This hypothesis proposes that lncRNA-9969, when upregulated by CREB1 activation in parvalbumin (PV) interneurons, employs a sophisticated two-factor recognition mechanism to selectively sequester miR-6361 and enhance autophagy. The mechanism operates through canonical seed complementarity paired with favorable local RNA secondary structures that distinguish miR-6361 from other seed-sharing microRNAs. Upon gamma oscillation entrainment via transcranial focused ultrasound, PV interneurons undergo calcium influx leading to CREB1 phosphorylation at Ser133. This drives transcriptional upregulation of lncRNA-9969, which contains multiple miR-6361 binding sites characterized by both perfect seed complementarity and specific hairpin loop structures that create high-affinity binding pockets. The dual recognition system explains why lncRNA-9969 can function as an effective competing endogenous RNA (ceRNA) despite the presence of other microRNAs with overlapping seed sequences. Importantly, the local secondary structure requirement ensures that only miR-6361, among seed-sharing candidates, achieves sufficient binding affinity to be sequestered effectively.

This hypothesis proposes that lncRNA-9969, when upregulated by CREB1 activation in parvalbumin (PV) interneurons, employs a sophisticated two-factor recognition mechanism to selectively sequester miR-6361 and enhance autophagy. The mechanism operates through canonical seed complementarity paired with favorable local RNA secondary structures that distinguish miR-6361 from other seed-sharing microRNAs. Upon gamma oscillation entrainment via transcranial focused ultrasound, PV interneurons undergo calcium influx leading to CREB1 phosphorylation at Ser133. This drives transcriptional upregulation of lncRNA-9969, which contains multiple miR-6361 binding sites characterized by both perfect seed complementarity and specific hairpin loop structures that create high-affinity binding pockets. The dual recognition system explains why lncRNA-9969 can function as an effective competing endogenous RNA (ceRNA) despite the presence of other microRNAs with overlapping seed sequences. Importantly, the local secondary structure requirement ensures that only miR-6361, among seed-sharing candidates, achieves sufficient binding affinity to be sequestered effectively. This selective binding liberates autophagy-related transcripts (ATG5, ATG7, BECN1, LC3B) from miR-6361-mediated suppression specifically in PV interneurons, creating a circuit-specific neuroprotective response. The hypothesis predicts that mutations disrupting either the seed complementarity or the local RNA structure will abolish the therapeutic effect, while preserving both elements maintains selective miR-6361 sequestration and enhanced autophagy in the gamma oscillation network.