Project Details
Projekt
The role of TSPO expression in neurons, microglia, and the noradrenergic system following acute and chronic stress
Applicants
Professor Dr. Jochen W. Herms; Dr. Lars Paeger
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 403161218
Translocator protein (18kDa) (TSPO), recently, has been identified as an interesting target for the treatment of psychiatric and neurological disorders. TSPO is expressed in the outer mitochondrial membrane and mediates cholesterol transport to the inner mitochondrial membrane. In turn, neurosteroids have broad physiological functions and, via binding to different receptors, exert modulatory effects on neurotransmitter release such as GABA, glutamate, and norepinephrine. Our own research highlights a role of TSPO in microglia-dependent synaptic turnover, which is altered by the TSPO-ligand diazepam ultimately resulting in cognitive impairment in mice. Here, we will explore specifically the role of TSPO in microglia and neurons on structural plasticity upon exposure to acute and chronic stress. We will further assess the role of TSPO neurons of the locus coeruleus noradrenergic system, which is rapidly activated upon stress exposure and malfunctioning after chronic stress. To this end, we will use models of acute (acute restraint stress) and chronic stress (chronic subordinate colony housing) in mice in combination with well-established chronic in vivo 2 photon imaging of dendritic spines in the two cortical regions. We will assess behavioural alterations and cognition of these animals, and probe whether the TSPO-ligands Etifoxine and ONO-2952 are able to attenuate or reverse symptoms of stress exposure. We will further assess the specific role of neuronal TSPO by perforated patch-clamp experiment in combination with in vitro pharmacology and use state-of-the-art optogenetic and chemogenetic tools. We will dissect the role of locus coeruleus derived noradrenalin on synaptic plasticity and the contribution of TSPO in mediating the animal’s response to acute and chronic stress. Ultimately, in vivo miniature-endomicroscopy will depict neuronal activity before, during and after exposure to acute and chronic stress and indicate how neuronal TSPO and how TSPO-dependent microglia activation alter circuit dynamics and whether the TSPO-ligands are suitable tools in the treatment of stress, anxiety and related psychiatric disorders.
DFG Programme
Research Units
