Stress Preconditioning of Spreading Depression in the Locust CNS

Abstract

Cortical spreading depression (CSD) is closely associated with important pathologies including stroke, seizures and migraine. The mechanisms underlying SD in its various forms are still incompletely understood. Here we describe SD-like events in an invertebrate model, the ventilatory central pattern generator (CPG) of locusts. Using K+ -sensitive microelectrodes, we measured extracellular K+ concentration ([K+]o) in the metathoracic neuropile of the CPG while monitoring CPG output electromyographically from muscle 161 in the second abdominal segment to investigate the role K+ in failure of neural circuit operation induced by various stressors. Failure of ventilation in response to different stressors (hyperthermia, anoxia, ATP depletion, Na+/K+ ATPase impairment, K+ injection) was associated with a disturbance of CNS ion homeostasis that shares the characteristics of CSD and SD-like events in vertebrates. Hyperthermic failure was preconditioned by prior heat shock (3 h, 45°C) and induced-thermotolerance was associated with an increase in the rate of clearance of extracellular K+ that was not linked to changes in ATP levels or total Na+/K+ ATPase activity. Our findings suggest that SD-like events in locusts are adaptive to terminate neural network operation and conserve energy during stress and that they can be preconditioned by experience. We propose that they share mechanisms with CSD in mammals suggesting a common evolutionary origin.

Metabolic Stress Modulates Motor Patterning via AMP-Activated Protein Kinase

“…NaN 3 (10 Ϫ3 and 5 ϫ 10 Ϫ4 M) induced vCPG arrest and an associated SD-like event, and the time to vCPG arrest was also concentration dependent. In a previous study, early motor pattern arrest in response to hyperthermia was correlated with a longer time to recovery when temperature returned to normal levels (Rodgers et al, 2007). We found a similar tradeoff in this study such that early vCPG arrest induced by NaN 3 was associated with shorter times to recovery.…”

“…K ϩ -sensitive and reference microelectrodes were connected to a pH/ion amplifier (Model 2000, A-M Systems). A K ϩ -sensitive and reference microelectrode pair were calibrated at room temperature (ϳ21°C) using 15 and 150 mM KCl solutions to obtain the voltage change, or "slope," which was required for determination of [K ϩ ] o (in mM) using the Nernst equation (Rodgers et al, 2007). Pharmacological treatments.…”

“…Continuous bath-application of 10 Ϫ4 M ouabain induces repetitive vCPG arrest, with each period of electrical silence coinciding with an abrupt surge in [K ϩ ] o (Rodgers et al, 2007 (Fig. 5a).…”

“…Our hypothesis is that stress-induced comas and associated SD-like events in the locust represent a protective strategy to cope with environmental stress by preventing neuronal hyperexcitation and energy collapse (Rodgers et al, 2010). Conceivably, energy levels would be maintained by entering a state of coma during which energyusing mechanisms that restore ion gradients are suspended (Rodgers et al, 2007;Staples and Buck, 2009). Notably, metabolic stresses can trigger the activation of signaling pathways before changes in ATP can be detected (Evans, 2006;Hardie et al, 2006).…”

“…Upon removal from anoxic conditions, nervous and muscular systems completely recover and locusts behave normally. Stress-induced coma, including arrest of vCPG operation, is associated with spreading depression (SD)-like events that share properties of SD in mammalian cerebral cortical tissue (Rodgers et al, 2007Armstrong et al, 2009). These are characterized by abrupt 50 -80 mM increases in extracellular potassium concentration ([K ϩ ] o ) within the ventilatory neuropile that coincide with vCPG shutdown.…”