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Multimodal single-neuron, intracranial EEG, and fMRI brain responses during movie watching in human patients.
Umit Keles, Julien Dubois, , J. Michael Tyszka, David A. Kahn, Chrystal M. Reed, Jeffrey M. Chung, Adam N. Mamelak, Ralph Adolphs, Ueli Rutishauser
Scientific Data (2024) DOI: 10.1038/s41597-024-03029-1
[Abstract] [Code] [EEG Data] [fMRI Data]
We present a multimodal dataset of intracranial recordings, fMRI, and eye tracking in 20 participants during movie watching. Recordings consist of single neurons, local field potential, and intracranial EEG activity acquired from depth electrodes targeting the amygdala, hippocampus, and medial frontal cortex implanted for monitoring of epileptic seizures. Participants watched an 8-min long excerpt from the video “Bang! You're Dead” and performed a recognition memory test for movie content. 3T fMRI activity was recorded prior to surgery in 11 of these participants while performing the same task. This NWB- and BIDS-formatted dataset includes spike times, field potential activity, behavior, eye tracking, electrode locations, demographics, and functional and structural MRI scans. For technical validation, we provide signal quality metrics, assess eye tracking quality, behavior, the tuning of cells and high-frequency broadband power field potentials to familiarity and event boundaries, and show brain-wide inter-subject correlations for fMRI. This dataset will facilitate the investigation of brain activity during movie watching, recognition memory, and the neural basis of the fMRI-BOLD signal.
Activity-induced MeCP2 phosphorylation regulates retinogeniculate synapse refinement
Christopher P. Tzeng*, Tess Whitwam*, Lisa Boxer*, Emmy Li, Andrew Silberfeld, Sara Trowbridge, , Cindy Lin, Rebecca Shamah, Eric C. Griffith, William Renthal, Chinfei Chen, Michael E. Greenberg
PNAS (2023) DOI: 10.1073/pnas.2310344120
bioRxiv (2023) DOI: 10.1101/2023.07.03.547549
Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MECP2 causes miswiring of neural circuits due to defects in the brain’s capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the mouse brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from the synapse refinement defect previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.
Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability
Gabriella L. Boulting*, Ershela Durresi*, Bulent Ataman*, Maxwell A. Sherman*, , David A. Harmin, Ava C. Carter, Daniel R. Hochbaum, Adam J. Granger, Jesse M. Engreitz, Sinisa Hrvatin, Michael R. Blanchard, Marty G. Yang, Eric C. Griffith, Michael E. Greenberg
Nature Neuroscience (2021) DOI: 10.1038/s41593-020-00786-1
Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk.
Nibbling 405 kb off the X: Viable deletion alleles eliminating 50 protein coding genes, including a chromatin factor involved in neuronal development
Gregory Minevich, Alex Bernstein, , Richard J. Poole, Oliver Hobert
microPublication Biology (2019) DOI: 10.17912/micropub.biology.000187
Evolution of Osteocrin as an activity-regulated factor in the primate brain
Bulent Ataman*, Gabriella L. Boulting*, David A. Harmin, Marty G. Yang, Mollie Baker-Salisbury, Ee-Lynn Yap, Athar N. Malik, , Alex A. Rubin, Ivo Spiegel, Ershela Durresi, Nikhil Sharma, Linda S. Hu, Mihovil Pletikos, Eric C. Griffith, Jennifer N. Partlow, Christine R. Stevens, Mazhar Adli, Maria Chahrour, Nenad Sestan, Christopher A. Walsh, Vladimir K. Berezovskii, Margaret S. Livingstone, Michael E. Greenberg
Nature 539(7628), 242-247. (2016) DOI: 10.1038/nature20111
Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.