Music-based interventions have shown promise in aiding recovery in individuals with brain damage (BD), including acquired and traumatic brain injury (ABI and TBI). To investigate the underlying molecular mechanisms, we conducted a study integrating transcriptomic and epigenomic data. We compared gene expression changes driven by musical stimuli in healthy individuals exposed to music with transcriptomic data from TBI patients, identifying 154 common differentially expressed genes (DEGs) affected in TBI and impacted by music, including STK35, HNRNPA0. These genes are notably involved in synaptic plasticity, and neurodegenerative processes. Epigenomic analysis revealed that 92 of these DEGs also exhibited significant differential methylation in TBI samples, particularly in genes associated with neurodevelopment, neuroinflammation, and mood regulation. Pathway enrichment and cross-validation in independent datasets of TBI patients highlighted the cGMP-PKG signaling pathway, a key regulator of memory and plasticity. Co-expression network analysis further revealed six gene modules significantly associated with TBI, including modules centered on TXNIP and ALG13 genes, previously implicated in neuroinflammation and epilepsy, two conditions commonly associated with TBI. Interestingly, several hub genes from these modules also showed sensitivity to musical stimuli, suggesting that music may target biologically relevant networks involved in TBI pathology. These findings reveal intriguing molecular parallels between signatures associated with TBI and the biological response to music exposure, providing a proof-of-concept for future investigation. This molecular insight suggests a potential role for music as a biologically grounded component of neurorehabilitation. However, future studies should directly assess transcriptomic and epigenomic responses to music-based interventions in BD patients.
Mathematics is a complex skill requiring the coordination of distributed gray matter brain regions connected by white matter tracts. Diffusion tensor imaging (DTI) studies have revealed a network of white matter tracts that support math processing, but the specific microstructural features driving this relationship remain unclear. Other magnetic resonance imaging (MRI) methods-neurite orientation dispersion and density imaging (NODDI), inhomogeneous magnetization transfer (ihMT), multicomponent driven-equilibrium single-pulse observation of T1 and T2 (mcDESPOT), and g-ratio imaging-can probe microstructural features like axon packing, fiber orientation, and myelin more specifically than DTI. We applied these methods alongside DTI to evaluate links between white matter microstructure and math in a longitudinal cohort of 33 6-16 year olds (66 datasets total). Partial correlations between metrics of white matter microstructure and math skill, controlling for age and gender, were carried out in the left superior longitudinal and inferior longitudinal fasciculi, corticospinal tract, and the splenium. Cross-sectionally, fiber coherence of the corticospinal tract and superior longitudinal fasciculus correlated to mathematics performance. Longitudinally, change in markers of axonal packing and myelin were linked to changes in both math skill and fluency in a regionally-specific manner, with links to myelin-sensitive metrics most prevalent. Notably, decreases in myelin were linked to improvements in mathematics over time, suggesting ongoing refinement of the math network. Findings presented here did not survive multiple comparisons corrections, but provide insight for future work elaborating upon these associations in larger samples.
Neonatal hypoxic-ischemic brain damage (HIBD) is a major cause of neurological disability. This study investigated the role of the transcription factor specificity protein 1 (SP1) and its target, Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), in regulating ferroptosis in neonatal HIBD. Using a neonatal mouse HIBD model and an in vitro neuronal oxygen-glucose deprivation/reperfusion (OGD/R) model, we applied gene knockdown/overexpression and pharmacological tools, analyzed via molecular and histological techniques. Ferroptosis was activated in HIBD. Hypoxic-ischaemic injury upregulated SP1, which transcriptionally activated ACSL4 by binding its promoter. SP1 knockdown attenuated neuronal and brain injury, reducing lipid peroxidation and iron accumulation while improving cell viability and cognitive function. These protections were abolished by ACSL4 overexpression or erastin co-treatment, and were associated with suppression of the ACSL4-dependent ferroptotic pathway. The SP1/ACSL4 axis critically aggravates neonatal hypoxic-ischaemic brain damage by promoting ferroptosis, representing a promising therapeutic target.
Microglia contribute to central nervous system homeostasis and neuroprotection partly through the release of small extracellular vesicles (sEVs) carrying regulatory cargoes such as microRNAs. Interleukin-4 (IL-4) alters microglial state and secretory output; however, whether sEVs released from IL-4-treated microglia protect neurons against toxic injury, and which cargoes mediate these effects, remains unclear. Here, we investigated the protective effects of sEVs derived from the IL-4-treated HMC3 human microglial cell line in a rotenone-induced injury model in the SH-SY5Y cell line and examined the contribution of microRNA-191-5p to neuroprotection. Small RNA sequencing revealed a distinct miRNA profile in IL-4-sEVs, with microRNA-191-5p emerging as the most statistically significant upregulated candidate. Its enrichment was confirmed by RT-qPCR. PKH67-labeled sEV-associated fluorescence was detected in SH-SY5Y cells, indicating uptake of microglia-derived sEVs by recipient cells. Functionally, pretreatment with IL-4-sEVs significantly reduced rotenone-induced cell death and preserved cell morphology compared with untreated and control sEV-treated cells. To assess the contribution of microRNA-191-5p, IL-4-sEVs were loaded with a microRNA-191-5p antagomir, which reduced microRNA-191-5p levels and partially attenuated the protective effect of IL-4-sEVs. Together, these findings suggest that sEVs derived from the IL-4-treated HMC3 microglial cell line mitigate rotenone-induced injury in the SH-SY5Y cell line in vitro and that microRNA-191-5p contributes, at least in part, to this effect.
