generation-on-demand-initiation-acute-ictal-activity-rodent-human

Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue

Controlling seizures remains a challenging issue for the medical community. To make progress, researchers need a way to extensively study seizure dynamics ...

KREMBIL RESEARCH INSTITUTE

University of Toronto

Extracellular potassium concentration, [K⁺], plays a fundamental role in the physiological functions of the brain. Studies investigating changes in [K⁺] have predominantly relied upon glass capillary electrodes with K⁺-sensitive solution gradients for their measurements. However, such electrodes are unsuitable for taking spatio-temporal measurements and are limited by the surface area of their tips. We illustrate seizures invoked chemically and in optogenetically modified mice using blue light exposure while impedimetrically measuring the response. A sharp decrease of 1-2 mM in [K⁺] before each spike has shown new physiological events not witnessed previously when measuring extracellular potassium concentrations during seizures in mice. We propose a novel approach that uses multichannel monolayer coated gold microelectrodes for in vivo spatio-temporal measurements of [K⁺] in a mouse brain as an improvement to the conventional glass capillary electrode.

Biofouling-Resistant Impedimetric Sensor for Array High-Resolution Extracellular Potassium Monitoring in the Brain.

Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal  study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.

Oophorectomy Reduces Estradiol Levels and Long-Term Spontaneous Neurovascular Recovery in a Female Rat Model of Focal Ischemic Stroke.

Background and Purpose- Recent evidence suggests great potential of metabolically targeted interventions for treating neurological disorders. We investigated the use of the endogenous ketone body β-hydroxybutyrate (BHB) as an alternate metabolic substrate for the brain in the acute phase of ischemia because postischemic hyperglycemia and brain glucose metabolism elevation compromise functional recovery. Methods- We delivered BHB (or vehicle) 1 hour after ischemic insult induced by cortical microinjection of endothelin-1 in sensorimotor cortex of rats. Two days after ischemic insult, the rats underwent multimodal characterization of the BHB effects. We examined glucose uptake on 2-Deoxy-d-glucose chemical exchange saturation transfer magnetic resonance imaging, cerebral hemodynamics on continuous arterial spin labeling magnetic resonance imaging, resting-state field potentials by intracerebral multielectrode arrays, Neurological Deficit Score, reactive oxygen species production, and astrogliosis and neuronal death. Results- When compared with vehicle-administered animals, BHB-treated cohort showed decreased peri-infarct neuronal glucose uptake which was associated with reduced oxidative stress, diminished astrogliosis and neuronal death. Functional examination revealed ameliorated neuronal functioning, normalized perilesional resting perfusion, and ameliorated cerebrovascular reactivity to hypercapnia, suggesting improved functioning. Cellular and functional recovery of the neurogliovascular unit in the BHB-treated animals was associated with improved performance on the withdrawal test. Conclusions- We characterize the effects of the ketone body BHB administration at cellular and system levels after focal cortical stroke. The results demonstrate that BHB curbs the peri-infarct glucose-metabolism driven production of reactive oxygen species and astrogliosis, culminating in improved neurogliovascular and functional recovery.

Article	Year
Biofouling-Resistant Impedimetric Sensor for Array High-Resolution Extracellular Potassium Monitoring in the Brain. Biosensors\| PubMed ID: 27754393	2016
Oophorectomy Reduces Estradiol Levels and Long-Term Spontaneous Neurovascular Recovery in a Female Rat Model of Focal Ischemic Stroke. Frontiers in molecular neuroscience\| PubMed ID: 30271324	2018
Imaging the Effects of β-Hydroxybutyrate on Peri-Infarct Neurovascular Function and Metabolism. Stroke\| PubMed ID: 30354983	2018

Peter L. Carlen

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