Neuropathic Pain Causes Pyramidal Neuronal Hyperactivity in the Anterior Cingulate Cortex.

Ruohe Zhao,Jing Wang,Hang Zhou,Lianyan Huang,Wen-Biao Gan,Zhongcong Xie,Guang Yang

doi:10.3389/fncel.2018.00107

Abstract

The anterior cingulate cortex (ACC) is thought to be important for acute pain perception as well as the development of chronic pain after peripheral nerve injury. Nevertheless, how ACC neurons respond to sensory stimulation under chronic pain states is not well understood. Here, we used an in vivo two-photon imaging technique to monitor the activity of individual neurons in the ACC of awake, head restrained mice. Calcium imaging in the dorsal ACC revealed robust somatic activity in layer 5 (L5) pyramidal neurons in response to peripheral noxious stimuli, and the degree of evoked activity was correlated with the intensity of noxious stimulation. Furthermore, the activation of ACC neurons occurred bilaterally upon noxious stimulation to either contralateral or ipsilateral hind paws. Notably, with nerve injury-induced neuropathic pain in one limb, L5 pyramidal neurons in both sides of the ACC showed enhanced activity in the absence or presence of pain stimuli. These results reveal hyperactivity of L5 pyramidal neurons in the bilateral ACC during the development of neuropathic pain.

Highlights

Acute pain is a physiological response vital for the organism to avoid potential tissue damage
When animals were under a quiet resting condition, spontaneous Ca2+ transients can be detected in the somata of layer 5 (L5) pyramidal neurons (Figures 1E,F)
Because 0.16 g von Frey (vF) filament delivered a force that is below the animals’ mechanical paw withdrawal threshold (Supplementary Figure S1), these data suggest that non-noxious stimuli do not induce significant responses in L5 pyramidal neurons in the anterior cingulate cortex (ACC)

Summary

Introduction

Acute pain is a physiological response vital for the organism to avoid potential tissue damage. The neural pathway for acute pain involves peripheral nociceptors, spinal cord, brain stem, thalamus and a variety of cerebral structures, including somatosensory, insular and anterior cingulate cortices (Talbot et al, 1991; Casey, 1999). Pain perception is thought to occur in the anterior cingulate cortex (ACC; Rainville et al, 1997; Vogt, 2005) which receives nociceptive inputs from the medial thalamus (Robertson and Kaitz, 1981; Vogt and Sikes, 2000) and reciprocally connects with a variety of cortical regions (Shyu et al, 2010). Nociceptive responses from ACC neurons have been demonstrated by in vivo electrophysiological recordings in anesthetized mice (Koga et al, 2010), rats (Yamamura et al, 1996) and rabbits (Sikes and Vogt, 1992; Shyu et al, 2010), as well as in conscious, behaving animals (Koyama et al, 1998, 2001; Wang et al, 2003; Kuo and Yen, 2005; Zhang et al, 2011, 2017; Chen et al, 2017).

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