Molecular neurobiology of loss: a role for basolateral amygdala extracellular matrix

Abstract

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an environmental enrichment removal (ER) paradigm in male rats. The basolateral amygdala (BLA) was identified as a region of interest, demonstrating differential Fos responsivity to ER and having an established role in stress processing and adaptation. A comprehensive multi-omics investigation of the BLA, spanning multiple cohorts, platforms, and analyses, revealed alterations in microglia and the extracellular matrix (ECM). Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition within the BLA following loss. Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, leading to a mismatch between stimulus and reaction intensity. These loss-like behaviors could be rescued by depleting BLA ECM during the removal period, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.

Degradation of Perineuronal Nets in the Ventral Hippocampus of Adult Rats Recreates an Adolescent-Like Phenotype of Stress Susceptibility

“…It has been observed previously that bilateral injection of ChABC into the vHip increased the activity of vHip pyramidal neurons and VTA dopamine neurons 1 week after drug infusion ( 65 ). ChABC rapidly degrades PNNs by about 90%, and PNNs gradually regenerate over time ( 66 ). In the current study, behavioral tests and electrophysiological recordings were performed between 5 and 8 weeks after surgery, when PNNs were reconstituted.…”