Biology subjects

Molkov, Y. I.

Publications and source records attributed to Molkov, Y. I..

9 recordsLinked to original sources

bioRxiv2026

Functional Synaptic Interactions and Inhibitory Circuitry of the PreBötzinger Complex in the Rhythmic Slice

The preBotzinger Complex (preBotC) within the medulla oblongata contains neuronal circuits critical for generating the mammalian respiratory rhythm, but the functional connectivity among its core excitatory and inhibitory populations remains debated. Defining this connectivity requires disentangling synaptic interactions of functionally identified excitatory and inhibitory preBotC neurons with various electrophysiological phenotypes. We applied a novel synaptic conductance inference method to whole-cell recordings from genetically specified VgluT2-expressing (excitatory) and VGAT-expressing (inhibitory) preBotC neurons active in the rhythmic medullary slice in vitro, which contains core inhibitory-excitatory circuitry with an excitatory rhythmogenic kernel. We found that this circuitry consists of a self-exciting inspiratory VgluT2 population coupled to inspiratory and expiratory VGAT populations that interact reciprocally through inhibition. The functional inhibitory connectome is more complex than previously understood. However, compared with functional synaptic interactions inferred from recordings in the preBotC in situ, the neuronal synaptic conductance profiles in the rhythmic slice reveal a functionally reduced inhibitory connectome, characterized by prominent tonic expiratory inhibition and phasic inspiratory inhibition, without the characteristic multiphasic structure in situ. These results indicate that the functional excitatory and inhibitory circuit interactions within the preBotC isolated in vitro, although reduced relative to more intact states in situ, are intrinsically designed to generate coordinated inspiratory and expiratory population activity. Tonic expiratory phase inhibition together with inspiratory phasic inhibition serves to regulate excitability and phase transitions of the excitatory rhythmogenic kernel.

neuroscience↗

bioRxiv2026

Speed-Dependent Turning Strategies in Quadrupedal Locomotion: Insights from Computational Modeling

Quadrupedal animals like mice navigate their environments through complex coordination of neural signals and biomechanical movements, enabling stable and directed locomotion. While many computational models simplify this process by assuming left-right symmetrical body movements and focusing on straight-line paths, real animals rely heavily on asymmetrical body movements to execute turns and adjust speed effectively. This study builds upon a previously developed model of quadrupedal locomotion proposed by Molkov et al., 2024) in which forward movement of the body was driven by central neural interactions, biomechanics, and proprioceptive feedback. We extended this model to comparatively investigate possible mechanisms of steering by introducing three distinct asymmetrical strategies-body bending, lateral force application, and lateral limb shifting as well as their combinations-to explore their potential involvement in turning performance. By simulating these strategies across a walking speed range, we measured and compared their impact on turning curvature the sharpness of the turn) and limb coordination. The latter was quantified through ratios of duty factors representing the relative time that a limb spent in contact with the ground compared to its counterpart on the opposite side. Our findings reveal that each strategy excels at different speeds: body bending allows sharp turns at low speeds, lateral force is most effective at medium speeds, and lateral shifting performs best at higher speeds. Our results suggest that animals select or combine turning strategies based on their locomotor speed or adjust speed to use a specific strategy. We also show that the forelimbs consistently play a primary role in steering, while the hindlimbs adjust propulsion and stability in ways that depend on the specific turning strategy. These results provide valuable insights into how spinal circuits and mechanical asymmetries work together to produce flexible, adaptive movement patterns, offering a robust framework for understanding locomotion in both biological organisms and robotic systems designed to mimic such behaviors.

systems biology↗

bioRxiv2024

Inference technique for the synaptic conductances in rhythmically active networks and application to respiratory central pattern generation circuits

Unraveling synaptic interactions between excitatory and inhibitory interneurons within rhythmic neural circuits, such as central pattern generation (CPG) circuits for rhythmic motor behaviors, is critical for deciphering circuit interactions and functional architecture, which is a major problem for understanding how neural circuits operate. Here we present a general method for extracting and separating patterns of inhibitory and excitatory synaptic conductances at high temporal resolution from single neuronal intracellular recordings in rhythmically active networks. These post-synaptic conductances reflect the combined synaptic inputs from the key interacting neuronal populations and can reveal the functional connectome of the active circuits. To illustrate the applicability of our analytic technique, we employ our method to infer the synaptic conductance profiles in identified rhythmically active interneurons within key microcircuits of the mammalian (mature rat) brainstem respiratory CPG and provide a perspective on how our approach can resolve the functional interactions and circuit organization of these interneuron populations. We demonstrate the versatility of our approach, which can be applied to any other rhythmic circuits where conditions allow for neuronal intracellular recordings.

neuroscience↗

bioRxiv2021

Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator

Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (INaP) and calcium-activated non-selective cation current (ICAN) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian preBotzinger complex (preBotC) respiratory oscillator. Here, we experimentally tested and confirmed three predictions of the model from new simulations concerning the roles of INaP and ICAN: (1) INaP and ICAN blockade have opposite effects on the relationship between network excitability and preBotC rhythmic activity; (2) INaP is essential for preBotC rhythmogenesis; (3) ICAN is essential for generating the amplitude of rhythmic output but not rhythm generation. These predictions were confirmed via optogenetic manipulations of preBotC network excitability during graded INaP or ICAN blockade by pharmacological manipulations in neonatal mouse slices in vitro. Our results support and advance the hypothesis that INaP and ICAN mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBotC.

neuroscience↗

bioRxiv2021

Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid

Alzheimers disease (AD) is the most common cause of dementia affecting millions of people. Neuronal death in AD is initiated by oligomeric amyloid-{beta} (A{beta}) peptides. Recently, we proposed the amyloid degradation toxicity hypothesis, which explains multiple major observations associated with AD - such as autophagy failure and a decreased metabolism. According to the hypothesis, the key event in the cellular toxicity of amyloid is the formation of non-selective membrane channels in lysosomal membranes by amyloid fragments that are produced by the digestion of A{beta} previously absorbed by endocytosis. Electrophysiological data suggest that amyloid-formed channels have different sizes, which can be explained by the fact that barrel-shaped amyloid aggregates which create channels can consist of different number of monomers. To estimate the ability of channels to leak molecules of various molecular weights, we modeled the channels as saline-filled cylinders in non-conductive membranes that pass spheres with a density of average globular proteins. As a basis, we used the conductance distribution taken from the previously published experimental dataset, in which single channels with a conductance reaching one nanosiemens were registered. Our calculations show that channels with a giant conductance can allow for passing macromolecules such as lysosomal cathepsins implicated in the activation of apoptosis. The formation of giant channels is disproportionally promoted in an acidic environment. Also, amyloid fragments leaking from permeabilized lysosomes can reach the internal leaflet of the plasma membrane and permeabilize it. We conclude that while dissipation of the proton gradient by any - even the smallest amyloid channel - readily explains lysosomal failure, the relatively rare events of lysosomal permeabilization to large macromolecules can be an alternative mechanism of cellular death induced by exposure to A{beta}.

neuroscience↗

bioRxiv2020

Heartbeats entrain breathing via baroreceptor-mediated modulation of expiratory activity

Cardio-ventilatory coupling refers to a heartbeat (HB) occurring at a preferred latency before the onset of the next breath. We hypothesized that the pressure pulse generated by a HB activates baroreceptors that modulates brainstem expiratory neuronal activity and delays the initiation of inspiration. In supine male subjects, we recorded ventilation, electrocardiogram, and blood pressure during 20-min epochs of baseline, slow-deep breathing, and recovery. In in situ rodent preparations, we recorded brainstem activity in response to pulses of perfusion pressure. We applied a well-established respiratory network model to interpret these data. In humans, the latency between HBs and onset of inspiration was consistent across different breathing patterns. In in situ preparations, a transient pressure pulse during expiration activated a subpopulation of expiratory neurons normally active during post-inspiration; thus, delaying the next inspiration. In the model, baroreceptor input to post-inspiratory neurons accounted for the effect. These studies are consistent with baroreflex activation modulating respiration through a pauci-synaptic circuit from baroreceptors to onset of inspiration.

neuroscience↗

bioRxiv2020

On the organization of the locomotor CPG: insights from split-belt locomotion and mathematical modeling

Rhythmic limb movements during locomotion are controlled by a central pattern generator (CPG) circuits located in the spinal cord. It is considered that these circuits are composed of individual rhythm generators (RGs) for each limb interacting with each other through multiple commissural and long propriospinal circuits. The organization and operation of each RG are not fully understood, and different competing theories exist about interactions between its flexor and extensor components, as well as about left-right commissural interactions between the RGs. The central idea of circuit organization proposed in this study is that with an increase of excitatory input to each RGs (or an increase in locomotor speed) the rhythmogenic mechanism within the RGs changes from "flexor-driven" rhythmicity to a "classical half-center" mechanism. We test this hypothesis using our experimental data on changes in duration of stance and swing phases in the intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) or split-belt treadmills with different left and right belt speeds (asymmetric conditions). We compare these experimental data with the results of mathematical modeling, in which simulated CPG circuits operate in similar symmetric and asymmetric conditions with matching or differing control drives to the left and right RGs. The obtained results support the proposed concept of state-dependent changes in RG operation and specific commissural interactions between the RGs. The performed simulations and mathematical analysis of model operation under different conditions provide new insights into CPG network organization and limb coordination during locomotion. Key Point SummaryO_LILimb movements during locomotion are controlled by neural circuits located within the spinal cord. These circuits include rhythm generators (RGs) controlling each limb interacting through multiple commissural pathways. C_LIO_LIThe organization and operation of spinal RGs are not fully understood, and different competing concepts exists. We suggest that the operation of RGs is state-dependent, so that with an increase of external excitation the rhythmogenesis changes from "flexor-driven" oscillations to a "classical half-center" mechanism. C_LIO_LIA mathematical model of spinal circuits representing bilaterally-interacting RGs has been developed based on the above suggestion and used to interpret experimental data from intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) as well as on split-belt treadmills with different left and right belt speeds (asymmetric conditions). C_LIO_LIThe performed simulations and mathematical analysis of the model under different conditions provide new insights into operation of spinal circuits and limb coordination during locomotion. C_LI

neuroscience↗

bioRxiv2019

Inhibitory control of active expiration by the Botzinger complex in rats

The expiratory neurons of the Botzinger complex (BotC) provide inhibitory inputs to the respiratory network, which, during eupnea, are critically important for respiratory phase transition and duration control. Herein, we investigated how the BotC neurons interact with the expiratory oscillator located in the parafacial respiratory group (pFRG) and control the abdominal activity during active expiration. Using the decerebrated, arterially perfused in situ rat preparations, we recorded the neuronal activity and performed pharmacological manipulations of the BotC and pFRG during hypercapnia or after the exposure to short-term sustained hypoxia - conditions that generate active expiration. The experimental data were integrated in a mathematical model to gain new insights in the inhibitory connectome within the respiratory central pattern generator. Our results reveal a complex inhibitory circuitry within the BotC that provides inhibitory inputs to the pFRG thus restraining abdominal activity under resting conditions and contributing to abdominal expiratory pattern formation during active expiration.

physiology↗

bioRxiv2018

Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model

An autorhythmic population of excitatory neurons in the brainstem pre-Botzinger complex is a critical component of the mammalian respiratory oscillator. Two intrinsic neuronal biophysical mechanisms--a persistent sodium current (INaP) and a calcium-activated non-selective cationic current (ICAN)--were proposed to individually or in combination generate cellular-and circuit-level oscillations, but their roles are debated without resolution. We re-examined these roles with a new computational model of an excitatory population with randomly distributed INaP and ICAN conductances and synaptic connections. This model robustly reproduces experimental data showing contrary to previous hypotheses, rhythm generation is independent of ICAN activation, which instead determines population activity amplitude. The novel insight is that this occurs when ICAN is primarily activated by neuronal calcium fluxes driven by synaptic mechanisms. Rhythm depends critically on INaP in a subpopulation forming the rhythmogenic kernel. The model explains how the rhythm and amplitude of respiratory oscillations involve distinct biophysical mechanisms.

bioinformatics↗