Deciphering the role of locus coeruleus for hippocampus-dependent learning and its impairment in a mouse model of Alzheimer´s disease
1 German Center for Neurodegenerative Diseases (DZNE)
2 Institute of Experimental Epileptology and Cognition Research (IEECR)
Locus Coeruleus (LC) is a neuromodulatory system that is heavily affected at an early stage of Alzheimer´s Disease (AD) progression. In human AD patients, the LC shows an extensive loss of neurons. Therefore, the goals of this project are to examine the influence of the LC on HPC-dependent mnemonic processes under AD-like conditions in a mouse model. To achieve this, we explored, whether the structural and functional connectivity between the LC and the HPC is altered in the APPswe/PSEN1dE9 mouse model of AD. We found a significant reduction of LC to HPC projections identified by immunohistochemically staining in brain tissue of APPswe/PSEN1dE9 mice with a norepinephrine marker protein, and a probe that detects amyloid β (Aβ) plaques. For the functional analysis of LC-HPC projections, we imaged axonal LC-projections in hippocampal CA1 in head-fixed awake mice performing a treadmill task. For this, we achieved precise expression of an axonal GCaMP in LC-originating fibers. A structural analysis of LC-HPC projections revealed Aβ-plaque-associated axonal dystrophies of LC-originating neurites in the CA1 region of APPswe/PSEN1dE9 mice. Our results indicate an important role for the LC for the cognitive deficits under AD-like conditions. Our next experiments will examine the role of the LC-CA1 pathway for spatial memory formation by performing a novel object location task, and by conducting Ca2+-imaging of hippocampal CA1 neurons, while testing the mice on a treadmill. During the tests, we will manipulate the activity of LC-originating axons via chemogenetics.