Molecular Neurobiology of Loss

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, making it challenging to develop treatment strategies. Here, we investigate the mechanisms of loss using an enrichment removal (ER) paradigm in rats. A comprehensive multi-omics investigation of the basolateral amygdala (BLA), spanning multiple cohorts, platforms, and analyses, revealed alterations in microglia and 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 in the BLA. Behavioral analyses suggests that these molecular effects are linked to impaired BLA salience evaluation and flexibility, phenotypes that resemble emotional blunting observed in human loss. Taken together, these experiments help us understand the mechanisms underlying loss and reveal novel molecular targets to ameliorate its impact.