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Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor-ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.

Our findings indicate a need to revise the Chompret criteria. However, in younger adults (<40 yr old) with ACC, screening for TP53 germline mutations may be justified.

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Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD) and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI) fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.

MicroRNAs (miRNA) are a class of small non-coding RNAs that have recently emerged as epigenetic modulators of gene expression in psychiatric diseases like schizophrenia and major depression. So far, miRNAs have neither been studied in patients suffering from posttraumatic stress disorder (PTSD) nor in PTSD animal models. Here, we present the first study exploring the connection between miRNAs and PTSD. Employing our previously established PTSD mouse model, we assessed miRNA profiles in prefrontal cortices (PFCs) dissected from either fluoxetine or control-treated wildtype C57BL/6N mice 74 days after their subjection to either a single traumatic electric footshock or mock-treatment. Fluoxetine is an antidepressant known to be effective both in PTSD patients and in mice suffering from a PTSD-like syndrome. Screening for differences in the relative expression levels of all potential miRNA target sequences of miRBase 18.0 by pairwise comparison of the PFC miRNA profiles of the four mouse groups mentioned resulted in identification of five miRNA candidate molecules. Validation of these miRNA candidates by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) revealed that the therapeutic action of fluoxetine in shocked mice is associated with a significant reduction in mmu-miR-1971 expression. Furthermore, our findings suggest that traumatic stress and fluoxetine interact to cause distinct alterations in the mouse PFC miRNA signature in the long-term.

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