Stress-Induced Aberrations in the Mitochondrial Redox Environment Impact Developing Neural Circuits Supporting Cognitive Control

Conflict monitoring, decision making abilities, and emotional regulation are generally considered to be part of the cognitive control construct, which undergoes extensive refinement during adolescence and early adulthood. In parallel, individuals in this key developmental window experience increasing levels and types of stress as they mature toward functional independence in adulthood. While everyone experiences stress, there are significant individual differences and the concept of allostatic load (AL) has been used as an index of one’s chronic stress burden, which includes the psychosocial and physical demands (e.g., academic or professional pressures, family dynamics, peer relationships, physical and mental health, household socioeconomic status, etc.) that coalesce and accumulate over the lifespan. While the mechanisms whereby elevated AL leads to physiological aberrations remain poorly understood, one theorized molecular contributor is a mitochondrial-induced redox imbalance. Importantly, we first demonstrated the differential predictive abilities of mitochondrial redox environments (i.e., accumulation of reactive oxygen species (ROS) and aberrant antioxidant scavenger activity induced by mitochondrial dysfunction) on functional brain dynamics and behavioral outcomes in healthy and pathological middle-aged and older adults. The proposed project will extend this work to 15-25 year-old participants to determine whether elevated stress (i.e., AL) during this key period may affect the development of higher-order brain and cognitive function and the emergence of psychopathology. Specifically, we will leverage a novel, multidisciplinary fusion of systems biology, neurophysiology and cognitive neuroscience to comprehensively characterize the bioenergetic-neural-behavioral pathways supporting cognitive control in adolescents and young adults with varying levels of AL. Using spatiotemporally-precise magnetoencephalography (MEG) and structural MRI, we will determine the neurophysiological substrates of cognitive control and evaluate whether redox status and mitochondrial bioenergetics are predictive of age- and AL-related variations in these neural responses during this sensitive window of emerging adulthood. Cellular markers of mitochondrial respiration and redox status will be assessed using state-of-the-art techniques, including Seahorse Analyzer of real-time mitochondrial respiration, electron paramagnetic resonance spectroscopy of cellular oxidants, and antioxidant activity assays in blood samples. Finally, using advanced structural equation modeling of path dynamics, we aim to determine how alterations in the mitochondrial redox environment with elevated AL affects the neurobiological refinement of brain-behavior interactions as it pertains to domain-specific constructs of cognitive control. Taken together, these data will inform our understanding of normative and altered development trajectories using a novel, integrated, multidisciplinary approach. Project Number: 5P20GM144641-05 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Rachel Spooner | Institution: FATHER FLANAGAN'S BOYS' HOME, BOYS TOWN, NE | Award Amount: $391,933 | Activity Code: P20 | Study Section: ZGM1-RCB-W(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11522008