Neuroinflammation and aberrant hippocampal plasticity in a mouse model of emotional stress evoked by exposure to ultrasound of alternating frequencies

Emotional stress is a form of stress evoked by processing negative mental experience rather than an organic or physical disturbance and is a frequent cause of neuropsychiatric pathologies, including depression. Susceptibility to emotional stress is commonly regarded as a human- specific trait that is challenging to model in other species. Recently, we showed that a 3-week-long exposure to ultrasound of unpredictable alternating frequencies within the ranges of 20-25kHz and 25-45kHz can induce depression-like characteristics in laboratory mice and rats. In an anti-depressant sensitive manner, exposure decreases sucrose preference, elevates behavioural despair, increases aggression, and alters serotonin-related gene expression. To further investigate this paradigm, we studied depression/distress-associated markers of neuroinflammation, neuroplasticity, oxidative stress and the activity of glycogen synthase kinase-3 (GSK-3) isoforms in the hippocampus of male mice. Stressed mice exhibited a decreased density of Ki67-positive and DCX-positive cells in the subgranular zone of hippocampus, and altered expression of brain- derived neurotrophic factor (BDNF), its receptor TrkB, and anti-apoptotic protein kinase B phosphorylated at serine 473 (AktpSer473). The mice also exhibited increased densities of Iba- 1-positive cells, increased oxidative stress, increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) in the hippocampus and plasma, and elevated activity of GSK-3 isoforms. Together, the results of our investigation have revealed that unpredictable alternating ultrasound evokes behavioural and molecular changes that are characteristic of the depressive syndrome and validates this new and simple method of modeling emotional stress in rodents