NORADRENERGIC MODULATION OF HIPPOCAMPAL POST-NATAL DEVELOPMENT

Many brain disorders with cognitive impairment originate during development, when synaptic and neuromodulatory circuits progressively emerge and mature. In adulthood, the hippocampus is a key integrative node where various neuromodulatory inputs, including arousal-related noradrenaline, are thought to tune single-neuron activity, shape network computation and thus guide behavioral output. Yet surprisingly little is known about the developmental origins of hippocampal neuromodulation in general, and of noradrenaline transmission in particular, neither in health nor in diseases implicating both hippocampal and noradrenergic dysfunction such as schizophrenia. Here, we investigate how noradrenergic transmission contributes to postnatal hippocampal development – “if”, “when” and “how” noradrenaline signals acquire their cellular and circuit-level properties. First, using projection tracing, immunohistochemistry, spatial transcriptomics and slice electrophysiology, we dissect the spatiotemporal maturation of noradrenergic inputs and their pre- and postsynaptic machinery in the developing hippocampus. Functionally, two-photon dual-color imaging of noradrenaline release and single-neuron calcium activity in mouse pups revealed that movement elicits robust, time-locked noradrenaline signals in hippocampus as early as the first postnatal week, coinciding with profound shifts in hippocampal network dynamics. Next, we will perturb noradrenergic transmission to causally test its role in modulating hippocampal activity and behavior. Together, this work reveals early noradrenergic signaling as a key feature of hippocampal neurodevelopment and reciprocally uncovers previously unknown developmental aspects of noradrenaline transmission, providing a solid preclinical framework to further interrogate neuromodulatory contributions to neurodevelopmental disorders.