Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine\'s effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine\'s mechanisms in adolescent FE, our study suggests that ketamine\'s effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

Fear conditioning and extinction serve as a dominant model for the development and maintenance of pathological anxiety, particularly for phasic fear to specific stimuli or situations. The validity of this model would be supported by differences in the physiological or subjective fear response between patients with fear-related disorders and healthy controls, whereas the model\'s validity would be questioned by a lack of such differences. We derived pupillometry, skin conductance response and startle electromyography as well as unconditioned stimulus expectancy in a two-day fear acquisition, immediate extinction and recall task and compared an unmedicated group of patients (n = 73) with phobias or panic disorder and a group of patients with posttraumatic stress disorder (PTSD, n = 21) to a group of carefully screened healthy controls (n = 35). Bayesian statistics showed no convincing evidence for a difference in physiological and subjective responses between the groups during fear acquisition, extinction learning or recall. Only the PTSD subgroup had altered startle reactions during extinction learning. Our data do not provide evidence for general differences in associative fear or extinction learning in fear-related pathologies and thereby question the diagnostic validity of the associative fear learning model of these disorders.

Extensive evidence from both animal model and human research indicates that glucocorticoid hormones are crucially involved in modulating memory performance. Glucocorticoids, which are released during stressful or emotionally arousing experiences, enhance the consolidation of new memories, including extinction memory, but reduce the retrieval of previously stored memories. These memory-modulating properties of glucocorticoids have recently received considerable interest for translational purposes because strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias. Moreover, exposure-based psychological treatment of these disorders relies on successful fear extinction. In this review, we argue that glucocorticoid-based interventions facilitate fear extinction by reducing the retrieval of aversive memories and enhancing the consolidation of extinction memories. Several clinical trials have already indicated that glucocorticoids might be indeed helpful in the treatment of fear-related disorders.