We examined in live coronal slices from rat and mouse which brain regions generate potassium-triggered spreading depolarization (SDKt). This technique simulates cortical spreading depression, which underlies migraine aura in the intact brain. An SDKt episode was evoked by increasing bath [K+](o) and recorded as a propagating front of elevated light transmittance representing transient neuronal swelling in gray matter of neocortex, hippocampus, striatum, and thalamus. In contrast, SDKt was not imaged in hypothalamic nuclei or brainstem with exception of those nuclei near the dorsal brainstem surface. In rat slices, single neurons were whole-cell current clamped during SDKt. "Higher" neurons depolarized to near zero millivolts indicating SDKt generation. In contrast, seven types of neurons in hypothalamus and brainstem only slowly depolarized without generating SDKt, supporting our imaging findings. Therefore, SDKt is not a default of CNS neurons but rather displays a region-specific susceptibility, similar to anoxic depolarization, which we have proposed is correlated with a region's vulnerability to traumatic brain injury. In the higher brain, SDKt may be a vestigial spreading depolarization that originally evolved to shut down and vasoconstrict gray matter regions more exposed to impact and contusion.