Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model

Abstract

Background and purpose Data from both humans and animal models suggest that most recovery from motor impairment occurs in a sensitive period that lasts only weeks after stroke and is mediated in part by an increased responsiveness to training. Here we used a mouse model of focal cortical stroke to test two hypotheses. First we investigated if responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Methods Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area (CFA). The mice were then retrained after a 1-day or 7-day delay with and without fluoxetine. Results Recovery of prehension after a CFA stroke was complete if training was initiated one day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine appeared to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. Conclusions There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke.

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke

“…Specifically, using custom built cages (schematized in Figure 1B – E) we trained wild-type adult male mice to perform a skilled prehension task to an asymptotic level of performance, photothrombotically induced a focal CFA infarction (t1; Figure 2 A and B), and retrained them after a 7-day delay. Assessment on the prehension task on day 18 (eight days after stroke) revealed that there was little spontaneous recovery of performance, which is in agreement with our prior results [7], and subsequent training over 19 days total led to only mild performance gains that never returned to pre-stroke levels (Figure 3A and B days 18 – 36). A second focal stroke was then induced in the ipsilesional medial premotor area (AGm) at time point t2 (figure 2 A and B).…”

“…during days 18–36) that we saw here in the mouse is consistent with studies in the rat that failed to show a benefit of late tune-ups despite a response to training early after stroke [20]. That the impact of training falls off rapidly within one week post-stroke is consistent with our prior results [7] and also consistent with results in rats showing only a modest response to training and enrichment given 2 weeks post-stroke, compared to when given early [1]. Human data also suggest a short-lived plasticity window after stroke with most spontaneous recovery, which follows a predictable proportionality rule [3, 21], occurring in the first 3 months [4, 22].…”

“…We have previously shown that the medial agranular cortex (AGm), a medial premotor area, reorganizes after a focal caudal forelimb area (CFA), rodent primary motor cortex, stroke and mediates recovery if post-stroke training is initiated after a one-day post-stroke delay (i.e. 48 hours after stroke) but not if initiation of training is delayed for a week [6, 7]. We refer to this period of increased responsiveness to training as the post-stroke “sensitive period,” which represents a unique, time-limited environment of heightened plasticity [8].…”

Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

“…Proficiency in other motor tests appears to improve spontaneously after injury, especially when end-point measures are used. Indeed, it has been clearly shown that sensory-motor performances (including reaching success in the pellet grasping task) improve already after 2 weeks3940414243.…”

Duality of Antidepressants and Neuroprotectants

“…However, controversy over fluoxetine’s exact mechanism of action in stroke remains. Although fluoxetine may increase neurogenesis (Corbett et al 2015; Imoto et al 2015; Sun et al 2015), its beneficial effect in stroke may be due to reducing inhibitory interneuron expression in the premotor cortex (Ng et al 2015). Nonetheless, taken together, it may be suggested that elevated levels of neurotrophins in general and BDNF in particular following antidepressants administration are at least partially responsible for the enhanced neurogenesis and hence beneficial effects in neurodegenerative diseases such as AD.…”