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Tchumatchenko, T.

Publications and source records attributed to Tchumatchenko, T..

18 recordsLinked to original sources

Input-space geometry shapes adaptation dynamics underlying repetition suppression in a neural network model of relatedness priming

A key function of the human brain is its ability to dynamically adapt to novel contexts by integrating prior experience. While neural adaptation is widely observed across cortical systems, the microcircuit-level mechanisms governing its intensity and temporal dynamics remain unclear. To bridge this gap, we develop a recurrent network of adaptive exponential integrate-and-fire neurons governed by a triplet spike-timing-dependent plasticity rule, designed to reproduce neural dynamics recorded via intracranial electrophysiology and single-unit recordings from the medial temporal lobe of neurosurgical patients performing a priming task. Using input organizations inspired by the experimental paradigm, we systematically vary input geometry to investigate its impact on adaptation dynamics. We find that neural adaptation emerges from recurrent dynamics shaped by learned connectivity, with both its magnitude and temporal profile depending on the geometry of the input space. This dependence gives rise, at the simulated single-neuron level, to a continuum of response regimes ranging from sharpening-like to fatiguing-like dynamics. Sharpening-like responses dominate when inputs exhibit high within-meta-category similarity and strong between-meta-category separation, whereas fatiguing-like responses emerge under the opposite regime.

neuroscience↗

Push-and-pull protein dynamics leads to log-normal synaptic sizes and probabilistic multi-spine plasticity

A typical neuron receives thousands of inputs and is able to adapt the strength of its synapses to store new information and meet ongoing computational demands. The synaptic response to plasticity induction is stochastic and spatially structured but is traditionally described by deterministic models representing the "average" dynamics. Growing experimental evidence indicates that not only the stimulation protocol determines the plasticity outcome but that the initial synaptic sizes, their fluctuations, and the spatial competition for the plasticity-relevant proteins play a decisive role. This probabilistic perspective makes it hard to predict the fate of a given synapse and requires a conceptual shift from a single synapse view to a probabilistic multi-spine competitive process where the plasticity needs and the available resources are considered together. Here, we propose a data-driven modeling framework able to predict collective plasticity outcomes along a dendrite based on the initial size, the number, and the spatial distance between simultaneously stimulated synapses. Our data analysis reveals a log-normal distribution of protein numbers for many plasticity-mediating proteins and shows that this log-normal protein allocation constrains and controls the collective plasticity outcome across multiple stimulated and non-stimulated synapses while preserving a global size distribution. Our findings highlight how local stochastic processes and global protein allocation rules give rise to synaptic plasticity outcomes, offering a new framework to understand and predict dendritic computation.

neuroscience↗

Data-driven model reveals increased stability of CAG-expanded huntingtin RNA due to MID1 binding

RNA-binding proteins (RBP) are important regulators of RNA metabolism. In neurode-generative disorders such as Huntingtons Disease (HD), disrupted RBP-RNA interactions contribute to neuronal dysfunction. One such RBP, Midline 1 (MID1), has been shown to aberrantly associate with mutant huntingtin (Htt) RNA, enhancing its translation, yet the mechanism driving this effect remains unknown. Here, we develop a computational model to understand the role of MID1. Based on previously published data, our model predicts that MID1 increases the stability of the Htt RNA. We experimentally validate this prediction, showing that overexpression of MID1 significantly prolongs the half-life of mutant Htt RNA. Furthermore, we evaluate model refinements, including clustering of MID1-bound RNA, which allow capturing all key observations in the data. Together, we provide a data-driven framework that underlines the importance of RBP-RNA interaction in post-transcriptional regulation. This framework also shows how individual molecular reactions jointly determine RNA stability and protein levels in HD.

systems biology↗

Proteo-transcriptomic reprogramming and resource reallocation define the aging mammalian brain

Brain aging is a major risk for neurodegeneration, yet the underlying molecular mechanisms remain poorly understood. Here we performed an integrative proteo-transcriptomic analysis of the aging mouse brain, uncovering molecular signatures of aging through the assessment of protein aggregation, mRNA relocalization, and comparative proteomics across eight models of premature aging and neurodegeneration. We identified dynamic changes in physiological aging highlighting differences in synaptic maintenance and energy-allocation. These were linked to changes associated with fundamental protein biochemical properties such as size and net charge. Network analysis highlighted a decrease in mitochondrial complex I proteins not compensated at the mRNA level. Aggregation of 60S ribosome subunits indicated deteriorating translation efficiency and was accompanied by mitochondrial and proteasomal imbalance. The analysis of the nine models revealed key similarities and differences between physiological aging and pathology. Overall, our study provides an extensive resource on molecular aging, and offers insights into mechanisms predisposing to neurodegeneration, easily accessible at our Brain Aging and Molecular Atlas Project (BrainAging-MAP) website.

neuroscience↗

Nanoscale dendritic shaft constrictions shape synaptic integration in fine caliber principal neuron dendrites

Traditionally, theoretical studies typically described dendritic morphology as optimized for efficient synaptic voltage transfer from spines to the soma, implemented as a tubular design respecting Ralls 3/2 rule for impedance matching at branch points. Here, we reveal that this view is an oversimplification. Using three high-resolution imaging techniques, we demonstrate that dendrites in cortical and hippocampal neurons contain nanoscale constrictions, comparable in diameter to spine necks. We provide theoretical and experimental evidence that these constrictions partition the dendrite into distinct electrical compartments, significantly shaping dendritic integration of synaptic potentials.

neuroscience↗

Transformations of the spatial activity manifold convey aversive information in CA3

Hippocampal circuits form cognitive maps representing spatial position and integrating contextual information, including affective cues, within episodic memory representations. We investigated how spatial and affective information combine in the population activity of CA3 axons by imaging intermediate-to-dorsal and dorsal-to-dorsal projections in mice navigating a linear track before, during, and after exposure to an aversive air puff stimulus. Our analyses reveal that both axonal populations maintain a robust, time-invariant spatial coding manifold across recordings, independent of affective context. Alterations to this common manifold encode the presence of the aversive stimulus without disrupting the spatial representation. Both axonal pathways encoded affective information with similar efficacy. This population-level encoding was distributed similarly across place and non-place cells. Our findings demonstrate that hippocampal CA3 axons integrate spatial and affective information within a common representational geometry while preserving the ability to extract each information type separately.

neuroscience↗

An integrative model of AMPA receptor trafficking reveals the central contribution of local translation in subtype-specific kinetics

AMPA-type glutamate receptors (AMPARs) underlie most of the excitatory synaptic transmission in the brain and are crucial for implementing long-term synaptic plasticity. AMPARs are multi-protein complexes composed of two types of subunits: pore-forming subunits GluA1-4 that assemble in the endoplasmic reticulum and form the glutamate-gated ion channel, and auxiliary subunits that modulate receptor bio-physical properties and mediate their forward trafficking to the plasma membrane. Here, using a combination of theoretical and experimental approaches, we elucidate the kinetics of essential trafficking steps and the protein sources necessary to explain the experimentally observed distribution of AMPARs and the response of different AMPAR subtypes to LTP induction. Our data indicate that the mRNA coding for one of the most abundant AMPAR auxiliary subunits, CNIH-2, is abundant in dendrites. Consistent with this mRNA distribution, CNIH-2 is locally synthesized. In contrast, the pore-forming subunits GluA1 and GluA2 are mostly synthesized in the cell body. CNIH-2 synthesis increases after the (chemical) induction of long-term potentiation. Strikingly, the translation of CNIH-2 is required for the plasma membrane insertion of GluA2-containing receptors and not GluA1-homomeric AMPARs. Using the selective trafficking of GluA2-containing AMPARs by CNIH-2, our computational model can explain the distinct temporal profiles in response to plasticity induction of two major subtypes of AMPARs, the slow-response of the calciumimpermeable (GluA2-containing) and fast kinetics of the calcium-permeable (GluA2-lacking) AMPARs.

neuroscience↗

SpyDen: Automating molecular and structural analysis across spines and dendrites

Investigating the molecular composition across neural compartments such as axons, dendrites, or synapses is critical for our understanding of learning and memory. State-of-the-art microscopy techniques can now resolve individual molecules and pinpoint their position with micrometre or even nanometre resolution across tens or hundreds of micrometres, allowing the labelling of multiple structures of interest simultaneously. Algorithmically, tracking individual molecules across hundreds of micrometres and determining whether they are inside any cellular compartment of interest can be challenging. Historically, microscopy images are annotated manually, often using multiple software packages to detect fluorescence puncta (e.g. labelled mRNAs) and then trace and quantify cellular compartments of interest. Advanced ANN-based automated tools, while powerful, are often able to help only with selected parts of the data analysis pipeline, may be optimised for specific spatial resolutions or cell preparations or may not be fully open source and open access to be sufficiently customisable. To address these challenges, we developed SpyDen. SpyDen is a Python package based upon three principles: i) ease of use for multi-task scenarios, ii) open-source accessibility and data export to a common, open data format, iii) the ability to edit any software-generated annotation and generalise across spatial resolutions. Equipped with a graphical user interface and accompanied by video tutorials, SpyDen provides a collection of powerful algorithms that can be used for neurite and synapse detection as well as fluorescent puncta and intensity analysis. We validated SpyDen using expert annotation across numerous use cases to prove a powerful, integrated platform for efficient and reproducible molecular imaging analysis.

neuroscience↗

Deciphering the astrocytic contribution to learning and relearning

Astrocytes play a key role in the regulation of synaptic strength and are thought to orchestrate synaptic plasticity and memory. Yet, how specifically astrocytes and their neuroactive transmitters control learning and memory is currently an open question. Recent experiments have uncovered an astrocyte-mediated feedback loop in CA1 pyramidal neurons which is started by the release of endocannabinoids by active neurons and closed by astrocytic regulation of the D-serine levels at the dendrites. D-serine is a co-agonist for the NMDA receptor regulating the strength and direction of synaptic plasticity. Activity-dependent D-serine release mediated by astrocytes is therefore a candidate for mediating between long-term synaptic depression (LTD) and potentiation (LTP) during learning. Here, we show that the mathematical description of this astrocytic regulation is consistent with the classic Bienenstock Cooper Munro (BCM) model for synaptic plasticity, which postulated the existence of an activity-dependent LTP/LTD threshold. We show how the resulting mathematical framework can explain the experimentally observed behavioral effects of astrocytic cannabinoid receptor knock-out on mice during a place avoidance task and give rise to new testable predictions about the learning process advancing our understanding of the functional role of neuron-glia interaction in learning.

neuroscience↗

Linking spontaneous and stimulated spine dynamics

Our brains continuously acquire and store memories through synaptic plasticity. However, spontaneous synaptic changes can also occur and pose a challenge for maintaining stable memories. Despite fluctuations in synapse size, recent studies have shown that key population-level synaptic properties remain stable over time. This raises the question of how local synaptic plasticity affects the global population-level synaptic size distribution and whether individual synapses undergoing plasticity escape the stable distribution to encode specific memories. To address this question, we (i) studied spontaneously evolving spines and (ii) induced synaptic potentiation at selected sites while observing the spine distribution pre- and post-stimulation. We designed a stochastic model to describe how the current size of a synapse affects its future size under baseline and stimulation conditions and how these local effects give rise to population-level synaptic shifts. Our study offers a new understanding of how seemingly spontaneous synaptic fluctuations and local plasticity both contribute to population-level synaptic dynamics.

neuroscience↗

A quantitative rule to explain multi-spine plasticity

Neurons receive thousands of inputs onto their dendritic arbour, where individual synapses undergo activitydependent changes in strength. The durable forms of synaptic strength change, long-term potentiation (LTP) and long-term depression (LTD) require calcium entry through N-methyl-D-aspartate receptors (NMDARs) that triggers downstream protein signalling cascades in the dendrite. Notably, changes in postsynaptic strengths associated with LTP and LTD are correlated to changes in spine head volume, referred to as structural LTP (sLTP) and structural LTD (sLTD). Intriguingly, LTP and LTD, including sLTP and sLTD, are not necessarily restricted to the active, targeted synapses (homosynapses), and the changes in synaptic strength can spread and affect the strengths of inactive or non-stimulated synapses (heterosynapses) on the same cell. Moreover, the plasticity outcome at both homo- and heterosynapses can depend on the number of stimulated sites when eliciting multi-spine plasticity. Precisely how neurons allocate resources for implementing the changes in strength at individual synapses depending on their proximity to input activity across space and time remains an open question. In order to gain insights into the elementary processes underlying multi-spine plasticity that engages both homosynaptic and heterosynaptic changes, we have combined experimental and mathematical modelling approaches. On the one hand, we used glutamate uncaging to precisely and systematically stimulate variable numbers of homosynapses sharing the same dendritic branch whilst monitoring tens of other heterosynapses on the same dendrite. Homosynaptic potentiation of clusters of dendritic spines leads to heterosynaptic changes that are dependent on NMDAR, CaMKII and calcineurin. On the other hand, inspired by the Ca2+ levels hypothesis where different amounts of Ca2+ lead to either growth or shrinkage of spines, we have built a model based on a dual-role Ca2+-dependent protein that induces sLTP or sLTD. Comparing our experimental results with model predictions, we find that (i) both collaboration and competition among spines for protein resources are key drivers of heterosynaptic plasticity and (ii) the temporal and spatial distance between simultaneously stimulated spines impact the resulting spine dynamics. Moreover, our model can reconcile disparate experimental reports of sLTP and sLTD at homo- and heterosynaptic spines. Our results provide a quantitative description of the heterosynaptic footprint over minutes and hours post-stimulation across tens of microns of dendritic space. This broadens our knowledge about the operation of non-linear dendritic summation rules and how they impact spiking decisions.

neuroscience↗

Targeting diverse operational regimes in recurrent spiking networks

Neural computations emerge from recurrent neural circuits that comprise hundreds to a few thousand neurons. Continuous progress in connectomics, electrophysiology, and calcium imaging require tractable spiking network models that can consistently incorporate new information about the network structure and reproduce the recorded neural activity features. However, it is challenging to predict which spiking network connectivity configurations and neural properties can generate fundamental operational states and specific experimentally reported nonlinear cortical computations. Theoretical descriptions for the computational state of cortical spiking circuits are diverse, including the balanced state where excitatory and inhibitory inputs balance almost perfectly or the inhibition stabilized state (ISN) where the excitatory part of the circuit is unstable. It remains an open question whether these states can co-exist with experimentally reported nonlinear computations and whether they can be recovered in biologically realistic implementations of spiking networks. Here, we show how to identify spiking network connectivity patterns underlying diverse nonlinear computations such as XOR, bistability, inhibitory stabilization, supersaturation, and persistent activity. We established a mapping between the stabilized supralinear network (SSN) and spiking activity which allowed us to pinpoint the location in parameter space where these activity regimes occur. Notably, we found that biologically-sized spiking networks can have irregular asynchronous activity that does not require strong excitation-inhibition balance or large feedforward input and we showed that the dynamic firing rate trajectories in spiking networks can be precisely targeted without error-driven training algorithms.

neuroscience↗

Reconciling contrast invariance and non-linear computation in cortical circuits

Network selectivity for orientation is invariant to changes in the stimulus contrast in the primary visual cortex. Similarly, the selectivity for odor identity is invariant to changes in odorant concentration in the piriform cortex. Interestingly, invariant network selectivity appears robust to local changes in synaptic strength induced by synaptic plasticity, even though: i) synaptic plasticity can potentiate or depress connections between neurons in a feature-dependent manner, and ii) in networks with balanced excitation and inhibition, synaptic plasticity is a determinant for the network non-linearity. In this study, we investigate whether network contrast invariance is consistent with a variety of synaptic states and connectivities in balanced networks. By using mean-field models and spiking network simulations, we show how the synaptic state controls the non-linearity in the network response to contrast and how it can lead to the emergence of contrast-invariant or contrast-dependent selectivity. Different forms of synaptic plasticity sharpen or broaden the network selectivity, while others do not affect it. Our results explain how the physiology of individual synapses is linked to contrast-invariant selectivity at the network level.

neuroscience↗

Dopamine and serotonin interplay for valence-based spatial learning

Dopamine and serotonin are important modulators of synaptic plasticity and their action has been linked to our ability to learn the positive or negative outcomes or valence learning. In the hippocampus, both neuromodulators affect long-term synaptic plasticity but play different roles in the encoding of uncertainty or predicted reward. Here, we examine the differential role of these modulators on learning speed and cognitive flexibility in a navigational model. We compare two reward-modulated spike time-dependent plasticity (R-STDP) learning rules to describe the action of these neuromodulators. Our results show that the interplay of dopamine (DA) and serotonin (5-HT) improves overall learning performance and can explain experimentally reported differences in spatial task performance. Furthermore, this system allows us to make predictions regarding spatial reversal learning.

neuroscience↗

Unbiased choice of global clustering parameters in single-molecule localization microscopy

Single-molecule localization microscopy resolves objects below the diffraction limit of light via sparse, stochastic detection of target molecules. Single molecules appear as clustered detection events after image reconstruction. However, identification of clusters of localizations is often complicated by the spatial proximity of target molecules and by background noise. Clustering results of existing algorithms often depend on user-generated training data or user-selected parameters, which can lead to unintentional clustering errors. Here we suggest an unbiased algorithm (FINDER) based on adaptive global parameter selection and demonstrate that the algorithm is robust to noise inclusion and target molecule density. We benchmarked FINDER against the most common density based clustering algorithms in test scenarios based on experimental datasets. We show that FINDER can keep the number of false positive inclusions low while also maintaining a low number of false negative detections in densely populated regions.

bioinformatics↗

Formation and synaptic control of active transient working memory representations

Neural representations of working memory maintain information temporarily and make it accessible for processing. This is most feasible in active, spiking representations. State-of-the-art modeling frameworks, however, reproduce working memory representations that are either transient but non-active or active but non-transient. Here, we analyze a biologically motivated working memory model which shows that synaptic short-term plasticity and noise emerging from spiking networks can jointly produce a working memory representation that is both active and transient. We investigate the effect of a synaptic signaling mechanism whose dysregulation is related to schizophrenia and show how it controls transient working memory duration through presynaptic, astrocytic and postsynaptic elements. Our findings shed light on the computational capabilities of healthy working memory function and offer a possible mechanistic explanation for how molecular alterations observed in psychiatric diseases such as schizophrenia can lead to working memory impairments.

neuroscience↗

The Spatial Scale of Synaptic Protein Allocation during Homeostatic Plasticity

An individual neuron hosts up to 10,000 individual synapses that can be made stronger or weaker by local and cell-wide plasticity mechanisms, both of which require protein synthesis. To address over what spatial scale a neuron allocates synaptic resources, we quantified the distribution of newly synthesized proteins after global homeostatic upscaling using metabolic labeling and single-molecule localization (DNA-PAINT). Following upscaling, we observed a global increase in locally synthesized nascent protein in synapses and at dendrites, with a high degree of variability between individual synapses. We determined the smallest spatial scale over which nascent proteins were evenly distributed and found that it is best described by synaptic neighborhoods (~ 10 microns in length)-smaller than a dendritic branch and larger than an individual synapse. Protein allocation at the level of neighborhoods thus represents a solution to the problem of protein allocation within a neuron that balances local autonomy and global homeostasis.

neuroscience↗

A model of neuron-glia crosstalk explains stages of neural tissue resilience

Glia, the helper cells of the brain, are essential in maintaining neural resilience across time and varying challenges: By reacting to changes in neuronal health glia carefully balance repair or disposal of injured neurons to prevent further tissue damage. Malfunction of these interactions is implicated in many neurodegenerative diseases. Reductionist models with a minimal number of parameters provide the opportunity to gain insight into biological functions and inform experimental designs. We introduce such a model that mimics long-term implications of repair-or-dispose decisions. Depending on the functionality of the decision-making process, the model assumes four distinct tissue states: healthy, challenged, primed tissue at risk of acute damage propagation, and chronic neurodegeneration. These states of the model correspond to the progression stages observed in the most common neurodegenerative conditions. The underlying mechanisms are in agreement with experimental observations of glia-neuron crosstalk and reproduce a homeostatic balance between repairing and damage-inducing reactions. The model suggests that the onset of neurodegeneration results from a tug-of-war between two conflicting goals: short-term resilience to stressors vs long-term prevention of tissue damage.

systems biology↗