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 Therapeutics

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 1

Fear extinction recruits low-gamma oscillatory synchrony between the LEC and vCA1.

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Fear extinction recruits low-gamma oscillatory synchrony between the LEC...
(A) Schematics of electrode implantation and experimental design for mice subject to fear conditioning (context A) and extinction training (context B). (B) Left: Time courses of freezing responses to the CS during fear conditioning and extinction training. Right: Freezing responses to the CS during early extinction training (CS1–4, referred to as Early-Ext.) and late extinction training (CS17–20, referred to as Late-Ext.). Data are mean ± SEM. n = 5 mice. **P < 0.01. (C) Representative images showing electrode placements. Scale bars: 200 μm. (D) Representative traces of LFP recordings. (E) Representative spectrograms of LFP recorded in vCA1 during Baseline (left), Early-Ext. (middle), and Late-Ext. (right) sessions. Zero to thirty seconds represents the tone given during extinction training. (F) Power spectrum of vCA1 LFP during Baseline, Early-Ext., and Late Ext. Solid lines represent averages and shaded areas indicate SEM. (G) Average power of vCA1 LFP during Baseline, Early-Ext., and Late Ext. Data are mean ± SEM. n = 5. *P < 0.05. (H) Linear regression of freezing responses versus vCA1 low-gamma power during Early-Ext. and Late Ext. sessions. (I) Examples of low-gamma-frequency filtered LEC and vCA1 LFP recordings recorded during Baseline, Early-Ext., and Late Ext. sessions. (J) Phase synchrony for LEC-vCA1 LFPs in the Baseline, Early-Ext., and Late-Ext. sessions, respectively. Inset shows different phase synchrony quantified using the weighted phase lag index (wPLI) between LEC and vCA1 LFPs. Data are mean ± SEM. n = 5. *P < 0.05. (K and L) The same as I and J for MEC-vCA1 LFPs and wPLI. n = 5. *P < 0.05. Paired Student’s t test (B) and repeated-measures 1-way ANOVA with Tukey’s multiple-comparison test (G, J, and L).