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

Abstract

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 μM) 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.

Brainstem Neurons Survive the Identical Ischemic Stress That Kills Higher Neurons: Insight to the Persistent Vegetative State

“…Swelling by ‘upper’ CA1 neurons is pronounced compared to the small range displayed by ‘lower’ MES neurons in response to 10 minutes OGD. Results are similar to [26] comparing ‘upper’ neocortical pyramidal neurons and ‘lower’ hypothalamic magnocellular endocrine neurons.…”

“…The cells do not repolarize based on non-reversible light scattering and lost evoked excitability [19], [20], [24], [26], [33], [34]. Here we show that milder events can be observed in brainstem in the same coronal slices that support strong AD in hippocampus or cerebellar cortex.…”

“…Of note, MES neurons maintain their resting potential in the face of OGD. Note that hippocampal and striatal neurons are similar to neocortical and thalamic neurons; the brainstem neurons are similar to hypothalamic neurons [24], [26]. We propose that the properties noted above are most easily explained by brainstem and hypothalamic neurons possessing more resilient versions of the Na + /K + pump than higher neurons.…”

“…The mouse aCSF composition was the same but with 20 mM mannitol added to balance the higher mouse plasma osmolality. These mice have a proportion of pyramidal neurons that express yellow fluorescent protein (YFP) [32] and so the neurons can be imaged in real time during OGD [19], [20], [24], [26], [33], [34]. Structural responses to OGD by mouse slices [30], [34] are similar to the cell swelling and dendritic beading observed in rat slices [35].…”

“…The extent of AD reliably determines ensuing neuronal damage in higher brain [18]. In contrast, ‘lower’ neurons in hypothalamus generate a weak version of AD in vivo [11] and resist acute injury caused by OGD [24], [26]. Previous work has shown that, perhaps like hypothalamus, some brainstem nuclei of adult rat do not support strong spreading depolarization [27], [28] unless chemically depolarized [29].…”