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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Dose | subanesthetic-dose |
| Topics | Ketamine PTSD Esketamine |
| Keywords | Basolateral amygdala Dopamine d2 receptor Memory engram cells Trauma Therapy PTSD Psychopharmacology ketamine Drugs Medication Recall Fear memory Brain anatomy basolateral |
| Citations | 30 |
| Key findings | 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.
Comparable studies
Other preclinical and animal studies on ketamine for PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Molecular signatures of astrocytes and microglia maladaptive responses to acute stress are rescued by a single administration of ketamine in a rodent model of PTSD. Rats | 2024 | Animal study | |
| Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents | 2024 | Review | |
| Ketamine alleviates PTSD-like effect and improves hippocampal synaptic plasticity via regulation of GSK-3β/GR signaling of rats. Single prolonged stress-induced PTSD rat model | 2024 | Animal study | |
| (2R, 6R)-hydroxynorketamine ameliorates PTSD-like behaviors during the reconsolidation phase of fear memory in rats by modulating the VGF/BDNF/GluA1 signaling pathway in the hippocampus. Rats (single prolonged stress and contextual fear conditioning models) | 2025 | Animal study | |
| Esketamine attenuates post-traumatic stress disorder via suppressing neuroinflammation and abnormal myelination. Mice | 2025 | Animal experimental study |
Citations in the library
Cited by 7
- Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD. Psychopharmacology June 1, 2025
- Effects of ketamine on fear memory extinction: a review of preclinical literature. Frontiers in Neuroscience 2025
- Combining DNA methylation features and clinical characteristics predicts ketamine treatment response for PTSD. iScience January 16, 2026
- Time‐Dependent Therapeutic Effect of S ‐Ketamine on PTSD Mediated by VTA‐OFC Dopaminergic Neurocircuit Advanced Science September 25, 2025
- Ketamine Reduces Avoidance Responses During Re-Exposition to Aversive Stimulus: Comparison Between (S)-Isomer and Racemic Mixture. Brain Sciences December 22, 2024
and 2 more in the library
Cites 7
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis American Journal of Psychiatry October 3, 2017
- A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. American Journal of Psychiatry January 5, 2021
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacology January 2024
and 2 more in the library