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Abstract Mitochondrial abnormalities underscore a variety of neurologic injuries and diseases and are well-studied in adult populations. Clinical studies identify critical roles of mitochondria in a wide range of developmental brain injuries, but models that capture mitochondrial abnormalities in systems representative of the neonatal brain environment are lacking. Here, we develop an organotypic whole-hemisphere (OWH) brain slice model of mitochondrial dysfunction in the neonatal brain. We extended the utility of complex I inhibitor rotenone (ROT), canonically used in models of adult neurodegenerative diseases, to inflict mitochondrial damage in OWH slices from term-equivalent rats. We quantified whole-slice health over 6 days of exposure for a range of doses represented in ROT literature. We identified 50 nM ROT as a suitable exposure level for OWH slices to inflict injury without compromising viability. At the selected exposure level, we confirmed exposure- and time-dependent mitochondrial responses showing differences in mitochondrial fluorescence and nuclear localization using MitoTracker imaging in live OWH slices and dysregulated mitochondrial markers via RT-qPCR screening. We leveraged the regional structures present in OWH slices to quantify cell density and cell death in the cortex and the midbrain regions, observing higher susceptibilities to damage in the midbrain as a function of exposure and culture time. We supplemented these findings with analysis of microglia and mature neurons showing time-, region-, and exposure-dependent differences in microglial responses. We demonstrated changes in tissue microstructure as a function of region, culture time, and exposure level using live-video epifluorescence microscopy of extracellularly diffusing nanoparticle probes in live OWH slices. Our results highlight severity-, time-, and region-dependent responses and establish a complimentary model system of mitochondrial abnormalities for high-throughput or live-tissue experimental needs.
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This content will become publicly available on September 17, 2026
Structural Regeneration and Functional Recovery of the Olfactory System of Adult Zebrafish Following Brain Injury
Olfactory dysfunction is a common outcome of brain injuries, negatively affecting quality of life. The adult mammalian nervous system has limited capacity for olfactory recovery, making it challenging to study olfactory regeneration and recovery. In contrast, zebrafish are ideal for such studies due to its extensive and lifelong regenerative abilities. In this work, we describe a model of excitotoxic injury in the olfactory bulb (OB) using quinolinic acid lesions in adult zebrafish of both sexes. We observed extensive neurodegeneration in both the OB and olfactory epithelium, including a reduction of bulbar volume, neuronal death, and impaired olfactory function. Recovery mechanisms involved tissue remodeling, cell proliferation, and neurogenesis, leading to full restoration of olfactory function by 21 d. This study provides a model to further investigate the effects of excitotoxicity on olfactory dysfunction and highlights zebrafish's remarkable regenerative abilities, providing insights into potential therapeutic strategies for restoring olfactory function following brain injuries.
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- PAR ID:
- 10641732
- Publisher / Repository:
- Journal of Neuroscience
- Date Published:
- Journal Name:
- The journal of neuroscience
- ISSN:
- 1529-2401
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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