Fig. 4: Bi-directional regulation of mPFC hyperexcitability by tonic versus phasic nRE stimulation under anesthesia in fAD model.

a Schematic depiction of the mPFC–nRE–HPC circuit connectivity: The HPC directly connects to the mPFC, with no direct projections from the mPFC to the HPC. The nRE serves as the critical link, forming the HPC–mPFC loop: HPC→mPFC→nRE→HPC. b Representative traces show IESs in simultaneous LFP recordings from CA1 stratum radiatum (top) and mPFC (bottom). Scale bars: 0.5 mV, 10 s. c Fraction of CA1 IESs within 100 ms of an mPFC-IES in APP/PS1 mice. d Cross-correlation between mPFC-IES and CA1-IES times in a single mouse. Top, raster plot of mPFC-IESs within 100 ms of CA1-IESs. Bottom, peri-CA1-IES time histogram. e Calculation of the mPFC-IES rate for the same mouse, focusing on various bin sizes around CA1 spikes. Grey lines represent rates from 1000 jittered mPFC spike trains (see methods). f Summary data from each mouse illustrating the mPFC-IES rate in different bin sizes around CA1-IESs. Significant values are marked in red, while insignificant ones are in grey. X-values are jittered for clarity. g Correlation between the mPFC-IES rate and the CA1-IES rate in the same mice during the same GA session (Spearman r = 0.53, P = 0.037, n = 16; 13 males, 3 females). h Inverse correlation of the mPFC-IES rate with spatial working memory after GA, normalized to baseline success rate, in the 90 seconds delay (Spearman r = −0.61, P = 0.049, n = 11 males). i The effect of tDBS and pDBS of the nRE on the mPFC-IES rate during GA (P < 0.0001, One-way ANOVA with Sidak’s multiple comparison tests: Sham vs Tonic P = 0.0051, Sham vs Phasic P = 0.0009, n = 7, 5, and 4 for Sham, tDBS, and pDBS, male/female ratio: 5/2, 4/1, 3/1, respectively). Error bars represent SEM; ns non-significant, *P < 0.05, **P < 0.01, ****P < 0.0001. P-values of (e, f) are in the source file.