ALTERED SENSORY ENCODING IN THE ACC DRIVES MECHANICAL ALLODYNIA THROUGH PV NEURONS PLASTICITY IN NEUROPATHIC PAIN

Chronic neuropathic pain is characterized by maladaptive plasticity and long-lasting alterations in pain circuits, leading to touch-evoked pain, also known as mechanical allodynia. Evidence suggests that neuropathic conditions disrupt the excitation/inhibition balance within the rostral anterior cingulate cortex (rACC), a key region for nociceptive processing in humans and rodents, potentially resulting in abnormal pain perception.
However, how mechanical sensory information is encoded in the rACC after nerve injury, and the mechanisms underlying rACC hyperexcitability, remain poorly understood. Here, we investigated how peripheral mechanical stimuli are processed by rACC pyramidal neurons in neuropathic conditions, and how nerve injury alters the intrinsic and synaptic properties of excitatory pyramidal neurons and parvalbumin-expressing (PV) inhibitory interneurons. Using in vivo calcium imaging, we recorded rACC pyramidal neuron activity in response to mechanical stimulation. We show that neuropathic pain induces a pain-like calcium response in rACC pyramidal neurons following innocuous stimulation. Using ex vivo whole-cell patch-clamp recordings, optogenetics in acute brain slices, and immunolabeling, we further show that this rACC hypersensitivity is associated with a reduction in PV-mediated inhibitory synaptic input onto pyramidal neurons, without changes in their intrinsic excitability. Reduced PV inhibition correlate with decreased PV expression and impaired neuron firing.
In parallel, neuropathy-induced changes in inhibitory signaling efficacy lead to atypical pyramidal neuron responses during PV activation. These findings identify PV interneuron plasticity and disrupted inhibitory control as central drivers of rACC disinhibition and aberrant sensory encoding. Restoring the rACC excitation/inhibition balance may therefore offer a promising therapeutic strategy for neuropathic pain.