Lesion Size- and Location-Dependent Recruitment of Contralesional Thalamus and Motor Cortex Facilitates Recovery after Stroke in Mice

Abstract

Brain lesions caused by cerebral ischemia or hemorrhage lead to a local breakdown of energy homeostasis followed by irreversible cell death and long-term impairment. Importantly, local brain lesions also generate remote functional and structural disturbances, which contribute to the behavioral deficit but also impact the recovery of function. While spontaneous recovery has been associated with endogenous repair mechanisms at the vascular, neural, and immune cell levels, the impact of structural plasticity on sensory-motor dysfunction and recovery thereof remains to be elucidated by longitudinal imaging in a mouse model. Here, we applied behavioral assessments, in vivo fiber tracking, and histological validation in a photothrombotic stroke mouse model. Atlas-based whole-brain structural connectivity analysis and ex vivo histology revealed secondary neurodegeneration in the ipsilesional brain areas, mostly in the dorsal sensorimotor area of the thalamus. Furthermore, we describe for the first time a lesion size-dependent increase in structural connectivity between the contralesional primary motor cortex and thalamus with the ipsilesional cortex. The involvement of the contralesional hemisphere was associated with improved functional recovery relative to lesion size. This study highlights the importance of in vivo fiber tracking and the role of the contralesional hemisphere during spontaneous functional improvement as a potential novel stroke biomarker and therapeutic targets. Electronic supplementary material The online version of this article (10.1007/s12975-020-00802-3) contains supplementary material, which is available to authorized users.

Secondary Degeneration of White Matter After Focal Sensorimotor Cortical Ischemic Stroke in Rats

“…The alteration of interhemispheric connectivity is a common phenomenon in most unilateral ischemic strokes, a finding which has been revealed using varying technologies such as resting-state functional MRI and manganese-enhanced MRI ( van der Zijden et al, 2008 ; van Meer et al, 2010 , 2012 ). Similar degeneration of interhemispheric fibers connecting lesioned areas with the sensorimotor cortex on the contralesional hemisphere has also recently been revealed by diffusion MRI in a photothrombotic stroke mouse model ( Aswendt et al, 2020 ). Interhemispheric connectivity mediates the transfer of signals between hemispheres and plays important roles in sensorimotor function ( van Meer et al, 2010 , 2012 ).…”

“…The ultra-high-field magnets with its higher signal-to-noise ratio (SNR) and spatial resolution could greatly enhance our ability to use diffusion tensor imaging (DTI) to study microstructure more exquisitely in a whole-brain level. However, animal studies on secondary WM damage using whole-brain neuroimaging tools are still few ( Jung et al, 2017 ; Aswendt et al, 2020 ), and their relation to primary ischemic lesions and functional outcomes have not yet been well understood.…”

“…In this study, we systematically explored secondary WM degeneration following induced focal sensorimotor cortex ischemia in rats using microstructure MRI, primarily diffusion MRI with high and isotropic resolution. The comparable plane but highly improved resolution in slice direction compared with previous ex vivo and in vivo studies ( Jiang et al, 2006 ; Aswendt et al, 2020 ) could help track WM more exquisitely and be beneficial for the quantitative assessments of WM secondary degeneration. The importance of isotropic resolution for fiber tractography has been demonstrated in some studies ( Mukherjee et al, 2008 ; Neher et al, 2013 ).…”

Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally

“…Our lesion experiment results imply a role for S1 and its intracortical connectivity in eliciting SWs. Alternatively, it is possible that the loss of global propagation is influenced by remote effects [e.g., secondary injury to corticothalamic connectivity (42)]. The role of the thalamus in cortical SWs has been historically controversial.…”

Reactive Astrocytes Prevent Maladaptive Plasticity after Ischemic Stroke

“…The mice underwent photothrombotic stroke and a longitudinal experimental protocol composed of repetitive MRI and three different sensorimotor behavioral tests until 4 weeks after stroke ( Figure 1a ). Photothrombosis was done as described (Aswendt et al, 2021) in the left hemisphere inducing a functional deficit in the right fore- and hindlimb. In brief, after intraperitoneal injection of 1.5 mg of Rose Bengal (in 150 μl of phosphate-buffered saline), 50 mW laser radiation at 561 nm was delivered over 15 min at brain coordinates M/L +2.0 and A/P +0.5 mm, targeting the primary somatosensory forelimb area and primary motor cortex.…”