Imperial College London

DrSadraSadeh

Faculty of MedicineDepartment of Brain Sciences

Advanced Research Fellow
 
 
 
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Contact

 

s.sadeh Website

 
 
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Location

 

515Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

19 results found

Feitosa Tomé D, Zhang Y, Aida T, Mosto O, Lu Y, Chen M, Sadeh S, Roy DS, Clopath Cet al., 2024, Dynamic and selective engrams emerge with memory consolidation, Nature Neuroscience, ISSN: 1097-6256

Episodic memories are encoded by experience-activated neuronal ensembles that remain necessary and sufficient for recall. However, the temporal evolution of memory engrams after initial encoding is unclear. In this study, we employed computational and experimental approaches to examine how the neural composition and selectivity of engrams change with memory consolidation. Our spiking neural network model yielded testable predictions: memories transition from unselective to selective as neurons drop out of and drop into engrams; inhibitory activity during recall is essential for memory selectivity; and inhibitory synaptic plasticity during memory consolidation is critical for engrams to become selective. Using activity-dependent labeling, longitudinal calcium imaging and a combination of optogenetic and chemogenetic manipulations in mouse dentate gyrus, we conducted contextual fear conditioning experiments that supported our model’s predictions. Our results reveal that memory engrams are dynamic and that changes in engram composition mediated by inhibitory plasticity are crucial for the emergence of memory selectivity.

Journal article

Radulescu CI, Doostdar N, Zabouri N, Melgosa-Ecenarro L, Wang X, Sadeh S, Pavlidi P, Airey J, Kopanitsa M, Clopath C, Barnes SJet al., 2023, Age-related dysregulation of homeostatic control in neuronal microcircuits, Nature Neuroscience, Vol: 26, Pages: 2158-2170, ISSN: 1097-6256

Neuronal homeostasis prevents hyperactivity and hypoactivity. Age-related hyperactivity suggests homeostasis may be dysregulated in later life. However, plasticity mechanisms preventing age-related hyperactivity and their efficacy in later life are unclear. We identify the adult cortical plasticity response to elevated activity driven by sensory overstimulation, then test how plasticity changes with age. We use in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduce cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also find overstimulation disrupts cognition in older but not younger animals. We propose that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance.

Journal article

Xie Y, Sadeh S, 2023, Computational assessment of visual coding across mouse brain areas and behavioural states, Frontiers in Computational Neuroscience, Vol: 17, ISSN: 1662-5188

Introduction: Our brain is bombarded by a diverse range of visual stimuli, which are converted into corresponding neuronal responses and processed throughout the visual system. The neural activity patterns that result from these external stimuli vary depending on the object or scene being observed, but they also change as a result of internal or behavioural states. This raises the question of to what extent it is possible to predict the presented visual stimuli from neural activity across behavioural states, and how this varies in different brain regions.Methods: To address this question, we assessed the computational capacity of decoders to extract visual information in awake behaving mice, by analysing publicly available standardised datasets from the Allen Brain Institute. We evaluated how natural movie frames can be distinguished based on the activity of units recorded in distinct brain regions and under different behavioural states. This analysis revealed the spectrum of visual information present in different brain regions in response to binary and multiclass classification tasks.Results: Visual cortical areas showed highest classification accuracies, followed by thalamic and midbrain regions, with hippocampal regions showing close to chance accuracy. In addition, we found that behavioural variability led to a decrease in decoding accuracy, whereby large behavioural changes between train and test sessions reduced the classification performance of the decoders. A generalised linear model analysis suggested that this deterioration in classification might be due to an independent modulation of neural activity by stimulus and behaviour. Finally, we reconstructed the natural movie frames from optimal linear classifiers, and observed a strong similarity between reconstructed and actual movie frames. However, the similarity was significantly higher when the decoders were trained and tested on sessions with similar behavioural states.Conclusion: Our analysis provides

Journal article

Sadeh S, Clopath C, 2022, Contribution of behavioural variability to representational drift, eLife, Vol: 11, Pages: 1-28, ISSN: 2050-084X

Neuronal responses to similar stimuli change dynamically over time, raising the question of how internal representations can provide a stable substrate for neural coding. Recent work has suggested a large degree of drift in neural representations even in sensory cortices, which are believed to store stable representations of the external world. While the drift of these representations is mostly characterized in relation to external stimuli, the behavioural state of the animal (for instance, the level of arousal) is also known to strongly modulate the neural activity. We therefore asked how the variability of such modulatory mechanisms can contribute to representational changes. We analysed large-scale recording of neural activity from the Allen Brain Observatory, which was used before to document representational drift in the mouse visual cortex. We found that, within these datasets, behavioural variability significantly contributes to representational changes. This effect was broadcasted across various cortical areas in the mouse, including the primary visual cortex, higher order visual areas, and even regions not primarily linked to vision like hippocampus. Our computational modelling suggests that these results are consistent with independent modulation of neural activity by behaviour over slower time scales. Importantly, our analysis suggests that reliable but variable modulation of neural representations by behaviour can be misinterpreted as representational drift, if neuronal representations are only characterized in the stimulus space and marginalised over behavioural parameters.

Journal article

Feitosa Tome D, Sadeh S, Clopath C, 2022, Coordinated hippocampal-thalamic-cortical communication crucial for engram dynamics underneath systems consolidation, Nature Communications, Vol: 13, ISSN: 2041-1723

Systems consolidation refers to the time-dependent reorganization of memory representations or engrams across brain regions. Despite recent advancements in unravelling this process, the exact mechanisms behind engram dynamics and the role of associated pathways remain largely unknown. Here we propose a biologically-plausible computational model to address this knowledge gap. By coordinating synaptic plasticity timescales and incorporating a hippocampus-thalamus-cortex circuit, our model is able to couple engram reactivations across these regions and thereby reproduce key dynamics of cortical and hippocampal engram cells along with their interdependencies. Decoupling hippocampal-thalamic-cortical activity disrupts systems consolidation. Critically, our model yields testable predictions regarding hippocampal and thalamic engram cells, inhibitory engrams, thalamic inhibitory input, and the effect of thalamocortical synaptic coupling on retrograde amnesia induced by hippocampal lesions. Overall, our results suggest that systems consolidation emerges from coupled reactivations of engram cells in distributed brain regions enabled by coordinated synaptic plasticity timescales in multisynaptic subcortical-cortical circuits.

Journal article

Geiller T, Sadeh S, Clopath C, Losonczy Aet al., 2021, Local circuit amplification of spatial selectivity in the hippocampus, Nature, Vol: 601, Pages: 105-109, ISSN: 0028-0836

Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex1. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs2 regulate the spatial receptive fields of pyramidal cells3. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing4 and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation. We found a local circuit mechanism in CA1 whereby the spatial tuning of an individual place cell can propagate to a functionally recurrent subnetwork5 to which it belongs. The emergence of place fields in individual neurons led to the development of inverse selectivity in a subset of their presynaptic interneurons, and recruited functionally coupled place cells at that location. Thus, the spatial selectivity of single CA1 neurons is amplified through local circuit plasticity to enable effective multi-neuronal representations that can flexibly scale environmental features locally without degrading the feedforward input structure.

Journal article

Sadeh S, Clopath C, 2021, Excitatory-inhibitory balance modulates the formation and dynamics of neuronal assemblies in cortical networks, Science Advances, Vol: 7, Pages: 1-16, ISSN: 2375-2548

Repetitive activation of subpopulations of neurons leads to the formation of neuronal assemblies, which can guide learning and behavior. Recent technological advances have made the artificial induction of such assemblies feasible, yet how various parameters of perturbation can be optimized for such induction is not clear. We found that the regime of cortical networks in terms of their excitatory-inhibitory balance can modulate the formation and dynamics of assemblies. Networks with dominant excitatory interactions enabled a fast formation of assemblies, and this was accompanied by recruitment of other non-perturbed neurons, thus leading to some degree of nonspecific assembly formation. On the other hand, strong excitatory-inhibitory interaction recruited lateral inhibition, which slowed down the formation of assemblies but constrained them to the perturbed neurons. Our results suggest that these two regimes can be suitable for different computational and cognitive tasks with different trade-offs between speed and specificity. More generally, our work provides a framework to study network-wide behaviorally-relevant plasticity in biologically realistic networks.

Journal article

Sadeh S, Clopath C, 2020, Inhibitory stabilization and cortical computation, Nature Reviews Neuroscience, ISSN: 1471-003X

Journal article

Sadeh S, Clopath C, 2020, Theory of neuronal perturbome in cortical networks., Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 26966-26976, ISSN: 0027-8424

To unravel the functional properties of the brain, we need to untangle how neurons interact with each other and coordinate in large-scale recurrent networks. One way to address this question is to measure the functional influence of individual neurons on each other by perturbing them in vivo. Application of such single-neuron perturbations in mouse visual cortex has recently revealed feature-specific suppression between excitatory neurons, despite the presence of highly specific excitatory connectivity, which was deemed to underlie feature-specific amplification. Here, we studied which connectivity profiles are consistent with these seemingly contradictory observations, by modeling the effect of single-neuron perturbations in large-scale neuronal networks. Our numerical simulations and mathematical analysis revealed that, contrary to the prima facie assumption, neither inhibition dominance nor broad inhibition alone were sufficient to explain the experimental findings; instead, strong and functionally specific excitatory-inhibitory connectivity was necessary, consistent with recent findings in the primary visual cortex of rodents. Such networks had a higher capacity to encode and decode natural images, and this was accompanied by the emergence of response gain nonlinearities at the population level. Our study provides a general computational framework to investigate how single-neuron perturbations are linked to cortical connectivity and sensory coding and paves the road to map the perturbome of neuronal networks in future studies.

Journal article

Sadeh S, Clopath C, 2020, Patterned perturbation of inhibition can reveal the dynamical structure of neural processing, eLife, Vol: 9, ISSN: 2050-084X

Perturbation of neuronal activity is key to understanding the brain's functional properties, however, intervention studies typically perturb neurons in a nonspecific manner. Recent optogenetics techniques have enabled patterned perturbations, in which specific patterns of activity can be invoked in identified target neurons to reveal more specific cortical function. Here, we argue that patterned perturbation of neurons is in fact necessary to reveal the specific dynamics of inhibitory stabilization, emerging in cortical networks with strong excitatory and inhibitory functional subnetworks, as recently reported in mouse visual cortex. We propose a specific perturbative signature of these networks and investigate how this can be measured under different experimental conditions. Functionally, rapid spontaneous transitions between selective ensembles of neurons emerge in such networks, consistent with experimental results. Our study outlines the dynamical and functional properties of feature-specific inhibitory-stabilized networks, and suggests experimental protocols that can be used to detect them in the intact cortex.

Journal article

Gleeson P, Cantarelli M, Marin B, Quintana A, Earnshaw M, Sadeh S, Piasini E, Birgiolas J, Cannon RC, Cayco-Gajic NA, Crook S, Davison AP, Dura-Bernal S, Ecker A, Hines ML, Idili G, Lanore F, Larson SD, Lytton WW, Majumdar A, McDougal RA, Sivagnanam S, Solinas S, Stanislovas R, van Albada SJ, van Geit W, Silver RAet al., 2019, Open Source Brain: A Collaborative Resource for Visualizing, Analyzing, Simulating, and Developing Standardized Models of Neurons and Circuits., Neuron, Vol: 103, Pages: 395-411.e5

Computational models are powerful tools for exploring the properties of complex biological systems. In neuroscience, data-driven models of neural circuits that span multiple scales are increasingly being used to understand brain function in health and disease. But their adoption and reuse has been limited by the specialist knowledge required to evaluate and use them. To address this, we have developed Open Source Brain, a platform for sharing, viewing, analyzing, and simulating standardized models from different brain regions and species. Model structure and parameters can be automatically visualized and their dynamical properties explored through browser-based simulations. Infrastructure and tools for collaborative interaction, development, and testing are also provided. We demonstrate how existing components can be reused by constructing new models of inhibition-stabilized cortical networks that match recent experimental results. These features of Open Source Brain improve the accessibility, transparency, and reproducibility of models and facilitate their reuse by the wider community.

Journal article

Sadeh S, Silver RA, Mrsic-Flogel TD, Muir DRet al., 2017, Assessing the Role of Inhibition in Stabilizing Neocortical Networks Requires Large-Scale Perturbation of the Inhibitory Population, JOURNAL OF NEUROSCIENCE, Vol: 37, Pages: 12050-12067, ISSN: 0270-6474

Journal article

Sadeh S, Clopath C, Rotter S, 2015, Processing of Feature Selectivity in Cortical Networks with Specific Connectivity (vol 10, e0127547, 2015), PLOS ONE, Vol: 10, ISSN: 1932-6203

Journal article

Sadeh S, Clopath C, Rotter S, 2015, Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity, PLOS Computational Biology, Vol: 11, ISSN: 1553-734X

In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational studies of sensory proc

Journal article

Sadeh S, Clopath C, Rotter S, 2015, Processing of Feature Selectivity in Cortical Networks with Specific Connectivity, PLOS One, Vol: 10, ISSN: 1932-6203

Although non-specific at the onset of eye opening, networks in rodent visual cortex attain a non-random structure after eye opening, with a specific bias for connections between neurons of similar preferred orientations. As orientation selectivity is already present at eye opening, it remains unclear how this specificity in network wiring contributes to feature selectivity. Using large-scale inhibition-dominated spiking networks as a model, we show that feature-specific connectivity leads to a linear amplification of feedforward tuning, consistent with recent electrophysiological single-neuron recordings in rodent neocortex. Our results show that optimal amplification is achieved at an intermediate regime of specific connectivity. In this configuration a moderate increase of pairwise correlations is observed, consistent with recent experimental findings. Furthermore, we observed that feature-specific connectivity leads to the emergence of orientation-selective reverberating activity, and entails pattern completion in network responses. Our theoretical analysis provides a mechanistic understanding of subnetworks’ responses to visual stimuli, and casts light on the regime of operation of sensory cortices in the presence of specific connectivity.

Journal article

Sadeh S, Rotter S, 2014, Distribution of Orientation Selectivity in Recurrent Networks of Spiking Neurons with Different Random Topologies, PLOS ONE, Vol: 9, ISSN: 1932-6203

Journal article

Sadeh S, Rotter S, 2014, Statistics and geometry of orientation selectivity in primary visual cortex, BIOLOGICAL CYBERNETICS, Vol: 108, Pages: 631-653, ISSN: 0340-1200

Journal article

Sadeh S, Cardanobile S, Rotter S, 2014, Mean-field analysis of orientation selectivity in inhibition-dominated networks of spiking neurons, SPRINGERPLUS, Vol: 3, ISSN: 2193-1801

Journal article

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