Degeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: May 3, 2023

Abstract Due to its complex and multifaceted nature, developing effective treatments for epilepsy is still a major challenge. To deal with this complexity we introduce the concept of degeneracy field research: ability disparate elements cause an analogous function or malfunction. Here, review examples epilepsy-related at multiple levels brain organisation, ranging from cellular network systems level. Based on these insights, outline new multiscale population modelling approaches disentangle web interactions underlying design personalised multitarget therapies.

Language: Английский

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A half-centre oscillator encodes sleep pressure

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 28, 2024

Summary Oscillatory neural dynamics are an inseparable part of mammalian sleep. Characteristic rhythms associated with different sleep stages and variable levels pressure, but it remains unclear whether these oscillations passive mirrors or active generators Here we report that sleep-control neurons innervating the dorsal fan-shaped body Drosophila (dFBNs) produce slow-wave activity (SWA) in delta frequency band (0.2–1 Hz) is causally linked to The dFBN ensemble contains one two rhythmic cells per hemisphere whose membrane voltages oscillate anti-phase between hyperpolarized DOWN depolarized UP states releasing bursts action potentials. rely on direct interhemispheric competition inhibitory half-centres connected by glutamatergic synapses. Interference glutamate release from synapses disrupts SWA baseline as well rebound sleep, while optogenetic replay (with help intersectional, dFBN-restricted driver) induces Rhythmic dFBNs generate throughout sleep–wake cycle—despite a mutually antagonistic ‘flip-flop’ arrangement arousing dopaminergic neurons—but adjust its power need via interplay history-dependent increases excitability homeostatic depression their efferent synapses, demonstrate transcriptionally, structurally, functionally, simple computational model. oscillatory format permits durable encoding pressure over long time scales requires downstream mechanisms convert amplitude-modulated periodic signal into binary states.

Language: Английский

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New insights from small rhythmic circuits

Current Opinion in Neurobiology, Journal Year: 2022, Volume and Issue: 76, P. 102610 - 102610

Published: Aug. 17, 2022

Small rhythmic circuits, such as those found in invertebrates, have provided fundamental insights into how circuit dynamics depend on individual neuronal and synaptic properties. Degenerate circuits are with different network parameters similar behavior. New work degenerate their modulation illustrates some of the rules that help maintain stable robust function despite environmental perturbations. Advances neuropeptide isolation identification provide enhanced understanding neuromodulation for The advent molecular studies mRNA expression provides new insight animal-to-animal variability homeostatic regulation excitability neurons networks.

Language: Английский

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Degenerate Neuronal and Circuit Mechanisms Important for Generating Rhythmic Motor Patterns

Physiological Reviews, Journal Year: 2024, Volume and Issue: 105(1), P. 95 - 135

Published: June 13, 2024

In 1996, we published a review article (Marder E, Calabrese RL.

Language: Английский

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Functional mapping of the molluscan brain guided by synchrotron X-ray tomography

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(9)

Published: Feb. 27, 2025

Molluscan brains are composed of morphologically consistent and functionally interrogable neurons, offering rich opportunities for understanding how neural circuits drive behavior. Nonetheless, detailed component-level CNS maps often lacking, total neuron numbers unknown, organizational principles remain poorly defined, limiting a full systematic characterization circuit operation. Here, we establish an accessible, generalizable approach, harnessing synchrotron X-ray tomography, to rapidly determine the three-dimensional structure multimillimeter-scale Lymnaea . Focusing on feeding ganglia, generate neuron-level reconstruction, revealing key design revising cell count estimates upward threefold. Our atlas uncovers superficial but also nonsuperficial ganglionic architecture, reveals organization in normally hidden regions—ganglionic “dark sides”—and details features single-neuron morphology, together guiding targeted follow-up functional investigation based intracellular recordings. Using this identify three pivotal classes: command-like food-signaling type, central pattern generator interneuron, unique behavior-specific motoneuron, significantly advancing function classical control circuit. Combining our morphological electrophysiological data, as shared scalable resource research community. approach enables rapid construction atlases large-scale nervous systems, with relevance interrogation diverse range model organisms.

Language: Английский

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Feeding-state dependent modulation of reciprocally interconnected inhibitory neurons biases sensorimotor decisions inDrosophila

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 26, 2023

Abstract Animals’ feeding state changes behavioral priorities and thus influences even non-feeding related decisions. How is the information transmitted to circuits what are circuit mechanisms involved in biasing decisions remains an open question. By combining calcium imaging, neuronal manipulations, analysis computational modeling, we determined that competition between different aversive responses mechanical cues biased by changes. We found this achieved differential modulation of two types reciprocally connected inhibitory neurons promoting opposing actions. This results a more frequent active type response less frequently protective if larvae fed sugar compared when they balanced diet. The about internal conveyed through homologues vertebrate neuropeptide Y known be regulating behavior.

Language: Английский

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Diversity of neuropeptidergic modulation in decapod crustacean cardiac and feeding systems

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 83, P. 102802 - 102802

Published: Nov. 2, 2023

All nervous systems are multiply modulated by polypeptides. However, a bulk of transmitter and modulation research has historically focused on small molecule transmitters released at synaptic sites. The stomatogastric system (controls digestive movements the foregut) cardiac decapod crustaceans have long been used to understand processes that underlie neuromodulation. circuits governing rhythmic output from these comprised relatively number identified neurons, details well-defined. Here we discuss recent highlighting advances in our understanding peptidergic systems. In particular, focus ability identify specific signaling peptide sequences relate their expression patterns physiological effects, as well multiple sites within pattern generator-effector which takes place. Recent efforts enabled us how co-modulation two or more peptides can generate surprising effects circuit physiology different receptor produce supra-additive effects. Finally, examine protective role plays making robust perturbations, this case, changes temperature.

Language: Английский

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Ih block reveals separation of timescales in pyloric rhythm response to temperature changes in Cancer borealis

eLife, Journal Year: 2024, Volume and Issue: 13

Published: July 11, 2024

Motor systems operate over a range of frequencies and relative timing (phase). We studied the role hyperpolarization-activated inward current (Ih) in regulating these features pyloric rhythm stomatogastric ganglion (STG) crab, Cancer borealis, as temperature was altered from 11°C to 21°C. Under control conditions, frequency increased monotonically with temperature, while phases dilator (PD), lateral (LP), (PY) neurons remained constant. Blocking Ih cesium (Cs+) phase advanced PD offset, LP onset, offset at 11°C, latter two further increased. In Cs+ increase diminished Q10 dropped ~1.75 ~1.35. Unexpectedly Cs+, dynamics became non-monotonic during transitions; initially increased, then rose once stabilized, creating characteristic 'jag'. Interestingly, jags persisted transitions when pacemaker isolated by picrotoxin, although temperature-induced change recovered levels. Overall, data suggest that plays an important maintaining smooth transitory responses persistent increases different mechanisms circuitry fluctuations.

Language: Английский

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Inspiratory rhythm generation is stabilized by I_h

Journal of Neurophysiology, Journal Year: 2022, Volume and Issue: 128(1), P. 181 - 196

Published: June 8, 2022

Cellular and network properties must be capable of generating rhythmic activity that is both flexible stable. This particularly important for breathing, a behavior dynamically adapts to environmental, behavioral, metabolic changes from the first last breath. The pre-Bötzinger complex (preBötC), located within ventral medulla, responsible producing inspiration. Its cellular tunable, as well stabilizing. Here, we explore role hyperpolarization-activated, nonselective cation current (Ih) stabilizing PreBötC during opioid exposure reduced excitatory synaptic transmission. Introducing Ih into an in silico preBötC predicts loss this depolarizing should significantly slow inspiratory rhythm. By contrast, vitro vivo experiments revealed minimally affected breathing frequency, but destabilized rhythmogenesis through generation incompletely synchronized bursts (burstlets). Associated with was increased susceptibility opioid-induced respiratory depression or weakened interactions, paradoxical depolarization at level, suppression tonic spiking. Tonic spiking generated by nonrhythmic inhibitory neurons, which large percentage express Ih. Together, our results suggest maintaining spiking, rhythmogenesis, protecting against perturbations state.NEW & NOTEWORTHY plays multiple roles preBötC. promoting intrinsic neurons preserving function conditions dampen excitability, such context depression. We therefore propose expands dynamic range buffers perturbations, stabilizes preventing unsynchronized bursts.

Language: Английский

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Dynamics of antiphase bursting modulated by the inhibitory synaptic and hyperpolarization-activated cation currents

Frontiers in Computational Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 9, 2024

Antiphase bursting related to the rhythmic motor behavior exhibits complex dynamics modulated by inhibitory synaptic current (Isyn), especially in presence of hyperpolarization-activated cation (Ih). In present paper, antiphase Ih and Isyn is studied three aspects with a theoretical model. Firstly, slow strong strength are identified be necessary conditions for bursting. The dependence on two currents different low (escape mode) high (release threshold voltages (Vth) synapse. Secondly, more detailed co-regulations induce opposite changes period obtained. For escape mode, increase induces elevated membrane potential silence inhibited shortened duration go beyond Vth, resulting reduced period. release tough value former part burst nearly zero lengthen fall below prolonged Finally, fast-slow acquired. Using one-and two-parameter bifurcations fast subsystem single neuron, stable limit cycle, equilibrium certain extent. mainly modulates within quiescent state. Furthermore, coupled neurons, associated unstable point. results explanations Ih, which helpful understanding modulating patterns.

Language: Английский

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