Biology subjects

Taher, H.

Publications and source records attributed to Taher, H..

9 recordsLinked to original sources

bioRxiv2026

Brain network modeling with The Virtual Brain derives pharmacodynamics of ketamine

Ketamine, an N-Methyl-D-aspartate receptor (NMDAR) antagonist, is used clinically as an anesthetic and antidepressant, and is also known for its psychotomimetic effects. Its impact on brain dynamics and behavior varies significantly with dosage likely via a dose-dependent modulation of the NMDARergic transmission. Currently, it is unclear how molecular changes at the microscopic level of NMDAR antagonism lead to large-scale changes in brain dynamics. We implement a dose-dependent NMDAR antagonism based on ketamines disinhibition theory into a biophysically grounded mean-field model within The Virtual Brain (TVB) framework to replicate ketamines key signatures across its dose spectrum. Our results imply that in low doses ketamine preferentially impairs excito-inhibitory neurotransmission while in higher doses antagonism on excito-excitatory connections plays a role. These findings highlight the utility of computational modeling for disentangling dose-specific mechanisms of action and provide a framework for exploring NMDAR-related interventions. Author summaryKetamine is a dissociative anesthetic at high doses, but at lower, sub-anesthetic doses, it has garnered significant interest for its rapid-acting antidepressant and anxiolytic effects. Despite its growing clinical use in psychiatric conditions, the precise neural mechanisms underlying ketamines dose-dependent effects remain incompletely understood. Ketamine primarily acts as a non-competitive antagonist of the NMDAR, which is expressed on both excitatory and inhibitory neurons throughout the cortex. One of the leading hypotheses explaining its antidepressant effects is the disinhibition theory which proposes that low doses of ketamine preferentially block NMDARs on inhibitory interneurons, resulting in increased cortical excitability. At high doses ketamine exerts anesthetic effects potentially through more widespread NMDAR antagonism including on excitatory neurons. In this study, we used a computational model to explore how selective NMDAR antagonism at different doses affects large-scale brain dynamics. A key novelty of our work is the integration of ketamines full dose spectrum within a single computational modeling framework, allowing us to relate distinct neural effects from disinhibition to anesthesia to experimental findings. This modeling approach contributes to a deeper understanding of how ketamine modulates cortical activity across different contexts.

neuroscience↗

bioRxiv2025

The Virtual Brain Ontology: A Digital Knowledge Framework for Reproducible Brain Network Modeling

Computational models of brain network dynamics offer mechanistic insights into brain function and disease, and are utilized for hypothesis generation, data interpretation, and the creation of personalized digital brain twins. However, results remain difficult to reproduce and compare because equations, parameters, networks, and numerical settings are reported inconsistently across the literature, and shared code is often not fully documented, standardized, or executable. We introduce The Virtual Brain Ontology (TVB-O), a semantic knowledge base, minimal metadata standard, and Python toolbox that simplifies the description, execution, and sharing of network simulations. TVB-O offers 1) a common vocabulary and ontology for core concepts and axioms representing current domain knowledge for simulating brain network dynamics, 2) a minimal, human- and machine-readable metadata specification for the information needed to reproduce an experiment, 3) a curated database of published models, brain networks, and study configurations, and 4) software that generates executable code for various simulation platforms and programming languages, including The Virtual Brain, Jax, or Julia. FAIR metadata and provenance-aware reports can be exported from TVB-Os model specification. It hereby enables a flexible framework for adopting new models and enhances reproducibility, comparability, and portability across simulators, while making assumptions explicit and linking models to biomedical knowledge and observation pathways. By reducing technical barriers and standardizing workflows, TVB-O broadens access to computational neuroscience and establishes a foundation for transparent, shareable "digital brain twins" that integrate with clinical pipelines and large-scale data resources.

neuroscience↗

bioRxiv2024

Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity

Human cytomegalovirus (HCMV) encodes four viral Fc-gamma receptors (vFc{gamma}Rs) that counteract antibody-mediated activation in vitro, but their role in infection and pathogenesis is unknown. To examine the in vivo function of vFc{gamma}Rs in animal hosts closely related to humans, we identified and characterized vFc{gamma}Rs encoded by rhesus CMV (RhCMV). We demonstrate that Rh05, Rh152/151 and Rh173 represent the complete set of RhCMV vFc{gamma}Rs, each displaying functional similarities to their respective HCMV orthologs with respect to antagonizing host Fc{gamma}R activation in vitro. When RhCMV-naive rhesus macaques were infected with vFc{gamma}R-deleted RhCMV, peak plasma viremia levels and anti-RhCMV antibody responses were comparable to wildtype infections. However, the duration of plasma viremia was significantly shortened in immunocompetent, but not in CD4+ T cell-depleted animals. Since vFc{gamma}Rs were not required for superinfection, we conclude that vFc{gamma}Rs delay control by virus-specific adaptive immune responses, particularly antibodies, during primary infection.

microbiology↗

bioRxiv2023

The pentameric complex is not required for vertical transmission of cytomegalovirus in seronegative pregnant rhesus macaques

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neonatal neurological impairment but essential virological determinants of transplacental CMV transmission remain unclear. The pentameric complex (PC), composed of five subunits, glycoproteins H (gH), gL, UL128, UL130, and UL131A, is essential for efficient entry into non-fibroblast cells in vitro. Based on this role in cell tropism, the PC is considered a possible target for CMV vaccines and immunotherapies to prevent cCMV. To determine the role of the PC in transplacental CMV transmission in a non-human primate model of cCMV, we constructed a PC-deficient rhesus CMV (RhCMV) by deleting the homologues of the HCMV PC subunits UL128 and UL130 and compared congenital transmission to PC-intact RhCMV in CD4+ T cell-depleted or immunocompetent RhCMV-seronegative, pregnant rhesus macaques (RM). Surprisingly, we found that the transplacental transmission rate was similar for PC-intact and PC-deleted RhCMV based on viral genomic DNA detection in amniotic fluid. Moreover, PC-deleted and PC-intact RhCMV acute infection led to similar peak maternal plasma viremia. However, there was less viral shedding in maternal urine and saliva and less viral dissemination in fetal tissues in the PC-deleted group. As expected, dams inoculated with PC-deleted RhCMV demonstrated lower plasma IgG binding to PC-intact RhCMV virions and soluble PC, as well as reduced neutralization of PC-dependent entry of the PC-intact RhCMV isolate UCD52 into epithelial cells. In contrast, binding to gH expressed on the cell surface and neutralization of entry into fibroblasts by the PC-intact RhCMV was higher for dams infected with PC-deleted RhCMV compared to those infected with PC-intact RhCMV. Our data demonstrates that the PC is dispensable for transplacental CMV infection in our non-human primate model. One Sentence SummaryCongenital CMV transmission frequency in seronegative rhesus macaques is not affected by the deletion of the viral pentameric complex.

microbiology↗

bioRxiv2023

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n=15), CD4+ T cell-depleted with (n=6) and without (n=6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings. Author summaryCytomegalovirus (CMV) is the most common infectious cause of birth defects globally, but we still do not have licensed medical interventions to prevent vertical transmission of CMV. We utilized a non-human primate model of primary CMV infection during pregnancy to study virological and humoral factors that influence congenital infection. Unexpectedly, we found that the levels virus in maternal plasma were not predictive of virus transmission to the amniotic fluid (AF) in immunocompetent dams. In contrast, CD4+ T cell depleted pregnant rhesus macaques with virus detected in AF had higher plasma viral loads than dams not showing placental transmission. Virus-specific antibody binding, neutralizing, and Fc-mediated antibody effector antibody responses were not different in immunocompetent animals with and without virus detectable in AF, but passively infused neutralizing antibodies and antibodies binding to key glycoproteins were higher in CD4+ T cell-depleted dams who did not transmit the virus compared to those that did. Our data suggests that the natural development of virus-specific antibody responses is too slow to prevent congenital transmission following maternal infection, highlighting the need for the development of vaccines that confer levels of pre-existing immunity to CMV-naive mothers that can prevent congenital transmission to their infants during pregnancy.

immunology↗

bioRxiv2021

Patient-specific network connectivitycombined with a next generation neural massmodel to test clinical hypothesis of seizurepropagation

Dynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population. In this study we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine the mathematical modelling with structural information from non-invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values. We demonstrate, along the example of diffusion-weighted magnetic resonance imaging (MRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e. the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.

neuroscience↗

bioRxiv2020

Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy

Simian immunodeficiency virus (SIV) insert-expressing, 68-1 Rhesus Cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex (MHC)-E- and -II-restricted, SIV-specific CD8+ T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) has not been characterized. We demonstrate that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/.4 and Rh158-161). Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (UL128/130; UL146/147) leads to either of two distinct CD8+ T cell response types - MHC-Ia-restricted-only, or a mix of MHC-II- and MHC-Ia-restricted CD8+ T cells. Despite response magnitude and functional differentiation being similar to RhCMV 68-1, neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8+ T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all the genes that inhibit these responses from the HCMV/HIV vector. One-sentence summaryEight genes in two spatially distinct RhCMV gene regions control induction of unconventionally restricted CD8+ T cell responses and the efficacy of RhCMV/SIV vaccine vectors against SIV challenge.

immunology↗

bioRxiv2020

Exact neural mass model for synaptic-based working memory

A synaptic theory of Working Memory (WM) has been developed in the last decade as a possible alternative to the persistent spiking paradigm. In this context, we have developed a neural mass model able to reproduce exactly the dynamics of heterogeneous spiking neural networks encompassing realistic cellular mechanisms for short-term synaptic plasticity. This population model reproduces the macroscopic dynamics of the network in terms of the firing rate and the mean membrane potential. The latter quantity allows us to get insigth on Local Field Potential and electroencephalographic signals measured during WM tasks to characterize the brain activity. More specifically synaptic facilitation and depression integrate each other to efficiently mimic WM operations via either synaptic reactivation or persistent activity. Memory access and loading are associated to stimulus-locked transient oscillations followed by a steady-state activity in the {beta}-{gamma} band, thus resembling what observed in the cortex during vibrotactile stimuli in humans and object recognition in monkeys. Memory juggling and competition emerge already by loading only two items. However more items can be stored in WM by considering neural architectures composed of multiple excitatory populations and a common inhibitory pool. Memory capacity depends strongly on the presentation rate of the items and it maximizes for an optimal frequency range. In particular we provide an analytic expression for the maximal memory capacity. Furthermore, the mean membrane potential turns out to be a suitable proxy to measure the memory load, analogously to event driven potentials in experiments on humans. Finally we show that the{gamma} power increases with the number of loaded items, as reported in many experiments, while{theta} and {beta} power reveal non monotonic behaviours. In particular, {beta} and{gamma} rhytms are crucially sustained by the inhibitory activity, while the{theta} rhythm is controlled by excitatory synapses. Author summaryWorking Memory (WM) is the ability to temporarily store and manipulate stimuli representations that are no longer available to the senses. We have developed an innovative coarse-grained population model able to mimic several operations associated to WM. The novelty of the model consists in reproducing exactly the dynamics of spiking neural networks with realistic synaptic plasticity composed of hundreds of thousands neurons in terms of a few macroscopic variables. These variables give access to experimentally measurable quantities such as local field potentials and electroencephalografic signals. Memory operations are joined to sustained or transient oscillations emerging in different frequency bands, in accordance with experimental results for primate and humans performing WM tasks. We have designed an architecture composed of many excitatory populations and a common inhibitory pool able to store and retain several memory items. The capacity of our multi-item architecture is around 3-5 items, a value corresponding to the WM capacities measured in many experiments. Furthermore, the maximal capacity is achievable only for presentation rates within an optimal frequency range. Finally, we have defined a measure of the memory load analogous to the event-related potentials employed to test humans WM capacity during visual memory tasks.

neuroscience↗

bioRxiv2020

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome

Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the commonly used 68-1 strain of RhCMV has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptation that cause reduced viremia in RhCMV-naive animals and limited shedding compared to low passage isolates. Using sequence information from primary RhCMV isolates we constructed a full-length (FL) RhCMV by repairing all presumed mutations in the 68-1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naive RM with the reconstituted virus resulted in significant replication in the blood similar to primary isolates of RhCMV and furthermore led to extensive viremia in many tissues at day 14 post infection. In contrast, viral dissemination and viremia was greatly reduced upon deletion of genes also lacking in 68-1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68-1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques. Author SummaryHuman cytomegalovirus (HCMV) infections are generally asymptomatic in healthy immunocompetent individuals, but HCMV can cause serious disease after congenital infection and in individuals with immunocompromised immune systems. Since HCMV is highly species specific and cannot productively infect immunocompetent laboratory animals, experimental infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a closely related animal model for HCMV. By employing the unique ability of CMV to elicit robust and lasting cellular immunity, this model has also been instrumental in developing novel CMV-based vaccines against chronic and recurring infections with pathogens such as the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb). However, most of this work was conducted with derivatives of the 68-1 strain of RhCMV which has acquired multiple genomic alterations in tissue culture. To model pathogenesis and immunology of clinical HCMV isolates we generated a full-length (FL) RhCMV clone representative of low passage isolates. Infection of RhCMV-naive RM with FL-RhCMV demonstrated viremia and tissue dissemination that was comparable to that of non-clonal low passage isolates. We further demonstrate that FL-RhCMV is strongly attenuated upon deletion of gene regions absent in 68-1 thus demonstrating the usefulness of FL-RhCMV to study RhCMV pathogenesis.

microbiology↗