Concussive Injury in Human Forebrain Organoids Alters Neurogenesis and Neuroimmune Signaling
Year: 2026
Type: preprint
Abstract: Traumatic brain injury (TBI) is a major cause of long-term neurological disability, yet the mechanisms underlying human-specific injury responses remain poorly understood. Rodent models of TBI have yielded significant insights into mechanisms and pathophysiology of TBI but may not capture human-specific developmental and molecular responses. Here, we establish a human forebrain organoid (hFBO) injury paradigm to examine developmental stage and region-specific responses to concussive injury. Dorsal and ventral hFBOs, enriched in glutamatergic and GABAergic neurons, respectively, showed progressive physiological maturation with rudimentary firing characteristics at 80 days in vitro (DIV) and spontaneous synaptic activity by 150 DIV. Injury to dorsal and ventral hFBOs at 25 DIV, when neural progenitors dominate, caused cell death that scaled with severity and increased expression of neural proliferation markers and TLR4/NF-κB associated neuroimmune signaling. Injury to physiologically mature organoids at 150 DIV produced severity-dependent acute intracellular calcium dysregulation. Together, these findings establish a human organoid-based platform that captures developmental stage-dependent neurogenic, molecular, and cellular dysfunction in responses to concussive injury.
Institution: University of California, Riverside
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: microRNA tuning of neural crest osteogenesis, Inhibitory Network Plasticity in Neurological Disease, next-generation sequencing approaches to identify genotype-phenotype relationships during miRNA tuning of neural crest osteogenesis, Contribution of Innate Immune Receptors to Neurological Dysfunction After Traumatic Brain Injury: Mechanisms and Therapeutic Implications, Research Training in Environmental Toxicology
OpenAlex ID: W7224759844