Multimodal approach for understanding the immune system of the brain in a depression model induced by chronic mild stress

Sophie Crux1, Felix Nebeling1, Fabrizio Musacchio1, Julia Steffen1, Andrea Baral1, Maren Koehne1, Svenja Bourry1, Marc Beyer1, Maciej Lalowski2, Martin Fuhrmann1

1 German Center for Neurodegenerative Diseases
2 University of Helsinki

Major depressive disorder is a substantial health challenge for our society. Chronic stress is considered a major risk factor for depression, but there is limited understanding of the molecular mechanisms underlying the disease. Accumulating evidence suggests that microglia, innate immune cells of the brain, are implicated in the synaptic dysfunction that plays a crucial role in the etiology and course of depression. To address, whether microglia are involved in hippocampal synapse impairments, we use a mouse model of depression induced by chronic mild stress in combination with a multimodal approach that enables us to correlate behavior, changes in neuronal structural plasticity and microglial RNA and protein profiles in the hippocampus. The chronic mild stress protocol is applied by the standardized and automated IntelliCage, requiring minimal human intervention. During the stress paradigm, mice are exposed to mild unpredictable stressful events, resulting in depressive-like symptoms such as anhedonia. Morphological changes of microglia and neurons, namely microglia motility, dendritic spine density and microglia-neuron interaction in the hippocampus, are monitored by chronic in vivo 2-photon microscopy and correlated to the behavioral effects of chronic mild stress. Finally, the brain is harvested for microglial FACS sorting and subsequent proteomics and RNASeq analysis. By focusing on microglia-synapse interactions from manifold perspectives, this project gives novel insights into the cellular and molecular mechanisms underlying synaptic dysfunction in major depressive disorders.