Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Zeng, Hui; Zhao, Shichao; Zhao, Ping; Wang, Shiqi; Cao, Luxi; Zhang, Yimin

doi:10.31083/j.jin2202044

Cited by 5 publications

(3 citation statements)

References 122 publications

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“…Each of the 7 pathways identified in mecp2 mutant ze-brafish have also been reported in studies of Mecp2-deficient mouse models and/or patients with RTT (see Table 1 for citations). GSEA is a computational method that assesses whether a set of genes, defined by a biological pathway or a functional category, is enriched at the top or bottom of a ranked list of genes (44). We performed GSEA on the expression data and identified 14 molecular pathways that were activated and 26 that were suppressed (Fig.…”

Section: Resultsmentioning

confidence: 99%

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Santistevan,

Ford,

Gilsdorf

et al. 2023

Preprint

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Rett Syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5-7 days post-fertilization (dpf). We show that zebrafish mecp2 function is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.

show abstract

Section: Resultsmentioning

confidence: 99%

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Santistevan,

Ford,

Gilsdorf

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…TBI also upregulates and activates MAPKs ( Zeng et al, 2023 ). ERK and p38 MAPKs and protein kinase C (PKC) activation were involved in N/OFQ-mediated vasoconstrictive actions in the parietal cortex post-FPI TBI ( Armstead, 2003 ; Philip and Armstead, 2003 ; Ross and Armstead, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, further studies are needed to explore the effect of systemic administration of NOP receptor antagonists on cerebrovascular dysregulation post-TBI. TBI also upregulates and activates MAPKs (Zeng et al, 2023). ERK and p38 MAPKs and protein kinase C (PKC) activation were involved in N/OFQ-mediated vasoconstrictive actions in the parietal cortex post-FPI TBI (Armstead, 2003;Philip and Armstead, 2003;Ross and Armstead, 2005).…”

Section: Discussionmentioning

confidence: 99%

The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury

Al Yacoub,

Tarantini,

Zhang

et al. 2023

Front. Pharmacol.

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Traumatic brain injury (TBI) affects more than 2.5 million people in the U.S. each year and is the leading cause of death and disability in children and adults ages 1 to 44. Approximately 90% of TBI cases are classified as mild but may still lead to acute detrimental effects such as impaired cerebral blood flow (CBF) that result in prolonged impacts on brain function and quality of life in up to 15% of patients. We previously reported that nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonism reversed mild blast TBI-induced vestibulomotor deficits and prevented hypoxia. To explore mechanisms by which the NOP receptor-N/OFQ pathway modulates hypoxia and other TBI sequelae, the ability of the NOP antagonist, SB-612111 (SB), to reverse TBI-induced CBF and associated injury marker changes were tested in this study. Male Wistar rats randomly received sham craniotomy or craniotomy + TBI via controlled cortical impact. Injury severity was assessed after 1 h (modified neurological severity score (mNSS). Changes in CBF were assessed 2 h post-injury above the exposed cortex using laser speckle contrast imaging in response to the direct application of increasing concentrations of vehicle or SB (1, 10, and 100 µM) to the brain surface. TBI increased mNSS scores compared to baseline and confirmed mild TBI (mTBI) severity. CBF was significantly impaired on the ipsilateral side of the brain following mTBI, compared to contralateral side and to sham rats. SB dose-dependently improved CBF on the ipsilateral side after mTBI compared to SB effects on the respective ipsilateral side of sham rats but had no effect on contralateral CBF or in uninjured rats. N/OFQ levels increased in the cerebral spinal fluid (CSF) following mTBI, which correlated with the percent decrease in ipsilateral CBF. TBI also activated ERK and cofilin within 3 h post-TBI; ERK activation correlated with increased CSF N/OFQ. In conclusion, this study reveals a significant contribution of the N/OFQ-NOP receptor system to TBI-induced dysregulation of cerebral vasculature and suggests that the NOP receptor should be considered as a potential therapeutic target for TBI.

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Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Santistevan,

Ford,

Gilsdorf

et al. 2024

American J of Med Genetics Pt B

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Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl‐CpG‐binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus‐evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5 to 7 days post‐fertilization (dpf). We show that zebrafish mecp2 function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA‐seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.

show abstract

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Cited by 5 publications

References 122 publications

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

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