A neuronal population in hypothalamus that dramatically resists acute ischemic injury compared to neocortex

Brisson CD, Andrew RD. A neuronal population in hypothalamus that dramatically resists acute ischemic injury compared to neocortex. J Neurophysiol 108: 419-430, 2012. First published April 18, 2012; doi:10.1152/jn.00090.2012.-Pyramidal neurons (PyNs) of the cortex are highly susceptible to acute stroke damage, yet lower brain regions like hypothalamus and brain stem better survive global ischemia. Here we show for the first time that a lower neuron population intrinsically resists acute strokelike injury. In rat brain slices deprived of oxygen and glucose (OGD), we imaged anoxic depolarization (AD) as it propagated through neocortex or hypothalamus. AD, the initial electrophysiological event of stroke, is a front of depolarization that drains residual energy in compromised gray matter. The extent of AD reliably determines ensuing cortical damage, but do all CNS neurons generate a robust AD? During 10 min of OGD, PyNs depolarize without functional recovery. In contrast, magnocellular neuroendocrine cells (MNCs) in hypothalamus under identical stress generate a weak and delayed AD, resist complete depolarization, and rapidly repolarize when oxygen and glucose are restored. They recover their membrane potential, input resistance, and spike amplitude and can survive multiple OGD exposures. Two-photon microscopy in slices derived from a fluorescent mouse line confirms this protection, revealing PyN swelling and dendritic beading after OGD, whereas MNCs are not injured. Exposure to the Na+-K+-ATPase inhibitor ouabain (100 mu M) induces AD similar to OGD in both cell types. Moreover, elevated extracellular K+ concentration ([K+](o)) evokes spreading depression (SD), a milder version of AD, in PyNs but not MNCs. Therefore overriding the pump by OGD, ouabain, or elevated [K+](o) evokes a propagating depolarization in higher gray matter but not in MNCs. We suggest that variation in Na+-K+-ATPase pump efficiency during ischemia injury determines whether a neuronal type succumbs to or resists stroke.