Closed-loop transcranial focused ultrasound (cl-tFUS) restoring cortical alpha-beta oscillations (8-20 Hz) via somatostatin (SST) interneuron recruitment upregulates lncRNA-9969 expression in SST neurons, enhancing miR-6361 sequestration and mitochondrial biogenesis gene expression including PGC1α, TFAM, and NRF1. This circuit-RNA synergy creates a positive feedback loop: alpha-beta entrainment promotes lncRNA-9969 transcription through CREB activation in SST interneurons, while enhanced mitochondrial function reduces SST interneuron metabolic stress and calcium dysregulation, maintaining alpha-beta rhythm stability.
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Closed-loop transcranial focused ultrasound (cl-tFUS) restoring cortical alpha-beta oscillations (8-20 Hz) via somatostatin (SST) interneuron recruitment upregulates lncRNA-9969 expression in SST neurons, enhancing miR-6361 sequestration and mitochondrial biogenesis gene expression including PGC1α, TFAM, and NRF1. This circuit-RNA synergy creates a positive feedback loop: alpha-beta entrainment promotes lncRNA-9969 transcription through CREB activation in SST interneurons, while enhanced mitochondrial function reduces SST interneuron metabolic stress and calcium dysregulation, maintaining alpha-beta rhythm stability. SST interneurons, which provide dendritic inhibition and modulate synaptic integration, require robust mitochondrial function for sustained neurotransmitter release and calcium buffering. The lncRNA-9969/miR-6361 axis specifically targets mitochondrial dysfunction by sequestering microRNAs that normally suppress oxidative phosphorylation complexes and mitochondrial DNA replication machinery. Alpha-beta oscillations, critical for attention and working memory, depend on precise SST interneuron timing and metabolic capacity. Combined cl-tFUS targeting alpha-beta frequencies + targeted mitochondrial enhancer therapy could achieve durable circuit restoration by addressing the bioenergetic foundations of SST interneuron function, potentially reversing age-related cognitive decline through coordinated oscillatory and mitochondrial recovery.
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