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Chemotherapy frequently results in long-lasting sensory, motor and cognitive disabilities that point to neuronal impairment. Dying-back neuropathy is widely acknowledged to account for chronic sensory dysfunction. This explanation alone is insufficient, however, to account for various clinical reports. To examine other possibilities, we established a clinically-relevant animal model of chronic sensory deficits: rats with colon cancer (APC+/Pirc) studied after a full course of treatment with the commonly used chemotherapeutic agent oxaliplatin (OX). In behavioral studies, these rats demonstrated sensorimotor disability similar to that seen in human recipients of OX chemotherapy subjects as well as in transgenic mice lacking proprioceptors. Consistent with an earlier clinical report, we found no physical evidence for sensory nerve degeneration. Instead, we found a stereotypical deficit in mechanosensory encoding by muscle proprioceptors characterized by decreased static and dynamic signaling, i.e. general hypo-excitability. Transcriptional profiling of dorsal root ganglia revealed broad dysregulation with prominent downregulation of select voltage-gated channels, corroborated by immunostaining of muscle spindle innervation. Collectively, our findings for sensory neurons demonstrate hypo-excitability resulting from possible channelopathy, but occurring independently of structural degeneration. Next, we wondered whether hypo-excitability might extend to other types of neurons, even ones in the CNS, that might explain symptoms including motor fatigue and cognitive disorders. Beginning with spinal motoneurons, we discovered hypo-excitability and erratic firing for the first time in a CNS neuron in vivo. As with sensory neurons, motoneurons expressed imbalanced functional disruption of ionic channels, together with a shift in the axon initial segment in a direction consistent with reduced excitability. At least for motoneurons, but possibly for other CNS neurons, we conclude that OX treatment of cancer results in hypo-excitability. Our attempt to identify the origin of hypo-excitability led us to observe that the hyper-excitability seen in motoneurons early in OX treatment originates unexpectedly within the CNS and associates with the OX presence within the motoneuron soma.