Experience-dependent plasticity of Locus Coeruleus glutamatergic synapses during the adolescence to adulthood transition

The prefrontal cortex (PFC) integrates emotion and cognitive control upon novel salient experiences, and it provides one of the main cortical glutamatergic inputs to the neuromodulatory nucleus Locus Coeruleus (LC), the major source of Norepinephrine (NE) for the entire forebrain. The LC is promptly recruited by salient and arousing stimuli, and through NE release, modulates the animals’ internal states and behavior. While the role of LC-mediated NE release in target brain regions has been extensively studied, it remains to be established how LC activity is shaped by impinging PFC inputs. Adaptive changes at the PFC→LC synapse may occur upon exposure to salient novel experience, or during critical developmental periods for PFC maturation, like adolescence. During adolescence, the maturation of the PFC is protracted, and emotional responses are mainly driven by subcortical brain regions, such as the Central Nucleus of the Amygdala (CeA). Notably, CeA sends strong Corticotropin-releasing factor (CRF)-containing innervation to the LC; the contribution of this neuropeptidergic input to the modulation of PFC afferents across different post-natal developmental stages is unknown. We combined neurophysiological, optogenetic, and behavioral approaches to probe the PFC→LC synapses at two different age-periods. Our data show that PFC→LC synapses undergo developmental changes in synaptic strength and long-term synaptic plasticity mechanisms. This is accompanied by differences in valence assignment to novel stimuli and divergent dynamic modulation of the Endocannabinoid signaling (eCB) in adolescents compared to adult mice. Finally, we provide evidence of developmentally regulated functional interaction between the CRF and the eCB signaling in the LC. In summary, our results reveal a new mechanism of experience-dependent neuromodulated plasticity at PFC→LC synapses and uncover diverse molecular players involved in shaping these synapses during the transition from adolescence to adulthood. Our findings contribute to the understanding of how LC activity is regulated by cortical and subcortical inputs during different neurodevelopmental stages.