Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats

Abstract

BackgroundThe amygdala plays a key role in fear learning and extinction and has emerged as an important node of emotional-affective aspects of pain and pain modulation. Impaired fear extinction learning, which involves prefrontal cortical control of amygdala processing, has been linked to neuropsychiatric disorders. Here, we tested the hypothesis that fear extinction learning ability can predict the magnitude of neuropathic pain.ResultsWe correlated fear extinction learning in naive adult male rats with sensory and affective behavioral outcome measures (mechanical thresholds, vocalizations, and anxiety- and depression-like behaviors) before and after the induction of the spinal nerve ligation model of neuropathic pain compared to sham controls. Auditory fear conditioning, extinction learning, and extinction retention tests were conducted after baseline testing. All rats showed increased freezing responses after fear conditioning. During extinction training, the majority (75%) of rats showed a decline in freezing level to 50% in 5 min (fear extinction+), whereas 25% of the rats maintained a high freezing level (>50%, fear extinction−). Fear extinction− rats showed decreased open-arm preference in the elevated plus maze, reflecting anxiety-like behavior, but there were no significant differences in sensory thresholds, vocalizations, or depression-like behavior (forced swim test) between fear extinction+ and fear extinction− types. In the neuropathic pain model (four weeks after spinal nerve ligation), fear extinction− rats showed a greater increase in vocalizations and anxiety-like behavior than fear extinction+ rats. Fear extinction− rats, but not fear extinction+ rats, also developed depression-like behavior. Extracellular single unit recordings of amygdala (central nucleus) neurons in behaviorally tested rats (anesthetized with isoflurane) found greater increases in background activity, bursting, and evoked activity in fear extinction− rats than fear extinction+ rats in the spinal nerve ligation model compared to sham controls.ConclusionThe data may suggest that fear extinction learning ability predicts the magnitude of neuropathic pain-related affective rather than sensory behaviors, which correlates with differences in amygdala activity changes.

How to study anxiety and depression in rodent models of chronic pain?

“…Animals are placed in the middle of the apparatus and let free to explore the maze. The number of entries as well as time spent in both closed and open arms is assessed over 5–15 min depending on the protocols (Ji, Yakhnitsa, Kiritoshi, Presto, & Neugebauer, 2018; Narita, Kaneko, et al, 2006). Arm entry and exit are often considered when all four paws are into or out of a given arm.…”

Diversified Learning Environment Alleviates Learning Impairment Caused by Contextual Stress

“…In human studies, increased activity was found in the amygdala of patients with depression [36,37]. Further studies have reported that depression could be relieved by suppressing the amygdala [30,38]. In the meantime, researchers also suggested that living in a stressful urban environment could also enhance amygdala activity [1,6,14].…”

“…Such environmental stress is likely to interfere with and down-regulate the success rate of the animal's active avoidance behavior. In other words, when an animal perceives a conditional stimulus, it is supposed to balance the conditional punishment with environmental punishment before making a decision[26, 29,30].…”

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