Spontaneous Pain Disrupts Ventral Hippocampal CA1-Infralimbic Cortex Connectivity and Modulates Pain Progression in Rats with Peripheral Inflammation

Pain is an intrinsically dynamic connectome characterized by fluctuating spontaneous activity and continuous neuroplastic changes of relevant circuits. With its strong impact on resting brain activity, persistent spontaneous pain may induce hypersensitivity to noxious stimuli and negative emotion, thus affecting overall progression of chronic pain. Hippocampus-medial prefrontal cortex (mPFC) pathway has recently been suggested to correlate with spontaneous pain behaviors and pain chronicity. However, causal evidence for this relationship is lacking. We adopted a circuit dynamics-based strategy with combined longitudinal in vivo multichannel recording and behavioral testing, and revealed that persistent spontaneous pain disrupted ventral hippocampal CA1-infralimbic cortex (vCA1-IL) connectivity and hippocampal modulation of IL neuronal activity in rats with inflammatory pain. Transient chemo- and opto-genetic activation of vCA1-IL pathway specifically relieved spontaneous pain in inflammatory rats, and long-term chemogenetic rescue of vCA1-IL dysfunction produced additional relief from other behavioral dimensions including evoked pain and anxiety-like behaviors. Spontaneous pain in inflammatory rats was accompanied by decreased level of brain-derived neurotrophic factor (BDNF) in vCA1 and IL. Circuit-specific overexpression of BDNF in vCA1-IL reversed electrophysiological changes, relieved spontaneous pain, and accelerated overall recovery from inflammatory pain. The present study identifies a novel neural pathway that specifically correlates spontaneous pain behaviors and modulates overall pain progression in rats with peripheral inflammation, and supports the significance of circuit dynamics-based strategy for more comprehensive understanding of central mechanisms underlying chronic pain.