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With a total lifetime prevalence of 12 % and nearly 70 million people affected in Europe alone, anxiety disorders are among the most prevalent psychiatric disorders. Despite the advances in psycho- and pharmacotherapy, a considerable group of patients remains symptomatic (30-60 %) and is considered treatment-refractory. A last-resort option for these patients is deep brain stimulation (DBS), which has therapeutic effects in patients suffering from obsessive-compulsive disorder and major depression. In this project, we aim to investigate the usefulness of DBS for anxiety in an animal model and refine the method of stimulation.For this purpose, we target the bed nucleus of the stria terminalis (BST), a brain region with a key role in the expression of anxiety. First, we will electrically stimulate the BST in a rat model of anxiety and evaluate its anxiolytic effects through freezing and startle measurements. Next, we will measure local field potentials (LFPs) in anxious and control rats, in search of a biomarker of anxiety. Identification of such a biomarker can improve DBS effects since stimulation should only occur during symptomatic intervals (i.e. during biomarker expression), rather than continuously, which is currently the case. In summary, this project aims to (1) strengthen the evidence for DBS-in-BST therapy for patients suffering from pathological anxiety and (2) refine current DBS techniques.
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The bed nucleus of the stria terminalis (BST) plays an important role in the expression of anxiety. Our research group previously demonstrated that bilateral, electrolytic lesions in the BST significantly reduced contextual anxiety in rats. Intriguingly, more recent studies have suggested that the left BST might be stronger involved in anxiety responses than the right BST. In the current study, we hypothesized that unilateral lesions in the left BST might be equally effective as bilateral lesions. To test this hypothesis, we applied post-training, electrolytic lesions in context-conditioned rats in either the left (n = 12), right (n = 12) or bilateral (n = 14) BST. In a different group, SHAM lesions were applied (n = 10). Twenty-four hours after lesioning, anxiety was assessed through freezing and startle responses. In addition, c-Fos activation was quantified throughout different parts of the anxiety network, including the basolateral amygdala (BLA), nucleus accumbens (NAc, core and shell) and the infralimbic and prelimbic cortex (IL and PL). A significant decrease in contextual freezing was observed in animals with bilateral lesions compared to SHAM. However, animals with unilateral lesions did not show significant reduction in either freezing or startle. Within the scope of this master’s thesis, c-Fos analysis was only completed within the BLA, since our main hypothesis regarding cellular activity focused on c-Fos activity in this particular region. No significant differences were observed in c-Fos intensity between different groups or between hemispheres. These results indicate that lesions of the left BST are not as efficient in relieving anxiety as bilateral lesions on the behavioural level. In addition, BLA activity does not seem to be affected by bi- or unilateral lesions of the BST in our experiment.
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