The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view linking these processes remains elusive. Here, we identify a convergent circuit for antidepressant response and plasticity modulation. We demonstrate that chemogenetic activation of the infralimbic cortex (IL) exerts rapid antidepressant-like effects across multiple behavioral domains in a mouse model of stress-induced depression. IL stimulation exerts top-down control over the hippocampus, enhancing structural plasticity, restoring long-term potentiation deficits and improving state-dependent network dynamics in the ventral hippocampus (vHIPP). We identify the thalamic nucleus reuniens (RE) as a necessary mediator of these effects. Notably, direct inhibition of RE, its inputs from IL or projections to vHIPP, blocks both IL stimulation-induced antidepressant response and the therapeutic and neuroplastic effects of ketamine. Our findings demonstrate that the functional IL → RE→vHIPP circuit plays a central role in the antidepressant response, linking circuit activity, hippocampal plasticity, and depressive-like behaviors. Neural mechanisms underlying depression are not fully understood. This study identifies a prefrontal–thalamic–hippocampal circuit that links antidepressant-like behavior with restored neural plasticity and is required for ketamine’s behavioral and neuroplastic effects in mice.
M. Veleanu, Louise Schuberth, Antje Kilias et al.· Nature Communications· 0 citations
Social anxiety disorder (SAD) is a common anxiety disorder (ANX) with moderate heritability that often co-occurs with other mental disorders. Until now, sample sizes in genetic analyses of SAD have been limited, so that the genetic basis of SAD and its subphenotypes is still largely unknown. In a large cohort comprising n = 1,194 SAD patients derived from five German cohorts and n = 3,409 controls from the Heinz Nixdorf Recall Study, we computed polygenic risk scores (PRS) at six p-thresholds using PRSice-2 based on large-scale genome-wide association studies for depression, major depressive disorder (MDD), ANX, schizophrenia (SCZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), and alcohol dependence (AD). We used general linear models to examine the association between the PRS and SAD status. In SAD subsamples, we investigated whether the PRS are associated with SAD subphenotypes (i.e., SAD severity, current depressive symptoms, comorbid MDD) using correlation analyses and a general linear model. Results were corrected for multiple testing. The SAD status was significantly associated with PRS for depression, MDD, ANX, SCZ, BD, AN, and ASD (pBH-adjusted<0.05), but not with PRS for ADHD and AD. In SAD subsamples, the subphenotype analyses revealed no significant associations after correction for multiple testing (pBH-adjusted>0.05). Our results support that SAD seems to be genetically highly overlapping with other mental disorders, which might underline a common psychopathological factor. No significant association was found with SAD severity, current depressive symptoms or comorbid MDD. A better understanding of the genetic architecture of SAD may help to develop new diagnostic and treatment approaches.
L. Sindermann, Angelina Röhrig, F. David et al.· Translational Psychiatry· 0 citations
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