Disruption of GABA-Regulated Network Resilience in Human Cerebral Organoids Leads to Fragmented Small-World States and Reduced Connectivity

Abstract

Neuronal network resilience, the ability of brain circuits to maintain and recover functional connectivity following perturbation, is fundamental to cognitive stability and adaptability. Using human cerebral organoids and multi-electrode arrays (MEAs), we investigated how mechanical stress disrupts network stability and identified key mechanisms regulating recovery. Blast overpressure exposure destabilized small-world network (SWN) organization, increasing network fragmentation and reducing overall integration. Merged SWNs, which exhibit high connectivity, were particularly vulnerable, while fragmented and single SWNs persisted for extended periods, indicating a shift toward less resilient network states. Optogenetic stimulation promoted network recovery, reducing the persistence of fragile states and facilitating transitions toward more cohesive network structures. GABAergic signaling emerged as a critical regulator of network resilience, with pharmacological inhibition exacerbating fragmentation and impairing network reorganization. These findings reveal fundamental principles of how inhibitory networks regulate circuit stability, with implications extending beyond mechanical injury to broader conditions characterized by network dysfunction, including anxiety, depression, PTSD, and neurodegenerative disorders. Understanding the mechanisms governing network adaptation and resilience could inform new therapeutic strategies aimed at stabilizing disrupted neural circuits across a range of neurological conditions. Significance statementNeuronal networks must dynamically adapt to maintain function in the face of disruption, yet the mechanisms that govern network resilience remain poorly understood. Using human cerebral organoids, we demonstrate that primary blast overpressure destabilizes small-world networks, increasing fragmentation and reducing overall connectivity. Critically, GABAergic signaling emerges as a key stabilizer, with inhibition of GABA receptors amplifying network fragmentation and impairing recovery. These findings provide fundamental insight into how neural circuits resist and recover from mechanical stress, bridging gaps between basic neuroscience, injury pathology, and potential therapeutic interventions. By identifying inhibitory signaling as a regulator of network resilience, our work informs not only traumatic brain injury treatment strategies but also broader efforts to restore functional connectivity in neurological disorders, from epilepsy to neurodegeneration.