Program Official

Principal Investigator

Timothy C
Awardee Organization

Georgia Institute Of Technology
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Novel Path to Chronic Sensorimotor Dysfunction and Treatment for Chemotherapy

Chemotherapy is often accompanied by neuropathic sensory disorders that can limit or end treatment and cause long-term disability. Current research supports axon degeneration and hyperexcitability as underlying mechanisms. However, our recent research reveals an additional, absolutely novel mechanism having the potential to account for loss of patient function in chemotherapy-related neuropathy. We obtained in vivo electrophysiological measures which showed functional impairment of neuronal signaling from sensory and motor neurons in rats several weeks after receiving a clinically-relevant regimen of oxaliplatin (OX) chemotherapy. Hypo-excitability was consistently expressed as conspicuous failure to sustain firing in response to fixed levels of stimulation. The specificity of this defect, which leaves transient firing unaffected, suggests that OX treatment may impair sodium persistent inward currents (NaPIC) in sensory and motor neurons. Recent findings published in our lab promote this notion by showing that pharmacological block of NaPIC mimics the effect of OX on sustained firing. While our findings isolate chronic effects of chemotherapy on neuronal excitability, there is no chemotherapy without cancer. Cancer and OX therapy may act synergistically on common signaling pathways (e.g. oxidative and inflammatory) to produce neuronal hypoexcitability. The possibility of an interaction between cancer and OX therapy gains excitement from our preliminary reports that discovered sensory and motor neuron hypo-excitability is significantly amplified in rats with colorectal cancer. Here we propose incisive tests of our working hypothesis that OX treatment chronically impairs static neuronal signaling by reducing NaPIC in a rat model of cancer. We will measure the firing behavior of sensory and motor neurons via in vivo electrophysiological studies of cancer rats treated with OX, in order to achieve the following four specific aims: 1) test the hypothesis that interactions with cancer-related processes exacerbate chemotherapy-induced hypo-excitability in sensory and motor neurons; 2) test the hypothesis that chronic defects in repetitive firing by motor neurons result from an OX-induced decrease in persistent inward current; 3) develop therapy that normalizes firing of sensory and motor neurons in rats treated for cancer with OX; 4) identify factors related to the development of hypo-excitability induced by OX in a rat model of colorectal cancer. Successful accomplishment of these studies will: 1) determine for the first time in the CIPN field, of the extent to which chronic deficits in neuronal excitability arise from OX therapy, colorectal cancer, and their combination; 2) identify biophysical mechanisms underlying firing deficits of a CNS neuron after OX treatment; 3) develop pre-clinically a viable therapy for rescuing neurons from OX-induced firing deficits; 4) take the first step forward in understanding the pathogenesis of OX-induced hypo-excitability by relating its development and underlying biophysics to changes in gene expression of sensory and MNs.


  • Wang AB, Housley SN, Ludvig D, Franz CK, Flores AM, Cope TC, Perreault EJ. Cancer survivors post-chemotherapy exhibit unimpaired short-latency stretch reflexes in the proximal upper extremity. Journal of neurophysiology. 2023 Oct 1;130(4):895-909. Epub 2023 Sep 6. PMID: 37671425
  • Wang AB, Housley SN, Flores AM, Kircher SM, Perreault EJ, Cope TC. A review of movement disorders in chemotherapy-induced neurotoxicity. Journal of neuroengineering and rehabilitation. 2021 Jan 25;18(1):16. PMID: 33494755
  • Housley SN, Rotterman TM, Nardelli P, Carrasco DI, Noel RK, O'Farrell L, Cope TC. Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat. Neurotoxicology. 2021 Sep;86:162-165. Epub 2021 Aug 4. PMID: 34363843
  • Housley SN, Nardelli P, Rotterman TM, Cope TC. Neural circuit mechanisms of sensorimotor disability in cancer treatment. Proceedings of the National Academy of Sciences of the United States of America. 2021 Dec 21;118. (51). PMID: 34911753
  • Rich MM, Housley SN, Nardelli P, Powers RK, Cope TC. Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target? The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2022 Apr;28(2):103-120. Epub 2020 Dec 21. PMID: 33345706
  • Housley SN, Nardelli P, Carrasco DI, Rotterman TM, Pfahl E, Matyunina LV, McDonald JF, Cope TC. Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy. Cancer research. 2020 Jul 1;80(13):2940-2955. Epub 2020 Apr 28. PMID: 32345673
  • Rotterman TM, Carrasco DI, Housley SN, Nardelli P, Powers RK, Cope TC. Axon initial segment geometry in relation to motoneuron excitability. PloS one. 2021 Nov 19;16(11):e0259918. doi: 10.1371/journal.pone.0259918. eCollection 2021. PMID: 34797870
  • Housley SN, Powers RK, Nardelli P, Lee S, Blum K, Bewick GS, Banks RW, Cope TC. Biophysical model of muscle spindle encoding. Experimental physiology. 2024 Jan;109(1):55-65. Epub 2023 Mar 26. PMID: 36966478
  • Housley SN, Nardelli P, Powers RK, Rich MM, Cope TC. Chronic defects in intraspinal mechanisms of spike encoding by spinal motoneurons following chemotherapy. Experimental neurology. 2020 Sep;331:113354. Epub 2020 Jun 5. PMID: 32511953
  • Blum KP, Campbell KS, Horslen BC, Nardelli P, Housley SN, Cope TC, Ting LH. Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics. eLife. 2020 Dec 28;9. PMID: 33370235
  • Wang AB, Housley SN, Flores AM, Cope TC, Perreault EJ. Cancer survivors post-chemotherapy exhibit unique proprioceptive deficits in proximal limbs. Journal of neuroengineering and rehabilitation. 2022 Mar 23;19(1):32. PMID: 35321749