Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats

Abstract

Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.

No evidence for cognitive impairment in an experimental rat model of knee osteoarthritis and associated chronic pain

“…In the present study, MIA treatment did not impair operant performance and operant measures of behavioural flexibility, including rule shifting and reversal learning. Previous studies in rat models of neuropathic pain reported impaired operant performance, including slower adaptation to optimal choices [15], and impaired spatial reversal learning in the watermaze [31]. These measures do appear to have translational relevance as chronic pain patients with fibromyalgia and primary Sjögren syndrome with small fibre neuropathy show impaired behavioural flexibility on the Wisconsin Card Sorting Test [22,63].…”

Role of the Prefrontal Cortex in Pain Processing

“…In the SNI model of neuropathy, chronic pain reduces the overall amount of information flowing in the fronto-hippocampal circuit [ 324 ]. Chronic pain also impairs cognitive flexibility and engages novel learning strategies in rats [ 325 ]. Surgical incision-induced nociception reduces the level of synaptic NMDA receptor 2B in the mPFC of mice, and this reduction has been suggested to contribute to a loss of cognition [ 326 ].…”

Differential synaptic mechanism underlying the neuronal modulation of prefrontal cortex, amygdala, and hippocampus in response to chronic postsurgical pain with or without cognitive deficits in rats

“…Substantial evidence suggests the detrimental effect of chronic pain on cognition (Cowen et al, 2018;Matthewson et al, 2019;Phelps et al, 2021). Nonetheless, whether cognitively compromised animals with pain have the exact same synaptic mechanisms as those in the cognitively normal animals with pain remains to be elucidated so far.…”