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

Abstract

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.

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

“…[109][110][111] In contrast, deletion of the repressor CC2D1A/ Freud-1 in 5-HT neurons of adult mice (both sexes) led to an upregulation of 5-HT 1A autoreceptors, and an SSRIresistant anxiety and depression-like phenotype. 112 Importantly, these effects were dependent on increased 5-HT 1A autoreceptors and were not seen in a 5-HT 1A autoreceptordeficient background. 113 Like the Freud-1 knockout mice, knockout in adult 5-HT neurons of MeCP2, an X-linked methyl-binding protein that interacts with and augments DEAF1 activity, induced 5-HT 1A autoreceptors and led to a sex-dependent behavioural phenotype: females had reduced anxiety, whereas males showed increased anxiety and reduced depression-like behaviours.…”

Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression

“…At 6 weeks post-stroke including 2-3 weeks of behavioral testing, there was a global increase in FosB-stained cells at the lesion site and throughout the corticolimbic system 35 . Chronic treatment with FLX for 3 weeks was associated with a reduction in FosB-stained cells towards normal, suggesting a restoration of neuronal activity 35 . We hypothesized that SSRI-induced recovery involves plasticity of 5-HT projections to regions affected by the stroke.…”

“…After 6 weeks, the stroke lesion site spontaneously refills with neurons and glia, yet the behavioral and cognitive phenotypes persist. Treatment of PSD mice with chronic fluoxetine (FLX) reversed these phenotypes, while chronic exercise (free running wheel) was ineffective 34,35 . At 6 weeks post-stroke including 2-3 weeks of behavioral testing, there was a global increase in FosB-stained cells at the lesion site and throughout the corticolimbic system 35 .…”

“…Treatment of PSD mice with chronic fluoxetine (FLX) reversed these phenotypes, while chronic exercise (free running wheel) was ineffective 34,35 . At 6 weeks post-stroke including 2-3 weeks of behavioral testing, there was a global increase in FosB-stained cells at the lesion site and throughout the corticolimbic system 35 . Chronic treatment with FLX for 3 weeks was associated with a reduction in FosB-stained cells towards normal, suggesting a restoration of neuronal activity 35 .…”

Is poststroke depression the same as major depression?

“…25 Another model used endothelin-1 microinjection to induce a small lesion of the left medial prefrontal cortex, resulting in anxietyand depression-like behaviour, as well as cognitive impairment, with no sensorimotor impairment. 26,27 In this model, chronic SSRI treatment, but not free running wheel exercise, reversed the behavioural and cognitive phenotypes. Interestingly, the small lesion became refilled with neurons, which may be recruited by SSRI treatment.…”