Interactions of brain TSPO and stress-related systems under acute and chronic stress conditions

以前的动物研究，包括我们自己使用的乙氧西林或类似的TSPO化合物，已经证明TSPO以一种性别依赖的方式参与调节压力相关的行为，特别是焦虑相关的行为。然而，大脑TSPO系统本身在多大程度上受到急性或慢性应激的影响，并具有在不同水平上调节特征应激参数的能力，在很大程度上尚不清楚。因此，我们将首先表征急性或慢性应激对不同神经元群体TSPO表达的影响，如下丘脑促肾上腺皮质激素释放因子(CRF)、催产素和加压素神经元，这些神经元与雄性和雌性小鼠的情绪性和应激处理有关。反之亦然，我们将进一步研究在暴露于急性或慢性应激后，操纵TSPO系统对选定的神经内分泌和神经元应激参数的潜在性别依赖性影响。在这种情况下，我们将以神经元特异性的方式针对TSPO系统，即使用病毒方法在CRF神经元和CRF-CRE小鼠中，使用TSPO基因敲除小鼠，或者系统地应用TSPO配体替福辛或TSPO拮抗剂ONO-2952来促进该项目的翻译价值。作为急性应激源，雄性和雌性小鼠将暴露在60-S强迫游泳中，这允许同时额外评估压力应对行为。在慢性应激源暴露方面，雄性小鼠将暴露在慢性从属群体(CSC)环境中--这是一种与长期焦虑和基础皮质症相关的慢性心理社会应激模型，但下丘脑-垂体-肾上腺(HPA)轴对异型应激源的反应性增加等。作为神经内分泌读数参数，我们将重点关注反映HPA轴活动的激素，即ACTH和皮质酮、血浆催产素和孕烯醇酮-一种与HPA轴活动相关的神经活性类固醇。此外，与C3项目合作，我们将量化选定大脑区域如PVN、杏仁核、前额皮质和海马区的脊柱密度，以应对急性应激，无论是否操纵TSPO系统。我们的研究范围从行为到神经内分泌和细胞水平，将破译翻译研究的可能靶点，可能导致应激相关疾病的新治疗选择。因此，如果我们发现TSPO配体乙氧福辛影响HPA轴反应性的证据，特别是依赖于应激源的性质或性别，这可能会促进TSPO配体的临床应用，并对医疗保健产生各自的影响。

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.