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ABSTRACT Achieving targeted perturbations of neural activity is essential for dissecting the causal architecture of brain circuits. A crucial challenge in targeted manipulation experiments is the identification ofhigh efficacyperturbation sites whose stimulation exerts desired effects, currently done with costly trial-and-error procedures. Can one predict stimulation effects solely based on observations of the circuit activity, in the absence of perturbation? We answer this question in dissociated neuronal cultures on High-Density Microelectrode Arrays (HD-MEAs), which, compared toin vivopreparations, offer a controllablein vitroplatform that enables precise stimulation and full access to network dynamics. We first reconstruct theperturbome- the full map of network responses to focal electrical stimulation - by sequentially activating individual single sites and quantifying their network-wide effects. The measured perturbome patterns cluster into functional modules, with limited spread across clusters. We then demonstrate that the perturbome can be predicted from spontaneous activity alone. Using short baseline recordings in the absence of perturbations, we estimate Effective Connectivity (EC) and show that it predicts the spatial organization of the perturbome, including spatial clusters and local connectivity. Our results demonstrate that spontaneous dynamics encode the latent causal structure of neural circuits and that EC metrics can serve as effective, model-free proxies for stimulation outcomes. This framework enables data-driven targeting and causal inferencein vitro, with potential applications to more complex preparations such as human iPSC-derived neurons and brain organoids, with implications for both basic research and therapeutic strategies targeting neurological disorders. Significance StatementNeuronal cultures are increasingly used as controllable platforms to study neuronal network dynamics, neuromodulation, and brain-inspired therapies. To fully exploit their potential, we need robust methods to probe and interpret causal interactions. Here, we develop a framework to reconstruct the perturbome—the network-wide map of responses to localized electrical stimulation—and show that it can be predicted from spontaneous activity alone. Using simple, model-free metrics of Effective Connectivity, we reveal that ongoing activity encodes causal structure and provides reliable proxies for stimulation outcomes. This validates EC as a practical measure of causal influence in vitro. Our methodology refines the use of neuronal cultures for brain-on-a-chip approaches, and paves the way for data-driven neuromodulation strategies in human stem cell–derived neurons and brain organoids.
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Recurrent neural circuits overcome partial inactivation by compensation and re-learning
Technical advances in artificial manipulation of neural activity have precipitated a surge in studying the causal contribution of brain circuits to cognition and behavior. However, complexities of neural circuits challenge interpretation of experimental results, necessitating new theoretical frameworks for reasoning about causal effects. Here, we take a step in this direction, through the lens of recurrent neural networks trained to perform perceptual decisions. We show that understanding the dynamical system structure that underlies network solutions provides a precise account for the magnitude of behavioral effects due to perturbations. Our framework explains past empirical observations by clarifying the most sensitive features of behavior, and how complex circuits compensate and adapt to perturbations. In the process, we also identify strategies that can improve the interpretability of inactivation experiments. Significance StatementNeuroscientists heavily rely on artificial perturbation of the neural activity to understand the function of brain circuits. Current interpretations of experimental results often follow a simple logic, that the magnitude of a behavioral effect following a perturbation indicates the degree of involvement of the perturbed circuit in the behavior. We model a variety of neural networks with controlled levels of complexity, robustness, and plasticity, showing that perturbation experiments could yield counter-intuitive results when networks are complex enough-to allow unperturbed pathways to compensate for the perturbed neurons-or plastic enough-to allow continued learning from feedback during perturbations. To rein in these complexities we develop a Functional Integrity Index that captures alterations in network computations and predicts disruptions of behavior with the perturbation.
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- Award ID(s):
- 1922658
- PAR ID:
- 10492787
- Publisher / Repository:
- DOI PREFIX: 10.1523
- Date Published:
- Journal Name:
- The Journal of Neuroscience
- ISSN:
- 0270-6474
- Format(s):
- Medium: X Size: Article No. e1635232024
- Size(s):
- Article No. e1635232024
- Sponsoring Org:
- National Science Foundation
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