Many critically ill patients in intensive care units suffer from an infection-induced whole body inflammatory state known as sepsis, which causes severe weakness in patients who survive. The mechanisms by which sepsis triggers intensive care unit-acquired weakness (ICUAW) remain unclear. Currently, research into ICUAW is focused on dysfunction of the peripheral nervous system. During electromyographic studies of patients with ICUAW, we noticed that recruitment was limited to few motor units, which fired at low rates. The reduction in motor unit rate modulation suggested that functional impairment within the central nervous system contributes to ICUAW. To understand better the mechanism underlying reduced firing motor unit firing rates, we moved to the rat cecal ligation and puncture model of sepsis. In isoflurane-anesthetized rats, we studied the response of spinal motoneurons to injected current to determine their capacity for initiating and firing action potentials repetitively. Properties of single action potentials and passive membrane properties of motoneurons from septic rats were normal, suggesting excitability was normal. However, motoneurons exhibited striking dysfunction during repetitive firing. The sustained firing that underlies normal motor unit activity and smooth force generation was slower, more erratic, and often intermittent in septic rats. Our data are the first to suggest that reduced excitability of neurons within the central nervous system may contribute to ICUAW.

Objective Weakness induced by critical illness (intensive care unit acquired weakness) is a major cause of disability in patients and is currently untreatable. We recently identified a defect in repetitive firing of lower motor neurons as a novel contributor to intensive care unit acquired weakness. In order to develop therapy for intensive care unit acquired weakness, it was necessary to determine the mechanism underlying the defect in repetitive firing. Methods Both computer simulation and in vivo dynamic voltage clamp of spinal motor neurons in septic rats were employed to explore potential mechanisms underlying defective repetitive firing. Results Our results suggested alteration in subthreshold voltage-activated currents might be the mechanism underlying defective repetitive firing. It has been shown previously that pharmacologic activation of serotonin receptors on motor neurons increases motor neuron excitability, in part by enhancing subthreshold voltage-activated inward currents. Administration of a food and drug administration approved serotonin agonist (lorcaserin) to septic rats greatly improved repetitive firing and motor unit force generation. Interpretation Our findings suggest activation of serotonin receptors with lorcaserin may provide the first ever therapy for intensive care unit acquired weakness in patients.

e24064 Background: For the constellation of neurological disorders known as chemotherapy-induced neuropathy, mechanistic understanding, and treatment remain deficient. This might be due to the fact that studies on the effects of chemotherapies on the nervous system have utilized experimental models that exclude cancer perhaps due to the presumption that chemotherapy alone explains the neuropathology. However, the convergence of cancer and chemotherapy on the same biological processes seems likely to yield non-linear interactions. This led us to hypothesize that clinically relevant neuropathy emerges from codependent actions of cancer and chemotherapy. Methods: We established a clinically-relevant animal model of chronic sensory neuropathy in rats with cancer (adenomatous polyposis coli in rat colon: Apc+/Pirc) and age-matched animals without cancer ( ApcWT) that were randomly assigned to receive a human-scaled course of oxaliplatin (OX) or control treatment (4 groups). We quantified behavioral deficits during precision ladder walking, a validated measure of locomotor performance. Neuronal signaling was measured during terminal in vivo experiments to examine the response of sensory neurons to physiologically-relevant stimuli. We defined statistical significance as when 95% of a highest density interval (HDI) of posterior probabilities do not overlap (hierarchical Bayesian modeling). Results: Apc+/Pirc+OX (n = 11) rats exhibited significantly higher error rate (19.2±5.6%, 95%HDI) during precision ladder walking in comparison to ApcWT+control (2.4±2.7%: n = 9) or Apc+/Pirc +control (2.5±2.9%: n = 7) and significantly exceeded the error rate observed in animals treated with OX alone (8.4±3.1%: n = 10). In contrast to the observations in all other groups, we found drastically impaired neuronal signaling in Apc+/Pirc+OX rats which manifested as significantly reduced sensitivity and attenuated static and dynamic firing patterns (95%HDI). Conclusions: We present the first evidence that chronic neuropathy cannot be explained by the effects of chemotherapy alone but instead depend on non-linear interactions between cancer and chemotherapy. This understanding is a prerequisite for developing meaningful treatment or prevention of neuropathy.