C02 Locus ceruleus directed cell autonomous and non-cell autonomous changes of neuronal activity

The locus ceruleus (LC) is the chief source of central noradrenaline (NA) generation in the mammalian brain. From there projections arise, which target in particular the limbic system and neocortex. During the first funding period, our work suggests that there are two principle mechanisms by which such a NA-mediated regulation of neuronal activity can be achieved: First, neuronal β1- and β2-adrenoreceptors may be activated by NA leading to a cell-autonomous regulation of neuronal activity. To test this hypothesis, we will use AAV- and cre-lox-mediated cell-specific knock-down strategies to test whether genetic ablation of either the β1- or β2-adrenoreceptor alters the LC-mediated changes of neuronal activity in the cortex and hippocampus. Second, LC derived NA may modulate microglial release of immune factors, including those, which have been shown to affect neuronal integrity and functioning. Given the strong evidence for a β1- or β2-adrenoreceptor-mediated regulation of microglial activation and function, LC-derived NA may modulate the activity of cortical neurons through such an indirect, non-cell autonomous and microglia-dependent mechanism. This hypothesis will be tested by microglia depletion experiments using the anti-CSF1R strategy and subsequent analysis of the described parameters. In case, microglia depletion is going to influence LC-directed changes of cortical neuron activity, we will generate mice carrying a microglia-specific gene knockout for the β1- or β2-adrenoreceptor. Since LC neurons degenerate early during the course of Alzheimer’s disease (AD), we will test whether the presence of amyloid pathology in murine models of AD is further aggravating neuronal dysfunction induced by optogenetic LC modulation using the aforementioned strategies to investigate the proposed cell- and non-cell autonomous regulation mechanisms in a murine AD model.