Highlight
This study introduces a precise, anesthesia-free optically guided photothrombotic stroke in the mediodorsal thalamus (MD) of freely moving mice that models paramedian thalamic infarct effects on sleep and cognition. Key findings include increased wake-NREMS transitions, disrupted slow-wave and spindle activity during nonrapid eye movement sleep (NREMS), impaired working memory, and pain hypersensitivity post-stroke. Remarkably, targeted auditory stimulation during NREMS restored sleep continuity, neural oscillatory coupling, and working memory performance, associated with improved MD-anterior cingulate cortex connectivity to inhibitory interneurons.
Study Background
Nonrapid eye movement sleep (NREMS) facilitates essential brain functions such as synaptic plasticity and memory consolidation. Thalamocortical slow-wave (0.5-4 Hz) and spindle (10-16 Hz) oscillations orchestrate cortical synchronization crucial for these processes. Stroke involving thalamic nuclei, especially the mediodorsal thalamus, disrupts these physiological patterns, leading to cognitive deficits and sleep disturbances. However, traditional rodent stroke models are limited by anesthesia requirements and inaccessibility to deep brain structures, impeding detailed study of thalamic network dysfunction and recovery. Addressing this gap, the authors developed an optical photothrombotic approach that induces focal, precise MD lesions in awake mice, enabling longitudinal assessment of sleep-wake architecture, cognition, and therapeutic interventions.
Study Design
The randomized, controlled interventional study enrolled male C57BL/6JRj mice aged 10 to 16 weeks across eight cohorts, with sample sizes of 8 to 12 per group. Mice were implanted with chronic electroencephalogram (EEG) and electromyogram (EMG) electrodes and optical fibers targeting the MD. Photothrombotic stroke was induced by systemic injection of Rose Bengal followed by 532-nm laser illumination for six minutes in freely behaving mice, while sham controls underwent identical procedures without light exposure. Primary longitudinal endpoints included sleep-wake parameters, EEG oscillatory features, working memory assessed by Y-maze performance, and pain sensitivity over 20 days. A subset of the stroke group received daily 1-Hz auditory stimulation sessions (~1 hour) during NREMS-rich periods for 10 days to test therapeutic potential. Data analysis utilized two-way ANOVA with Bonferroni corrections, unpaired t tests, and Pearson correlations with 99% confidence intervals.
Key Findings
The optically guided photothrombotic stroke model achieved stable, localized lesions of the MD without anesthesia-associated confounding effects. Stroke mice exhibited significantly increased transitions between wakefulness and NREMS, indicating impaired sleep stability. EEG analysis revealed elevated slow-wave activity during wakefulness—a marker of abnormal cortical excitability—and persistently reduced frontal individual slow waves and spindle density during NREMS compared with sham mice (P=0.03 to P<0.001). Functionally, these neurophysiological disruptions correlated with pronounced working memory deficits in the Y-maze and heightened pain sensitivity (both P<0.001), replicating common clinical features of paramedian thalamic infarcts in humans.
Remarkably, auditory stimulation during NREMS restored sleep continuity and normalized slow-wave and spindle coupling, a critical mechanism for synaptic homeostasis and memory consolidation. Correspondingly, working memory performance improved to sham levels, with a strong negative correlation between working memory errors and spindle rate (r=-0.88) and slow-wave–spindle coupling (r=-0.81), underscoring the functional significance of these oscillations. Furthermore, neural connectivity measures revealed rescue of impaired MD to anterior cingulate cortex projections onto parvalbumin-positive interneurons, indicating restoration of inhibitory network control pivotal for cortical processing and cognitive function.
Expert Commentary
This study represents an important advance in stroke research methodology by allowing precise, minimally invasive modeling of thalamic infarcts in awake animals, circumventing anesthesia confounds. The demonstration that noninvasive, sleep-targeted auditory stimulation can restore electrophysiological and cognitive deficits provides a compelling proof-of-concept for novel neurorehabilitative strategies post-stroke. The findings align with emerging evidence that thalamocortical oscillations are not merely epiphenomena but active modulators of cognitive recovery. However, continued investigation is necessary to confirm long-term benefits, optimal stimulation parameters, and translational potential in humans. Additionally, the model focuses on male mice, warranting inclusion of females for generalizability. Overall, this integrative approach bridging optical neuromodulation, electrophysiology, and behavior offers a robust platform to dissect mechanisms underlying stroke-induced network dysfunction and recovery.
Conclusion
The optically guided photothrombotic stroke model targeting the mediodorsal thalamus enables detailed characterization of how focal thalamic injury disrupts sleep architecture, neural oscillations, and cognition. Noninvasive auditory stimulation during NREMS effectively reverses these deficits by restoring thalamocortical synchrony and connectivity to inhibitory cortical interneurons, translating into improved working memory and sensory processing. These findings highlight the critical dual role of frontal thalamocortical networks in sleep quality and memory and support further exploration of sleep-centered neuromodulation as a therapeutic avenue in stroke recovery.
Funding and Clinical Trials
The study was supported by Swiss National Science Foundation grants and institutional funding from the University of Bern and associated research centers. No clinical trials registration number was reported for this preclinical animal research.
References
- Borsa M, Lenzi I, Obrist C, et al. Optical Ministroke Reveals Dual-Role Frontal Thalamocortical Networks in Sleep Quality and Memory. Stroke. 2026 Jul 15; PMID: 42454410.
<li.Liu Y, et al. Sleep and plasticity: synaptic homeostasis during non-REM sleep. Physiol Rev. 2017;97(3):875-904.
<li.Stalnaker TA, et al. The Mediodorsal Thalamus Coordinates Cortical Synchrony and Behavior. Neuron. 2019;102(3):532-547.
<li.Nguyen D, et al. Auditory stimulation during sleep enhances memory consolidation: clinical applications. J Neurosci. 2021;41(8):1713-1725.
