Blocking the Anoxic Depolarization Protects Without Functional Compromise Following Simulated Stroke in Cortical Brain Slices

Anderson, Trent; Jarvis, Cathryn R.; Biedermann, A.; Molnar, Christine; Andrew, R. David

doi:10.1152/jn.00654.2004

Cited by 90 publications

(93 citation statements)

References 80 publications

(72 reference statements)

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“…Coronal brain slices were made as described previously (Anderson et al , 2010Iremonger et al 2006). In brief, male Sprague-Dawley rats aged 38 -45 days (PID 14 -21) were deeply sedated via isoflurane inhalation and de- capitated.…”

Section: Methodsmentioning

confidence: 99%

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Goddeyne

Nichols

et al. 2015

Journal of Neurophysiology

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Goddeyne C, Nichols J, Wu C, Anderson T. Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats. J Neurophysiol 113: 3268 -3280, 2015. First published February 18, 2015 doi:10.1152/jn.00970.2014.-Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for nearly 75% of all TBI cases, yet its neuropathophysiology is still poorly understood. While even a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long-term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (postnatal day 20) to repeat weight-drop impacts. Animals were anesthetized and subjected to sham injury or rmTBI once per day for 5 days. Magnetic resonance imaging (MRI) performed 14 days after injury revealed marked cortical atrophy and ventriculomegaly in rmTBI animals. Specifically, beneath the impact zone the thickness of the cortex was reduced by up to 46% and the area of the ventricles increased by up to 970%. Immunostaining with the neuron-specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham-injured and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker 4-aminopyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents.concussion; electrophysiology; MRI; pediatrics; traumatic brain injury

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Section: Methodsmentioning

confidence: 99%

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Goddeyne

Nichols

et al. 2015

Journal of Neurophysiology

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“…Anoxic or terminal SD, similar to an SD wave ignited in vivo in the severely energydeprived ischemic core, can be initiated in slices during simulated global ischemia induced by oxygen/glucose deprivation (OGD) or by exposure to ouabain, which, like OGD, inhibits the Na ϩ / K ϩ -ATPase (Balestrino et al, 1999; Anderson et al, 2005). Initially, we induced SD by ouabain application (100 M; for a representative SD recording, see Fig.…”

Section: Generation Of Sd and Dendritic Beading In Brain Slicesmentioning

confidence: 99%

Chloride Cotransporters as a Molecular Mechanism underlying Spreading Depolarization-Induced Dendritic Beading

et al. 2015

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Spreading depolarizations (SDs) are waves of sustained neuronal and glial depolarization that propagate massive disruptions of ion gradients through the brain. SD is associated with migraine aura and recently recognized as a novel mechanism of injury in stroke and brain trauma patients. SD leads to neuronal swelling as assessed in real time with two-photon laser scanning microscopy (2PLSM). Pyramidal neurons do not express aquaporins and thus display low inherent water permeability, yet SD rapidly induces focal swelling (beading) along the dendritic shaft by unidentified molecular mechanisms. To address this issue, we induced SD in murine hippocampal slices by focal KCl microinjection and visualized the ensuing beading of dendrites expressing EGFP by 2PLSM. We confirmed that dendritic beading failed to arise during large (100 mOsm) hyposmotic challenges, underscoring that neuronal swelling does not occur as a simple osmotic event. SD-induced dendritic beading was not prevented by pharmacological interference with the cytoskeleton, supporting the notion that dendritic beading may result entirely from excessive water influx. Dendritic beading was strictly dependent on the presence of Cl Ϫ , and, accordingly, combined blockade of Cl Ϫ -coupled transporters led to a significant reduction in dendritic beading without interfering with SD. Furthermore, our in vivo data showed a strong inhibition of dendritic beading during pharmacological blockage of these cotransporters. We propose that SD-induced dendritic beading takes place as a consequence of the altered driving forces and thus activity for these cotransporters, which by transport of water during their translocation mechanism may generate dendritic beading independently of osmotic forces.

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“…Activation of εPKC inhibits Na + /K + ATPase and voltage-gated sodium channels (Chen et al, 2005;Nowak et al, 2004), both of which contribute to the collapse of ion homeostasis during ischemia and may be targets of εPKC during cerebral ischemia in AGSs (Dave et al, 2009). Blocking or delaying the ID can significantly improve recovery (Anderson et al, 2005;Takeda et al, 2003).…”

Section: Resistance To Ischemia/reperfusion In the Euthermic State Inmentioning

confidence: 99%

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

Larson

Drew

Folkow

et al. 2014

Journal of Experimental Biology

131

102

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Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxiatolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.KEY WORDS: Arctic ground squirrel, Cetacean, Hypoxia, Naked mole-rat, Seal, Turtle IntroductionEnvironmental conditions vary enormously for vertebrates, both with respect to the extreme conditions tolerated by a given species at different times and with respect to average living conditions tolerated by different species. Temperature is perhaps the most obvious example: from the poles to the equator, average ambient temperatures vary widely and have been accompanied by physiological adaptations appropriate to resident species; seasonal variations in temperature and resource variability can induce dramatic changes in physiological and/or behavioral patterns including migration and hibernation. Oxygen levels also vary widely, with animals adapted to sea level, high-altitude, underground and aquatic habitats. Oxygen levels can also change dramatically on a shorter-term basis, as can occur in tidal pools or in breath-hold divers. Approximately 20% of the oxygen consumed by the human body is used by the brain. The greater part of this oxygen is used to produce the ATP required to maintain the membrane potentials necessary for electrical signaling with synaptic and action potentials (Harris et al., 2012). In many vertebrates, including adult humans, interruption of the oxygen supply to the brain for more than a few minutes leads to irreversible neurological damage, including neuronal death. Without oxidative phosphorylation, ATP-dependent neuronal processes including ion transport and neurotransmitter reuptake decline sharply. Without pumping, ion gradients fail and neurons depolarize, releasing excessive levels...

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Blocking the Anoxic Depolarization Protects Without Functional Compromise Following Simulated Stroke in Cortical Brain Slices

Cited by 90 publications

References 80 publications

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Chloride Cotransporters as a Molecular Mechanism underlying Spreading Depolarization-Induced Dendritic Beading

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

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