α2δ-1-NMDAR1 complex in the hypothalamic paraventricular nucleus mediates anxiety-induced sympathetic hyperactivity

To explore changes in sympathetic nerve activity in anxiety, clarify mechanisms underlying increased sympathetic discharge, and evaluate an electrocardiogram (ECG)-derived high-frequency signal, termed skin sympathetic nerve activity (SKNA), as a potential noninvasive correlate of sympathetic outflow.

Male Sprague-Dawley rats (n = 120) were divided into control and chronic unpredictable mild stress (CUMS) groups (n = 60 each). Anxiety-like behavior was assessed using the open field test and elevated plus maze. Stellate ganglion nerve activity (SGNA) and SKNA were recorded. The relationship between SGNA and SKNA was assessed in both time and frequency domains. The NMDAR1 inhibitor AP-5, Tat-fused α2δ-1 C-terminal peptide, or control peptide were microinjected into the hypothalamic paraventricular nucleus (PVN). PVN expression of GluN1 and α2δ-1 was analyzed via qPCR, western blotting, and co-immunoprecipitation. Plasma norepinephrine (NE) and corticosterone (CORT) levels were measured by ELISA.

CUMS rats showed significant anxiety-like behaviors (reduced center time and open arm entries, p < 0.001), along with elevated SGNA and SKNA (p < 0.001). SGNA and SKNA were significantly correlated in the time domain (r = 0.538, p < 0.001) and showed strong concordance in their power spectral density (PSD) profiles, though not linear coherence. PVN GluN1 and α2δ-1 mRNA and protein levels were upregulated, with enhanced interaction. AP-5 and the Tat-fused α2δ-1 peptide normalized SGNA/SKNA in CUMS rats. No further reduction was seen when both were applied sequentially. Control peptide had no effect.

Anxiety increases sympathetic activity via upregulation of the PVN α2δ-1-NMDAR1 complex. SKNA is an ECG-derived high-frequency signal that correlates with SGNA under anesthesia and shows potential as a noninvasive index for sympathetic function in anxiety research.