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Macrophages Rapidly Seal off the Punctured Zebrafish Larval Brain through a Vital Honeycomb Network Structure.

ABSTRACT: There is accumulating evidence that macrophages play additional important roles in tissue damage besides their typical phagocytosis. Although the aggregation of macrophages on injured sites has long been observed, few researchers have focused on the role of the overall structure of macrophage aggregation. In this study, we developed a standardized traumatic brain injury (TBI) model in zebrafish larvae to mimic edema and brain tissue spillage symptoms after severe brain trauma. Using time-lapse imaging, we showed that macrophages/microglia in zebrafish larvae responded rapidly and dominated the surface of injured tissue, forming a meaningful honeycomb network structure through their compact aggregation and connection. Disrupting this structure led to fatal edema-like symptoms with severe loss of brain tissue. Using the RNA-Seq, together with the manipulation of in vitro cell lines, we found that collagen IV was indispensable to the formation of honeycomb network structures. Our study thus revealed a novel perspective regarding macrophages forming a protective compact structure with collagen IV. This honeycomb network structure acted as a physical barrier to prevent tissue loss and maintain brain homeostasis after TBI. This study may provide new evidence of macrophages' function for the rapid protection of brain tissue after brain injury.

SUBMITTER: Zou D

PROVIDER: S-EPMC9503817 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Macrophages Rapidly Seal off the Punctured Zebrafish Larval Brain through a Vital Honeycomb Network Structure.

Zou Dandan D Qin Jie J Hu Wenlong W Wei Zongfang Z Zhan Yandong Y He Yuepeng Y Zhao Congjian C Li Li L

International journal of molecular sciences 20220911 18

There is accumulating evidence that macrophages play additional important roles in tissue damage besides their typical phagocytosis. Although the aggregation of macrophages on injured sites has long been observed, few researchers have focused on the role of the overall structure of macrophage aggregation. In this study, we developed a standardized traumatic brain injury (TBI) model in zebrafish larvae to mimic edema and brain tissue spillage symptoms after severe brain trauma. Using time-lapse i ...[more]

PMID: 36142462

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Project description:IntroductionAngiopoietin 1 (angpt1) is essential for angiogenesis. However, its role in neurogenesis is largely undiscovered. This study aimed to identify the role of angpt1 in brain development, the mode of action of angpt1, and its prime targets in the zebrafish brain.MethodsWe investigated the effects of embryonic brain angiogenesis and neural development using qPCR, in situ hybridization, microangiography, retrograde labeling, and immunostaining in the angpt1sa14264, itgb1bmi371, tekhu1667 mutant fish and transgenic overexpression of angpt1 in the zebrafish larval brains.ResultsWe showed the co-localization of angpt1 with notch, delta, and nestin in the proliferation zone in the larval brain. Additionally, lack of angpt1 was associated with downregulation of TEK tyrosine kinase, endothelial (tek), and several neurogenic factors despite upregulation of integrin beta 1b (itgb1b), angpt2a, vascular endothelial growth factor aa (vegfaa), and glial markers. We further demonstrated that the targeted angpt1sa14264 and itgb1bmi371 mutant fish showed severely irregular cerebrovascular development, aberrant hindbrain patterning, expansion of the radial glial progenitors, downregulation of cell proliferation, deficiencies of dopaminergic, histaminergic, and GABAergic populations in the caudal hypothalamus. In contrast to angpt1sa14264 and itgb1bmi371 mutants, the tekhu1667 mutant fish regularly grew with no apparent phenotypes. Notably, the neural-specific angpt1 overexpression driven by the elavl3 (HuC) promoter significantly increased cell proliferation and neuronal progenitor cells but decreased GABAergic neurons, and this neurogenic activity was independent of its typical receptor tek.DiscussionOur results prove that angpt1 and itgb1b, besides regulating vascular development, act as a neurogenic factor via notch and wnt signaling pathways in the neural proliferation zone in the developing brain, indicating a novel role of dual regulation of angpt1 in embryonic neurogenesis that supports the concept of angiopoietin-based therapeutics in neurological disorders.

Project description:Animals engaged in naturalistic behavior can exhibit a large degree of behavioral variability even under sensory invariant conditions. Such behavioral variability can include not only variations of the same behavior, but also variability across qualitatively different behaviors driven by divergent cognitive states, such as fight-or-flight decisions. However, the neural circuit mechanisms that generate such divergent behaviors across trials are not well understood. To investigate this question, here we studied the visual-evoked responses of larval zebrafish to moving objects of various sizes, which we found exhibited highly variable and divergent responses across repetitions of the same stimulus. Given that the neuronal circuits underlying such behaviors span sensory, motor, and other brain areas, we built a novel Fourier light field microscope which enables high-resolution, whole-brain imaging of larval zebrafish during behavior. This enabled us to screen for neural loci which exhibited activity patterns correlated with behavioral variability. We found that despite the highly variable activity of single neurons, visual stimuli were robustly encoded at the population level, and the visual-encoding dimensions of neural activity did not explain behavioral variability. This robustness despite apparent single neuron variability was due to the multi-dimensional geometry of the neuronal population dynamics: almost all neural dimensions that were variable across individual trials, i.e. the "noise" modes, were orthogonal to those encoding for sensory information. Investigating this neuronal variability further, we identified two sparsely-distributed, brain-wide neuronal populations whose pre-motor activity predicted whether the larva would respond to a stimulus and, if so, which direction it would turn on a single-trial level. These populations predicted single-trial behavior seconds before stimulus onset, indicating they encoded time-varying internal modulating behavior, perhaps organizing behavior over longer timescales or enabling flexible behavior routines dependent on the animal's internal state. Our results provide the first whole-brain confirmation that sensory, motor, and internal variables are encoded in a highly mixed fashion throughout the brain and demonstrate that de-mixing each of these components at the neuronal population level is critical to understanding the mechanisms underlying the brain's remarkable flexibility and robustness.

Dataset Information

Macrophages Rapidly Seal off the Punctured Zebrafish Larval Brain through a Vital Honeycomb Network Structure.

Publications

Macrophages Rapidly Seal off the Punctured Zebrafish Larval Brain through a Vital Honeycomb Network Structure.

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