Biology subjects

Hazan, H.

Publications and source records attributed to Hazan, H..

9 recordsLinked to original sources

bioRxiv2026

Computational Framework for Identifying Ion Channel Mutation-Compensating Interventions

We present an automated pipeline for finding therapeutic interventions in channelopathies. It starts from patch clamp recordings of the variant channel, searches over the pharmacologically accessible conductances, and says which currents must change and by how much. The intervention never touches the mutated channel: it compensates by modulating others. The feasibility of this approach is demonstrated through two computational strategies, each addressing a specific capability gap. First, we employ high-fidelity NEURON simulations combined with exploratory search algorithms to model two clinically described variants, and identify "stability windows" in which channel modulations restore the reference firing pattern. The compensating configurations are degenerate: 37 conductance triples fire the same number of action potentials at every one of the 35 injected-current levels, and the 10,780 triples reaching the best intervention value produce only six distinct firing patterns. Second, to address the computational cost of such detailed modeling, we implement a differentiable Hodgkin-Huxley model in PyTorch. Applied here to theoretical mutation screening, this approach trades granular detail for speed, treating the search as a continuous optimization problem that makes very large, non-local searches of the conductance parameter space affordable: the differentiable forward model evaluates 34,000-64,000 candidate parameter sets per second on a single consumer graphics card, against 11.9-16.9 per second for the non-differentiable pipeline on a 72-core node. The gain arises from forward-model throughput feeding a search rather than from the gradient itself, and it is what makes the 32,000,000-point survey of the solution topology reported here affordable. These computational predictions can inform practical drug development and high-throughput screening by naming the currents that must change and by how much.

bioinformatics↗

bioRxiv2026

A platform for automated training of mammalian cell physiology

Controlling cell physiology is difficult, not only because of cells complexity, but also their capacity for real-time adaptation to interventions, leading to challenges such as drug resistance and transgene silencing. Accumulating evidence suggests that this adaptivity resembles classical forms of learning defined in behavioral science. However, a lack of appropriate platforms has led to gaps in our understanding of cells capacity for adaptive problem-solving in physiological and transcriptional space. Here, we present a device, the Cell Trainer, capable of performing a wide variety of automated training experiments on non-neural mammalian cells, using timed drug pulses as the stimulus, and a mobile fluorescence microscope to capture images of responses, across replicate cultures. The Cell Trainer can operate in either an open-loop (feedforward) or closed-loop (feedback-controlled) mode, and our image analysis pipeline can report the behaviors of individual cells throughout each experiment and quantify population heterogeneity. We showcase the ability of the Cell Trainer to execute experimental protocols and perform single-cell analyses in both modes. We first demonstrate with a feedforward experiment in which myoblasts are repeatedly pulsed with dimethyl sulfoxide (DMSO) and their discrete calcium responses are analyzed, revealing sensitization-like dynamics. Next, we demonstrate a feedback control scheme wherein the fluorescence of a pH/voltage reporter in kidney cells is maintained below a threshold level with controlled pulses of acid. To accelerate research in the field of cell training, learning, and memory, we are openly sharing the Cell Trainer schematics and software with the research community. This platform provides a flexible tool for studying how cellular physiological states can be shaped by patterned stimulation and feedback control through approaches that work with the native adaptive competencies of cells.

bioengineering↗

bioRxiv2026

Context-Aware Evidence-Gated Plasticity for Multi-Goal Learning in Spiking Neural Networks

Background / IntroductionBiologically inspired spiking neural networks can model adaptive behavior, but learning multiple goals is difficult because synaptic updates for different targets can interfere. We tested whether multi-timescale plasticity and context-specific credit assignment could improve continual multi-goal learning in a spiking navigation system inspired by entorhinal-hippocampal circuitry. MethodsWe developed a closed-loop spiking model containing grid-like, place-like, target-related, association, and motor-output populations. An agent navigated in a two-dimensional environment with randomized starting locations and learned through reward-modulated spike-timing dependent plasticity (STDP/RL) and a novel evidence-gated plasticity (EGP) framework. EGP accumulates candidate synaptic modifications, evaluates them using reward evidence, and consolidates only changes that improve performance. A target-context variant maintained separate proposal stores and reward evaluation for each target. ResultsSTDP/RL learned and retained a single-target navigation policy, but multi-target training produced substantial interference, including attraction to incorrect targets after learning. Across 10 connectivity seeds, target-context EGP achieved higher late-stage reward than global EGP, improved weakest-target performance, and increased the fraction of targets achieving positive reward. In a longer continual-learning simulation, reward increased for all targets, TEST-phase performance increasingly exceeded TRAIN-phase performance, and proposal magnitudes grew over learning. Dwell-time confusion analyses showed that target-context EGP reduced wrong-target attraction and improved target selectivity relative to multi-target STDP/RL. ConclusionsThese results demonstrate that spiking navigation circuits can learn goal-directed behavior using local plasticity, but robust multi-goal learning benefits from context-specific evidence-based consolidation. Target-context EGP provides a biologically motivated mechanism for reducing interference during continual reinforcement learning in spiking neural networks.

neuroscience↗

bioRxiv2026

DeltaQ: Value-Guided Hebbian Learning in Spiking Neuronal Networks for Multi-Goal Navigation

Animals must often navigate environments where feedback about progress toward a goal is sparse or delayed, requiring internal representations of space and memory of prior experience. The hippocampal-entorhinal system is believed to support this capability through distributed spatial representations that guide goal-directed behavior. However, many computational models of these circuits focus primarily on reproducing neural dynamics rather than demonstrating how such representations support learning on navigation tasks. We present a biologically inspired spiking neuronal network (SNN) model that combines grid-cell-derived spatial representations, {Delta}Q-modulated Hebbian plasticity, and context-dependent modulation to support navigation under sparse reward conditions. Grid Cell populations generate distributed spatial codes that are transformed by an Association Cell population into more spatially selective internal representations. Learning is driven by changes in Q-values ({Delta}Q) computed from a goal-conditioned Q-table, allowing local synaptic plasticity to incorporate information about long-term navigation outcomes. For environments containing multiple navigation objectives, a Context Cell population provides task-dependent modulation that enables a shared network architecture to support distinct navigation policies. Across two complementary maze environments, the model demonstrates three core capabilities: generation of distinct spatial representations, learning of efficient navigation policies under sparse and delayed reward, and support for multiple navigation objectives within a shared environment. The results further show that contextual modulation introduces subtle task-dependent variations into a largely shared population representation, allowing identical spatial locations to support different navigation behaviors. These findings demonstrate that biologically inspired spatial representations, value-guided plasticity, and contextual modulation can jointly support flexible navigation in spiking neuronal networks, providing a bridge between mechanistic neural circuit models and functional reinforcement learning.

neuroscience↗

bioRxiv2024

A Systems Biology Analysis of Chronic Lymphocytic Leukemia

Whole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, ZAP70 are often mutated in CLL, but not consistently across all CLL patients. This paper employs a statistical thermo-dynamics approach in combination with the systems biology of the CLL protein-protein interaction networks to identify the most significant participant proteins in the cancerous transformation. Betti number (a topology of complexity) estimates highlight a protein hierarchy, primarily in the Wnt pathway known for aberrant CLL activation. These individually identified proteins suggest a network-targeted strategy over single-target drug development. The findings advocate for a multi-target inhibition approach, limited to several key proteins to minimize side effects, thereby providing a foundation for designing therapies. This study emphasizes a shift towards a comprehensive, multi-scale analysis to enhance personalized treatment strategies for CLL, which could be experimentally validated using siRNA or small molecule inhibitors. The result is not just the identification of these proteins but their rank-order, offering a potent signal amplification in the context of the 20,000 proteins produced by the human body, thus providing a strategic basis for therapeutic intervention in CLL, underscoring the necessity for a more holistic, cellular, chromosomal, and genome-wide study to develop tailored treatments for CLL patients. Author SummaryChronic Lymphocytic Leukemia (CLL) is a unique and slowly progressing cancer affecting white blood cells, and research on CLL has highlighted the inconsistency of gene mutations across patients. Using a novel approach that merges statistical thermodynamics and systems biology, this research examines the CLL protein-protein interaction networks to pinpoint proteins integral to the onset of the disease. Betti number (a topology of complexity) estimates, which measure the importance of individual proteins when removed from the network, helped identify numerous potential therapeutic targets, notably within the Wnt signaling pathway, a pathway implicated in various cellular processes and known for its defective expression in CLL. The finding advocates for a multi-target inhibition approach, focusing on several key proteins to minimize side effects, thereby laying a foundation for designing more effective therapies for CLL. This paper emphasizes the potential benefits of a comprehensive study, spanning cellular to genome-wide scales, to design personalized treatments for CLL patients.

systems biology↗

bioRxiv2022

Exploring The Behavior of Bioelectric Circuits using Evolution Heuristic Search

Characteristic spatial differences of cellular resting potential across tissues have been shown to act as instructive bioelectric prepatterns regulating embryonic and regenerative morphogenesis, as well as cancer suppression. Indeed, modulation of bioelectric patterns via specific ion channel-targeting drugs, channel misexpression, or optogenetics has been used to control growth and form in vitro, showing promise in regenerative medicine and synthetic bioengineering. Repair of defects, injury, and transformation requires quantitative understanding of bioelectric dynamics within tissues so that these can be modulated toward desired outcomes in organ patterning or the creation of entirely novel synthetic constructs. The major gap in the discovery of interventions for rational control of organ-level outcomes is the inability to predict large-scale bioelectric patterns - their emergence from symmetry breaking (given a set of channels expressed on the tissue) and their change as a function of time under specific bioelectrical interventions. It is thus essential to develop machine learning and other computational tools to help human scientists identify bioelectric states with desirable properties. Here, we tested the ability of a heuristic search algorithm to explore the parameter space of bio-electrical circuits by adjusting the parameters of simulated cells. We show that while bioelectrical space is not easy to search, it does contain parameter sets that encode rich and interesting patterning behaviors. We demonstrate proof of principle of using a computational search platform to identify circuits with desired properties, as a first step toward the design of machine learning tools for improved bioelectric control of growth and form.

biophysics↗

bioRxiv2021

Multi-timescale biological learning algorithms train spiking neuronal network motor control

Despite being biologically unrealistic, artificial neural networks (ANNs) have been successfully trained to perform a wide range of sensory-motor behaviors. In contrast, the performance of more biologically realistic spiking neuronal network (SNN) models trained to perform similar behaviors remains relatively suboptimal. In this work, we aimed at pushing the field of SNNs forward by exploring the potential of different learning mechanisms to achieve optimal performance. Inspired by biological learning mechanisms operating at multiple timescales, we used spike-timing-dependent reinforcement learning (STDP-RL) and evolutionary strategy (EVOL) with SNNs to solve the CartPole reinforcement learning (RL) control problem. Though the role of STDP-RL in biological systems is well established, several other mechanisms, though not fully understood, work in concert during learning in vivo. Recreating accurate models that capture the interaction of STDP-RL with these diverse learning mechanisms is extremely difficult. EVOL is an alternative method, and has been successfully used in many studies to fit model neural responsiveness to electrophysiological recordings and in some cases for classification problems. One advantage of EVOL is that it may not need to capture all interacting components of synaptic plasticity, and thus provides a better alternative to STDP-RL. Here, we compared the performance of each algorithm after training, which revealed EVOL as a powerful method to training SNNs to perform sensory-motor behaviors. Our modeling opens up new capabilities for SNNs in RL and could serve as a testbed for neurobiologists aiming to understand multi-timescale learning mechanisms and dynamics in neuronal circuits.

neuroscience↗

bioRxiv2021

Training a spiking neuronal network model of visual-motor cortex to play a virtual racket-ball game using reinforcement learning

Recent models of spiking neuronal networks have been trained to perform behaviors in static environments using a variety of learning rules, with varying degrees of biological realism. Most of these models have not been tested in dynamic visual environments where models must make predictions on future states and adjust their behavior accordingly. The models using these learning rules are often treated as black boxes, with little analysis on circuit architectures and learning mechanisms supporting optimal performance. Here we developed visual/motor spiking neuronal network models and trained them to play a virtual racket-ball game using several reinforcement learning algorithms inspired by the dopaminergic reward system. We systematically investigated how different architectures and circuit-motifs (feed-forward, recurrent, feedback) contributed to learning and performance. We also developed a new biologically-inspired learning rule that significantly enhanced performance, while reducing training time. Our models included visual areas encoding game inputs and relaying the information to motor areas, which used this information to learn to move the racket to hit the ball. Neurons in the early visual area relayed information encoding object location and motion direction across the network. Neuronal association areas encoded spatial relationships between objects in the visual scene. Motor populations received inputs from visual and association areas representing the dorsal pathway. Two populations of motor neurons generated commands to move the racket up or down. Model-generated actions updated the environment and triggered reward or punishment signals that adjusted synaptic weights so that the models could learn which actions led to reward. Here we demonstrate that our biologically-plausible learning rules were effective in training spiking neuronal network models to solve problems in dynamic environments. We used our models to dissect the circuit architectures and learning rules most effective for learning. Our model shows that learning mechanisms involving different neural circuits produce similar performance in sensory-motor tasks. In biological networks, all learning mechanisms may complement one another, accelerating the learning capabilities of animals. Furthermore, this also highlights the resilience and redundancy in biological systems.

neuroscience↗

bioRxiv2019

Dynamic clamp constructed phase diagram of the Hodgkin-Huxley action potential model

Excitability - a threshold governed transient in transmembrane voltage - is a fundamental physiological process that controls the function of the heart, endocrine, muscles and neuronal tissues. The 1950s Hodgkin and Huxley explicit formulation provides a mathematical framework for understanding excitability, as the consequence of the properties of voltage-gated sodium and potassium channels. The Hodgkin-Huxley model is more sensitive to parametric variations of protein densities and kinetics than biological systems whose excitability is apparently more robust. It is generally assumed that the models sensitivity reflects missing functional relations between its parameters or other components present in biological systems. Here we experimentally construct excitable membranes using the dynamic clamp and voltage-gated potassium ionic channels (Kv1.3) expressed in Xenopus oocytes. We take advantage of a theoretically derived phase diagram, where the phenomenon of excitability is reduced to two dimensions defined as combinations of the Hodgkin-Huxley model parameters. This biological-computational hybrid enabled us to explore functional relations in the parameter space, experimentally validate the phase diagram of the Hodgkin-Huxley model, and demonstrate activity-dependence and hysteretic dynamics due to the impacts of slow inactivation kinetics. The experimental results presented here provide new in-sights into the gap between technology-guided high-dimensional descriptions, and a lower, physiological dimensionality, within which biological function is embedded.

neuroscience↗