Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate?
The existence of human adult hippocampal neurogenesis (AHN) has been at the center of a fierce scientific debate for many years. The advent of single-cell transcriptomic technologies was initially viewed as a panacea to resolving this controversy. However, recent single-cell RNA sequencing studies in the human hippocampus yielded conflicting results. Here, we critically discuss and re-analyze previously published AHN-related single-cell transcriptomic datasets.
Together with the Salta lab from the NIN, we argue in Neuron that single-cell transcriptomic profiling of AHN in the human brain can be confounded by methodological, conceptual, and biological factors that need to be consistently addressed across studies and openly discussed within the scientific community.
A roadmap to understand the relevance of adult hippocampal neurogenesis for Alzheimer's disease
Adult neurogenesis occurs in the hippocampus and has been linked to several aspects of cognition, a.o. in rodent studies. Recent work in postmortem human brain has identified an early drop in neurogenesis in Alzheimer’s disease, while the extent of neurogenesis was correlated to antemortem cognitive measures.
Together with the Salta Lab at the Netherlands Institute for Neuroscience (NIN), we discuss in a perspective article in Cell Stem Cell, a possible roadmap to interpret the clinical relevance of adult hippocampal neurogenesis for Alzheimer's disease.
piRNAs sustains neurogenesis in the postnatal hippocampus
In a new collaboration with the the Davide de Pietri Tonelli's lab at the Italian Institute of technology in Genoa, we show in EMBO Reports for the first time that the small RNAs generated by Piwi proteins (piRNAs) control neural stem cell differentiation toward a neural fate, cellular senescence, and the generation of reactive glia from them. These novel observations have received online attention and have been highlighted in scientific news websites due to their relevance for neurodegenerative diseases and aging.
A dream come(ing) true
At the Fitzsimons Lab we dream to repair the brain, and now it seems we are starting to make this dream come true, almost completely prevent the development cortex lesions 14 days after an experimental traumatic brain injury in mice!
Traumatic brain injury (TBI) is the leading cause of death in people younger than 45 years. Now, in an intrinsically collaborative work (42 authors, 16 research centers) we show for the first time that IL-2 delivery protects against neuroinflammation through the expansion of resident regulatory T cells in the brain, in a TBI model established in our lab a by Pascal Bielefeld in 2017.
We are hoping this work moves soon into clinical trials as therapy for TBI, as the preclinical data is compelling.
Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions
Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders, including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, was unknown.
Together with the Eggen group (UMCG), we determined effects of ELS on later microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice.
We report in Translational Psychiatry on changes in microglia morphology in ELS exposed mice, as well as microglial transcriptomic changes related to the tumor necrosis factor and protein ubiquitination. ELS also lead to distinct gene expression profiles in young and older mice, and in response to an inflammatory challenge.
Functionally, synaptosomes from ELS-exposed mice were phagocytosed less well by age-matched microglia. We further validated the ELS-induced increased expression of the phagocytosis-related gene GAS6 in mice, now also in the dentate gyrus of individuals with a history of child abuse. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.
Glucocorticoids Promote Fear Generalization by Increasing the Engram size
Traumatic experiences are often present as enduring memories that can lead to generalization, ie the (re-) expression of fear in safe environments. However, the neurobiological mechanisms underlying such threat generalization after trauma and the role of stress hormones in this process remain poorly understood.
Together with the vd Oever (VU) and Kushner (EUR) labs, we examined the influence of glucocorticoid hormones on the strength and specificity of conditioned fear memory at the level of sparsely distributed dentate gyrus (DG) engram cells in male mice. In Biological Psychiatry, we report that elevating glucocorticoid hormones after fear conditioning induces a generalized contextual fear response. This was accompanied by a selective and persistent increase in the excitability and number of activated DG granule cells. Selective chemogenetic suppression of these sparse cells in the DG prevented glucocorticoid-induced fear generalization and restored contextual memory specificity. These results implicate the sparse ensemble of DG engram cells as a critical cellular substrate underlying fear generalization induced by stress.