Chronic stress is a major cause of neuropsychiatric conditions such as depression. Stress vulnerability varies individually in mice and humans, measured by behavioral changes. In contrast to affective symptoms, motor retardation as a consequence of stress is not well understood. We repeatedly imaged dendritic spines of the motor cortex in Thy1-GFP M mice before and after chronic social defeat stress. Susceptible and resilient phenotypes were discriminated by symptom load and their motor learning abilities were assessed by a gross and fine motor task. Stress phenotypes presented individual short- and long-term changes in the hypothalamic–pituitary–adrenal axis as well as distinct patterns of altered motor learning. Importantly, stress was generally accompanied by a marked reduction of spine density in the motor cortex and spine dynamics depended on the stress phenotype. We found astrogliosis and altered microglia morphology along with increased microglia-neuron interaction in the motor cortex of susceptible mice. In cerebrospinal fluid, proteomic fingerprints link the behavioral changes and structural alterations in the brain to neurodegenerative disorders and dysregulated synaptic homeostasis. Our work emphasizes the importance of synaptic integrity and the risk of neurodegeneration within depression as a threat to brain health.

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Vagus nerve stimulation (VNS) is an established tool in the psychiatric armamentarium for patients with therapy-resistant depression (TRD) with response rates of approximately 60%. So far, VNS is titrated slowly during ambulatory in-office visits. Thus, antidepressive effects can be expected after approximately six months. We report our experiences with a rapid dosing regime (RDR) with titration start shortly after VNSimplantation. We retrospectively analysed data of six patients with TRD who received VNS. Stimulation parameters were evaluated with regard to clinical side effects, heart rates (HR) and blood pressures (BP). Depressive symptoms were measured by Montgomery-Asberg Depression Rating Scale (MADRS) one week before and three months after implantation of the VNS. All patients received first stimulation between one and four days after surgery. We elevated output current using 0.25 mA titration steps. We increased output current between one and four days after the last titration. All patients received 1.0 mA output current after eight to 14 days post-surgery. HR and BP remained stable in all patients. All side effects were mild and temporary. MADRS scores were significantly lower three months after VNS-implantation (24 ± 8) than one week before VNS-implantation (42 ± 4; p = 0.028). The therapeutic range of VNS-parameters for antidepressive effect was reached quicker without finding increased numbers of side effects. Consequently, by using RDR the antidepressive effect of VNS-therapy for patients with TRD could be reached earlier than using slow titration. Our presented RDR might be able to significantly shorten the ''clinical effect gap" due to the neurobiological and titration-related latency.

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