Biology subjects

Berdichevsky, Y.

Publications and source records attributed to Berdichevsky, Y..

6 recordsLinked to original sources

bioRxiv2025

Early Brain Functional Connectivity Changes Induced by Antidepressants and Placebo

Major depressive disorder (MDD) is a common and debilitating condition with limited treatment precision. While brain imaging has linked neural features to MDD diagnosis and treatment response, the underlying circuits and their early modulation by treatment remain unclear. To examine changes in functional connectivity within the first two weeks of treatment, we analyzed two independent cohorts of MDD patients receiving antidepressants or placebo. Across patients, a visual-precuneus-thalamus network showed increased functional connectivity regardless of treatment arm or clinical outcome. Placebo response involved attention and striatal systems, while drug-specific effects were localized to the amygdala, mid-cingulate, orbitofrontal cortex, and cerebellum, emerging only in a subset of medicated patients. Notably, the responses of those without drug-specific changes can be predicted with a placebo response prediction model. These early functional connectivity changes reveal common and distinct mechanisms of treatment effects, offering insights that could inform more personalized interventions for MDD.

neuroscience↗

bioRxiv2025

Cell-generated mechanical forces play a role in epileptogenesis after injury

Traumatic brain injury (TBI) is associated with a significantly increased risk of epilepsy. One of the consequences of severe TBI is progressive brain atrophy, which is frequently characterized by organized tissue retraction. Retraction is an active process synchronized by mechanical interactions between surviving cells. This results in unbalanced mechanical forces acting on surviving neurons, potentially activating mechanotransduction and leading to hyperexcitability. This novel mechanism of epileptogenesis was examined in organotypic hippocampal cultures, which develop spontaneous seizure-like activity in vitro. Cell-generated forces in this model resulted in contraction of hippocampal tissue. Artificial imbalances in mechanical forces were introduced by placing cultured slices on surfaces with adhesive and non-adhesive regions. This modeled disbalance in mechanical forces that may occur in the brain after trauma. Portions of the slices that were not stabilized by substrate adhesion underwent increased contraction and compaction, revealing the presence of cell-generated forces capable of shaping tissue geometry. Changes in tissue geometry were followed by excitability changes that were specific to hippocampal sub-region and orientation of contractile forces relative to pyramidal cell apical-basal axis. Results of this study suggest that imbalanced cell-generated forces contribute to development of epilepsy, and that force imbalance may represent a novel mechanism of epileptogenesis after trauma.

neuroscience↗

bioRxiv2024

Temporal Information Encoding in Isolated Cortical Networks

Time-dependent features are present in many sensory stimuli. In the sensory cortices, timing features of stimuli are represented by spatial as well as temporal code. A potential mechanism by which cortical neuronal networks perform temporal-to-spatial conversion is reservoir computing. The state of a recurrently-connected network (reservoir) represents not only the current stimulus, or input, but also prior inputs. In this experimental study, we determined whether the state of an isolated cortical network could be used to accurately determine the timing of occurrence of an input pattern - or, in other words, to convert temporal input features into spatial state of the network. We used an experimental system based on patterned optogenetic stimulation of dissociated primary rat cortical cultures, and read out activity via fluorescent calcium indicator. We delivered input sequences of patterns such that a pattern of interest occurred at different times. We developed a readout function for network state based on a support vector machine (SVM) with recursive feature elimination and custom error correcting output code. We found that the state of these experimental networks contained information about inputs for at least 900 msec. Timing of input pattern occurrence was determined with 100 msec precision. Accurate classification required many neurons, suggesting that timing information was encoded via population code. Trajectory of network state was largely determined by spatial features of the stimulus, with temporal features having a more subtle effect. Local reservoir computation may be a plausible mechanism for temporal/spatial code conversion that occurs in sensory cortices. Significance StatementHandling of temporal and spatial stimulus features is fundamental to the ability of sensory cortices to process information. Reservoir computation has been proposed as a mechanism for temporal-to-spatial conversion that occurs in the sensory cortices. Furthermore, reservoirs of biological, living neurons have been proposed as building blocks for machine learning applications such as speech recognition and other time-series processing. In this work, we demonstrated that living neuron reservoirs, composed of recurrently connected cortical neurons, can carry out temporal-spatial conversion with sufficient accuracy and at sufficiently long time scale to be a plausible model for information processing in sensory cortices, and to have potential computational applications.

neuroscience↗

bioRxiv2023

A dynamic balance between neuronal death and clearance after acute brain injury

After acute brain injury, neuronal apoptosis may overwhelm the capacity for microglial phagocytosis, creating a queue of dying neurons awaiting clearance. The size of this queue should be equally sensitive to changes in neuronal death and the rate of phagocytosis. Using rodent organotypic hippocampal slice cultures as a model of acute perinatal brain injury, serial imaging demonstrated that the capacity for microglial phagocytosis of dying neurons was overwhelmed for two weeks. Altering phagocytosis rates, e.g. by changing the number of microglia, dramatically changed the number of visibly dying neurons. Similar effects were generated when the visibility of dying neurons was altered by changing the membrane permeability for vital stains. Canonically neuroprotective interventions such as seizure blockade and neurotoxic maneuvers such as perinatal ethanol exposure were mediated by effects on microglial activity and the membrane permeability of apoptotic neurons, and had either no or opposing effects on healthy surviving neurons. SignificanceAfter acute brain injury, microglial phagocytosis is overwhelmed by the number of dying cells. Under these conditions, the assumptions on which assays for neuroprotective and neurotoxic effects are based are no longer valid. Thus longitudinal assays of healthy cells, such as assessment of the fluorescence emission of transgenically-expressed proteins, provide more accurate estimates of cell death than do single-time-point anatomical or biochemical assays. More accurate estimates of death rates will increase the translatability of preclinical studies of neuroprotection and neurotoxicity.

neuroscience↗

bioRxiv2022

Localized network hyperconnectivity leads to hyperexcitability after injury

Brain injury increases the risk of the development of epilepsy. Axonal sprouting and synaptogenesis are homeostatically mediated responses by neurons to injury-induced de-afferentation and de-efferentation. Rewiring which occurs due to axonal sprouting and synaptogenesis may alter network excitability and lead to epilepsy. Excitatory and inhibitory connectivity are both subject to homeostatic rewiring. Thus, post-sprouting hyperexcitability cannot be simply explained as result of altered inhibitory/excitatory balance. In this work, we show computationally and experimentally that hyperconnected local networks are created by homeostatic rewiring near the injury site. These local networks are characterized by altered system dynamics despite preservation of excitatory/inhibitory balance. Hyperconnected local networks have a lower threshold for burst initiation, and generate spontaneous bursts, which in turn ignite seizure-like activity in the larger network. Our findings demonstrate a novel network mechanism of hyperexcitability and seizure generation due to maladaptive recovery after injury.

neuroscience↗

bioRxiv2022

Polyalanine disease mutations impair UBA6-dependent ubiquitination

Expansion mutations in polyalanine stretches are now associated with a growing number of human diseases with common genotypes and similar phenotypes 1-6. These similarities prompted us to query the normal function of physiological polyalanine stretches, and investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme 7, 8, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme, USE1. Aberrations in this polyalanine stretch reduced ubiquitin transfer to USE1 and downstream target, the E3 ubiquitin ligase, E6AP. Intriguingly, we identified competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. In mouse primary neurons, the deleterious interactions of expanded polyalanine proteins with UBA6, alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affected the levels of the synaptic protein, Arc. These effects could be observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations. Our results suggest a shared mechanism for such mutations, which may contribute to the congenital malformations seen in polyalanine diseases.

cell biology↗