title: High-Speed imaging reveals opposing effects of chronic stress and antidepressants on neuronal activity propagation through the hippocampal trisynaptic circuit.
abstract: Antidepressants (ADs) are used as first-line treatment for most stress-related psychiatric disorders. The alterations in brain circuit dynamics that can arise from stress exposure and underlie therapeutic actions of ADs remain, however, poorly understood. Here, enabled by a recently developed voltage-sensitive dye imaging (VSDI) assay in mouse brain slices, we examined the impact of chronic stress and concentration-dependent effects of eight clinically used ADs (belonging to different chemical/functional classes) on evoked neuronal activity propagations through the hippocampal trisynaptic circuitry (HTC: perforant path → dentate gyrus (DG) → area CA3 → area CA1). Exposure of mice to chronic social defeat stress led to markedly weakened activity propagations ("HTC-Waves"). In contrast, at concentrations in the low micromolar range, all ADs, which were bath applied to slices, caused an amplification of HTC-Waves in CA regions (invariably in area CA1). The fast-acting "antidepressant" ketamine, the mood stabilizer lithium, and brain-derived neurotrophic factor (BDNF) exerted comparable enhancing effects, whereas the antipsychotic haloperidol and the anxiolytic diazepam attenuated HTC-Waves. Collectively, we provide direct experimental evidence that chronic stress can depress neuronal signal flow through the HTC and demonstrate shared opposing effects of ADs. Thus, our study points to a circuit-level mechanism of ADs to counteract stress-induced impairment of hippocampal network function. However, the observed effects of ADs are impossible to depend on enhanced neurogenesis.
authors.affiliation: Max Planck Institute of Psychiatry Munich, Germany ; Department Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry Munich, Germany ; Scientific Core Unit "Electrophysiology and Neuronal Network Dynamics", Max Planck Institute of Psychiatry Munich, Germany ; Clinical Department, Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Stepan
authors.affiliation: Max Planck Institute of Psychiatry Munich, Germany ; Department Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry Munich, Germany ; Scientific Core Unit "Electrophysiology and Neuronal Network Dynamics", Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Hladky
authors.affiliation: Max Planck Institute of Psychiatry Munich, Germany ; Department Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry Munich, Germany ; Research Group "Stress Resilience", Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Andrés
authors.initials: A
authors.lastname: Uribe
authors.affiliation: Max Planck Institute of Psychiatry Munich, Germany ; HMNC GmbH Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Max Planck Institute of Psychiatry Munich, Germany ; Department Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry Munich, Germany ; Research Group "Stress Resilience", Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute of Psychiatry Munich, Germany ; Department Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry Munich, Germany ; Scientific Core Unit "Electrophysiology and Neuronal Network Dynamics", Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D002908:Chronic Disease; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D005473:Fluoxetine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology*; D007649:Ketamine / Q000494:pharmacology; D018020:Lithium Compounds / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology*; D046509:Tissue Culture Techniques; D056969:Voltage-Sensitive Dye Imaging
chemical_list: C559317:ANA 12 compound; D000928:Antidepressive Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D002491:Central Nervous System Agents; D018020:Lithium Compounds; D005473:Fluoxetine; D007649:Ketamine; D006220:Haloperidol; D003975:Diazepam
keywords: activity propagation; antidepressants; hippocampus; imaging; ketamine; stress; trisynaptic circuit; voltage-sensitive dye