The role of perineuronal nets in the anterior bed nucleus of the stria terminalis in regulating emotional behaviour and neuronal transmission

Abstract

Anxiety disorders are the most common mental health disorders suffered globally, affecting upwards of 300 million people. Despite the prevalence of anxiety disorders, the currently available therapies lack efficacy, with only 50-85% of patients experiencing at least a 50% improvement in symptoms, and can cause adverse reactions. As such, greater insight into the molecular underpinnings of anxiety disorders is essential to provide a rationale for novel effective treatments. Exposure to severe or prolonged stress promotes the development of anxiety, through aberrant changes to neuronal plasticity in the cortex, hippocampus and amygdala, three well-characterised brain regions involved in the stress response. However, the role of the bed nucleus of the stria terminalis (BNST), uniquely placed to modulate the stress response, in anxiety disorders is not fully understood. Here, I investigated the role of specialised organisations of extracellular matrix, perineuronal nets (PNNs), within the BNST in regulating emotional behaviour and neuronal transmission in relation to stress. The experimental work presented in this thesis characterises the spatiotemporal development of PNNs in the anterior BNST and identifies the anteromedial BNST as the region with densest PNN expression. Morphological studies determine that the structure of PNNs in the anteromedial BNST is the most vulnerable seven days following exposure to repeated restraint stress, a period which coincides with increased anxiety-like behaviour in the elevated plus maze and changes to plasticity of BNST neurons. However, such behavioural changes cannot be recapitulated by PNN degradation, suggesting that PNN alterations are highly specific following stress. Altogether these experiments provide evidence of a relationship between stress and PNNs in the BNST and open an avenue for future research, which may one day inform discovery of novel therapeutics for anxiety disorders.