Abstract
BackgroundRecurrent spreading depolarizations (SDs) occur in stroke and traumatic brain injury and are considered as a hallmark of injury progression. The complexity of conditions associated with SD in the living brain encouraged researchers to study SD in live brain slice preparations, yet methodological differences among laboratories complicate integrative data interpretation. Here we provide a comparative evaluation of SD evolution in live brain slices, in response to selected SD triggers and in various media, under otherwise standardized experimental conditions.MethodsRat live coronal brain slices (350 μm) were prepared (n = 51). Hypo-osmotic medium (Na+ content reduced from 130 to 60 mM, HM) or oxygen-glucose deprivation (OGD) were applied to cause osmotic or ischemic challenge. Brain slices superfused with artificial cerebrospinal fluid (aCSF) served as control. SDs were evoked in the control condition with pressure injection of KCl or electric stimulation. Local field potential (LFP) was recorded via an intracortical glass capillary electrode, or intrinsic optical signal imaging was conducted at white light illumination to characterize SDs. TTC and hematoxylin-eosin staining were used to assess tissue damage.ResultsSevere osmotic stress or OGD provoked a spontaneous SD. In contrast with SDs triggered in aCSF, these spontaneous depolarizations were characterized by incomplete repolarization and prolonged duration. Further, cortical SDs under HM or OGD propagated over the entire cortex and occassionally invaded the striatum, while SDs in aCSF covered a significantly smaller cortical area before coming to a halt, and never spread to the striatum. SDs in HM displayed the greatest amplitude and the most rapid propagation velocity. Finally, spontaneous SD in HM and especially under OGD was followed by tissue injury.ConclusionsWhile the failure of Na+/K+ ATP-ase is thought to impair tissue recovery from OGD-related SD, the tissue swelling-related hyper excitability and the exhaustion of astrocyte buffering capacity are suggested to promote SD evolution under osmotic stress. In contrast with OGD, SD propagating under hypo-osmotic condition is not terminal, yet it is associated with irreversible tissue injury. Further investigation is required to understand the mechanistic similarities or differences between the evolution of SDs spontaneously occurring in HM and under OGD.
Highlights
Recurrent spreading depolarizations (SDs) occur in stroke and traumatic brain injury and are considered as a hallmark of injury progression
Prolonged SDs occur upon acute osmotic stress and in response to oxygen glucose deprivation First, we compared the electrophysiological features of spontaneous SDs occurring in Hypoosmotic medium (HM) or during oxygen-glucose deprivation (OGD) to SDs evoked in normal artificial cerebrospinal fluid
Prolonged SDs and incomplete direct current (DC) potential recovery were observed during OGD incubation and HM exposure compared to SDs evoked by KCl or electric stimulation (ES) in artificial cerebrospinal fluid (aCSF) (33.95 ± 26.615 vs. 54.75 ± 26.72 vs. 195.65 ± 117.05 vs. 112.14 ± 88.39 s, KCl vs. ES vs. HM vs. OGD) (Fig. 1b, d)
Summary
Recurrent spreading depolarizations (SDs) occur in stroke and traumatic brain injury and are considered as a hallmark of injury progression. Stroke and anoxic brain injury caused by cardiac arrest, spreading depolarization (SD) plays a central pathophysiological role [1]. SD has been proposed to exacerbate ischemic or traumatic brain injury by deepening the metabolic crisis of tissue at risk [14, 15], and to correlate with unfavorable neurological outcome in these states [16,17,18]. SD may not cause direct, gross injury [19], SD has been implicated in the activation of trigeminal circuits and the evolution of migraine headache [20, 21], and the suspension of cardiorespiratory pacemaking in the brain stem in transgenic mouse models of SUDEP [3, 22]
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