WP 6: Janitzky
Dr. Kathrin Janitzky (University of Magdeburg, Clinic for Neurology and LIN, Department Behavioral Neurology)
Impact of monoaminergic activity in disease related to the Locus coeruleus
Recent evidence indicates functional roles of the Locus coeruleus (LC) beyond its traditionally recognized function in controlling general arousal. For example, its degeneration has been related to Alzheimer’s disease. Further, primarily noradrenergic LC-neurons corelease dopamine in frontal cortex, which implicates a role in schizophrenia and diseases of abuse. However, evidence beyond pharmacology, histochemistry and behavioral assays (Janitzky et al. 2007, 2009, 2011), investigating a causal relationship between LC activity and the suggested pathologies is still lacking.
The establishment of optogenetic methods targeting tyrosine-hydroxylase expressing neurons in our laboratories overcomes this problem. Through these tools – initially developed for interference with the dopamine system – LC activity can be accurately controlled on a millisecond scale, even chronically and for long time spans.
Due to the already existing collaboration with WP2, this new approach has already been proven to be feasible. We therefore aim to apply optogenetics in two clinically relevant settings, related to the LC. First, we will optically stimulate the LC of APP-PS1 Alzheimer model mice with different frequencies and assess cognitive ability of the animals over time. This experiment will draw from our existing experience with this mouse line and behavioral assays and test for a causal relationship between LC function and progress of Alzheimer-like pathology. In a second line of research we will investigate contributions of the LC to frontal dopamine function. To this end we will combine optogenetic stimulation of the LC in mice and a pre-pulse inhibition experiment, a clinically meaningful paradigm to investigate disturbances in dopamine related brain function (e.g. schizophrenia, alcoholism). Our laboratories already possess the necessary experience with the task – applied not only to rodents but also to human patients, generating a direct link between optogenetic animal research and future human clinical application.