Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells.
Ming Li, Xue-Ke Yang, Jian Yang, Tong-Xia Li, Chi Cui, Xiang Peng, Jie Lei, Kun Ren, Jie Ming, Pei Zhang, Bo Tian
Neuron September 25, 2024 DOI: 10.1016/j.neuron.2024.06.026 via PubMed
Summary
AI-generated from the abstractTraumatic memories from social defeat stress in mice are stored in engram cells of the basolateral amygdala (BLA). A single low dose of ketamine given during, but not after, a brief re-exposure to the trauma context reduces social avoidance behavior. This effect lowers both the activity and number of reactivated BLA engram cells. Dopamine projections from the ventral tegmental area to the BLA, acting through dopamine D2 receptors, can mimic or block the therapeutic effect. Single-cell RNA sequencing shows that re-exposure with ketamine alters memory-related pathways in the BLA. The findings suggest a mechanism for how ketamine may alleviate PTSD symptoms and point to potential treatments for trauma-related disorders.
Study at a glance
| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Dose | subanesthetic-dose |
| Topics | Ketamine PTSD |
| Keywords | Basolateral amygdala Dopamine d2 receptor Memory engram cells Neuroscience |
| Citations | 30 |
| Key finding | A single subanesthetic dose of ketamine given within the re-exposure time window reduces social avoidance in mice by decreasing the activity and quantity of reactivated basolateral amygdala engram cells, an effect dependent on dopamine D2 receptor signaling from the ventral tegmental area. |
Abstract
Erasing traumatic memory during memory reconsolidation is a promising retrieval-extinction strategy for post-traumatic stress disorder (PTSD). Here, we developed an acute social defeat stress (SDS) mouse model with short-term and re-exposure-evoked long-term social avoidance. SDS-associated traumatic memories were identified to be stored in basolateral amygdala (BLA) engram cells. A single intraperitoneal administration of subanesthetic-dose ketamine within, but not beyond, the re-exposure time window significantly alleviates SDS-induced social avoidance, which reduces the activity and quantity of reactivated BLA engram cells. Furthermore, activation or inhibition of dopaminergic projections from the ventral tegmental area to the BLA effectively mimics or blocks the therapeutic effect of re-exposure with ketamine and is dopamine D2 receptor dependent. Single-cell RNA sequencing reveals that re-exposure with ketamine triggered significant changes in memory-related pathways in the BLA. Together, our research advances the understanding of how ketamine mitigates PTSD symptoms and offers promising avenues for developing more effective treatments for trauma-related disorders.