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Cholecystokinin (CCK) causes panic attacks in humans and increases fear-associated behaviours in rodents by way of CCK-B receptors. The aim of this thesis was to investigate the CCK system behaviourally and anatomically in C57BL6/J mice and to assess the suitability of CCK-IRES-Cre mouse lines for amygdala manipulation. The behavioural results failed to support the startle-activating effect of CCK-4 or the startle-inhibiting effects of CCK-B receptor antagonists, in spite of evidence showing CCK-4 induced activation of c-Fos in the central amygdala. The anatomical results show that CCK-8 expression in the basolateral amygdala (BLA) is comparable to the CCK mRNA expression pattern. These results suggest that viral manipulations in the CCK-IRES-Cre line will induce changes in endogenous CCK systems in the mouse amygdala.

Cholecystokinin (CCK) causes panic attacks in humans and increases fear-associated behaviours in rodents by way of CCK-B receptors. The aim of this thesis was to investigate the CCK system behaviourally and anatomically in C57BL6/J mice and to assess the suitability of CCK-IRES-Cre mouse lines for amygdala manipulation. The behavioural results failed to support the startle-activating effect of CCK-4 or the startle-inhibiting effects of CCK-B receptor antagonists, in spite of evidence showing CCK-4 induced activation of c-Fos in the central amygdala. The anatomical results show that CCK-8 expression in the basolateral amygdala (BLA) is comparable to the CCK mRNA expression pattern. These results suggest that viral manipulations in the CCK-IRES-Cre line will induce changes in endogenous CCK systems in the mouse amygdala.

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disorder with severely debilitating effects and no current cure. FRDA is mainly caused by the hyper-expansion of a GAA repeat present in intron 1 of the FXN gene, which results in decreased gene expression and consequently a deficiency of the mitochondrial protein frataxin. In the first instance, frataxin deficiency renders an impaired protection from oxidative stress. Antioxidant therapy with cannabinoids (CBD and THC) and CTMIO was investigated in GAA repeat FXN YAC transgenic mouse models of FRDA, but no significant improvements were detected on functional measurements such as rotarod performance and locomotor activity. Additionally such compounds failed to protect the brain of treated mice from oxidative insults. Therefore, the use of such antioxidant compounds cannot be advocated for FRDA therapy. Recent findings indicate that FXN silencing in FRDA may be mediated by repressive heterochromatin, suggesting the use of histone deacetylase inhibitors (HDACi) as FXN up-regulators. Therefore, therapy with a benzamide-type HDACi (106) was similarly investigated on the FXN YAC GAA mouse model. No significant improvements were detected by functional and histochemical analysis. However, significant changes were produced in global acetylation levels of H3 and H4 in the brain of treated mice, suggesting that the drug is capable of crossing the blood-brain barrier and producing an effect. Additionally, significant increases in frataxin expression were detected in the brain of treated mice. To identify further FRDA disease mechanisms, characterization of the FXN gene for the presence of the CCCTC-binding factor (CTCF) was also performed on FRDA patient cerebellum samples. Overall, lower levels of CTCF were detected in FRDA-associated FXN alleles, suggesting the potential involvement of CTCF in the regulation of FXN transcription.