Previous animal studies including our own using etifoxine or comparable TSPO compounds have demonstrated that TSPO is involved in the regulation of stress-related, especially anxiety-related behavior in a sex-dependent manner. However, to which extent the brain TSPO system itself is affected by acute or chronic stress, and has the capacity to modulate characteristic stress parameters at various levels is largely unknown. Therefore, we will first characterize the consequences of exposure to either acute or chronic stress on the expression of TSPO in distinct neuronal populations, such as hypothalamic corticotropin releasing factor (CRF), oxytocin and vasopressin neurons, relevant for emotionality and stress processing in male and female mice. Vice versa, we will further study potential sex-dependent effects of manipulation of the TSPO system on selected neuroendocrine and neuronal stress parameters after exposure to either acute or chronic stress. In this context we will either target the TSPO system in a neuron-specific manner, i.e., in CRF neurons using a viral approach and CRF-CRE mice, use TSPO knockout mice, or apply the TSPO ligand etifoxine or the TSPO antagonist ONO-2952 systemically to promote the translational value of the project. As acute stressor, male and female mice will be exposed to 60-s forced swimming, which allows in parallel to additionally assess stress-coping behavior. With respect to chronic stressor exposure, male mice will be exposed to chronic subordinate colony (CSC) housing - a clinically relevant model of chronic psychosocial stress associated with long-term anxiogenesis and basal hypocorticism, but increased reactivity of the hypothalamo-pituitary-adrenal (HPA) axis towards heterotypic stressors, among others. As neuroendocrine readout parameters we will focus on hormones reflecting the activity of the HPA axis, i.e., ACTH and corticosterone, plasma oxytocin and pregnenolone - a neuroactive steroid associated with the activity of the HPA axis. Moreover, in cooperation with project C3 we will quantify spine densities in selected brain regions such as the PVN, amygdala, prefrontal cortex and hippocampus in response to acute stress with and without manipulation of the TSPO system.Our studies ranging from behavioral to neuroendocrine and cellular levels will decipher possible targets for translational research potentially leading to new treatment options in stress-related disorders. Thus, if we find evidence that the TSPO ligand etifoxine affects HPA axis reactivity especially depending on the nature of the stressor or on sex, this may promote the clinical application of TSPO ligands with respective consequences on health care.
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