BEHAVIORAL ANALYSIS OF MOTIVATED-BEHAVIOR-DEFICITS IN PACLITAXEL-INDUCED NEUROPATHY MODEL MICE

Abstract Numerous clinical studies have shown that chronic pain patients very often suffer from affective disorders, such as depression accompanied by decreased motivation. It has been proposed that they share a common neuronal mechanism since it has been reported that the rate of psychiatric disorders in chronic pain patients is approximately two to three times higher than in non-patients (McWilliams et al. Pain, 106:127-133, 2003). Central sensitization is one of the prominent hypotheses for the neuropathology of chronic pain of which pain information is abnormally amplified in the brain due to altered function of sensory-related regions which also affects emotion-related regions as well. Several preclinical studies have shown that deficit in motivated-behavior in animal persistent-pain models. However, the underlying neuronal mechanism remains largely unraveled. In rodents, locomotion is known to be essential for seeking and obtaining reward while licking behavior have been indicated as a crucial behavioral signal for expectation of reward. In this study, we examined these behavioral parameters in a paclitaxel-induced peripheral neuropathy (PIPN) mouse model. These mice exhibit mechanical allodynia and depression-like behavior for 2-3 weeks after intraperitoneal injection of paclitaxel (Toma et al. Neuropharmacology 17:305–315, 2017). We examined their changes of behavioral parameters during operant conditioning task that enabled us to quantitatively analyze licking and locomotion. Mice were water-restricted, placed on a polystyrene disc with their head fixed and trained to perform a locomotor operant task that required them to start running spontaneously to trigger the following trial. After running for 1 second, a drop of water was delivered from the spout as a reward, followed by a 2 second quiescence period. Trained mice achieved success rate over 80 % after 8-10 sessions were randomly assigned to PIPN group (n = 6) or control group (n = 7) and examined task performance for 4 weeks. PIPN mice showed altered performance during the second week after injection. During this period, the mean success rate in PIPN group significantly dropped (as low as 66%) but not in control group. In unsuccessful trials, mice typically stopped prematurely before reaching the goal. Moreover, the frequency of anticipatory licking significantly decreased in PIPN mouse. However, total running distance during the task remained unchanged. These results indicate that PIPN mice show deficits in motivational behavioral parameters during the period which they go through persistent pain. The behavioral paradigm in this study could be a useful to study mouse pain models to elucidate the neuronal mechanism of deficits in motivational behavior. This work was supported by JST SPRING, Grant Number, JPMJSP2145 (TO), Tamura Science &Technology Foundation (HN), Takeda Science Foundation (HN), KAKENHI No, 23H04673 (HN).