Abstract
Anxiety is reportedly one of the most common mental changes after traumatic brain injury (TBI). Perineuronal nets (PNNs) produced by astrocytes in the lateral hypothalamus (LHA) that surround gamma-aminobutyric acid-ergic (GABAergic) neurons have been associated with anxiety. The potent anti-tumor effects of Spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma; moreover, the inhibition of autophagy is reported to mitigate anxiety disorders. However, little is known about the ability of spautin-1 to alleviate anxiety. In this study, we sought to investigate whether spautin-1 could alleviate anxiety-like behaviors post-TBI by reducing the loss of PNNs in the LHA. A mild TBI was established in mice through Feeney’s weight-drop model. Then, Spautin-1 (20 mmol/2 μl) was immediately administered into the left lateral ventricle. Behavioral and pathological changes were assessed at 24 h, 7 days, 30 days, 31 days and 32 days after TBI by the neurological severity scores (NSS), open field test (OFT), elevated plus-maze (EPM) test, western blot, immunofluorescence assays and electron microscopy. Spautin-1 significantly reversed TBI-induced decreased time in the central zone during OFT and in the open-arm during the EPM test. Spautin-1 also increased PNNs around GABAergic neurons indicated by WFA- plus GAD2- positive A2-type astrocytes and attenuated M1-type microglia in the LHA 32 days after TBI compared to TBI alone. Moreover, compared to mice that only underwent TBI, spautin-1 downregulated autophagic vacuoles, abnormal organelles, the expression of Beclin 1, USP13, phospho-TBK1, and phospho-IRF3 and upregulated the levels of cleaved caspase-3, -7 and -9, but failed to increase TUNEL-positive cells in the LHA at 24 h. Spautin-1 alleviated anxiety-like behavior in mice exposed to mild TBI; this protective mechanism may be associated with decreased PNNs loss around GABAergic neurons via immunologically silent apoptosis induced by the caspase cascade.
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Acknowledgements
This study was supported by the National Natural Science foundation of China (No. 81701296, 82171455), and Natural Science foundation of Hebei Province (No. H2021110004).
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This study was supported by Natural Science foundation of Hebei Province, H2021110004, National Natural Science Foundation of China, 81701296, National Natural Science foundation of China, 82171455.
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Design of the study: L-MZ. Editing the manuscript: L-MZ, R-XS, H-TM. Statistical analysis: L-MZ, D-XZ. Experiment and data collection: H-TM, R-XS, YX, L-YW, J-ML, N-NL, Z-YW, WZ, YL. All authors read and approved the final manuscript.
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12017_2023_8737_MOESM2_ESM.tif
Supplementary file2 (TIF 664 KB)—Representative images of shift trajectories of each group in the open field test on day 30 after mild TBI. (A) Representative images of shift trajectories of each group in the open field test on day 30 after mild TBI. (B–D) Average speed, number of crossing grids, percentage of center time of each group on day 30 after mild TBI. (E) Representative images of shift trajectories of each group in the elevated plus maze test on day 31 after mild TBI. (F–G) Percentage of entries into the open-arm and percentage of open-arm time of each group on day 31 after mild TBI. Data are presented as the mean ± SD (n =12 per group). ****P <0.0001, ***P <0.001, **P <0.01, *P <0.05.
12017_2023_8737_MOESM5_ESM.tif
Supplementary file5 (TIF 2739 KB)—Representative images of Nissl staining of each group. (A) Representative images of Nissl staining of each group. scale bar =250 μm or 100 μm. (B) The lesion volume of each group. (C) The number of Nissl bodies in each group. ****P <0.0001.
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Miao, HT., Song, RX., Xin, Y. et al. Spautin-1 Protects Against Mild TBI-Induced Anxiety-Like Behavior in Mice via Immunologically Silent Apoptosis. Neuromol Med 25, 336–349 (2023). https://doi.org/10.1007/s12017-023-08737-2
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DOI: https://doi.org/10.1007/s12017-023-08737-2