Slow Waves Promote Sleep-Dependent Plasticity and Functional Recovery after Stroke

Abstract

Functional recovery after stroke is associated with a remapping of neural circuits. This reorganization is often associated with low-frequency, high-amplitude oscillations in the peri-infarct zone in both rodents and humans. These oscillations are reminiscent of sleep slow waves (SW) and suggestive of a role for sleep in brain plasticity that occur during stroke recovery; however, direct evidence is missing. Using a stroke model in male mice, we showed that stroke was followed by a transient increase in NREM sleep accompanied by reduced amplitude and slope of ipsilateral NREM sleep SW. We next used 5 ms optical activation of Channelrhodopsin 2-expressing pyramidal neurons, or 200 ms silencing of Archeorhodopsin T-expressing pyramidal neurons, to generate local cortical UP, or DOWN, states, respectively, both sharing similarities with spontaneous NREM SW in freely moving mice. Importantly, we found that single optogenetically evoked SW (SW opto ) in the peri-infarct zone, randomly distributed during sleep, significantly improved fine motor movements of the limb corresponding to the sensorimotor stroke lesion site compared with spontaneous recovery and control conditions, while motor strength remained unchanged. In contrast, SW opto during wakefulness had no effect. Furthermore, chronic SW opto during sleep were associated with local axonal sprouting as revealed by the increase of anatomic presynaptic and postsynaptic markers in the peri-infarct zone and corresponding contralesional areas to cortical circuit reorganization during stroke recovery. These results support a role for sleep SW in cortical circuit plasticity and sensorimotor recovery after stroke and provide a clinically relevant framework for rehabilitation strategies using neuromodulation during sleep. SIGNIFICANCE STATEMENT Brain stroke is one of the leading causes of death and major disabilities in the elderly worldwide. A better understanding of the pathophysiological mechanisms underlying spontaneous brain plasticity after stroke, together with an optimization of rehabilitative strategies, are essential to improve stroke treatments. Here, we investigate the role of optogenetically induced sleep slow waves in an animal model of ischemic stroke and identify sleep as a window for poststroke intervention that promotes neuroplasticity and facilitates sensorimotor recovery.

Optical mini-stroke of thalamic networks impairs sleep stability, topography and cognition

“…-0.75 mm; DV: -3.8 mm, 10°) and bilaterally over the reticular thalamic nucleus (TRN, AP −0.8 mm, ML +1.7 mm, DV −3.5 mm) and the anterior dorsal thalamus (AD, AP −0.86 mm, ML +0.75 mm, DV −2.71 mm) together with an EEG / EMG connector (Straight Male PCB Header: cat. # 852-10-100-10-001101, Preci-Dip) as previously reported (39) . Animals were instrumented with two screws over the frontal cortices (AP: 2 mm; ML: +/-2 mm), two over the posterior cortices (AP: -3 mm; ML: +/-2 mm) and one the cerebellum as ground (Stainless steel screws diameter: 1,9 x 3,18 mm, Paul Korth GmbH & Co. KG) were in planted.…”

“…Viral injections were performed in animals of 10 to 16 weeks old as previously described (39,50). Briefly, animals were anesthetized with isoflurane (4.0% induction, 1.5% maintenance).…”

“…Slow waves and spindles were detected via customised MATLAB scripts. For slow waves, adapted SWA-MATLAB detection toolbox (39,53) was used to detect the negative envelope across the four EEG channels, filtered between 0.5 and 4 Hz, and consecutive zero-crossings were detected. The threshold in the amplitude of the detected event eliminates the potential individual differences on distances between electrodes and electrode depth that would affect the record amplitude.…”

Deficient thalamo-cortical networks dynamics and sleep homeostatic processes in a redox dysregulation model relevant to schizophrenia

“…SWs amplitude and slope have been shown to be correlated to the frequency of δ2 in mice 26 . Using an automated algorithm detection of SWs in mice 50 , we confirmed that SW slope are increased in cortical and intra-thalamic structures during the first hour of the SR period in WT mice, but absent in KO mice consistent with their impaired sleep homeostasis (suppl. Figure 2C).…”

Driving Oscillatory Dynamics: Neuromodulation for Recovery After Stroke

“…Although the potential for targeting gamma oscillations as a recovery tool is increasingly understood, further evidence is needed to support their role in stroke recovery. A recent study in mice has also shown that optogenetic stimulation of pyramidal neurons at 1 Hz during sleep improves functional recovery and increases axonal sprouting (Facchin et al, 2020). However, these beneficial effects were only observed when the stimulation was induced from 5 days post-stroke and not earlier, further suggesting that different oscillatory frequencies may be important for recovery at different time points.…”