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Changes in resting-state functional connectivity after stroke in a mouse brain lacking extracellular matrix components.

ABSTRACT: In the brain, focal ischemia results in a local region of cell death and disruption of both local and remote functional neuronal networks. Tissue reorganization following stroke can be limited by factors such as extracellular matrix (ECM) molecules that prevent neuronal growth and synaptic plasticity. The brain's ECM plays a crucial role in network formation, development, and regeneration of the central nervous system. Further, the ECM is essential for proper white matter tract development and for the formation of structures called perineuronal nets (PNNs). PNNs mainly surround parvalbumin/GABA inhibitory interneurons, of importance for processing sensory information. Previous studies have shown that downregulating PNNs after stroke reduces the neurite-inhibitory environment, reactivates plasticity, and promotes functional recovery. Resting-state functional connectivity (RS-FC) within and across hemispheres has been shown to correlate with behavioral recovery after stroke. However, the relationship between PNNs and RS-FC has not been examined. Here we studied a quadruple knock-out mouse (Q4) that lacks four ECM components: brevican, neurocan, tenascin-C and tenascin-R. We applied functional connectivity optical intrinsic signal (fcOIS) imaging in Q4 mice and wild-type (129S1 mice) before and 14?days after photothrombotic stroke (PT) to understand how the lack of crucial ECM components affects neuronal networks and functional recovery after stroke. Limb-placement ability was evaluated at 2, 7 and 14?days of recovery through the paw-placement test. Q4 mice exhibited significantly impaired homotopic RS-FC compared to wild-type mice, especially in the sensory and parietal regions. Changes in RS-FC were significantly correlated with the number of interhemispheric callosal crossings in those same regions. PT caused unilateral damage to the sensorimotor cortex and deficits of tactile-proprioceptive placing ability in contralesional fore- and hindlimbs, but the two experimental groups did not present significant differences in infarct size. Two weeks after PT, a general down-scaling of regional RS-FC as well as the number of regional functional connections was visible for all cortical regions and most notable in the somatosensory areas of both Q4 and wild-type mice. Q4 mice exhibited higher intrahemispheric RS-FC in contralesional sensory and motor cortices compared to control mice. We propose that the lack of growth inhibiting ECM components in the Q4 mice potentially worsen behavioral outcome in the early phase after stroke, but subsequently facilitates modulation of contralesional RS-FC which is relevant for recovery of sensory motor function. We conclude that Q4 mice represent a valuable model to study how the elimination of ECM genes compromises neuronal function and plasticity mechanisms after stroke.

SUBMITTER: Quattromani MJ

PROVIDER: S-EPMC5851486 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Changes in resting-state functional connectivity after stroke in a mouse brain lacking extracellular matrix components.

Quattromani Miriana Jlenia MJ Hakon Jakob J Rauch Uwe U Bauer Adam Q AQ Wieloch Tadeusz T

Neurobiology of disease 20180131

In the brain, focal ischemia results in a local region of cell death and disruption of both local and remote functional neuronal networks. Tissue reorganization following stroke can be limited by factors such as extracellular matrix (ECM) molecules that prevent neuronal growth and synaptic plasticity. The brain's ECM plays a crucial role in network formation, development, and regeneration of the central nervous system. Further, the ECM is essential for proper white matter tract development and f ...[more]

PMID: 29367009

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Project description:Stroke causes direct structural damage to local brain networks and indirect functional damage to distant brain regions. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by regions functionally connected to the site of injury. Spontaneous functional recovery can be enhanced by rehabilitative strategies, which provides experience-driven cell signaling in the brain that enhances plasticity. Functional neuroimaging in humans and rodents has shown that spontaneous recovery of sensorimotor function after stroke is associated with changes in resting-state functional connectivity (RS-FC) within and across brain networks. At the molecular level, GABAergic inhibitory interneurons can modulate brain plasticity in peri-infarct and remote brain regions. Among this cell-type, a decrease in parvalbumin (PV)-immunoreactivity has been associated with improved behavioral outcome. Subjecting rodents to multisensory stimulation through exposure to an enriched environment (EE) enhances brain plasticity and recovery of function after stroke. Yet, how multisensory stimulation relates to RS-FC has not been determined. In this study, we investigated the effect of EE on recovery of RS-FC and behavior in mice after stroke, and if EE-related changes in RS-FC were associated with levels of PV-expressing neurons. Photothrombotic stroke was induced in the sensorimotor cortex. Beginning 2 days after stroke, mice were housed in either standard environment (STD) or EE for 12 days. Housing in EE significantly improved lost tactile-proprioceptive function compared to mice housed in STD environment. RS-FC in the mouse was measured by optical intrinsic signal imaging 14 days after stroke or sham surgery. Stroke induced a marked reduction in RS-FC within several perilesional and remote brain regions. EE partially restored interhemispheric homotopic RS-FC between spared motor regions, particularly posterior secondary motor. Compared to mice housed in STD cages, EE exposure lead to increased RS-FC between posterior secondary motor regions and contralesional posterior parietal and retrosplenial regions. The increased regional RS-FC observed in EE mice after stroke was significantly correlated with decreased PV-immunoreactivity in the contralesional posterior motor region. In conclusion, experimental stroke and subsequent housing in EE induces dynamic changes in RS-FC in the mouse brain. Multisensory stimulation associated with EE enhances RS-FC among distinct brain regions relevant for recovery of sensorimotor function and controlled movements that may involve PV/GABA interneurons. Our results indicate that targeting neural circuitry involving spared motor regions across hemispheres by neuromodulation and multimodal sensory stimulation could improve rehabilitation after stroke.

Project description:Recent resting-state functional MRI studies in stroke patients have identified two robust biomarkers of acute brain dysfunction: a reduction of inter-hemispheric functional connectivity between homotopic regions of the same network, and an abnormal increase of ipsi-lesional functional connectivity between task-negative and task-positive resting-state networks. Whole-brain computational modelling studies, at the individual subject level, using undirected effective connectivity derived from empirically measured functional connectivity, have shown a reduction of measures of integration and segregation in stroke as compared to healthy brains. Here we employ a novel method, first, to infer whole-brain directional effective connectivity from zero-lagged and lagged covariance matrices, then, to compare it to empirically measured functional connectivity for predicting stroke versus healthy status, and patient performance (zero, one, multiple deficits) across neuropsychological tests. We also investigated the accuracy of functional connectivity versus model effective connectivity in predicting the long-term outcome from acute measures. Both functional and effective connectivity predicted healthy from stroke individuals significantly better than the chance-level; however, accuracy for the effective connectivity was significantly higher than for functional connectivity at 1- to 2-week, 3-month and 1-year post-stroke. Predictive functional connections mainly included those reported in previous studies (within-network inter-hemispheric and between task-positive and -negative networks intra-hemispherically). Predictive effective connections included additional between-network links. Effective connectivity was a better predictor than functional connectivity of the number of behavioural domains in which patients suffered deficits, both at 2-week and 1-year post-onset of stroke. Interestingly, patient deficits at 1-year time-point were better predicted by effective connectivity values at 2 weeks rather than at 1-year time-point. Our results thus demonstrate that the second-order statistics of functional MRI resting-state activity at an early stage of stroke, derived from a whole-brain effective connectivity, estimated in a model fitted to reproduce the propagation of neuronal activity, has pertinent information for clinical prognosis.

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Changes in resting-state functional connectivity after stroke in a mouse brain lacking extracellular matrix components.

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Changes in resting-state functional connectivity after stroke in a mouse brain lacking extracellular matrix components.

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