, our findings can guide future experimental approaches to test this phenomenon and its physiological consequences.

neuroscience↗
bioRxiv2020

Omics integration analyses reveal the early evolution of malignancy in breast cancer

BackgroundThe majority of cancer evolution studies are done on individual-based approaches that neglect population dynamics necessity for the global picture of cancer evolution in each cancer type. Here, we conducted a population-based study in breast cancer to understand the timing of malignancy evolution and its correlation to the genetic evolution of pathological stages. ResultsIn an omics integrative approach, we integrated gene expression and genomic aberration data for pre-invasive (DCIS, early-stage) and post-invasive (IDC, late-stage) samples and investigated the evolutionary role of further genetic changes in late stages compared to the early ones. We found that single genetic alterations (SGAs) and copy number alterations (CNAs) conspire together for the fine-tuning of the operating signaling pathways of tumors in forward and backward evolution manners. The forward evolution applies to new genetic changes that boost the efficiency of selected signaling pathways. The backward evolution, which we detected for CNAs, is a mean to reverse unwanted SGAs of earlier stages. Analyses of the integrated point mutation and gene expression data show that (i) our proposed fine-tuning concept is also applicable in metastasis, and (ii) metastasis diverges from primary tumor sometimes at the DCIS stage. ConclusionsOur results indicate that malignant potency of breast tumors is constant over pre and post invasive pathological stages. Indeed, further genetic alterations in later stages do not establish de novo malignancy routes; however, they serve to fine-tune antecedent signaling pathways.

evolutionary biology↗