Systemic alterations and brain changes in physiology and pathologythe Octodon degus as a model of aging and multimorbidity

Resum

The main objective of this thesis was to characterize the O. degus as a natural model of aging by exploring systemic and brain changes, as well as their interaction, including sex as an experimental variable. Studies were performed on a total of 110 animals aged from 6 months old to 7 years old, which were divided according to age, sex or treatments. The data presented in this thesis are the result of combining in vivo analyses with the brain post mortem evaluation. Results are presented in 5 blocks: 1st) Determination of the sex-specific values of the biochemical profile in the blood of O. degus along aging. Most parameters were significantly altered in aged animals, with sex differences in most of them. Aged animals showed hepatic, renal and pancreatic dysfunction. Plasma oxidation and inflammation levels were significantly increased in older animals compared to younger animals. The biggest sex differences were related to oxidative status, suggesting higher oxidation in males versus females. 2nd) Study of in vivo cardiac function by electrocardiography. The highest sex-associated differences the higher incidence of arrhythmias and greater deviation of the electrical axis in males than in females. HR decreased significantly at older ages, with males being more affected than females. QRS complex duration was significantly increased in females along aging, but not in males. The QT interval duration of younger females was significantly shorter than that of males, while in the senile stage this situation was reversed. 3rd) Analysis of the age-related cognitive impairment and its possible relationship with the neuroinflammatory status in the dorsal hippocampus. Aged O. degus showed a significant cognitive decline compared to young animals. Sex-associated differences were also investigated: during the training sessions, the aged females showed a better performance than the aged males, opposite to the retrieval day. Neuroinflammation in the dorsal hippocampous was significantly increased in older animals, with higher levels in males compared to females. Correlation analyses indicated that increased neuroinflammation is related to worse cognitive performance. 4th) Analysis of the lipid composition of O. degus along aging in the prefrontal cortex (PFC), striatum, cortex and cerebellum. Changes in lipid species were region-specific, although alterations in glycosphingolipids were common to all regions. The greatest sex-associated differences were found in gangliosides, while sphingomyelin and sulfatides were significantly different when comparing males and females of senile age. Lipid peroxidation (LPO) in the PFC was significantly increased along aging, males showing significant higher levels of LPO than females. Higher POL significantly correlated with worse cognitive performance. 5th) Validation of the O. degus as a model of experimental Parkinsonism based on 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) intoxication. MPTP intoxicated animals showed dysregulation of blood glucose levels, together with motor and cognitive alterations. Post mortem analysis revealed a very significant loss of tyrosine hydroxylase-positive neurons in the Substantia Nigra pars compacta (SNpc), in the ventral tegmental area (VTA) and in the locus coeruleus (LC) of MPTP-intoxicated animals. A significant increase in neuroinflammatory markers in the SNpc, striatum, dorsal hippocampus and LC of parkinsonized animals was found. To conclude, this research represents a reasonable contribution to the scientific community in different aspects. On the one hand, a longitudinal study of these dimensons considering both sexes in the O. degus had never been done before. It validates different experimental procedures and protocols in this species. On the other hand, findings obtained support that this species is a unique tool for aging research in the context of multimorbidity, possesing similarities with humans that are not present in other preclinical models. The sex-related differences found offer the possibility of approaching different scientific questions from the sex perspective.