Biology subjects

Joseph, W.

Publications and source records attributed to Joseph, W..

10 recordsLinked to original sources

bioRxiv2026

Seizure control via astrocyte targeted optogenetic extracellular potassium modulation: computational analysis of K+ vs non-selective cation-conducting opsins

Aims: Seizure generation has been strongly linked to the accumulation of extracellular potassium. As astrocytes play a key role in potassium homeostasis, astrocyte targeted optogenetic modulation of extracellular potassium has been proposed as a novel strategy for seizure control. The effectiveness of such modulation is expected to depend strongly on the ion selectivity of the employed opsin. This study aims to mechanistically compare potassium-selective (WiChR) and cation-conducting (ChR2-like, ChR2*) opsins for astrocyte targeted modulation of extracellular potassium, and to determine how astrocytic properties and stimulation parameters influence modulation efficacy. Methods: A conductance-based computational framework was used to model astrocyte-extracellular space interactions, incorporating ion-specific photocurrents, Na+/K+-ATPase activity, and gap junction-mediated coupling within the astrocytic syncytium. Systematic parameter sweeps were performed to evaluate the influence of ion selectivity, astrocytic parameters, and stimulation paradigms on potassium dynamics. Results: WiChR-based modulation consistently produced more effective and robust reductions in [K+]e than ChR2*, via direct K+ inward currents and reduced dependence on pump activity. In contrast, ChR2* primarily limited potassium accumulation rather than reversing it and exhibited greater sensitivity to parameter variations, particularly Na+/K+-ATPase activity. The effectiveness of astrocyte-targeted modulation was strongly dependent on syncytial integrity, with reduced gap junction coupling impairing potassium clearance. Optimal stimulation performance for WiChR was observed for a pulse repetition period of 20 ms, with outcomes determined by the interaction between opsin kinetics and stimulation parameters. Conclusions: These results demonstrate that activation of WiChR opsins in astrocytes can reduce extracellular potassium levels and thereby modulate neuronal excitability. Ion selectivity emerges as a key determinant of modulation efficacy at the astrocytic level, with potassium-selective opsins providing a more direct and reliable approach than non-selective cation-conducting alternatives. Together, these findings establish a mechanistic basis for optogenetic activation of astrocytic potassium buffering as a potential strategy for seizure suppression and other neurological disorders associated with potassium dysregulation.

neuroscience↗

bioRxiv2026

Black women undergraduates' perspectives on how mentors and role models shape their beliefs about the attainability of science research careers

Undergraduate research experiences offer important paths into scientific research careers, yet students do not experience them uniformly. For Black women, these experiences occur within racialized and gendered environments that may shape whether they perceive research careers as attainable. Yet little is known about these influences, including how mentors, role models, and institutional contexts, could support or limit Black womens beliefs about research career attainability. To advance our understanding of these influences, we conducted interviews with 23 Black women who participated in undergraduate research at 18 institutions in the United States, including historically Black colleges and universities (HBCUs) and predominantly White institutions (PWIs). We conducted qualitative content analysis to understand Black women undergraduate researchers perceptions of the attainability of a scientific research career, including the influences of their mentors, role models, and institutional context. Three main themes emerged. First, Black women undergraduates varied in the importance they placed on sharing racial and gender identities with mentors and role models; some viewed such similarities as highly meaningful while others described them as less influential. Second, Black women undergraduates described that mentors and role models who shared similar life experiences, values, attitudes, or beliefs contributed to perceptions that scientific research careers were attainable, regardless of gender or racial similarity. Third, institutional context (HBCU, PWI) shaped how mentoring and role modeling influenced Black women undergraduates perceptions of research career attainability. We conclude by offering recommendations for individuals seeking to support Black women in undergraduate research and in their pursuit of research careers.

scientific communication and education↗

bioRxiv2026

Evaluation of Neuronal Activation Thresholds for Low-Frequency Electromagnetic Exposure Using Morphologically Realistic Neuron Models

International guidelines for low-frequency electromagnetic field exposure (LF EMF) are primarily intended to prevent substantiated adverse effects. In the frameworks, limits on internal electric fields are linked to external exposure levels through computational dosimetry. However, the relationship between internal electric fields and these adverse effects remains incompletely understood. In particular, current approaches often overlook the morphological complexity and diversity of cortical neurons, which may limit the realism of neuronal activation estimates used to support these assessments. This study evaluates LF EMF-induced neural activation using 25 morphologically realistic neuron models spanning all cortical layers, embedded within 11 detailed human head models. The internal electric fields were simulated for uniform magnetic field exposures (100 Hz-100 kHz) along the three anatomical directions, and excitation thresholds were computed using a multi-scale framework combining voxel-based dosimetry with biophysical neuron simulations. A real-world exposure scenario involving a child near an acousto-magnetic article-surveillance deactivator was also analyzed. Thresholds varied across cell type, morphology, cortical location, subject anatomy, frequency, and exposure direction, with L2/3 pyramidal, L4 basket, and L5 thick-tufted pyramidal cells showing the lowest thresholds. Despite this variability, all simulated thresholds were conservative with respect to the basic restrictions and dosimetric reference limits set by IEEE ICES and ICNIRP. The smallest margin occurred at 100 kHz, where the threshold remained a factor of 2.8 above the corresponding limit. These findings indicate that current LF EMF exposure limits remain conservative when evaluated using highly detailed, morphology-based CNS activation models.

neuroscience↗

bioRxiv2024

Computational analysis of optogenetic inhibition of CA1 neurons using a data-efficient and interpretable potassium and chloride conducting opsin model

Optogenetic inhibition of excitatory populations has been suggested as a novel technique for the treatment of refractory epilepsy. While this approach holds significant potential, achieving seizure suppression in animal models using optogenetics has proven challenging. This difficulty can be attributed to a suboptimal stimulation method that involves numerous complex variables. To provide insight into these parameters, the behavior of the chloride conducting opsin, GtACR2, was fitted to a mathematical description and combined with a conductance-based model of a pyramidal CA1 neuron. The resulting model was adapted to add the ability to study potassium conducting opsins and used to demonstrate that the effect of an optogenetic modulation setup is highly dependent on its parameters and the physiological conditions of the neuronal environment. Stronger inhibition is observed at higher pulse repetition frequencies and duty cycles. Furthermore, potassium conducting opsins were shown to be more stable in use than chloride conducting ones. The dependence of these observations on the opsin model fit was found to be negligible. To determine this, a simplified model (22OMs) is proposed that permits easy implementation of the experimentally derived parameters describing the opsins opening and closing dynamics into its mathematical description. This model was also employed to determine that the impact of varying the opsins dynamics is insignificant when the opening and closing time constants are altered by a factor between 0.5 and 2. Consequently, this study provides insights into the stimulation and physiological parameters influencing the outcome of an optogenetic inhibition approach and offers a new tool that will facilitate future research into the development of an improved optogenetic modulation protocol for seizure suppression.

bioengineering↗

bioRxiv2024

Action Potential Threshold Variability for Different Electrostimulation Models and the Impact on Occupational Exposure Limit Values

Occupational exposure limit values (ELVs) for body internal electric fields can be derived from thresholds for action potential generation. These thresholds can be calculated with electrostimulation models. The spatially extended nonlinear node model (SENN) is often used to determine such thresholds. An important part of these models are the membrane channel dynamics describing the ionic transmembrane currents. This work shows how ELVs change significantly with different ion channel dynamics (up to a factor of 22). Furthermore, two more detailed double-cable models by Gaines et al. (MRG-Sensory and MRG-Motor) are also considered in this work. Thresholds calculated with the SENN model (with Frankenhaeuser-Huxley membrane channel dynamics) and the MRG models are compared for frequencies between 1 Hz and 100 kHz and temperatures between 22 {degrees}C and 37 {degrees}C. Results show that MRG thresholds are lower than SENN thresholds. In the context of occupational ELVs, using the double cable model would lead to approximately ten times lower limit values. Therefore, future exposure guidelines should take the influence of different electrostimulation models into account when deriving ELVs. HighlightsO_LIDifferent membrane channel dynamics change derived exposure limit values by more than one order of magnitude. C_LIO_LIDouble-cable models result in a reduction of derived exposure limit values by one order of magnitude. C_LIO_LILower temperatures reduce the action potential thresholds at frequencies below 300 Hz. C_LI

physiology↗

bioRxiv2023

Quantitative Analysis of the Optogenetic Excitability of CA1 Neurons

Optogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Employing state-of-the-art computational models, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitability. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.

neuroscience↗

bioRxiv2022

Non-linearities and Timescales in Temporal Interference Deep Brain Stimulation

In temporal interference (TI) stimulation, neuronal cells react to two interfering sinusoidal electric fields with a slightly different frequency. It was previously seen that for the same input intensity, the neurons do not react to a purely sinusoidal signal. This study aims to get a better understanding of the mechanism underlying TI neuromodulation, which is largely unknown. To this end, single-compartment models are used to simulate computationally the response of neurons to the sinusoidal and TI waveform. This study compares different neuron models to get insight into which models are able to reproduce the experimental observations. It was found that integrate- and-fire models do not entirely reflect the experimental behavior while the Hodgkin-Huxley and Frankenhaeuser-Huxley model do reflect this behavior. Changing the characteristics of the ion gates in the Frankenhaeuser-Huxley model alters the response to both the sinusoidal and TI signal, possibly reducing the firing threshold of the sinusoidal input below that of the TI input. The model results show that TI stimulation is not qualitatively impacted by nonlinearities in the current-voltage relation. In contrast, ion channels have a significant impact on the neuronal response. This paper makes advances both in terms of biophysical insight into the neuron as well as the insight in computational modelling of TI stimulation.

neuroscience↗

bioRxiv2021

Improved alpha-beta power reduction via combined Electrical and Ultrasonic stimulation in a Parkinsonian Cortex-Basal Ganglia-Thalamus Computational Model

ObjectiveTo investigate computationally the interaction of combined electrical and ultrasonic modulation of isolated neurons and of the Parkinsonian cortex-basal ganglia-thalamus loop. MethodsContinuous-wave or pulsed electrical and ultrasonic neuromodulation is applied to isolated Otsuka plateau-potential generating subthalamic nucleus (STN) and Pospischil regular, fast and low-threshold spiking cortical cells in a temporally-alternating or simultaneous manner. Similar combinations of electrical/ultrasonic waveforms are applied to a Parkinsonian biophysical cortex-basal ganglia-thalamus neuronal network. Ultrasound-neuron interaction is modelled respectively for isolated neurons and the neuronal network with the NICE and SONIC implementations of the bilayer sonophore underlying mechanism. Reduction in --{beta} spectral energy is used as a proxy to express improvement in Parkinsons disease by insonication and electrostimulation. ResultsSimultaneous electro-acoustic stimulation achieves a given level of neuronal activity at lower intensities compared to the separate stimulation modalities. Conversely, temporally alternating stimulation with 50 Hz electrical and ultrasound pulses is capable of eliciting 100 Hz STN firing rates. Furthermore, combination of ultrasound with hyperpolarizing currents can alter cortical cell relative spiking regimes. In the Parkinsonian neuronal network, high-frequency pulsed separated electrical and ultrasonic deep brain stimulation (DBS) reduce pathological -- {beta} power by entraining STN-neurons. In contrast, continuous-wave ultrasound reduces pathological oscillations by silencing the STN. Compared to the separated stimulation modalities, temporally simultaneous or alternating electro-acoustic stimulation can achieve higher reductions in -- {beta} power for the same contraints on electrical/ultrasonic intensity. ConclusionContinuous-wave and pulsed ultrasound reduce pathological oscillations by different mechanisms. Electroacoustic stimulation further improves -- {beta} power for given safety limits and is capable of altering cortical relative spiking regimes. Significancefocused ultrasound has the potential of becoming a non-invasive alternative of conventional DBS for the treatment of Parkinsons disease. Here, we elaborate on proposed benefits of combined electro-acoustic stimulation in terms of improved dynamic range, efficiency, resolution, and neuronal selectivity.

neuroscience↗

bioRxiv2020

Hodgkin and Huxley Opsin Model for Computationally Efficient Optogenetic Neurostimulation in Cells and Networks

Optogenetics has a lot of potential to become an effective neuromodulative therapy for clinical application. Selecting the correct opsin is crucial to have an optimal optogenetic tool. With computational modeling, the neuronal response to the current dynamics of an opsin can be extensively and systematically tested. Unlike electrical stimulation where the effect is directly defined by the applied field, the stimulation in optogenetics is indirect, depending on the selected opsins non-linear kinetics. With the continuous expansion of opsin possibilities, computational studies are difficult due to the need for an accurate model of the selected opsin first. To this end, we propose a Hodgkin-and-Huxley based model (22HH) as alternative to the conventional three and four state Markov models used for opsin modeling. Furthermore, we provide a fitting procedure, which allows for nearly automatic model fitting starting from a vast parameter space. With this procedure, we successfully fitted two distinctive opsins ChR2(H134R) and MerMAID. Both models are able to represent the experimental data with great accuracy and were obtained within an acceptable time frame. This is due to the absence of differential equations in the fitting procedure, with an enormous reduction in computational cost as result. The performance of the proposed model with a fit to ChR2(H134R) was tested, by comparing the neural response in a regular spiking neuron to the response obtained with the non-instantaneous, four state Markov model (4SB), derived by Williams et al. (2013) [1]. Finally, a computational speed gain was observed with the 22HH model in a regular spiking and sparse Pyramidal-Interneuron-Network-Gamma (sPING) network simulation with respect to the 4SB-model, due to the former having two differential equations less. Consequently, the proposed model allows for computationally efficient optogenetic neurostimulation and with the proposed fitting procedure will be valuable for further research in the field of optogenetics.

bioengineering↗

bioRxiv2019

Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype

Glioblastoma Multiforme is a highly aggressive brain malignancy commonly refractory to classical and novel chemo-, radio- and immuno-therapies, with median survival times of ~15 months following diagnosis. Poor immunological responses exemplified by the down-regulation of T-cell activity, and upregulation of immunosuppressive cells within the tumour micro-environment have limited the effectiveness of immunotherapy in GBM to date. Here we show that GBM cells express a large repertoire of inhibitory checkpoint ligands. Furthermore, GBM cells with an enhanced stem cell-like phenotype exhibit heightened levels of inhibitory checkpoint ligands, compared to non-stem cell-like GBM cells. Understanding how GBM modulates an extensive repertoire of immune checkpoint ligands and the functional consequence on immune evasion are necessary to develop effective immuno-therapeutics.

cell biology↗