McMakin, D. | bioRxiv Science

bioRxiv2023

Nucleus Reuniens: Modulating Negative Overgeneralization in Preadolescent Anxiety

BackgroundAnxiety affects 4.4-million children in the United States 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. MethodsAs part of a secondary data analysis, we examined data from 34 participants between 9-14 years (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-hours, 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. ResultsNegative relative to neutral false alarmed stimuli displayed elevated RE activation (at Study and Test) and increased functional connectivity with the CA1 (at Test only). 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. ConclusionsOur findings demonstrate the importance of the RE in the overgeneralization of memories in anxious youth.

neuroscience↗

bioRxiv2020

Differential effects of emotional valence on mnemonic performance with greater hippocampal maturity

The hippocampal formation (HF) facilitates the creation of declarative memories, with subfields providing unique contributions to the discriminability and generalizability of events. The HF itself and its connections with other structures exhibit a protracted development. Maturational differences across subfields facilitate a shift towards memory specificity, with peri-puberty sitting at the inflection point. Peri-puberty also happens to be a sensitive period in the development of anxiety disorders. Taken together, we believe HF development is critical to negative overgeneralization, a common feature of anxiety disorders. To investigate the role of the HF in behavioral discrimination and generalization we examined the relation between behavior and cross-sectional indices of HF maturity derived from subfield volume. Participants aged 9-14 years, recruited from clinical and community sources, performed a recognition task with emotionally valent (positive, negative) and neutral images. T1-weighted and diffusion-weighted structural scans were collected. Partial least squares correlations were used to derive a singular metric of maturity for both HF volume and structural connectivity. We found our volumetric HF maturity index was positively associated with discrimination for neutral images and generalization for negative images. Hippocampal-medial prefrontal cortex structural connectivity maturity metric evidenced a similar trend with behavior as the HF volumetric approach. These findings are important because they reflect a novel developmentally related balance between discrimination and generalization behavior supported by the hippocampus and its connections with other regions. Maturational shifts in this balance may contribute to negative overgeneralization, a common feature of anxiety disorders that escalates during the same developmental window. Significance StatementThe hippocampal formation (HF) facilitates declarative memory specificity and is composed of subfields whose development during adolescence overlaps with the onset of anxiety disorders. Aberrations in mechanisms governing memory specificity may contribute to negative overgeneralization in anxious youth. Participants completed an emotional memory discrimination task while in the scanner. Using a multivariate maturity metric based on subfield volume we found individuals with more "mature" HF were better at differentiating similar neutral images and more likely to generalize similar negative images. These findings are important because they capture a novel developmental mechanism related to the balance between discrimination and generalization. Shifts in this balance, may contribute to negative overgeneralization, a common feature of anxiety disorders.

neuroscience↗