Spreading Depression in the Brainstem of the Adult Rat: Electrophysiological Parameters and Influences on Regional Brainstem Blood Flow

Abstract

Cortical spreading depression is a pathophysiological excitation wave that occurs during pathophysiological brain conditions such as ischemic brain infarction, migraine aura, and others. Judged from experiments in rodents, the brainstem is thought to be comparatively resistant to the generation of spreading depression. However, because spreading depression can be elicited in the brainstem of rat pups after superfusing the brainstem with solutions enhancing excitability, we reinvestigated spreading depression in the brainstem of the adult rat. Based on theoretical predictions indicating a major role of extracellular potassium in susceptibility to spreading depression, we used conditioning solutions in which chloride ions were replaced by acetate and tetraethylammonium chloride and a small amount of KCl were added. Under these conditions, spreading depression was reproducibly elicited in the brainstem either by topical application of KCl crystals to the brainstem surface or by local microinjection of KCl into the brainstem. The direct current shifts so elicited were accompanied by typical elevation of extracellular potassium ions, propagated in the brainstem, and were prevented by MK-801, an N-methyl D-aspartate blocker. During spreading depression, the regional blood flow in the brainstem was transiently increased. In addition, systemic arterial blood pressure, but not the heart rate, was transiently enhanced. In the nonconditioned brainstem, KCl stimulation neither elicited spreading depression nor induced changes in regional blood flow and blood pressure. These data show that proper conditioning renders the brainstem susceptible to spreading depression, and that spreading depression at this site elicits changes in local circulation and systemic blood pressure.

Where does a migraine attack originate? In the brainstem

“…During SD, the regional blood flow in the brainstem is transiently increased. These data show that proper conditioning renders the brainstem susceptible to SD, and that SD at this brain location elicits changes in local circulation and systemic blood pressure (Richter et al 2008). …”

Altered responses of MeCP2-deficient mouse brain stem to severe hypoxia

“…We recently found that spreading depression, which is detectable as a sudden propagating negative deflection in the extracellular DC potential and arises from a massive synchronized neuronal and glial depolarization as well as severe derangements of ionic distribution (for review see Somjen 2001), can also occur in rat brain stem, especially at infant stages (Funke et al 2009), a finding that extended earlier observations from in vivo recordings (Richter F et al , 2008(Richter F et al , 2010. Because the Mecp2 Ϫ/y hippocampus was found to be more susceptible to hypoxia and HSD, and HIF-1␣ expression was also increased in Mecp2 Ϫ/y brain stem (Fischer et al 2009), we now asked whether the generation of HSD episodes might be facilitated in brain stem as well.…”

Enhanced Neuronal Excitability in Adult Rat Brainstem Causes Widespread Repetitive Brainstem Depolarizations with Cardiovascular Consequences

“…In all, 10 mmol/L TEA (Sigma, Seelze, Germany) and 10 mmol/L KCl were added to the acetate-ACSF (acetate-ACSF + TEA + KCl). This superfusate had successfully conditioned the adult rat brainstem for SD in previous experiments (Richter et al, 2008). The superfusion lasted for at least 1 hour and was only interrupted when 1 mol/L KCl (see above) was injected into the brainstem to test the elicitation of SD by KCl during a period of RD waves.…”

“…V) to a depth of 1,200 to 1,400 mm. To elicit SD by KCl, we injected B0.5 mL of 1 mol/L KCl as in our previous study (Richter et al, 2008) with a pressure of 100 kPa for 1 second using a microinjector (picoinjector PLI-100; Harvard Apparatus, Holliston, MA, USA). All electrodes were connected by Ag/AgCl wires to a custom built 4-channel-high impedance amplifier (Meyer, Munich, Germany).…”

“…In adult rat brainstem, KCl-evoked SD can be elicited by a stronger conditioning, i.e., with superfusion of a solution containing acetate, the potassium channel blocker tetraethylammonium chloride (TEA), and 10 mmol/L KCl. KCl-evoked SDs also depolarize centers of cardiovascular control in the brainstem, as indicated by transient increases in heart rate (HR), in systemic arterial blood pressure (ABP) and regional blood flow in the brainstem (Richter et al, 2008).…”