Targeting hippocampal adult neurogenesis using transcription factors to reduce Alzheimer's disease-associated memory impairments.

Hippocampal adult neurogenesis results in the persisting formation of new neurons that contribute to hippocampal-dependent learning and memory. This has led to the hypothesis that memory impairments associated with neurodegenerative diseases such as Alzheimer's disease may involve abnormal neurogenesis. Supporting this idea, evidence for decreased adult neurogenesis has been reported in the brain of Alzheimer's disease patients and in several mouse models of the disease. Thus, the development of strategies designed to stimulate the production of new neurons in the diseased brain has raised growing interest. In this review, we discuss putative strategies and present recent studies showing that it is now possible to instruct hippocampal endogenous neural progenitors to adopt an exclusive neuronal fate. We further report how such strategies lead to the rescue of cognitive functions in mouse models of Alzheimer's disease. Altogether, these findings provide the proof-of-concept that neurogenesis can be stimulated in the adult brain in vivo, and consequently overcomes pathological memory deficits.

Cortical neuronal assemblies coordinate with EEG microstate dynamics during resting wakefulness.

The disruption of cortical assembly activity has been associated with anesthesia-induced loss of consciousness. However, the relationship between cortical assembly activity and the variations in consciousness associated with natural vigilance states remains unclear. Here, we address this by performing vigilance state-specific clustering analysis on 2-photon calcium imaging data from the sensorimotor cortex in combination with global electroencephalogram (EEG) microstate analysis derived from multi-EEG signals obtained over widespread cortical locations. We report no difference in the structure of assembly activity during quiet wakefulness (QW), non-rapid eye movement sleep (NREMs), or REMs, despite the latter two vigilance states being associated with significantly reduced levels of consciousness relative to QW. However, we describe a significant coordination between global EEG microstate dynamics and general local cortical assembly activity during periods of QW, but not sleep. These results suggest that the coordination of cortical assembly activity with global brain dynamics could be a key factor of sustained conscious experience.

Protocol to image and analyze hippocampal network dynamics in non-anesthetized mouse pups.

Two-photon calcium imaging is a powerful technique that has revolutionized our understanding of how neural circuit dynamics supports different behaviors and cognitive processes. However, performing imaging during development remains challenging. Here, we provide a protocol to image CA1 neurons in mouse pups as well as a pipeline of analysis to analyze and share the data. We describe steps for intracerebroventricular injection, cranial window surgery, two-photon calcium imaging, and analysis of imaging data. For complete details on the use and execution of this protocol, please refer to Dard et al.1 and Denis et al.2.

Neuronal hyperexcitability in the Tg2576 mouse model of Alzheimer's disease - the influence of sleep and noradrenergic transmission.

The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony. Over and above confirming the previously described early presence and predominance of epileptic events during rapid-eye-movement (REM) sleep, we also show that these events do not worsen with age and are highly phase-locked to the section of the theta cycle during REM sleep where hippocampal pyramidal cells reach their highest firing probability. Finally, we reveal an antiepileptic mechanism of noradrenergic transmission via α1-adrenoreceptors that could explain the intriguing distribution of epileptic events over the sleep-wake cycle in this model, with potential therapeutic implications in the treatment of the epileptic events occurring in many AD patients.

Extrinsic control of the early postnatal CA1 hippocampal circuits.

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.

The rapid developmental rise of somatic inhibition disengages hippocampal dynamics from self-motion.

Early electrophysiological brain oscillations recorded in preterm babies and newborn rodents are initially mostly driven 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 developmental timeline 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 two postnatal weeks of mouse development using two-photon calcium imaging in non-anesthetized pups. We show that the first postnatal week ends with an abrupt shift 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 the majority of GABAergic neurons remain positively modulated throughout this period. This rapid switch occurs within 2 days and follows the rapid anatomical and functional surge of local somatic GABAergic innervation. The observed change in dynamics is consistent with a two-population model undergoing a strengthening of inhibition. We propose that this abrupt developmental transition inaugurates the emergence of internal hippocampal dynamics.

DeepCINAC: A Deep-Learning-Based Python Toolbox for Inferring Calcium Imaging Neuronal Activity Based on Movie Visualization.

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 (GUI) 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 movies from mouse pups using a convolutional neural network (CNN) with an attention process and a bidirectional long-short term memory (LSTM) 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.