Fear extinction induced by activation of PKA ameliorates anxiety-like behavior in PTSD mice. 2023

Feng Gao, and Juan Wang, and Shaojie Yang, and Manman Ji, and Guoqi Zhu
Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China.

Prolonged exposure (PE) therapy aiming to promote fear extinction is a useful treatment for post-traumatic stress disorder (PTSD). However, the mechanisms underlying fear extinction and effective methods used to promote fear extinction in PTSD are still lacking. In this study, we displayed dysfunctions of cyclic adenosine 3,5-monophosphate (cAMP)-protein kinase A (PKA), protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and calcium signaling in peripheral serum of PTSD patients using bioinformatics analysis. Later, we confirmed the dysfunctions of cAMP-PKA, AKT/mTOR and calcium signaling in the hippocampus of PTSD mice. Moreover, the reduction of calpain1 in the hippocampus enhanced fear memory acquisition. Single activation of PKA by systemic application of rolipram (ROL) or meglumine cyclic adenylate (M-cAMP) before re-exposure promoted fear extinction and improved anxiety-like behavior in PTSD mice. Moreover, systemic application of ROL before re-exposure improved hippocampal brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling and calpain1/AKT/mTOR signaling. Interestingly, the effects of activation of PKA could be partially blocked by TrkB antagonist, ANA-12 and mTOR inhibitor, RAPA. Finally, intranasal administration of ROL could also adjust the abnormality of fear memory and improve anxiety-like behaviors in PTSD mice. Collectively, activation of PKA could promote fear extinction, which correlated with the reduction of anxiety-like behavior. The mechanisms were related to the BDNF/TrkB and calpain1/AKT/mTOR signaling pathways. PKA activation might be a useful complementary therapy for PE in the symptom elimination of PTSD.

UI MeSH Term Description Entries
D008322 Mammals Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young. Mammalia,Mammal
D005108 Extinction, Psychological The procedure of presenting the conditioned stimulus without REINFORCEMENT to an organism previously conditioned. It refers also to the diminution of a conditioned response resulting from this procedure. Psychological Extinction,Extinction (Psychology),Extinctions (Psychology),Extinctions, Psychological,Psychological Extinctions
D005239 Fear The affective response to an actual current external danger which subsides with the elimination of the threatening condition. Threat Cues,Threat Sensitivity,Cue, Threat,Fears,Sensitivity, Threat,Threat Cue,Threat Sensitivities
D000241 Adenosine A nucleoside that is composed of ADENINE and D-RIBOSE. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Adenocard,Adenoscan
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001007 Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with ANXIETY DISORDERS. Angst,Anxiousness,Hypervigilance,Nervousness,Social Anxiety,Anxieties, Social,Anxiety, Social,Social Anxieties
D013313 Stress Disorders, Post-Traumatic A class of traumatic stress disorders with symptoms that last more than one month. Moral Injury,Neuroses, Post-Traumatic,PTSD,Post Traumatic Stress Disorder,Post-Traumatic Stress Disorders,Acute Post-Traumatic Stress Disorder,Chronic Post-Traumatic Stress Disorder,Delayed Onset Post-Traumatic Stress Disorder,Neuroses, Posttraumatic,Posttraumatic Stress Disorders,Stress Disorder, Post Traumatic,Stress Disorders, Posttraumatic,Acute Post Traumatic Stress Disorder,Chronic Post Traumatic Stress Disorder,Delayed Onset Post Traumatic Stress Disorder,Injury, Moral,Moral Injuries,Neuroses, Post Traumatic,Post Traumatic Stress Disorders,Post-Traumatic Neuroses,Post-Traumatic Stress Disorder,Posttraumatic Neuroses,Posttraumatic Stress Disorder,Stress Disorder, Post-Traumatic,Stress Disorder, Posttraumatic
D051057 Proto-Oncogene Proteins c-akt Protein-serine-threonine kinases that contain PLECKSTRIN HOMOLOGY DOMAINS and are activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. They play a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells. akt Proto-Oncogene Protein,c-akt Protein,AKT1 Protein Kinase,AKT2 Protein Kinase,AKT3 Protein Kinase,Akt-alpha Protein,Akt-beta Protein,Akt-gamma Protein,Protein Kinase B,Protein Kinase B alpha,Protein Kinase B beta,Protein Kinase B gamma,Protein-Serine-Threonine Kinase (Rac),Proto-Oncogene Protein Akt,Proto-Oncogene Protein RAC,Proto-Oncogene Proteins c-akt1,Proto-Oncogene Proteins c-akt2,Proto-Oncogene Proteins c-akt3,RAC-PK Protein,Rac Protein Kinase,Rac-PK alpha Protein,Rac-PK beta Protein,Related to A and C-Protein,c-akt Proto-Oncogene Protein,Akt alpha Protein,Akt beta Protein,Akt gamma Protein,Akt, Proto-Oncogene Protein,Protein, akt Proto-Oncogene,Protein, c-akt Proto-Oncogene,Proteins c-akt1, Proto-Oncogene,Proteins c-akt2, Proto-Oncogene,Proteins c-akt3, Proto-Oncogene,Proto Oncogene Protein Akt,Proto Oncogene Protein RAC,Proto Oncogene Proteins c akt,Proto Oncogene Proteins c akt1,Proto Oncogene Proteins c akt2,Proto Oncogene Proteins c akt3,Proto-Oncogene Protein, akt,Proto-Oncogene Protein, c-akt,RAC PK Protein,RAC, Proto-Oncogene Protein,Rac PK alpha Protein,Rac PK beta Protein,Related to A and C Protein,akt Proto Oncogene Protein,alpha Protein, Rac-PK,c akt Proto Oncogene Protein,c-akt, Proto-Oncogene Proteins,c-akt1, Proto-Oncogene Proteins,c-akt2, Proto-Oncogene Proteins,c-akt3, Proto-Oncogene Proteins
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058570 TOR Serine-Threonine Kinases A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that SIROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity. TOR Kinase,TOR Kinases,TOR Serine-Threonine Kinase,Target of Rapamycin Protein,mTOR Serine-Threonine Kinase,mTOR Serine-Threonine Kinases,FK506 Binding Protein 12-Rapamycin Associated Protein 1,FKBP12-Rapamycin Associated Protein,FKBP12-Rapamycin Complex-Associated Protein,Mammalian Target of Rapamycin,Mechanistic Target of Rapamycin Protein,RAFT-1 Protein,Rapamycin Target Protein,Target of Rapamycin Proteins,mTOR Protein,FK506 Binding Protein 12 Rapamycin Associated Protein 1,FKBP12 Rapamycin Associated Protein,FKBP12 Rapamycin Complex Associated Protein,Kinase, TOR,Kinase, TOR Serine-Threonine,Kinase, mTOR Serine-Threonine,Kinases, TOR Serine-Threonine,Kinases, mTOR Serine-Threonine,Protein Target, Rapamycin,Protein, RAFT-1,Protein, mTOR,RAFT 1 Protein,Rapamycin Protein Target,Serine-Threonine Kinase, TOR,Serine-Threonine Kinase, mTOR,Serine-Threonine Kinases, TOR,Serine-Threonine Kinases, mTOR,TOR Serine Threonine Kinase,TOR Serine Threonine Kinases,mTOR Serine Threonine Kinase,mTOR Serine Threonine Kinases

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