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

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 3

vCA1 PV-INs receive strong excitatory inputs from Sim1+ fan cells in LEC layer 2a.

Options: View larger image (or click on image) Download as PowerPoint
vCA1 PV-INs receive strong excitatory inputs from Sim1+ fan cells in LEC...
(A) Schematic of AAV injections and experimental design (left) and a representative image of TVA-EGFP and RV-DsRed expression (right). Scale bar: 100 μm. (B) Representative images of the main upstream inputs. Scale bars: 200 μm. (C) Distribution of RV-DsRed–labeled neurons. n = 5 mice. CLA, claustrum; MS, medial septal nucleus; HDB, nucleus of the horizontal limb of the diagonal band; BLA, basolateral amygdalar nucleus; dHPC, dorsal hippocampus; RSA, retrosplenial agranular cortex; RSG, retrosplenial granular cortex; LH, lateral hypothalamic; SuM, supramammillary nucleus; IPN, interpeduncular nucleus; LEC, lateral entorhinal cortex; MEC, medial entorhinal cortex. (D–F) LEC layer 2a–vCA1 PV-IN projectors are Sim1+ fan cells. (D) Schematic of AAV injections. (E) Representative images of BFP+ (blue), RV-DsRed+ (red), and Reelin+ (purple) immunofluorescence in LEC. Scale bars: 100 μm (top), 50 μm (bottom). (F) LEC neurons projecting to vCA1 PV-INs are mainly located in layer 2a (left) and are characterized by the expression of Reelin (right). n = 5. (G) Patch clamp recordings of activity of vCA1 PV-INs in brain slices upon optogenetic stimulation of LEC layer 2a–vCA1 projection (left), showing example traces evoked by blue lights in the presence of ACSF, TTX (1 μM), TTX plus 4-AP (100 μM), and NBQX (10 μM). The blue vertical bar above traces indicates photostimulation. n = 6 neurons. **P < 0.01, ***P < 0.001, repeated-measures 1-way ANOVA with Tukey’s multiple-comparison test.