Hypoxia increases neural proliferation, alters vascular structure, and reprograms the transcriptome and proteome of the speckled sanddab brain

Abstract

Hypoxia (low oxygen availability) is a common environmental stressor in estuarine ecosystems that negatively affects fish survival as well as physiological and behavioral responses. However, the effects of hypoxia on the brain remains poorly understood, particularly in non-model species. Here, we investigated how prolonged hypoxia influences neural, vascular, and molecular responses in the brain of the speckled sanddab (Citharichthys stigmaeus), an ecologically relevant estuarine flatfish. Fish were exposed to normoxic or hypoxic conditions for seven days, and responses were assessed using histological analyses of neural proliferation and vascular structure, alongside transcriptomic and proteomic profiling. Hypoxia increased neural cell proliferation and progenitor activation in the hypothalamic nucleus recessus lateralis (NRL) and optic tectum, while reducing survival of newly generated cells. At the tissue level, hypoxia induced region-specific vascular remodeling, characterized by increased vessel area and vessel number without evidence of widespread endothelial proliferation. At the molecular level, transcriptomic and proteomic analyses revealed consistent enrichment of biological processes related to stress responses, development, metabolism, and cellular homeostasis, despite limited overlap between individual genes and proteins. Gene- and protein-level analyses further indicated activation of hypoxia-responsive pathways, including HIF signaling and oxidative stress protection, alongside selective metabolic reprogramming. Together, these findings demonstrate that hypoxia induces multi-level changes in the brain, linking neural plasticity, vascular remodeling, and molecular responses. This integrated response likely supports brain function under reduced oxygen availability in dynamic estuarine environments and highlights the role of the brain in regulating responses to environmental stress.