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SUMMARYThe adult CA1 region of the hippocampus produces coordinated neuronal dynamics with minimal reliance on its extrinsic inputs. In contrast, the neonatal CA1 is tightly linked to externally-generated sensorimotor activity but the circuit mechanisms underlying early synchronous activity in CA1 remain unclear. Here, using a combination of in vivo and ex vivo circuit mapping, calcium imaging and electrophysiological recordings in mouse pups, we show that early dynamics in the ventro-intermediate CA1 are under the mixed influence of entorhinal (EC) and thalamic (VMT) inputs. Both VMT and EC can drive internally-generated synchronous events ex vivo. However, movement-related population bursts detected in vivo are exclusively driven by the EC. These differential effects on synchrony reflect the different intrahippocampal targets of these inputs. Hence, cortical and subcortical pathways act differently on the neonatal CA1, implying distinct contributions to the development of the hippocampal microcircuit and related cognitive maps.

Early electrophysiological brain oscillations recorded in preterm babies and newborn rodents are initially mostly ignited by bottom-up sensorimotor activity and only later can detach from external inputs. This is a hallmark of most developing brain areas including the hippocampus, which in the adult brain, functions in integrating external inputs onto internal dynamics. Such developmental disengagement from external inputs is likely a fundamental step for the proper development of cognitive internal models. Despite its importance, the exact timing and circuit basis for this disengagement remain unknown. To address this issue, we have investigated the daily evolution of CA1 dynamics and underlying circuits during the first and second postnatal week of mouse development using a combination of two-photon calcium imaging of neuronal somata and axons in non-anesthetized pups, viral tracing and chemogenetics. We show that the first postnatal week ends with an abrupt switch in the representation of self-motion in CA1. Indeed, most CA1 pyramidal cells switch from activated to inhibited by self-generated movements at the end of the first postnatal week whereas GABAergic neurons remain positively modulated throughout this period. This rapid switch occurs within two days and is mediated by the rapid anatomical and functional surge of somatic inhibition. The observed dynamics is consistent with a two-population model undergoing strengthening inhibition. Remarkably, a transient silencing of local somatostatin-expressing interneurons both prevents the emergence of the perisomatic GABAergic coverage and the disengagement of CA1 hippocampal dynamics from self-motion. We propose that such activity-dependent emergence of feedback inhibitory circuits critically inaugurates the development of internal cognitive models.

Early electrophysiological brain oscillations recorded in preterm babies and newborn rodents are initially mostly ignited by bottom-up sensorimotor activity and only later can detach from external inputs. This is a hallmark of most developing brain areas including the hippocampus, which in the adult brain, functions in integrating external inputs onto internal dynamics. Such developmental disengagement from external inputs is likely a fundamental step for the proper development of cognitive internal models. Despite its importance, the exact timing and circuit basis for this disengagement remain unknown. To address this issue, we have investigated the daily evolution of CA1 dynamics and underlying circuits during the first and second postnatal week of mouse development using a combination of two-photon calcium imaging of neuronal somata and axons in non-anesthetized pups, viral tracing and chemogenetics. We show that the first postnatal week ends with an abrupt switch in the representation of self-motion in CA1. Indeed, most CA1 pyramidal cells switch from activated to inhibited by self-generated movements at the end of the first postnatal week whereas GABAergic neurons remain positively modulated throughout this period. This rapid switch occurs within two days and is mediated by the rapid anatomical and functional surge of somatic inhibition. The observed dynamics is consistent with a two-population model undergoing strengthening inhibition. Remarkably, a transient silencing of local somatostatin-expressing interneurons both prevents the emergence of the perisomatic GABAergic coverage and the disengagement of CA1 hippocampal dynamics from self-motion. We propose that such activity-dependent emergence of feedback inhibitory circuits critically inaugurates the development of internal cognitive models. Funding Information: This work was supported by the European Research Council under the European Union’s, Horizon 2020 research and innovation program Grant#646925, the Fondation Bettencourt Schueller, and a NWB seed grant # R20046AA. Declaration of Interest: None to declare. Ethics Approval Statement: All experiments were performed under the guidelines of the French National Ethics Committee for Sciences and Health report on "Ethical Principles for Animal Experimentation" in agreement with the European Community Directive 86/609/EEC (Apafis#18-185 and #30-959).

Two-photon calcium imaging is now widely used to infer neuronal dynamics from changes in fluorescence of an indicator. However, state of the art computational tools are not optimized for the reliable detection of fluorescence transients from highly synchronous neurons located in densely packed regions such as the CA1 pyramidal layer of the hippocampus during early postnatal stages of development. Indeed, the latest analytical tools often lack proper benchmark measurements. To meet this challenge, we first developed a graphical user interface allowing for a precise manual detection of all calcium transients from imaged neurons based on the visualization of the calcium imaging movie. Then, we analyzed the movies using a convolutional neural network with an attention process and a bidirectional long-short term memory network. This method is able to reach human performance and offers a better F1 score (harmonic mean of sensitivity and precision) than CaImAn to infer neural activity in the developing CA1 without any user intervention. It also enables automatically identifying activity originating from GABAergic neurons. Overall, DeepCINAC offers a simple, fast and flexible open-source toolbox for processing a wide variety of calcium imaging datasets while providing the tools to evaluate its performance.Significance statementInferring neuronal activity from calcium imaging data remains a challenge due to the difficulty in obtaining a ground truth using patch clamp recordings and the problem of finding optimal tuning parameters of inference algorithms. DeepCINAC offers a flexible, fast and easy-to-use toolbox to infer neuronal activity from any kind of calcium imaging dataset through visual inspection.

International audience; The adult CA1 region of the hippocampus produces coordinated neuronal dynamics with minimal reliance on its extrinsic inputs. By contrast, neonatal CA1 is tightly linked to externally generated sensorimotor activity, but the circuit mechanisms underlying early synchronous activity in CA1 remain unclear. Here, using a combination of in vivo and ex vivo circuit mapping, calcium imaging, and electrophysiological recordings in mouse pups, we show that early dynamics in the ventro-intermediate CA1 are under the mixed influence of entorhinal (EC) and thalamic (VMT) inputs. Both VMT and EC can drive internally generated synchronous events ex vivo. However, movement-related population bursts detected in vivo are exclusively driven by the EC. These differential effects on synchrony reflect the different intrahippocampal targets of these inputs. Hence, cortical and subcortical pathways act differently on the neonatal CA1, implying distinct contributions to the development of the hippocampal microcircuit and related cognitive maps.