Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment

Neurotherapeutics. 2018 Jan;15(1):200-215. doi: 10.1007/s13311-017-0590-3.


Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB+ cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII+ cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67+ cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.

Keywords: Antidepressant; Cognitive function; Exercise; Poststroke depression; Prefrontal cortex; Serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / drug therapy*
  • Anxiety / etiology
  • Behavior, Animal / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / etiology
  • Depression / drug therapy*
  • Depression / etiology
  • Disease Models, Animal
  • Fluoxetine / administration & dosage*
  • Glutamate Decarboxylase / metabolism
  • Male
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism
  • Physical Conditioning, Animal
  • Stroke / complications*
  • Tryptophan Hydroxylase / metabolism
  • Vesicular Glutamate Transport Proteins / metabolism


  • Vesicular Glutamate Transport Proteins
  • Fluoxetine
  • Tryptophan Hydroxylase
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1