Neuromodulated plasticity of the connectivity between the Prefrontal Cortex and the noradrenergic Locus Coeruleus

Incentive stimuli and environmental stressors are encoded at the level of the prefrontal cortex (PFC) circuits, which send their glutamatergic excitatory projections to several neuromodulatory regions, including the Locus Coeruleus (LC), the major source of noradrenaline (NA) for the entire forebrain. Despite the potential implications for NA-mediated regulation of action control and for the etiology of stress-related neuropsychiatric conditions, it remains to be established how LC neuronal activity is shaped by impinging PFC inputs (PFCLC) to affect behavior, and whether these inputs are modulated by in-vivo experience. By combining neurophysiological and optogenetic approaches together with behavioral paradigms in mice, we found that PFC LC stimulation supports learning and retrieval of contextual memory associations. Consistent with the occurrence of plasticity processes at LC synapses, long-lasting modulation of PFCLC projections relies on the endocannabinoid (eCB)-mediated signaling capacity, which is dynamically shaped by context adaptations and stress salience experiences. We also found that eCB-plasticity at PFC → LC synapses is regulated during the adolescence to adulthood transition. In summary, our results not only dissect the behavioral implications of neuromodulated plasticity at PFC inputs to the LC, but also unveil divergent synaptic substrates during postnatal development, which might be relevant to explain some of the different noradrenergic-mediated response in adolescents and adults.