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.
View: Text | PDF
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

×

Figure 4

Direct projection from LEC Sim1+ layer 2a fan cells to vCA1 PV-INs mediates fear extinction.

Options: View larger image (or click on image) Download as PowerPoint
Direct projection from LEC Sim1+ layer 2a fan cells to vCA1 PV-INs media...
(A) Schematic of AAV injections and experimental design (left) and representative image of mCherry expression (right). CNO was administered (i.p.) 30 minutes before extinction training. Scale bar: 200 μm. (B) Representative images of PV+ (purple) and c-Fos+ (green) immunofluorescence. White arrowheads denote colabeled cells. Scale bar: 100 μm. (C) Quantification for B. n = 5 mice per group. (D–F) Ca2+ recording of the LEC-vCA1 pathway during extinction. (D) Schematic of AAV injections and fiber implantation (left), with representative images of GCaMP6s expression (right). Scale bar: 200 μm. (E) Average calcium signals during Early-Ext. and Late-Ext. (F) Activity of Ca2+ signals (AUC) during Early-Ext. and Late-Ext. Data are mean ± SEM. n = 6 mice. (G and H) Effects of stimulating LEC layer 2a→vCA1 projection (G) and inhibiting LEC→vCA1 PV-IN projection (H) on extinction. Left: Schematic of AAV injections. Right: Time courses of freezing responses to the CS. Statistics are as follows: Main effect of AAV: (G) Conditioning, F1,17 = 1.157, P = 0.2971; extinction training, F1,17 = 8.686, P = 0.0090; extinction retrieval, F1,17 = 9.781, P = 0.0061. EGFP group, n = 10 mice; hM3Dq group, n = 9 mice. (H) Conditioning, F1,14 = 0.1024, P = 0.7537; extinction training, F1,14 = 14.23, P = 0.0021; extinction retrieval, F1,14 = 12.46, P = 0.0033. EYFP group, n = 8 mice; hM4Di group, n = 8 mice. Data are mean ± SEM. **P < 0.01, ***P < 0.001. Unpaired Student’s t test (C), paired Student’s t test (F), and repeated-measures 2-way ANOVA (G and H).