Stimulation of an entorhinal-hippocampal extinction circuit facilitates fear extinction in a post-traumatic stress disorder model
Ze-Jie Lin, … , Wei-Guang Li, Tian-Le Xu
Ze-Jie Lin, … , Wei-Guang Li, Tian-Le Xu
Published September 24, 2024
Citation Information: J Clin Invest. 2024;134(22):e181095. https://doi.org/10.1172/JCI181095.
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Research Article Neuroscience

Stimulation of an entorhinal-hippocampal extinction circuit facilitates fear extinction in a post-traumatic stress disorder model

Abstract

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging owing to the fragile nature of fear extinction, for which the ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low-gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells sufficed for fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhanced the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low-gamma-band oscillations that facilitate fear extinction. Finally, application of low-gamma DBS and tACS to a mouse model with persistent PTSD showed potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be stimulated for therapy to remove traumatic memory trace.

Authors

Ze-Jie Lin, Xue Gu, Wan-Kun Gong, Mo Wang, Yan-Jiao Wu, Qi Wang, Xin-Rong Wu, Xin-Yu Zhao, Michael X. Zhu, Lu-Yang Wang, Quanying Liu, Ti-Fei Yuan, Wei-Guang Li, Tian-Le Xu

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Figure 8

Low-gamma DBS strengthens the inputs from LEC driving PV IN–mediated feedforward inhibition in vCA1 and induces long-lasting suppression of fear-tagged neurons.

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Low-gamma DBS strengthens the inputs from LEC driving PV IN–mediated fee...
(A) Schematic of experimental design. CS is paired with 40 Hz DBS during extinction training, and CNO was administered (i.p.) 30 minutes before extinction training. (B) Schematic of AAV injections (top) and representative images of virus expression (bottom). Scale bars: 200 μm. (C) Effect of inhibiting LEC-vCA1 projectors on DBS-induced extinction promotion. Time courses of freezing responses to the CS during fear conditioning, extinction training, and extinction retrieval sessions. Statistics are as follows: Main effect of AAV, conditioning, F1,21 = 0.4901, P = 0.4916; extinction training, F1,21 = 8.408, P = 0.0086; extinction retrieval, F1,21 = 7.556, P = 0.0120. mCherry group, n = 12 mice; hM4Di group, n = 11 mice. Data are mean ± SEM. *P < 0.05, **P < 0.01. (D) Schematic of AAV injections and experimental design. 4-OHT was administered 30 minutes before fear conditioning. (E) Experimental scheme for simultaneous recording of light-evoked EPSCs and IPSCs on vCA1 fear-tagged neurons. (F) Representative traces of EPSCs and IPSCs evoked by optogenetic stimulation of LEC fibers. (G) IPSC/EPSC peak ratios (No DBS, n = 10 cells; DBS, n = 11 cells). Data are mean ± SEM. **P < 0.01. (H) Representative traces showing that light-evoked IPSC amplitudes were reduced with application of 0.5 μM ω-agatoxin IVA. (I) Light-evoked IPSC amplitudes in vCA1 fear-tagged neurons with and without ω-agatoxin IVA (n = 5 cells). Data are mean ± SEM. **P < 0.01. Repeated-measures 2-way ANOVA (C), unpaired Student’s t test (G), and paired Student’s t test (I).