TREM2 contributes to central sensitization through PI3K/Akt/mTOR-mediated autophagic dysfunction in a rat model of vestibular migraine

Vestibular migraine (VM) is a disabling neurological disorder where neuroinflammation and central sensitization constitute the core pathological mechanisms. Physiological levels of autophagy help maintain cellular homeostasis and regulate neuroinflammation, whereas autophagic dysfunction is closely associated with exacerbated neuroinflammatory responses. Although accumulating evidence has confirmed the presence of robust autophagic dysfunction in VM, the specific role of triggering receptor expressed on myeloid cells 2 (TREM2), a key microglial receptor, in this process remains to be elucidated. A rat model of VM was established via the intraperitoneal injection of nitroglycerin (NTG) combined with variable-speed rotation. To investigate the role of the TREM2/PI3K/Akt/mTOR pathway, we intraperitoneally administered a specific TREM2 inhibitor, a TREM2 agonist, and the mTOR inhibitor rapamycin to SD rats 30 min before each nitroglycerin (NTG) injection. To investigate the role of the TREM2/PI3K/Akt/mTOR pathway, we intraperitoneally administered a specific TREM2 inhibitor, a specific TREM2 agonist, and the mTOR inhibitor rapamycin separately to SD rats 30 min before each intraperitoneal nitroglycerin (NTG) injection. After modeling, pain sensitivity and vestibular function were evaluated. Mechanical pain threshold was measured using the von Frey test, thermal pain sensitivity by the tail-flick test, and vestibular function was assessed with the beam balance test and motion sickness index (MSI). Western blot and immunofluorescence assays were then performed to quantify the expression of TREM2, as well as autophagy-related, neuroinflammation-related, and central sensitization-related proteins in the trigeminocervical complex (TCC) and vestibular nuclei (VN). Meanwhile, microglial number and morphological alterations were analyzed to comprehensively characterize the status of autophagy, neuroinflammation, and central sensitization. In a rat model of VM, immunofluorescence staining confirmed clear co-localization of TREM2 with both neurons and microglia in the TCC and VN, with significantly upregulated TREM2 expression observed in these two nuclei. Notably, this TREM2 upregulation coincided with autophagic dysfunction, Nod-like receptor protein 3 (NLRP3) inflammasome activation, elevated expression of central sensitization markers, as well as microglial activation and proliferation. In vivo functional experiments further confirmed that TREM2 agonist intervention significantly exacerbated autophagic impairment, neuroinflammatory cascades, and central sensitization in the TCC and VN, accompanied by aggravated hyperalgesia and vestibular dysfunction in VM rats. Conversely, targeted inhibition of TREM2 or autophagy activation effectively reversed these molecular and cellular pathological alterations, and significantly alleviated hyperalgesia and vestibular impairment in VM rats. This study demonstrates that TREM2 drives neuroinflammation and central sensitization in VM via PI3K/Akt/mTOR-mediated autophagy inhibition. Targeting TREM2 or restoring autophagy effectively alleviates VM-related phenotypes, offering potential therapeutic strategies for VM and related neuroinflammatory disorders.