Exploring chronic stress-induced depressive-like phenotypes with PET imaging

Studying depressive phenotypes is challenging due to the brain’s complexity and isolation, but neuroimaging tools like Positron Emission Tomography (PET) can provide new insights. This thesis explored depressive phenotypes using PET imaging in animal models, focusing on two hypotheses for depression the ‘disconnection’ and ‘monoaminergic dysfunction’ using the repeated social defeat (RSD) paradigm to induce depressive-like phenotypes.

Brain connectivity was studied using [18F]FDG-PET. Key findings indicated alterations in brain connectivity in the default mode network simultaneously to occurrence of depressive-like behaviour; as well as, in the salience network after the remission. Hence, the alteration of connectivity in the brain networks may contribute to depressive symptoms.

PET was also used in this thesis to study neuroreceptors systems such the dopaminergic and serotoninergic. In one of these studies, agonistic and antagonistic treatments targeting the adenosinergic A2A receptor, caused an antidepressant effect and a reduction in the dopaminergic D2R receptor availability measured with [11C]raclopride-PET. Moreover, we found an increase in the serotonin transporter availability measured with [11C]DASB-PET in brain regions, such as amygdala, frontal and olfactory cortices and midbrain when the animals were sensitised to stress in early life.

Finally, we studied the optimal method for the quantification of the [11C]methylreboxetine-PET signal for its use in future studies.

Overall, these studies showcase the importance of animal models and the use of PET methods to investigate depressive phenotypes for improving our understanding of depression’s biological mechanisms and guiding future research and therapies.