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

Abstract

Modelling stroke in animals remains a challenge for translational research, especially for the infraction of small subcortical arteries. Using combined fibre optics and photothrombosis technologies, we developed a novel model of optically-induced infarcts (Opto-STROKE). Combining our model with electrophysiological recordings in freely-behaving mice, we studied early and late consequent patho-physiological changes in the dynamics of sleep-wake circuits and cognitive performance. Here, focusing on inducing Opto-STROKE lesions in the intralaminar thalamus (IL), which in humans cause severe impairments of arousal, cognition, and affective symptoms, our model recapitulated important deficits on sleep disorders presented in humans including arousal instability, concurrent to an augmented slow-wave activity and a reduction gamma power bands during wakefulness. Moreover, during NREM sleep, spindle density was decreased and topographically shifted to frontal cortices when compared to control animals. Remarkably, gamma power and spindle density were correlated with decreased pain threshold and impaired prefrontal cortex- dependent working memory in Opto-STROKE mice relative to controls. Collectively, our combined method influences both anatomical and functional outcomes of the classical stroke procedures and offers new insights on the fundamental role of the media thalamus as a hub for the regulation of both sleep-wake architecture and cognition.

Thalamic Stroke: An Opportunity to Study the Brain Mechanisms of Sleep–Wake and Cognition

“…While the lesions of the mediodorsal thalamic nucleus disrupt performance in spatial and working memory tasks, this is due to strategic components of the task rather than deficiencies in spatial memory [110]. Remarkably, memory deficits were correlated with spindle and slow wave decline following opto-stroke [54]. This supports the prevailing assumption that the mediodorsal thalamus plays a crucial role in working memory due to its projections to the prefrontal cortex [111,112].…”

“…Furthermore, a lesion in the medial thalamus reduced alpha EEG power during transitions from wakefulness to NREM sleep as well as a significant reduction in frontal sleep spindle power, which was positively correlated with deficiencies in working memory [54]. Interestingly, there was no alteration in motor performance and anxiety, highlighting the specificity of the effects related to medial thalamic lesions [54].…”

“…Despite the consistent evidence of the influence of the thalamic lesion per se on sleep and cognition, recent advances in stroke animal models (see Box 1 and Figure 2) allow precise experimental control and enable researchers to observe the effects of the manipulation of specific thalamic circuits on sleep and cognition [54,92,[130][131][132].…”

“…Lenzi et al adopted the following approach, using an "opto-Stroke" model (shown in Figure 2) to selectively induce a lesion in the medial thalamus [54]. Their study in mice effectively replicated the reduction in NREM sleep and increased sleep instability, common in patients with medial thalamic stroke [54].…”

“…Lenzi et al adopted the following approach, using an "opto-Stroke" model (shown in Figure 2) to selectively induce a lesion in the medial thalamus [54]. Their study in mice effectively replicated the reduction in NREM sleep and increased sleep instability, common in patients with medial thalamic stroke [54]. Furthermore, a lesion in the medial thalamus reduced alpha EEG power during transitions from wakefulness to NREM sleep as well as a significant reduction in frontal sleep spindle power, which was positively correlated with deficiencies in working memory [54].…”