High-Speed imaging reveals opposing effects of chronic stress and antidepressants on neuronal activity propagation through the hippocampal trisynaptic circuit

Front Neural Circuits. 2015 Nov 6:9:70. doi: 10.3389/fncir.2015.00070. eCollection 2015.

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.

Keywords: activity propagation; antidepressants; hippocampus; imaging; ketamine; stress; trisynaptic circuit; voltage-sensitive dye.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Azepines / pharmacology
  • Benzamides / pharmacology
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Central Nervous System Agents / pharmacology
  • Chronic Disease
  • Diazepam / pharmacology
  • Disease Models, Animal
  • Dominance-Subordination
  • Fluoxetine / pharmacology
  • Haloperidol / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology*
  • Ketamine / pharmacology
  • Lithium Compounds / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / physiopathology*
  • Tissue Culture Techniques
  • Voltage-Sensitive Dye Imaging

Substances

  • ANA 12 compound
  • Antidepressive Agents
  • Azepines
  • Benzamides
  • Brain-Derived Neurotrophic Factor
  • Central Nervous System Agents
  • Lithium Compounds
  • Fluoxetine
  • Ketamine
  • Haloperidol
  • Diazepam