Neural circuits underlying pain aversion

It is commonly hypothesized that hyperexcitability of local circuits within the rostral anterior cingulate cortex (rACC) underlies the affective features of chronic neuropathic pain, but the contribution of specific inputs to the rACC remains unexplored. Here we used optogenetics to study how inputs from the mediodorsal thalamus (MD) and basolateral amygdala (BLA) to the rACC influence pain-related aversion in sciatic nerve injury and chemotherapy-induced mouse models of neuropathic pain. Activating MD inputs elicited conditioned place aversion in mice with chronic neuropathic pain, whereas activating BLA inputs elicited conditioned preference. Strikingly, inhibiting BLA inputs elicited the same effects as activating MD inputs, i.e., exacerbated pain-related aversion. To assess whether these behavioral effects reflect a general pathological dysregulation of rACC neurons vs. changes at specific synapses, we recorded intrinsic properties of layer V rACC pyramidal neurons and their response to light-mediated activation of MD or BLA inputs. We focused on two subtypes of layer V rACC pyramidal projection neurons: intratelencephically-projecting (IT) and subcortically-projecting (SC). In slices from animals with chronic neuropathic pain, we found that both IT and SC neurons are hyperexcitable compared to control. Unexpectedly, however, excitatory responses of these neurons to MD input activation are significantly weakened in pain conditions compared to control. In fact, in mice with chronic neuropathic pain, the ratio between excitation and inhibition elicited by MD inputs shifted towards inhibition, specifically within SC neurons of the rACC. Responses of IT and SC neurons to BLA input activation are, in contrast, strengthened compared to control. We proposed a model positing that activating MD inputs and inhibiting BLA inputs both drive pain-related aversion through a net inhibition of subcortically-projecting (SC) rACC neurons. Indeed, direct inhibition of SC neurons elicited conditioned place aversion, specifically in mice with chronic neuropathic pain. Inhibition of IT neurons, in contrast, has no effect on pain-related aversion. Our findings reveal a novel role for specific rACC cell types and inputs on pain-related aversion. We conclude that chronic pain-related aversion may be better understood in terms of activity of specific input-output pathways of the rACC, rather than overall activity of the rACC