Early challenges of modulatory systems and consequences on Alzheimer pathology and rescue of learning

Scientific problem and state of the art. Early emotional challenges to modulatory brain systems (e.g. by stress and traumatic experiences) not only seriously affect the developmental maturation of the brain and may cause emotional and cognitive deficits, but are also thought to contribute to the rapid functional loss and/or degenerative vulnerability of the aged brain.
Pertinent previous work at MID. We and other laboratories have shown in rodents that such challenges cause imbalances between excitatory and inhibitory connectivities in dopaminergic and serotonergic afferent systems3. The South American semi-precocial Octodon degus was established in our lab as an early challenge model4, since it displays some striking similarities with human development. It is the only known rodent which naturally displays histological Alzheimer pathology (?- 11 APP695, deposits of human-like amyloid ?-peptide, tau proteine tangles and ubiquitin) in the aged brain1. Goals. This finding opens up new possibilities for exploring (1) whether the age-related pathology correlates with cognitive and learning deficits of these animals, (2) whether potential deficits can be reversed by training of specific skills or in discrimination learning, and (3) whether early challenges are linked to late Alzheimer-like pathology.
Work plan. Methods for imposing early challenges (social deprivation), immunohistochemical analyses of brains3 and conventional training methods1 are established for these animals, and a published brain atlas is available. A new facet to the training potential of these highly intelligent animals will be an automated self-training system (Intellicage-System).
As a further focus of the studies, early deprived and non-deprived animals at a later age will be analyzed with microdialysis in prefrontal cortex for differences in dopamine release during training. The animal will also serve as a model in attempts to image Alzheimer pathology in the brain in vivo with MR- and SPECT-based new echniques.