Perineuronal nets in the bed nucleus of stria terminalis mediate stress-induced anxiety behaviour in adult male mice

Abstract

Anxiety disorders affect an estimated 301.4 million people globally. However, they remain among the most challenging conditions to treat, with only around half of patients reporting a 50% or greater reduction in their symptoms. The discovery of novel and more effective treatments therefore requires a better understanding of the underlying mechanisms of anxiety at both the circuit and cellular levels. Stress induces aberrant changes in neuronal plasticity across brain regions within the anxiety circuitry including the bed nucleus of the stria terminalis (BNST). One mechanism through which synaptic plasticity is regulated is the organisation of perineuronal nets (PNNs), specialised extracellular matrix structures that are highly sensitive to stress. In rodent models, stress is associated with a reduction in PNN number and/or decreased Wisteria floribunda Agglutinin (WFA) labelling in limbic areas. However, the development of PNNs within the BNST and their role in the stress responsiveness remain largely unknown. In the current study we investigated the spatiotemporal development of PNNs within the BNST of male mice, where they first appear at P30 and continue to mature into adulthood, reaching their highest expression at P210 and specifically within the anteromedial BNST. We further showed that stress-induced anxiety is associated with a reduction in PNN number and significant changes to PNN fine structure including increased leakiness in the anteromedial BNST. Most importantly, enzymatic removal of PNNs by chondroitinase ABC in the mouse anteromedial BNST exacerbated behavioural responses to acute stress as demonstrated by increased anxiety-like behaviour. Collectively, these results highlight an indispensable role for PNNs within the anteromedial BNST in mediating a healthy emotional response to psychosocial stress.