Biology subjects

Lampert, A.

Publications and source records attributed to Lampert, A..

16 recordsLinked to original sources

bioRxiv2026

Reinforcement Learning Reveals Spatial Strategies for Slowing Biological Invasions

Managing biological invasions requires deciding where, when, and how to act while populations continue to grow and spread. Invasive species threaten ecosystems and livelihoods, but limited management resources mean that managers cannot treat every affected area. This study asks how control efforts can be directed across a landscape to slow an invasion while keeping costs low. We develop a reinforcement-learning framework that can use broader spatial context to control biological invasions, using the spongy moth as a case study. The stochastic simulator captures host-dependent growth, short- and long-distance dispersal, density-dependent mating, and the effects of multiple treatments. The reinforcement-learning strategies are compared with benchmarks that are based on local treatment rules. We find that reinforcement learning achieves the lowest mean cost, with its advantage widening as management complexity increases, such as with simultaneous advancing-front control, nascent-colony management, and established-colony containment on heterogeneous-host landscapes. The reinforcement-learning strategies exhibit highly context-dependent treatment behavior, adjusting treatment choices as invasion dynamics evolve and coordinating interventions across long distances, all of which is learned from scratch.

ecology↗

bioRxiv2026

In vitro programming and pseudounipolarization of human iPSC-derived sensory neurons

Ectopic expression of NGN1, BRN3A and ISLET1 (NBI) from a safe harbor locus in induced pluripotent stem cells (iPSCs) yielded robust differentiation into functional sensory neurons (iNBI-SNs) within seven days. Single nucleus transcriptomics identified peripheral sensory neuron profiles of nociceptors and mechanoreceptors. Electrophysiological studies showed that more than 98 % of iNBI-SNs display TTX-resistant sodium currents and that they establish functional connections to excitatory CNS neurons. iNBI-SNs derived from patients with inherited erythromelalgia, a pain disorder associated with gain-of-function mutations in the Nav1.7 sodium channel showed pathologically increased firing rates which could be partially rescued with a Nav1.7 inhibitor. Notably, iNBI-SNs acquire a characteristic pseudounipolar morphology upon co-culture with embryonic rodent DRG cells. Taken together, NBI-based forward programming of iPSCs represents a robust approach for the generation of human sensory neurons suitable for developmental, disease- and therapy-related studies.

neuroscience↗

bioRxiv2026

Polyclonal sensory neuron derivation from iPSCs as an efficient alternative to single clone strategies for pain relevant in vitro models

Induced pluripotent stem cell (iPSC) workflows typically rely on monoclonal cultures, requiring multiple independent cell lines to compensate for clonal variability. This increases workload, cost, and limits scalability for translational applications. Here, we establish polyclonal reprogramming strategies using Sendai virus to generate clonally diverse iPSC cultures already during reprogramming through FACS, MACS, manual selection, or prolonged culture. Both monoclonal and FACS-derived polyclonal cultures reached pluripotency. Reprogramming transgenes were silenced, whereas Sendai virus (SeV) mRNA persisted across passages in both culture types; heat treatment at 38.5C markedly reduced SeV levels. Monoclonal and polyclonal cultures differentiated efficiently into neural crest-like cells and sensory neurons. As a second polyclonal strategy, monoclonal cultures were pooled at day5 of sensory neuron differentiation to generate percentage-controlled progenitor mixtures. TRPA1 protein expression has not been shown reliably in iPS-derived sensory neurons. We hypothesized that increased clonal diversity might facilitate detection of TRPA1 protein expression. Despite rigorous antibody validation, TRPA1 protein expression was detectable only diffusely across the whole cell area. Together, our results show that polyclonal iPSC strategies enable clonally inclusive generation of patient-specific sensory neurons. These workflows reduce early workload and provide a robust foundation for scalable drug-screening and patient-in-a-dish applications.

neuroscience↗

bioRxiv2026

A Framework for NGN1-Induced Sensory Neuron Differentiation for Disease Modelling and Drug Screening

Background: Neuropathic pain is a burdensome, difficult-to-treat, and highly heterogeneous condition with limited therapeutic options, underscoring the need for robust and reproducible human disease models. Human induced pluripotent stem cell (iPSC)-derived sensory neurons provide a promising platform for patient specific disease modelling and drug screening; however, their translational use is hampered by variability in differentiation efficiency, cellular composition, and functional maturation across protocols and cell lines. Methods: Here, we present a standardized and potentially scalable framework for NGN1 driven differentiation of human iPSCs into sensory neurons. Building on a previously published two step protocol (1), we systematically deconstructed and optimized each stage of differentiation across a large panel of genetically diverse iPSC lines. Results: We identified robust parameters for neural crest like cell (NCLC) generation, established a flow cytometry-based quality control strategy for NCLCs, and defined optimal combinations of seeding density and lentiviral multiplicity of infection to maximize sensory neuron progenitor yield. To improve culture homogeneity, we compared antimitotic selection strategies and demonstrated that tightly timed Ara-C treatment combined with low progenitor seeding density yields consistently pure sensory neuron cultures. We further evaluated maturation under physiologically relevant glucose conditions and performed a systematic review of media compositions to derive two defined maturation media. Morphological, immunocytochemical, transcriptomic, and electrophysiological analyses revealed that time in culture is a major determinant of maturation, while specific supplements such as prostaglandin E2; (PGE2) selectively enhance transcriptional signatures associated with nociceptor identity without substantially altering global network activity. Bulk RNA sequencing demonstrated broad expression of sensory neuron and pain related markers and gene programs across conditions, with long term maturation and PGE2; treatment showing the highest similarity to human dorsal root ganglion reference data. Functional assessment using multi electrode arrays enabled the detection of donor specific electrophysiological phenotypes, including reproducible hyperexcitability in small fiber neuropathy patient derived lines. Conclusions: This study establishes a modular, reproducible NGN1 based differentiation workflow with integrated quality checkpoints that accommodates iPSC line to line variability. The framework provides a practical foundation for translational sensory neuron research, patient specific disease modelling, and scalable drug screening applications.

neuroscience↗

bioRxiv2026

Outer Pore Collapse as a Potential Mechanism of Partial Loss of Pain in Nav1.7 M899I

Complete loss of function of the voltage-gated sodium channel subtype Nav1.7, encoded by SCN9A, results in congenital insensitivity to pain. Here, we investigate a previously identified variant, M899I, in which methionine at position 899 is substituted by isoleucine. This variant was originally described in a Chinese patient with loss of pain. We confirmed membrane expression of the mutant channel in HEK cells using extracellular HA-tagging; however, no sodium currents were detectable from the variant in patch-clamp recordings. The M899I substitution is located within a tightly packed hydrophobic region of the pore module. Introducing the corresponding variant into Nav1.2 and Nav1.5 similarly abolished channel function, underscoring the high conservation and functional importance of this residue. To further investigate the underlying mechanism, we combined in-silico coarse-grained molecular dynamics simulations with in-vitro electrophysiological analysis. Our simulations predicted that the M899I substitution induces collapse of the outer pore, substantially reducing both pore radius and volume. Substitution with other hydrophobic residues was likewise predicted to alter pore geometry and, consequently, ion permeation to varying degrees. Whole-cell voltage-clamp recordings validated these predictions, with observed current densities closely correlating with the extent of pore collapse predicted in silico. Together, our findings establish pore collapse as a mechanism underlying disease-relevant loss-of-function variants in Nav1.7 and suggest that this principle may extend to other sodium channel subtypes. Moreover, our results demonstrate that in-silico molecular dynamics approaches can reliably predict structural and functional consequences of channel mutations, as confirmed by in-vitro electrophysiological data.

biophysics↗

bioRxiv2026

Creating resistance to the whitefly Bemisia tabaci in cassava through RNAi-mediated targeting of multiple insect metabolic processes

It is commonplace in East Africa for 100% of cassava fields to be infected with Cassava mosaic disease (CMD) and/or Cassava brown streak disease (CBSD), resulting in annual losses of more than US$1.25 billion and reduced food and economic security for farming households. The vector of both diseases is the African cassava species of the whitefly Bemisia tabaci. Since the late 1990s, there has been an unprecedented increase in whitefly populations, to the extent that they are referred to as "super-abundant". Research efforts since the late 1990s has focused mainly on developing plant resistance to the viral pathogens and paid scant attention to understanding the root causes of disease epidemics or the control of whitefly infestation. Here, we aimed at developing long-term whitefly-control solutions using an in-planta RNA interference (RNAi) approach. First, transcriptome analysis identified candidate genes that play key roles in whitefly biology: osmoregulation, sugar metabolism and transport, symbiosis with endosymbiotic bacteria and detoxification of phytotoxins. Then, fifteen RNAi inverted repeat constructs were produced, designed to target the candidate genes and 140 independent transgenic lines were generated in cassava variety NASE 13. Whole plant bioassays showed insecticidal activity of transgenic plants, reaching 58% lethality for adults within 7 days and 75-90% lethality of nymphs after 25 days, compared to control plants. Target genes were confirmed to be downregulated by up to 2.5-fold in adult whiteflies and nymphs. We used population dynamics modelling to predict the potential of the RNAi technology to control whiteflies under field conditions in East Africa.

bioengineering↗

bioRxiv2025

Integrating gene drives with established pest controls to mitigate spillover risk

Gene drives--artificial genetic constructs that can rapidly spread in a population due to biased inheritance--are a promising tool for controlling disease vectors and invasive species. While gene drives can eradicate target populations within several generations, their unintended spillover into non-target populations poses serious ecological concerns. Here, we examine how integrating gene drives with established pest control methods, such as pesticide application and sterile-male release, can mitigate spillover risk. We develop optimal control models to identify cost-effective treatment strategies that minimize total eradication costs, accounting for actual investments and potential damage from spillover. We show that pesticides are most cost-effective at the intermediate stage of eradication when gene drives have already slowed population growth but do not yet substantially suppress the population. For sterile-male release, however, we observe two distinct types of optimal strategies, the choice of which depends on parameter values: intensive early-stage releases, or mild later-stage releases. Using established pest controls also relaxes requirements to gene drive design, favoring milder suppressive effects as the treatment intensifies.

ecology↗

bioRxiv2025

Learning molecular traits of human pain disease via voltage-gated sodium channel structure renormalization

Mammalian neurophysiology vitally depends on the stable functioning of transmembrane, pore-forming voltage-sensing proteins known as voltage-gated sodium channels (NaVChs). Deciphering the principles of NaVCh spatial organization can illuminate fundamental structure-function aspects of pore-forming proteins and offer new opportunities for pharmacological treatment of associated diseases such as chronic pain. Here, we introduce a renormalization group flow paradigm permitting a formal investigation of NaVCh thermostability properties. Our procedures are solidified by deriving a q -deformed statistical mechanical entropy and validated over 121 experimentally resolved NaVCh structures of prokaryotic and eukaryotic origin. We uncover the universality of a critical inflection point regulating the thermostability of the pore domain relative to the voltage sensors, summarized in terms of a generalized Widom scaling law. A machine learning algorithm, rationalized in terms of the loosening of inertia and conductivity channel constraints, identifies pain-disease-associated mutation hotspots in the human NaV1.7 channel. Our work illustrates how first-principles-based machine learning approaches can deliver accurate insights for human pain medicine and clinicians at a reduced computational cost, while clarifying the self-organized critical nature of NaVChs.

bioinformatics↗

bioRxiv2024

Molecular architecture of human dermal sleeping nociceptors

Human dermal sleeping nociceptors display ongoing activity in neuropathic pain, affecting 10% of the population. Despite advances in rodents, a molecular marker for these mechano-insensitive C-fibers (CMis) in human skin remains elusive, preventing targeted therapy. In this translational Patch-seq study, we combine single-cell transcriptomics following electrophysiological characterization with single-nucleus and spatial transcriptomics from pigs and humans. We functionally identified CMis in pig sensory neurons with patch-clamp using adapted protocols from human microneurography. We identified oncostatin-M-receptor (OSMR) and somatostatin (SST) as marker genes for CMis. Following dermal injection in healthy human volunteers, oncostatin-M, the ligand of OSMR, exclusively modulates CMis. We identified the entire molecular architecture of human dermal sleeping nociceptors, providing new therapeutic targets and the basis for a mechanistic understanding of neuropathic pain. One Sentence SummaryWe identify the molecular architecture and specifically OSMR and SST as molecular markers for human dermal sleeping nociceptors, key players in the generation of neuropathic pain. Short versionIn this Patch-seq study, we identify OSMR and SST as molecular markers for human dermal sleeping nociceptors, key players in the generation of neuropathic pain.

neuroscience↗

bioRxiv2024

Cholesterol modifies Nav1.7 - an in-silico and in-vitro analysis

Cholesterol is a major component of plasma membranes and unsurprisingly plays a significant role in actively regulating the functioning of several membrane proteins in humans. Notably, recent studies have shown that cholesterol depletion can also impact transmission of potentially painful signals in the context of peripheral inflammation, via hyperexcitability of the voltage-gated sodium channel (Nav) subtype 1.9, but the structural mechanisms underlying this regulation remain to be elucidated. In this study, we focus on the role of cholesterol depletion on Nav1.7, which is primarily expressed in the peripheral sensory neurons and linked to various chronic inherited pain syndromes. Coarse-grained molecular dynamics simulations shed light on the dynamic changes of the geometry of Nav1.7 upon membrane cholesterol depletion: A loss of rigidity at key structural motifs linked to activation and fast-inactivation is observed, as well as changes in the geometry of drug-binding regions in the channel. Loss of rigidity in cholesterol depleted conditions should allow the channel to transition between different gating states more easily. In-vitro whole-cell patch clamp experiments on HEK293t cells expressing Nav1.7 validated these predictions made in silico at the functional level. Hyperpolarizing shifts in the voltage-dependence of activation and fast-inactivation were observed along with an acceleration of the time to peak and onset kinetics of fast inactivation. These results underline the critical role of membrane composition, and of cholesterol in particular, in influencing Nav1.7 gating characteristics. Furthermore, our results hint to a key role of the membrane environment in affecting drug effects and in pathophysiological dysregulation, sharpening our approaches for analgesics design. Supplementary datahttps://doi.org/10.5281/zenodo.10829175

physiology↗

bioRxiv2023

Biophysics of sodium channels during subthreshold depolarization in vitro and in silico

Voltage-gated sodium channels (VGSC) in the peripheral nervous system shape action potentials (AP) and thereby support the detection of sensory stimuli. Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Nav1.7 is suggested to be a (sub-)threshold channel, Nav1.8 is thought to support the fast AP upstroke. Nav1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential. We characterized gating of Nav1.1-Nav1.3 and Nav1.5-Nav1.9 in manual patch clamp with focus on the AP subthreshold depolarization phase. Nav1.9 exhibited the most hyperpolarized activation while its fast inactivation resembled the depolarized inactivation of Nav1.8. For some VGSCs (e.g., Nav1.1 and Nav1.2), a positive correlation between ramp current and window current was detected. Using a modified Hodgkin-Huxley model which accounts for the time needed for inactivation to occur, we used the acquired data to simulate two nociceptive nerve fiber types (an A{delta}-and a mechano-insensitive C-nociceptor) containing VGSC conductances according to published human RNAseq data. Our simulations suggest that Nav1.9 is supporting both the AP upstroke and its shoulder. A reduced threshold for AP generation was induced by enhancing Nav1.7 conductivity or shifting its activation to more hyperpolarized potentials, as observed in Nav1.7-related pain disorders. Here, we provide a comprehensive, comparative functional characterization of VGSCs relevant in nociception and describe their gating with Hodgkin-Huxley-like models, which can serve as a tool to study their specific contributions to AP shape and sodium channel-related diseases. DisclaimerParts of this study were published as a preprint on bioRxiv: Koster, P.A., T. Stiehl, J. Tigerholm, A. Maxion, B. Namer, and A. Lampert. 2023. Biophysics of sodium channels during subthreshold depolarization in vitro and in silico. bioRxiv. doi.org/10.1101/2023.09.03.556095 (Preprint posted September 6, 2023) SummarySubthreshold gating of seven sodium channels (Nav1.1-3, Nav1.5-8) is determined by manual patch clamp and, together with Nav1.9, integrated into a computer model of an A{delta}-and a mechano-insensitive nociceptor (CMi). Simulations reveal contribution of Nav1.9 to the action potential upstroke and shoulder and prove useful for Nav1.7-related disease modelling.

physiology↗

bioRxiv2023

The rules of sex and strain: deciphering the chemical language of inbred and wild mouse conspecific scents

In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex- / strain-selective "raw" chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animals sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary secretome, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.

neuroscience↗

bioRxiv2022

Diclofenac and other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are Competitive Antagonists of the human P2X3 Receptor

The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents. To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology. We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC50 values of 138.2 {micro}M and 76.7 {micro}M, respectively). A weaker inhibition of hP2X1R, hP2X4R and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) proved to inhibit hP2X3R, rP2X3R and hP2X7R (IC50 values of 221{micro}M, 264.1{micro}M and [~] 900{micro}M, respectively), questioning its widespread use as a nonselective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of the hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP-application or increasing concentrations of the agonist ,{beta}-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results strongly support a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains inhibits gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R and hP2X7R. Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac may contribute to the analgesic effect as well as the side effect of taste disturbances of diclofenac and represent an additional mode of action besides the well-known high potency COX inhibition.

pharmacology and toxicology↗

bioRxiv2022

Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents

Voltage-gated sodium channels (Nav) are key players in excitable tissues with the capability to generate and propagate action potentials. Mutations in the genes encoding Navs can lead to severe inherited diseases, and some of these so-called channelopathies are showing temperature sensitive phenotypes, for example paramyotonia congenita, Brugada-syndrome, febrile seizure syndromes and inherited pain syndromes like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nevertheless, most investigations of mutation-induced gating effects were conducted at room temperature and thus the role of cooling or warming in channelopathies remains poorly understood. Here, we investigated the temperature sensitivity of four Nav subtypes: Nav1.3, Nav1.5, Nav1.6, and Nav1.7 and two mutations in Nav1.7 causing IEM (Nav1.7/L823R) and PEPD (Nav1.7/I1461T), using an automated patch clamp system. Our experiments at 15 {degrees}C, 25 {degrees}C and 35 {degrees}C revealed a shift of the voltage dependence of activation to more hyperpolarized potentials with increasing temperature for all investigated subtypes. Nav1.3 exhibited strongly slowed inactivation kinetics compared to the other subtypes that resulted in enhanced persistent current especially at 15 {degrees}C, indicating a possible role in cold induced hyperexcitability. Impaired fast inactivation of Nav1.7/I1461T was significantly enhanced by cooling temperature to 15 {degrees}C. The subtype specific modulation as well as the intensified mutation induced gating changes stress the importance to consider temperature as regulator for channel gating and its impact on cellular excitability as well as disease phenotypes. SummaryActivation of the sodium channel subtypes Nav1.3, Nav1.5, Nav1.6, and Nav1.7 and two pain linked mutations is alleviated by warmth. Cooler temperatures, on the other hand, strongly enhance persistent currents of Nav1.3. The impaired fast inactivation of the pain-linked Nav1.7/I1461T mutation is further impaired by cooling, mimicking clinical findings.

physiology↗

bioRxiv2019

Uncoupling sodium channel dimers rescues phenotype of pain-linked Nav1.7 mutation

The voltage-gated sodium channel Nav1.7 is essential for an adequate perception of painful stimuli. Its mutations cause various pain syndromes in human patients. The hNav1.7/A1632E mutation induces symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current.\n\nUsing molecular simulations, we demonstrate that the disease causing persistent current of hNav1.7/A1632E is due to impaired binding of the IFM motif, thus affecting proper function of the recently proposed allosteric fast inactivation mechanism. By using native polyacrylamide gel electrophoresis (PAGE) gels, we show that hNav1.7 dimerizes. The disease-linked persistent current depends on the channels functional dimerization status: Using difopein, a 14-3-3 inhibitor known to uncouple dimerization of hNav1.5, we detect a significant decrease in hNav1.7/A1632E induced persistent currents.\n\nOur work identifies that functional uncoupling of hNav1.7/A1632E dimers rescues the pain-causing molecular phenotype by interferes with an allosteric fast inactivation mechanism, which we link for the first time to channel dimerization. Our work supports the concept of sodium channel dimerization and reveals its relevance to human pain syndromes.

neuroscience↗

bioRxiv2017

Voltage-gated sodium channels in neocortical pyramidal neurons display Cole-Moore activation kinetics

Exploring the properties of action potentials is a crucial step towards a better understanding of the computational properties of single neurons and neural networks. The voltage-gated sodium channel is a key player in action potential generation. A comprehensive grasp of the gating mechanism of this channel can shed light on the biophysics of action potential generation. Most models of voltage-gated sodium channels assume it obeys a concerted Hodgkin and Huxley kinetic gating scheme. Here we performed high resolution voltage-clamp experiments from nucleated patches extracted from the soma of layer 5 (L5) cortical pyramidal neurons in rat brain slices. We show that the gating mechanism does not follow traditional Hodgkin and Huxley kinetics and that much of the channel voltage-dependence is probably due to rapid closed-closed transitions that lead to substantial onset latency reminiscent of the Cole-Moore effect observed in voltage-gated potassium conductances. This may have key implications for the role of sodium channels in synaptic integration and action potential generation.

neuroscience↗