Source: Dingxiang Academic
The TV series “The Story of Roses” is currently popular. The inspirational life and painful experiences of the protagonist Su Gengsheng leave a deep impression on people. Being sexually abused by her stepfather in her childhood caused her to live in the shadows for the rest of her life, which is actually a common psychological disorder. In real life, about 9% of the population may experience PTSD (Post-Traumatic Stress Disorder) in their lifetime, which is a psychological health problem triggered by traumatic events. This disorder may occur after experiencing life-threatening events, serious injuries, sexual violence, or witnessing others being harmed. PTSD is a type of anxiety disorder where individuals may repeatedly recall the traumatic event through flashbacks, nightmares, or other disturbing psychological and physical experiences. People who experience PTSD may have persistent negative thoughts about the traumatic event, emotional numbness, or loss of interest in activities they once enjoyed. PTSD can have profound effects on individuals’ daily lives, work, and relationships.
On July 19, 2024, Professor Tian Bo and his team from Tongji Medical College, Huazhong University of Science and Technology, published a study in the top journal Neuron of neurobiology. They have developed for the first time an acute social defeat stress (SDS) mouse model. Traumatic memories related to SDS were identified to be stored in the basolateral amygdala (BLA), known as “engram cells” within a cluster of neurons. Administration of a low dose of ketamine via a single intraperitoneal injection to SDS mice within a specific time window significantly alleviated SDS-induced social avoidance, reduced the activity and number of reactivated memory engram cells in BLA. This study enhances our understanding of how ketamine mitigates PTSD symptoms, emphasizing the potential of combining ketamine with cognitive behavioral therapy to enhance PTSD treatment and providing a promising avenue for the development of more effective treatment methods!
Figure 1. Related study (Image source: Neuron)
1. Ketamine functions by reducing the activity and number of BLA engram cells
The authors first used the SDS mouse model of acute social defeat stress, which features short-term and long-term social avoidance induced by re-exposure, simulating short-term and long-term social avoidance behaviors. Through three-chamber social interaction tests and social preference-avoidance tests, mice treated with ketamine exhibited a significant reduction in social avoidance behavior in behavioral tests. Administering a low dose of ketamine immediately after re-exposure revealed that ketamine must be given within 6 hours post-re-exposure to effectively attenuate social avoidance behavior; administering ketamine beyond this time window showed less significant effects. By using optogenetic and chemogenetic techniques to activate or inhibit engram cells in the BLA region labeled with SDS, and monitoring the activity of BLA engram cells through in vivo fiber photometry, it was found that the activity and number of these cells significantly decreased after ketamine treatment. These results collectively indicate that ketamine functions by reducing the activity and number of BLA engram cells, which are reactivated during memory reconsolidation, and the intervention effects of ketamine depend on a specific time window.
Figure 2. Ketamine reduces neuronal activity and the number of reactivated BLA engram cells (Image source: Neuron)
2. The therapeutic effects of ketamine depend on dopamine D2 receptors in the BLA
Through in vivo electrophysiological recording techniques, researchers found a significant increase in the firing rate of ventral tegmental area (VTA) dopaminergic neurons following ketamine administration to mice. By using viral tracing technology, they identified the direct neural connection from VTA dopaminergic neurons to BLA, then specifically activating or inhibiting the dopamine pathway from VTA to BLA revealed the crucial role of the VTA-BLA dopaminergic pathway in the therapeutic effects of ketamine. Simultaneously administering a low dose of ketamine while microinjecting a dopamine D2 receptor antagonist (such as sulpiride) into the BLA region demonstrated that the D2 receptor antagonist could block the effect of ketamine in reducing social avoidance behavior. The study proved that the therapeutic effects of ketamine depend on the activation of the VTA-BLA dopamine pathway, mediated through the dopamine D2 receptor.
Figure 3. The therapeutic effect of ketamine upon re-exposure depends on BLA dopamine D2 receptors (Image source: Neuron)
3. scRNA-seq and assessment of BLA transcriptional changes induced by ketamine re-exposure
The authors have identified the VTA-BLA engram cells’ dopaminergic projections mediating the therapeutic effects of ketamine. To further understand the molecular targets of BLA and the related signaling pathway changes after re-exposure coupled with ketamine treatment, single-cell sequencing analysis was performed. The study found that ketamine-induced gene expression changes were not evenly distributed among all neuron types but specific to certain neuronal subtypes. KEGG pathway analysis identified 27 pathways commonly altered across all neuronal clusters, including pathways related to neurotransmitter release, signal transduction, cell cycle, and intercellular communication, all closely linked to memory processing. The study also found that ketamine-induced gene expression changes and memory effects depend on BLA dopamine D2 receptors, further confirming the importance of D2 receptors in regulating memory processes.
Figure 4. scRNA sequencing and assessment of BLA transcriptional changes induced by ketamine re-exposure (Image source: Neuron)
Summary
The researchers of this study developed an acute SDS mouse model featuring short-term and re-exposure induced long-term social avoidance, along with a behavioral paradigm for studying the mechanism of ketamine in PTSD treatment. However, the authors have also highlighted shortcomings in their research. While the study conducted an overall analysis of engram cells in the BLA region, the composition of neuronal types needs further exploration to determine which specific neuronal subtypes significantly influence the response to ketamine and its therapeutic effects. In conclusion, this research not only advances our understanding of the neurobiology of PTSD but also provides scientific basis for the development of new PTSD treatment methods, especially considering ketamine as an existing drug with well-studied safety and pharmacokinetic properties, offering new perspectives and strategies for clinical treatment.
Dr. Li Ming from Huazhong University of Science and Technology is the first author of the paper, and Associate Professor Zhang Pei and Professor Tian Bo are the corresponding authors.
