ErbB4 precludes the occurrence of PTSD-like fear responses by supporting the bimodal activity of the central amygdala

• Published in: Experimental & molecular medicine 2024, 56(0), , pp.2703-2713
• Main Authors: Sung, Kibong, Jeong, Min-Jae, Yoo, Taesik, Jung, Jung Hoon, Kang, Sumin, Yoo, Jong-Yeon, Kim, Hyun Jin, Park, Kyunghyun, Pyo, Jung Hyun, Lee, Hyun-Yong, Koo, Noah, Choi, Soo-Hee, Kim, Joung-Hun
• Format: Article
• Language: English
• Subjects: 14/19; 14/32; 42/44; 631/378/1457/1284; 631/378/1595/2636; 631/378/1831; 631/378/2583; 64/60; 9/74; Amygdala; Animal models; Animals; Anxiety; Artificial intelligence; Behavior, Animal; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Central Amygdaloid Nucleus - metabolism; CRISPR; Disease Models, Animal; ErbB-2 protein; Fear; Fear - physiology; Fear conditioning; Kinases; Male; Medical Biochemistry; Mental disorders; Mice; Mice, Knockout; Molecular Medicine; Neurons; Neurons - metabolism; Phenotypes; Physiology; Post traumatic stress disorder; Protein-tyrosine kinase receptors; Receptor, ErbB-4 - genetics; Receptor, ErbB-4 - metabolism; Schizophrenia; Somatostatin; Somatostatin - metabolism; Stem Cells; Stress Disorders, Post-Traumatic - genetics; Stress Disorders, Post-Traumatic - metabolism; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01365-1

Post-traumatic stress disorder (PTSD) often arises after exposure to traumatic events and is characterized by dysregulated fear responses. Although the associations of erb-b2 receptor tyrosine kinase 4 (ErbB4) with various neuropsychiatric diseases, including schizophrenia and bipolar disorder, have been widely examined, the physiological roles of ErbB4 in PTSD and fear responses remain unclear. Using Cre-dependent ErbB4 knockout (KO) mice, we observed that PTSD-like fear behaviors emerged in ErbB4-deficient mice, particularly in inhibitory neurons. Specifically, the loss of ErbB4 in somatostatin-expressing (SST + ) neurons was sufficient to induce PTSD-like fear responses. We also adopted the CRISPR/Cas9 system for region-specific KO of ErbB4, which revealed that ErbB4 deletion in SST + neurons of the lateral division of the amygdala (CeL) caused elevated anxiety and PTSD-like fear generalization. Consistent with its physiological role, ErbB4 expression was diminished in CeL SST neurons from mice that exhibited PTSD-like phenotypes. While fear On and Off cells identified in the CeL displayed distinct responses to conditioned and novel cues, as previously shown, the selectivity of those On and Off cells was compromised in SST ErbB4-/- and stressed mice, which displayed strong fear generalization. Therefore, the bimodal activity that CeL On/Off cells display is likely required for proper discrimination of fearful stimuli from ambient stimuli, which should be sustained by the presence of ErbB4. Taken together, our data substantiate the correlation between PTSD-like fear responses and ErbB4 expression in CeL SST neurons and further underscore the functional effects of ErbB4 in CeL SST neurons, supporting the bimodal responses of CeL neurons. ErbB4 deficiency triggers PTSD-like fear responses in mice Post-traumatic stress disorder is a mental health condition that can develop after experiencing traumatic events. Researchers tried to understand the biological basis of PTSD using animal models. The researchers investigated the role of a protein called ErbB4 in fear responses related to PTSD. They used mice to study how deleting ErbB4 in specific brain cells affects fear behavior. They focused on somatostatin(SST)-expressing neurons in a brain region called the central amygdala, which is involved in processing fear. The study involved genetic modification, behavioral tests, and in vivo recording to observe changes in fear responses. The findings showed that remov