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3. Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity.

Author

Guet-McCreight, Alexandre, Mazza, Frank, Prevot, Thomas D., Sibille, Etienne, and Hay, Etay

Subjects
MACHINE learning, MENTAL depression, PREDICTION models, SOMATOSTATIN, BIOMARKERS, ELECTROENCEPHALOGRAPHY, GABA receptors
Abstract

Treatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of α5-GABAA receptors (α5-PAM) offers a promising effective treatment. However, testing the effect of α5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and α5-PAM effects, to simulate EEG of individual microcircuits across depression severity and α5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for α5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of α5-PAM treatment to clinical use. Author summary: Inhibition from somatostatin-expressing (SST) interneurons is reduced in depression, and new pharmacology (α5-PAM) can selectively recover this inhibition to healthy level. However, α5-PAM has not been tested in humans, meriting the use of detailed simulations for dose prediction from EEG biomarkers of depression severity. We simulated a set of individual human neuronal microcircuits varying in severity of SST interneuron inhibition loss and across a range of α5-PAM doses. We then trained machine learning models to predict optimal dose from simulated EEG features, which recovered EEG profile and microcircuit activity to the healthy levels. Our study thus provides new tools for dose prediction and monitoring of α5-PAM efficacy using non-invasive EEG biomarkers of depression severity. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Large-Scale Mechanistic Models of Brain Circuits with Biophysically and Morphologically Detailed Neurons.

Author

Dura-Bernal, Salvador, Herrera, Beatriz, Lupascu, Carmen, Marsh, Brianna M., Gandolfi, Daniela, Marasco, Addolorata, Neymotin, Samuel, Romani, Armando, Solinas, Sergio, Bazhenov, Maxim, Hay, Etay, Migliore, Michele, Reinmann, Michael, and Arkhipov, Anton

Subjects
MEMBRANE potential, NEURAL stimulation, NEURAL codes, BRAIN diseases, MULTISCALE modeling, DEEP brain stimulation, THALAMOCORTICAL system
Abstract

Understanding the brain requires studying its multiscale interactions from molecules to networks. The increasing availability of large-scale datasets detailing brain circuit composition, connectivity, and activity is transforming neuroscience. However, integrating and interpreting this data remains challenging. Concurrently, advances in supercomputing and sophisticated modeling tools now enable the development of highly detailed, large-scale biophysical circuit models. These mechanistic multiscale models offer a method to systematically integrate experimental data, facilitating investigations into brain structure, function, and disease. This review, based on a Society for Neuroscience 2024 MiniSymposium, aims to disseminate recent advances in large-scale mechanistic modeling to the broader community. It highlights (1) examples of current models for various brain regions developed through experimental data integration; (2) their predictive capabilities regarding cellular and circuit mechanisms underlying experimental recordings (e.g., membrane voltage, spikes, local-field potential, electroencephalography/magnetoencephalography) and brain function; and (3) their use in simulating biomarkers for brain diseases like epilepsy, depression, schizophrenia, and Parkinson’s, aiding in understanding their biophysical underpinnings and developing novel treatments. The review showcases state-of-the-art models covering hippocampus, somatosensory, visual, motor, auditory cortical, and thalamic circuits across species. These models predict neural activity at multiple scales and provide insights into the biophysical mechanisms underlying sensation, motor behavior, brain signals, neural coding, disease, pharmacological interventions, and neural stimulation. Collaboration with experimental neuroscientists and clinicians is essential for the development and validation of these models, particularly as datasets grow. Hence, this review aims to foster interest in detailed brain circuit models, leading to cross-disciplinary collaborations that accelerate brain research. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Reconstruction and Simulation of Neocortical Microcircuitry

Author

Markram, Henry, Muller, Eilif, Ramaswamy, Srikanth, Reimann, Michael W., Abdellah, Marwan, Sanchez, Carlos Aguado, Ailamaki, Anastasia, Alonso-Nanclares, Lidia, Antille, Nicolas, Arsever, Selim, Kahou, Guy Antoine Atenekeng, Berger, Thomas K., Bilgili, Ahmet, Buncic, Nenad, Chalimourda, Athanassia, Chindemi, Giuseppe, Courcol, Jean-Denis, Delalondre, Fabien, Delattre, Vincent, Druckmann, Shaul, Dumusc, Raphael, Dynes, James, Eilemann, Stefan, Gal, Eyal, Gevaert, Michael Emiel, Ghobril, Jean-Pierre, Gidon, Albert, Graham, Joe W., Gupta, Anirudh, Haenel, Valentin, Hay, Etay, Heinis, Thomas, Hernando, Juan B., Hines, Michael, Kanari, Lida, Keller, Daniel, Kenyon, John, Khazen, Georges, Kim, Yihwa, King, James G., Kisvarday, Zoltan, Kumbhar, Pramod, Lasserre, Sébastien, Le Bé, Jean-Vincent, Magalhães, Bruno R.C., Merchán-Pérez, Angel, Meystre, Julie, Morrice, Benjamin Roy, Muller, Jeffrey, Muñoz-Céspedes, Alberto, Muralidhar, Shruti, Muthurasa, Keerthan, Nachbaur, Daniel, Newton, Taylor H., Nolte, Max, Ovcharenko, Aleksandr, Palacios, Juan, Pastor, Luis, Perin, Rodrigo, Ranjan, Rajnish, Riachi, Imad, Rodríguez, José-Rodrigo, Riquelme, Juan Luis, Rössert, Christian, Sfyrakis, Konstantinos, Shi, Ying, Shillcock, Julian C., Silberberg, Gilad, Silva, Ricardo, Tauheed, Farhan, Telefont, Martin, Toledo-Rodriguez, Maria, Tränkler, Thomas, Van Geit, Werner, Díaz, Jafet Villafranca, Walker, Richard, Wang, Yun, Zaninetta, Stefano M., DeFelipe, Javier, Hill, Sean L., Segev, Idan, and Schürmann, Felix

Published
2015
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14. An in vitro whole-cell electrophysiology dataset of human cortical neurons

Author

Howard, Derek, primary, Chameh, Homeira Moradi, additional, Guet-McCreight, Alexandre, additional, Hsiao, Huan Allen, additional, Vuong, Maggie, additional, Seo, Young Seok, additional, Shah, Prajay, additional, Nigam, Anukrati, additional, Chen, Yuxiao, additional, Davie, Melanie, additional, Hay, Etay, additional, Valiante, Taufik A, additional, and Tripathy, Shreejoy J, additional

Published
2022
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22. Reconstruction and Simulation of Neocortical Microcircuitry

Author

European Commission, Gatsby Charitable Foundation, Ministerio de Economía y Competitividad (España), Hebrew University of Jerusalem, École Polytechnique Fédérale de Lausanne, Swiss National Supercomputing Centre, Swiss National Science Foundation, Office of Naval Research (US), Markram, Henry, Muller, Eilif, Ramaswamy, Srikanth, Reimann, Michael W., Abdellah, Marwan, Aguado Sánchez, Carlos, Ailamaki, Anastasia, Alonso-Nanclares, Lidia, Antille, Nicolas, Arsever, Selim, Atenekeng Kahou, Guy Antoine, Berger, Thomas, Bilgili, Ahmet, Buncic, Nenad, Chalimourda, Athanassia, Chindemi, Giuseppe, Courcol, Jean-Denis, Delalondre, Fabien, Delattre, Vicent, Druckmann, Shaul, Dumusc, Raphael, Dynes, James, Eilemann, Stefan, Gal, Eyal, Gevaert, Michael Emiel, Ghobril, Jean-Pierre, Gidon, Albert, Graham, Joe W., Gupta, Anirudh, Haenel, Valentin, Hay, Etay, Heinis, Thomas, Hernando, Juan B., Hines, Michael, Kanari, Lida, Keller, Daniel, Kenyon, John, Khazen, Georges, Kim, Yihwa, King, James G., Kisvárday, Zoltán F., Kumbhar, Pramod, Lasserre, Sébastien, Le Bé, Jean-Vincent, Magalhães, Bruno R. C., Merchán-Pérez, Ángel, Meystre, Julie, Morrice, Benjamin Roy, Muller, Jeffrey, Muñoz Céspedes, Alberto, Muralidhar, Shruti, Muthurasa, Keerthan, Nachbaur, Daniel, Newton, Taylor H., Nolte, Max, Ovcharenko, Aleksandr, Palacios, Juan, Pastor, Luis, Perin, Rodrigo, Ranjan, Rajnish, Riachi, Imad, Rodríguez, J. Rodrigo, Riquelme, Juan Luis, Rössert, Christian, Sfyrakis, Konstantinos, Shi, Ying, Shillcock, Julian C., Silberberg, Gilad, Silva, Ricardo, Tauheed, Farhan, Telefont, Martin, Toledo-Rodriguez, Maria, Tränkler, Thomas, Geit, Werner van, Villafranca Díaz, Jafet, Walker, Richard, Wang, Yu, Zaninetta, Stefano M., DeFelipe, Javier, Hill, Sean L., Segev, Idan, Schürmann, Felix, European Commission, Gatsby Charitable Foundation, Ministerio de Economía y Competitividad (España), Hebrew University of Jerusalem, École Polytechnique Fédérale de Lausanne, Swiss National Supercomputing Centre, Swiss National Science Foundation, Office of Naval Research (US), Markram, Henry, Muller, Eilif, Ramaswamy, Srikanth, Reimann, Michael W., Abdellah, Marwan, Aguado Sánchez, Carlos, Ailamaki, Anastasia, Alonso-Nanclares, Lidia, Antille, Nicolas, Arsever, Selim, Atenekeng Kahou, Guy Antoine, Berger, Thomas, Bilgili, Ahmet, Buncic, Nenad, Chalimourda, Athanassia, Chindemi, Giuseppe, Courcol, Jean-Denis, Delalondre, Fabien, Delattre, Vicent, Druckmann, Shaul, Dumusc, Raphael, Dynes, James, Eilemann, Stefan, Gal, Eyal, Gevaert, Michael Emiel, Ghobril, Jean-Pierre, Gidon, Albert, Graham, Joe W., Gupta, Anirudh, Haenel, Valentin, Hay, Etay, Heinis, Thomas, Hernando, Juan B., Hines, Michael, Kanari, Lida, Keller, Daniel, Kenyon, John, Khazen, Georges, Kim, Yihwa, King, James G., Kisvárday, Zoltán F., Kumbhar, Pramod, Lasserre, Sébastien, Le Bé, Jean-Vincent, Magalhães, Bruno R. C., Merchán-Pérez, Ángel, Meystre, Julie, Morrice, Benjamin Roy, Muller, Jeffrey, Muñoz Céspedes, Alberto, Muralidhar, Shruti, Muthurasa, Keerthan, Nachbaur, Daniel, Newton, Taylor H., Nolte, Max, Ovcharenko, Aleksandr, Palacios, Juan, Pastor, Luis, Perin, Rodrigo, Ranjan, Rajnish, Riachi, Imad, Rodríguez, J. Rodrigo, Riquelme, Juan Luis, Rössert, Christian, Sfyrakis, Konstantinos, Shi, Ying, Shillcock, Julian C., Silberberg, Gilad, Silva, Ricardo, Tauheed, Farhan, Telefont, Martin, Toledo-Rodriguez, Maria, Tränkler, Thomas, Geit, Werner van, Villafranca Díaz, Jafet, Walker, Richard, Wang, Yu, Zaninetta, Stefano M., DeFelipe, Javier, Hill, Sean L., Segev, Idan, and Schürmann, Felix

Abstract

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies.

Published
2015

26. Preserving axosomatic spiking features despite diverse dendritic morphology

Author

Hay, Etay, Schuermann, Felix, Markram, Henry, and Segev, Idan

Subjects
pyramidal cell, model, ion channel, spiking, dendrite
Abstract

Throughout the nervous system, cells belonging to a certain electrical class (e-class)-sharing high similarity in firing response properties-may nevertheless have widely variable dendritic morphologies. To quantify the effect of this morphological variability on the firing of layer 5 thick-tufted pyramidal cells (TTCs), a detailed conductance-based model was constructed for a three-dimensional reconstructed exemplar TTC. The model exhibited spike initiation in the axon and reproduced the characteristic features of individual spikes, as well as of the firing properties at the soma, as recorded in a population of TTCs in young Wistar rats. When using these model parameters over the population of 28 three-dimensional reconstructed TTCs, both axonal and somatic ion channel densities had to be scaled linearly with the conductance load imposed on each of these compartments. Otherwise, the firing of model cells deviated, sometimes very significantly, from the experimental variability of the TTC e-class. The study provides experimentally testable predictions regarding the coregulation of axosomatic membrane ion channels density for cells with different dendritic conductance load, together with a simple and systematic method for generating reliable conductance-based models for the whole population of modeled neurons belonging to a particular e-class, with variable morphology as found experimentally.

27. Reconstruction and simulation of neocortical microcircuitry

Author

Markram, Henry, Muller, Eilif, Ramaswamy, Srikanth, Reimann, Michael W., Abdellah, Marwan, Sanchez, Carlos Aguado, Ailamaki, Anastasia, Alonso-Nanclares, Lidia, Antille, Nicolas, Arsever, Selim, Kahou, Guy Antoine Atenekeng, Berger, Thomas K., Bilgili, Ahmet, Buncic, Nenad, Chalimourda, Athanassia, Chindemi, Giuseppe, Courcol, Jean-Denis, Delalondre, Fabien, Delattre, Vincent, Druckmann, Shaul, Dumusc, Raphael, Dynes, James, Eilemann, Stefan, Gal, Eyal, Gevaert, Michael Emiel, Ghobril, Jean-Pierre, Gidon, Albert, Graham, Joe W., Gupta, Anirudh, Haenel, Valentin, Hay, Etay, Heinis, Thomas, Hernando, Juan B., Hines, Michael, Kanari, Lida, Keller, Daniel, Kenyon, John, Khazen, Georges, Kim, Yihwa, King, James G., Kisvarday, Zoltan, Kumbhar, Pramod, Lasserre, Sébastien, Le Bé, Jean-Vincent, Magalhães, Bruno R.C., Merchán-Pérez, Angel, Meystre, Julie, Morrice, Benjamin Roy, Muller, Jeffrey, Muñoz-Céspedes, Alberto, Muralidhar, Shruti, Muthurasa, Keerthan, Nachbaur, Daniel, Newton, Taylor H., Nolte, Max, Ovcharenko, Aleksandr, Palacios, Juan, Pastor, Luis, Perin, Rodrigo, Ranjan, Rajnish, Riachi, Imad, Rodríguez, José-Rodrigo, Riquelme, Juan Luis, Rössert, Christian, Sfyrakis, Konstantinos, Shi, Ying, Shillcock, Julian C., Silberberg, Gilad, Silva, Ricardo, Tauheed, Farhan, Telefont, Martin, Toledo-Rodriguez, Maria, Tränkler, Thomas, Van Geit, Werner, Díaz, Jafet Villafranca, Walker, Richard, Wang, Yun, Zaninetta, Stefano M., DeFelipe, Javier, Hill, Sean L., Segev, Idan, Schürmann, Felix, Markram, Henry, Muller, Eilif, Ramaswamy, Srikanth, Reimann, Michael W., Abdellah, Marwan, Sanchez, Carlos Aguado, Ailamaki, Anastasia, Alonso-Nanclares, Lidia, Antille, Nicolas, Arsever, Selim, Kahou, Guy Antoine Atenekeng, Berger, Thomas K., Bilgili, Ahmet, Buncic, Nenad, Chalimourda, Athanassia, Chindemi, Giuseppe, Courcol, Jean-Denis, Delalondre, Fabien, Delattre, Vincent, Druckmann, Shaul, Dumusc, Raphael, Dynes, James, Eilemann, Stefan, Gal, Eyal, Gevaert, Michael Emiel, Ghobril, Jean-Pierre, Gidon, Albert, Graham, Joe W., Gupta, Anirudh, Haenel, Valentin, Hay, Etay, Heinis, Thomas, Hernando, Juan B., Hines, Michael, Kanari, Lida, Keller, Daniel, Kenyon, John, Khazen, Georges, Kim, Yihwa, King, James G., Kisvarday, Zoltan, Kumbhar, Pramod, Lasserre, Sébastien, Le Bé, Jean-Vincent, Magalhães, Bruno R.C., Merchán-Pérez, Angel, Meystre, Julie, Morrice, Benjamin Roy, Muller, Jeffrey, Muñoz-Céspedes, Alberto, Muralidhar, Shruti, Muthurasa, Keerthan, Nachbaur, Daniel, Newton, Taylor H., Nolte, Max, Ovcharenko, Aleksandr, Palacios, Juan, Pastor, Luis, Perin, Rodrigo, Ranjan, Rajnish, Riachi, Imad, Rodríguez, José-Rodrigo, Riquelme, Juan Luis, Rössert, Christian, Sfyrakis, Konstantinos, Shi, Ying, Shillcock, Julian C., Silberberg, Gilad, Silva, Ricardo, Tauheed, Farhan, Telefont, Martin, Toledo-Rodriguez, Maria, Tränkler, Thomas, Van Geit, Werner, Díaz, Jafet Villafranca, Walker, Richard, Wang, Yun, Zaninetta, Stefano M., DeFelipe, Javier, Hill, Sean L., Segev, Idan, and Schürmann, Felix

Abstract

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies.

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