Stratification substantially reduces behavioral variability in the hypoxic–ischemic stroke model

Pollak, Julia; Doyle, Kristian P.; Mamer, Lauren E; Shamloo, Mehrdad; Buckwalter, Marion S.

doi:10.1002/brb3.77

Cited by 19 publications

(10 citation statements)

References 18 publications

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“…Ladder rung testing was performed on WT and OPN -/- mice to assess changes in motor recovery following stroke, as previously described ( Pollak et al, 2012 ). The test was performed at baseline, twice a week for the first four weeks post-surgery, and once a week between five and seven weeks post-surgery.…”

Section: Methodsmentioning

confidence: 99%

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism

Chung

Frye

Zbesko

et al. 2018

eNeuro

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Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between one and four weeks in the heart compared to between eight and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between four and eight weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at seven weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at seven weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.

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Section: Methodsmentioning

confidence: 99%

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism

Chung

Frye

Zbesko

et al. 2018

eNeuro

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“…The ladder rung test [ 69 ] was adapted from the ladder rung walking task [ 26 , 59 ]. The apparatus consisted of two plexiglass walls (0.64 cm width × 76.20 cm length × 15.24 cm height) spaced 3.18 cm apart, just wide enough for the animal to pass through.…”

Section: Methodsmentioning

confidence: 99%

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

Nguyen

Hayes

Zbesko

et al. 2018

acta neuropathol commun

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The goal of this study was to determine the chronic impact of stroke on the manifestation of Alzheimer’s disease (AD) related pathology and behavioral impairments in mice. To accomplish this goal, we used two distinct models. First, we experimentally induced ischemic stroke in aged wildtype (wt) C57BL/6 mice to determine if stroke leads to the manifestation of AD-associated pathological β-amyloid (Aβ) and tau in aged versus young adult wt mice. Second, we utilized a transgenic (Tg) mouse model of AD (hAPP-SL) to determine if stroke leads to the worsening of pre-existing AD pathology, as well as the development of pathology in brain regions not typically expressed in AD Tg mice. In the wt mice, there was delayed motor recovery and an accelerated development of cognitive deficits in aged mice compared to young adult mice following stroke. This corresponded with increased brain atrophy, increased cholinergic degeneration, and a focal increase of Aβ in areas of axonal degeneration in the ipsilateral hemisphere of the aged animals. By contrast, in the hAPP-SL mice, we found that ischemia induced aggravated behavioral deficits in conjunction with a global increase in Aβ, tau, and cholinergic pathology compared to hAPP-SL mice that underwent a sham stroke procedure. With regard to a potential mechanism, in both models, we found that the stroke-induced Aβ and tau deposits co-localized with increased levels of β-secretase 1 (BACE1), along with its substrate, neuregulin 1 (NGR1) type III, both of which are proteins integral for myelin repair. Based on these findings, we propose that the chronic sequelae of stroke may be ratcheting-up a myelin repair pathway, and that the consequent increase in BACE1 could be causing an inadvertent cleavage of its alternative substrate, AβPP, resulting in greater Aβ seeding and pathogenesis.

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“…This test was performed according to previous studies [43–45]. The ladder rung apparatus was composed of two Plexiglas transparent walls (100 cm × 20 cm).…”

Section: Methodsmentioning

confidence: 99%

Can Neonatal Systemic Inflammation and Hypoxia Yield a Cerebral Palsy-Like Phenotype in Periadolescent Mice?

Fragopoulou

Heijtz

et al. 2019

Mol Neurobiol

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Cerebral palsy (CP) is one of the most common childhood-onset motor disabilities, attributed to injuries of the immature brain in the foetal or early postnatal period. The underlying mechanisms are poorly understood, rendering prevention and treatment strategies challenging. The aim of the present study was to establish a mouse model of CP for preclinical assessment of new interventions. For this purpose, we explored the impact of a double neonatal insult (i.e. systemic inflammation combined with hypoxia) on behavioural and cellular outcomes relevant to CP during the prepubertal to adolescent period of mice. Pups were subjected to intraperitoneal lipopolysaccharide (LPS) injections from postnatal day (P) 3 to P6 followed by hypoxia at P7. Gene expression analysis at P6 revealed a strong inflammatory response in a brain region-dependent manner. A comprehensive battery of behavioural assessments performed between P24 and P47 showed impaired limb placement and coordination when walking on a horizontal ladder in both males and females. Exposed males also displayed impaired performance on a forelimb skilled reaching task, altered gait pattern and increased exploratory activity. Exposed females showed a reduction in grip strength and traits of anxiety-like behaviour. These behavioural alterations were not associated with gross morphological changes, white matter lesions or chronic inflammation in the brain. Our results indicate that the neonatal double-hit with LPS and hypoxia can induce subtle long-lasting deficits in motor learning and fine motor skills, which partly reflect the symptoms of children with CP who have mild gross and fine motor impairments. Electronic supplementary material The online version of this article (10.1007/s12035-019-1548-8) contains supplementary material, which is available to authorized users.

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Stratification substantially reduces behavioral variability in the hypoxic–ischemic stroke model

Cited by 19 publications

References 18 publications

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

Can Neonatal Systemic Inflammation and Hypoxia Yield a Cerebral Palsy-Like Phenotype in Periadolescent Mice?

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