Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex

Anterior cingulate cortex (ACC) plays important roles in sensory perception including pain and itch. Neurons in the ACC receive various neuromodulatory inputs from subcortical structures, including locus coeruleus noradrenaline (LC-NA) neurons. Few studies have been reported about synaptic and behavioral functions of LC-NA projections to the ACC. Using viral-genetic method (AAV-DIO-eYFP) on DBH-cre mice, we found that LC-NA formed synaptic connections to ACC pyramidal cells but not interneurons. This is further supported by the electron microscopic study showing NAergic fibers contact the presynaptic inputs and post-synaptic areas of the pyramidal cells. NA application produced both pre- and post-synaptic potentiation effects in ACC excitatory transmission in vivo and in vitro. Activation of LC-NA projection to the ACC by optogenetic method produced enhancement of excitatory transmission in vitro and induced scratching and behavioral sensitization for mechanical stimulation. Our results demonstrate that LC-NA projections enhance or facilitate brain responses to pain and itch by potentiating glutamatergic synaptic transmissions in the ACC.