Nucleus reuniens: Modulating emotional overgeneralization in peri-adolescents with anxiety

Anxiety affects 4.4-million children in the USA with an onset between childhood and adolescence, a period marked by neural changes that impact emotions and memory. Negative overgeneralization - or responding similarly to innocuous events that share features with past aversive experiences - is common in anxiety but remains mechanistically underspecified. The nucleus reuniens (RE) has been considered a crucial candidate in the modulation of memory specificity. Our study investigated its activation and functional connectivity with the medial prefrontal cortex (mPFC) and hippocampus (HPC) as neurobiological mechanisms of negative overgeneralization in anxious youth.

As part of a secondary data analysis, we examined data from 34 participants between 9 and 14 years of age (mean age ± SD, 11.4 ± 2.0 years; 16 females) with varying degrees of anxiety severity. During the Study session participants rated images as negative, neutral, and positive. After 12 h, participants returned for a Test session, where they performed a memory recognition test with repeated (targets) and similar (lures) images. Labeling negative relative to neutral lures as "old" (false alarms) was our operational definition of negative overgeneralization.

Negative relative to neutral false alarmed stimuli displayed elevated RE activation (at Study and Test) and increased functional connectivity with the Cornu Ammonis (CA) 1 (at Test). Elevated anxiety severity was associated with reductions in the RE-mPFC functional coupling for neutral relative to negative stimuli. Exploratory analyses revealed similar patterns in activation and functional connectivity with positive stimuli.

Our findings demonstrate the importance of the RE in negative overgeneralization and anxiety.