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Abstract:
Excessive or chronic stress can lead to maladaptive anxiety. Anxiety disorders are highly prevalent and there is a pressing demand for a more comprehensive understanding of the molecular mechanisms that underlie such disorders. Dysregulation of the stress response and genetic risk factors can contribute towards an increased susceptibility to maladaptive anxiety. The co-chaperone FKBP51 is an immunophilin protein best known as a regulator of the glucocorticoid receptor (GR) and the stress response system. Human and animal studies have shown that aberrant GR signalling as well as genetic variants within the gene encoding FKBP51, FKBP5, can precede stress-related pathology. Notably, the effects of FKBP51 are highly region- and cell type specific. The central extended amygdala, which comprises the central amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), more specifically the oval BNST (ovBNST), is a promising limbic structure of the forebrain that has been repeatedly associated with the modulation of anxiety states. However, the region-specific function of FKBP51 in this nucleus has not been explored yet. Moreover, Tachykinin 2 (Tac2) is an emerging neuropeptide that is also expressed in the BNST and highly likely involved in mediating anxiety-like behaviour. In this thesis, we aimed to elucidate molecular mechanisms mediated by the GR, FKBP51 and Tac2 that underlie stress-induced anxiety states. Initially we addressed whether GR signalling in forebrain neurons contributes to fear and anxiety-related behaviour. Interestingly, we found that forebrain glutamatergic, but not GABAergic, neurons mediate the anxiogenic effects of the GR. Moreover, virally-mediated GR deletion revealed that fear-related behaviour is regulated exclusively by GRs in the glutamatergic neurons of the basolateral amygdala (BLA). We then proceeded to explore whether the lack of FKBP51 would lead to alterations in brain architecture and connectivity in mice. Using in vivo structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) we reported two clusters of significantly larger volumes in the hypothalamus, periaqueductal grey (PAG), and dorsal raphe (DR) region of wildtype (WT) animals. DTI measurements, however, highlighted statistically higher fractional anisotropy (FA) values for FKBP51 knockout (51KO) animals in locations including the anterior commissure, fornix, and posterior commissure/superior colliculus region. In order to dissect the role of FKBP51 in anxiety, we characterised the function of FKBP51 in the ovBNST and assessed its impact on HPA axis function and anxiety-related behaviour. Notably, our data suggests that stress-induced increase of FKBP5 in the ovBNST may in fact have a protective role, leading to decreased anxiety and suppression of a future stress-induced HPA axis activation. Finally, we convey a first impression of the function of Tac2 within the ovBNST and its implication in anxiety-like behaviour. Here we show that Tac2 is upregulated by acute stress in the ovBNST and that ovBNST Tac2 positive neurons are involved in anxiety circuitry and behaviour. The collective findings of the current thesis provide novel evidence for the contribution of GR, Tac2 and FKBP51 towards the underlying molecular mechanisms of stress-induced anxiety-like states.
