Editorial: Molecular Mechanisms in Psychiatry 2023 Anxiety and Stress

Shinsuke Hidese^1*Francesco Rusconi²Dominik Strzelecki³Marco Grados⁴

• ¹School of Medicine, Teikyo University, Tokyo, Japan
• ²Department of Medical Biotechnology and Translational Medicine, Faculty of Medicine and Surgery, University of Milan, Milan, Lombardy, Italy
• ³Medical University of Lodz, Łódź, Łódź, Poland
• ⁴School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States

The research topic “Molecular Mechanisms in Psychiatry 2023 Anxiety and Stress” intends to collect the most advanced research on the molecular mechanisms of anxiety and stress from a variety of disciplines of neurobiology and psychopharmacology. Based on the collected articles, we aimed to highlight novel directions for future research on the field of molecular mechanisms in anxiety and stress. Anxiety disorders often have onset in youth and their longitudinal course has variable expression (1). The cellular level pathophysiology of acute and chronic has considered the effect of circadian rhythm mechanisms, epigenetics expression, neurotransmitter differences, immune effects, and sex hormone levels (2). In turn, neuroimaging studies suggest identifiable neural circuit vulnerabilities which can lead to the emergence and maintenance of pathological anxiety. These vulnerabilities are further impacted by maladaptive behaviors which engage in the avoidance of extinction learning opportunities, thus prolonging anxiety symptom expression (3). Advancing current knowledge in the area of molecular mechanisms of anxiety and stress, Guo et al. perform a bibliometric and visual analysis for the association between pathogenesis of anxiety disorders and gut microbiota. The design identfied 1,198 relevant articles, with an increased in interest in the past 2 decades in these topics, with China, the United States, and Canada being the countries with highest output. Key research themes included anxiety, gut microbiota, depression, stress, gut-brain axis, and probiotics, providing a broad array of coverage for anxiety and stress. Animal models illuminate the precise molecular mechanisms and brain circuitry differences associated with anxiety; a paramount use of these models is to provide a platform for the development of future anxiolytic drugs (4). In a preclinical study of this research topic, Yin et al. Report on the effect of electroacupuncture and its anxiolytic effects using a mouse model of social isolation-induced anxiety. Using a standard test of anxiety, and measuring stress responses (NADPH oxidase 2 (NOX2), microglial activation), there was an effect of electroacupunture on mice, which mitigated anxiety-like behaviors. At the same time, there was a reduction in NOX2 expression within the basolateral amygdala microglia, a reduction in reactive oxygen species and a restoration of microglia morphology. Also using animal models, Mottarlini et al. use the communal nesting (CN) environment, a nest sharing paradigm between several mothers of rat pups, and the early social isolation (ESI) setting to study its effects on pups. The CN environment increased prosocial behaviors in male pups, while ESI sensitized the glutamate synapse in the medial prefrontal cortex of males, but not female, rats. This sex-biased effect was pronounced at the molecular level, with concomitant NMDAR effects and recruitment of second messenger molecules occurring only in the male rats. The authors report that a CN environment contributes to shape social behavior and glutamate synapse homeostasis in the medial prefrontal cortex of ESI-exposed male rats, but in not female rats. These studies advance the understanding of specific mechanistic approaches to the amelioration of anxiety in humans. In clinical studies of this research topic, Shen et al. report the use of an affective flanker and flexibility tasks on 50 participants with generalized anxiety disorder (GAD). In those with GAD, there is poorer affective recognition abilities, accompanied by deficits in affective shifting, in comparison to 50 healthy controls. In turn, Qian et al. report on the use of a subliminal affective facial recognition task, wherein a positive response tendency is observed in 34 participants with panic disorder in comparison to 43 healthy controls. The test was conducted after a course of cognitive-behavior therapy (CBT); participants with diminished anxiety after CBT also had a decreased false fear response bias. In an interesting longitudinal study, Jin et al. report on perceived anxiety and stress during childhood, which may increase the risk of mental illness, using the China Health and Retirement Longitudinal Study (CHARLS). The participant report of “tense or anxious” caregivers, is paired to their own risk of later life depression. Childhood exposure to caregiver anxiety and stress significantly increased the risk of depression in later life (p < 0.05), with stronger effects observed among individuals with female caregivers. Li et al. Report on the use of friend leukemia virus integration 1 (FLI1) on 12 veterans with PTSD and 12 without PTSD. The authors found significantly increased FLI1 expression in peripheral blood mononuclear cells in those veterans with PTSD, compared to those without PTSD. In particular, CD4+ T cells were increased, with no notable changes in CD8+ T cells. With lipopolysaccharide (LPS) stimulation, there was a further increase in IL-6 and IFN-gamma in affected veterans. Microglia cells from PTSD-affected veterans also showed greater activation, suggesting that suppression of FLI1 may be a route to mitigate inflammation and microglial activation associated with PTSD. In summary, the field of molecular mechanisms associated with the phenomenology of anxiety and stress needs to consider multiple streams of input. Consideration for adverse childhood experiences, allostatic load, hormonal influences, DNA methylation, inflammatory mechanisms, and aging-oxidative processes are all worthy of consideration (5). The topic submissions highlight the importance of multiple determinants of anxiety and stress in humans which can then evolve into anxiety disorders.   Author contributions SH drafted the manuscript, while RF, SD, and GM revised the manuscript for the intellectual content. All authors approved the final version of the manuscript for publication. Conflict of interest None