Biology subjects

Goldfarb, M.

Publications and source records attributed to Goldfarb, M..

5 recordsLinked to original sources

bioRxiv2025

Role of Speed Regulation and Speed Modulation in Velocity-Field Based Control

The velocity vector field (flow) controller is a well-established control strategy for lower limb exoskeletons. In this paper, we analyze this controller and propose modifications to improve its performance. We demonstrate that flow control acts as a variable proportional-derivative error regulator, where the parameter {Gamma} represents the desired norm of the hip-knee joint velocity vector (path speed). Based on this, we introduce two modifications to {Gamma}: (1) a constant {Gamma} set to the mean desired path speed, and (2) a variable {Gamma} that mimics natural path speed during unassisted walking. We compared the modified flow controllers with a slow-{Gamma} version in experiments involving seven participants walking on a treadmill at 0.6m/s, 0.8m/s, and 1.0m/s. Compared to the slow-{Gamma} controller, the RMS tracking error decreased by 30.7{+/-} 11.3% and the range of motion of the knee increased by 48.2 {+/-} 5.5% for the mean-{Gamma} controller, while the variable-{Gamma} controller had 32.4 {+/-} 14.7% smaller RMS error and 50.5 {+/-} 6.5% larger range of motion of the knee. Additionally, the slow-{Gamma} controller consistently applied resistive power, whereas participants reported more comfortable and natural gait with the modified controllers. We also compared them with the original tuning of flow controller, with results indicating superior performance from the proposed modifications. These findings demonstrate effectiveness across different walking speeds and offer a tuning strategy for future flow controller use.

bioengineering↗

bioRxiv2025

Carboxyl Terminal Domain Missense Mutations Alter Distinct Gating Properties of the Cardiac Sodium Channel

Voltage-gated sodium channels undergo reversible voltage/time-dependent transitions from closed to open and inactivated states. The voltage setpoints and efficiency of cardiac sodium channel Nav1.5 state transitions are crucial for tuning the initiation and conduction of myocardial action potentials. The channels cytoplasmic carboxyl-terminal domain (CTD) regulates gating by intramolecular interactions and by serving as a hub for the binding of accessory proteins. We have investigated the roles of the CTD in intrinsic and FGF homologous factor (FHF)-modulated Nav1.5 gating through structure-guided CTD subdomain mutagenesis. The EF-hand module within the CTD was found to exert the most profound effects on channel gating, strongly influencing voltage-dependence of inactivation and activation, accelerating inactivation from the closed state, decelerating inactivation from the open state, minimizing persistent sodium current, and serving as the binding domain for FHF proteins. Nav1.5D1788K bearing a missense mutation in the EF-hand motif displayed a depolarizing shift in voltage dependence of activation and generated greatly enhanced persistent sodium current without altering the voltage dependence of channel inactivation. Reciprocally, Nav1.5L1861A bearing a different missense mutation in the EF-hand underwent closed-state inactivation at more negative membrane potential and at an accelerated rate, but did not display other phenotypes associated with CTD deletion. Nav1.5V1776A/T1778A bearing mutations in the juxtamembrane region between the EF-hand and the channel pore helices displayed wild-type intrinsic gating properties, while FHF modulation of inactivation gating was impaired. Our channel physiology studies together with prior structural data suggest that the voltage and rate of channel inactivation from the closed state are governed by an intramolecular hydrophobic interaction of the CTD EF-hand with the cytoplasmic inactivation loop helix and the extension of this binding interface upon FHF-induced restructuring of the juxtamembrane region, while a distinct CTD intramolecular electrostatic interaction modulates voltage-dependent activation and minimizes persistent sodium current.

physiology↗

bioRxiv2023

Sex-dependent contributions of ventrolateral orbitofrontal cortex and basolateral amygdala to learning under uncertainty

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach and particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory DREADDs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-post reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of vlOFC, but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment. Significance StatementInflexible learning is a feature of several neuropsychiatric disorders. We investigated how the ventrolateral orbitofrontal cortex (vlOFC) and basolateral amygdala (BLA) are involved in learning of stimuli or actions under reinforcement uncertainty. Following chemogenetic inhibition of these regions in both male and females, we measured learning and adjustments to deterministic and probabilistic reversals. For action learning, BLA, but not vlOFC, is needed for probabilistic reversal learning. However, BLA is not necessary for initial probabilistic learning or retention, indicating a critical role for learning of unexpected changes. For stimulus learning, vlOFC, but not BLA, is required for adjustments to reversals, particularly in females. These findings provide insight into the complementary cortico-amygdalar substrates of learning under different forms of uncertainty.

neuroscience↗

bioRxiv2022

Enhanced Sodium Channel Inactivation by Temperature and FHF2 Deficiency Blocks Heat Nociception

Transient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of sodium currents are tuned by intracellular fibroblast growth factor homologous factors (FHFs/iFGFs) that associate with the cytoplasmic tails of voltage-gated sodium channels (Navs), and genetic ablation of Fhf genes disturbs neurological and cardiac functions. Among reported phenotypes, Fhf2null mice undergo lethal hyperthermia-induced cardiac conduction block attributable to the combined effects of FHF2 deficiency and elevated temperature on the cardiac sodium channel (Nav1.5) inactivation rate. Fhf2null mice also display a lack of heat nociception, while retaining other somatosensory capabilities. Here, we use electrophysiological and computational methods to show that the heat nociception deficit can be explained by the combined effects of elevated temperature and FHF2 deficiency on the fast inactivation gating of Nav1.7 and tetrodotoxin-resistant sodium channels expressed in dorsal root ganglion C fibers. Hence, neurological and cardiac heat-associated deficits in Fhf2null mice derive from shared impacts of FHF deficiency and temperature towards Nav inactivation gating kinetics in distinct tissues.

neuroscience↗

bioRxiv2018

Hyper-excitability and hyper-plasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism

Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASD has been suggested but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 KO mice, which present a cerebellar phenotype associated with ASD. Granule cells showed a larger NMDA receptor-mediated current and enhanced intrinsic excitability raising the excitatory/inhibitory balance. Furthermore, the spatial organization of granular layer responses to mossy fibers shifted from a Mexican hat to stovepipe hat profile, with stronger excitation in the core and weaker inhibition in the surround. Finally, the size and extension of long-term synaptic plasticity was remarkably increased. These results show for the first time that hyper-excitability and hyper-plasticity disrupt signal transfer in the granular layer of IB2 KO mice supporting cerebellar involvement in the pathogenesis of ASD.

neuroscience↗