Prelimbic cortex layer 5 GABAergic neurons mediate chronic pain and memory impairment by regulating excitatory/inhibitory imbalance.

BACKGROUND

Chronic pain can cause both hyperalgesia and cognitive impairment symptoms and involves long-term alterations in the neural circuits, leading to abnormal cortical activity. GABAergic signaling are particularly emerging as relevant components of pain processing within the prefrontal cortex. The mechanism through which cortical circuits change and cause chronic pain and memory impairment remains unclear to date.

METHODS

We modeled chronic neuropathic pain in mice using chronic constrictive injury (CCI), an open field test, a Y maze spontaneous alternation experiment, a novel object recognition test and barnes maze were used to assess neurobehavioral changes in the mice. Whole-cell patch-clamp technique was used to assess the intrinsic activity of neurons, and fiber photometry recording was used to measure the calcium activity of GABAergic neurons. In vivo multi-channel technique was employed to assess alterations in cortical excitability. Western blot and immunofluorescence were used to measure the expression of activating transcription factor 4 (ATF4) and Neuronal excitability.

RESULTS

In this study, persistent elevation of GABAergic neuronal activity in prelimbic cortex layer 5 (PrL-L5) was demonstrated to regulate the chronic pain and memory impairment. This elevated GABAergic neuronal activity affects the excitatory/inhibitory (E/I) imbalance by influencing the excitability of pyramidal neurons. The inhibition of PrL-L5 GABAergic neuronal activity reversed the hypersensitivity and memory deficits. In contrast, the optogenetic activation of PrL-L5 GABAergic neurons induced hypersensitivity and memory impairment in naive mice. Furthermore, ATF4 regulates hyperpathia and memory impairment through impact GABAergic neuronal activity.

CONCLUSION

We revealed a cortical GABAergic neural microcircuit that involved chronic pain and memory impairment through modulating E/I imbalance by influencing the excitability of pyramidal neurons. These findings provide novel insights for targeted interventions in patients with comorbid chronic pain and memory impairment.

CLINICAL TRIAL NUMBER: Not applicable.