Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences

Abstract

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity. Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity

“…It has been suggested that ACC mainly plays a role in the affective (or aversive) component of pain. Several research groups, using multiple pain conditions and interventions, have shown that ACC excitation correlates with increased aversive responses to pain (LaGraize et al, 2004;LaGraize and Fuchs, 2007;Qu et al, 2011;Navratilova et al, 2015;Sellmeijer et al, 2018). Therefore, we tested whether ASIC1a in the ACC contributes to pain-related negative affect.…”

“…We next asked whether there is any cell type-related difference for the involvement of ASIC1a in pain hypersensitivity. Previous optogenetic studies have revealed that excitatory neurons are main contributors in ACC that modulate pain perception (Kang et al, 2015;Sellmeijer et al, 2018). Therefore, we first specifically knocked out ASIC1a in ACC excitatory neurons, by injecting AAV driven by the CaMKII promoter for excitatory neuron-specific Cre recombinase expression (AAV-CaMKII-Cre) into the ACC of ASIC1a flox/flox mice ( Fig.…”

“…On the other hand, pain perception eventually resides in the brain (Chen, 2018). ACC is an important forebrain structure involved in a variety of physiological and pathological functions, including chronic pain (Chen et al, 2018;Sellmeijer et al, 2018). Synaptic plasticity in ACC is considered one of the most critical mechanisms underlying the transition of pain from acute to chronic (Luo et al, 2014;Bliss et al, 2016).…”

The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities

“…Lesions of the ACC prevent the development of anxiodepressive behaviors without affecting hypersensitivity symptoms, whereas optogenetic activation of the ACC promotes depressive states (122). A study by Sellmeijer et al applied the cuff model of peripheral nerve injury to demonstrate a potent role of the ACC in modulating anxiodepressive behaviors (123). Using in vivo electrophysiological recordings, the investigators observed an increased firing rate and bursting activity within the ACC at time points at which anxiety and depression-like behaviors had developed (123).…”

“…A study by Sellmeijer et al applied the cuff model of peripheral nerve injury to demonstrate a potent role of the ACC in modulating anxiodepressive behaviors (123). Using in vivo electrophysiological recordings, the investigators observed an increased firing rate and bursting activity within the ACC at time points at which anxiety and depression-like behaviors had developed (123).…”