Although the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system is functional at birth, controlling mother–offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC)—the gatekeeper of limbic circuitry—during neonatal development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell–dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC of anesthetized mice via axonal projections confined to upper cortical layers. Acute pharmacological silencing of OB activity diminishes entorhinal oscillations, whereas odor exposure boosts OB–entorhinal coupling at fast frequencies. Chronic impairment of olfactory sensory neurons disrupts OB–entorhinal activity. Thus, OB activity shapes the maturation of entorhinal circuits.

Monitoring the hypnotic component of anesthesia during surgeries is critical to prevent intraoperative awareness and reduce adverse side effects. For this purpose, electroencephalographic (EEG) methods complementing measures of autonomic functions and behavioral responses are in use in clinical practice. However, in human neonates and infants existing methods may be unreliable and the correlation between brain activity and anesthetic depth is still poorly understood. Here, we characterized the effects of different anesthetics on brain activity in neonatal mice and developed machine learning approaches to identify electrophysiological features predicting inspired or end-tidal anesthetic concentration as a proxy for anesthetic depth. We show that similar features from EEG recordings can be applied to predict anesthetic concentration in neonatal mice and humans. These results might support a novel strategy to monitor anesthetic depth in human newborns.

While the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system reaches full maturity during intrauterine life, controlling mother-offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC) – the gatekeeper of limbic circuitry – during neonatal mouse development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell-dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC via axonal projections confined to upper cortical layers. Pharmacological silencing of OB activity diminishes entorhinal oscillations. Moreover, odor exposure boosts OB-entorhinal coupling at fast frequencies. Thus, early OB activity shapes the maturation of entorhinal circuits.

Cognitive processing relies on the functional refinement of the limbic circuitry during the first two weeks of life. During this developmental period, when the auditory, somatosensory and visual systems are still largely immature, the sense of olfaction acts as ‘door to the world’, providing an important source of environmental inputs. However, it is unknown whether early olfactory processing shapes the activity in the limbic circuitry during neonatal development. Here, we address this question by combining simultaneous in vivo recordings from the olfactory bulb (OB), lateral entorhinal cortex (LEC), hippocampus (HP) and prefrontal cortex (PFC) with olfactory stimulation as well as opto‐ and chemogenetic manipulations of mitral/tufted cells in the OB of non‐anaesthetized neonatal mice of both sexes. We show that the neonatal OB synchronizes the limbic circuity in the beta frequency range. Moreover, it drives neuronal and network activity in LEC, as well as subsequently, HP and PFC via long‐range projections from mitral cells to HP‐projecting LEC neurons. Thus, OB activity shapes the communication within limbic circuits during neonatal development. imageKey points During early postnatal development, oscillatory activity in the olfactory bulb synchronizes the limbic circuit. Olfactory stimulation boosts firing and beta synchronization along the olfactory bulb–lateral entorhinal cortex–hippocampal–prefrontal pathway. Mitral cells drive neuronal and network activity in the lateral entorhinal cortex (LEC), as well as subsequently, the hippocampus (HP) and the prefrontal cortex (PFC) via long‐range projections from mitral cells to HP‐projecting LEC neurons. Inhibition of vesicle release on LEC targeting mitral cell axons reveals direct involvement of LEC in the olfactory bulb‐driven oscillatory entrainment of the limbic circuitry.