Brain Behavior and Immunity. This is a leading journal in the field of neuroimmunology (IF:19.2).

Molecular underpinnings of programming by early-life stress and the protective effects of early dietary ω6/ω3 ratio, basally and in response to LPS: Integrated mRNA-miRNAs approach”

This work was lead by Kitty Reemst and involved also Maralinde Abbink from my team and has been a great collaborative effort with the University of Milan with Dr Annamaria Cattaneo.  We investigated molecular mechanisms underlying programming by early-life stress and the protective effects of early dietary PUFAs, basally and in response to an immune challenge.

We confirm our earlier findings that ELS-induced cognitive deficits can be reversed by an early low omega6/omega3 PUFA diet. By using an integrated approach of combining genome wide mRNA and miRNA expression data, we show that ELS-induced long-term miRNA/mRNA profile strongly depends on the early PUFA diet. Specifically in ELS-mice, the protective diet activated hippocampal plasticity related pathways. Lastly, both ELS and early diet determine the LPS-induced alterations in the miRNA and mRNA expression profile and associated molecular pathways, with strong anti-inflammatory properties of the protective diet, again, especially in ELS-mice.

These findings contribute to the evidence base for early preventive nutritional strategies for improving mental health, especially in vulnerable populations exposed to early-life stress.

https://pubmed.ncbi.nlm.nih.gov/38242369/

In a nice collaboration between UvA-SILS-CNS and VU-CNCR (Verheijen/Smit), Janssen Kotah (SILS) from the Korosi team and Mandy Kater (CNCR) studied how early life stress (ES) influenced the effects of transgenic Amyloid β overexpression on the hippocampal synaptosome at early (4 months) and late (10 months) pathological stages. Paul Lucassen and Harm Krugers also participated to the study that was published in the HI journal Alzheimer’s & Dementia.

At an early pathological stage, the hippocampal synaptosomes of early stress exposed wild-type mice and APP/PS1 ‘Alzheimer’ mice exhibit similar alterations in proteome signature, including alterations in mitochondrial and actin dynamic related proteins. At an advanced pathological stage, however, exposure to ES heavily affects the proteome of APP/PS1 mice including astrocytic proteins involved in lipid metabolism.

Our study highlights convergent mechanisms underlying ES- and AD pathology-induced synaptic (dys-)function, and thereby provides novel insights into how ES exposure might increase the risk to develop AD.

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13569

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.

https://pubmed.ncbi.nlm.nih.gov/37015226/

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. 
 

https://www.sciencedirect.com/science/article/pii/S1934590923000024?via%3Dihub

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.

https://www.embopress.org/doi/full/10.15252/embr.202153801

https://www.stemcellsciencenews.com/newsletter/198457/

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.

https://www.nature.com/articles/s41590-022-01208-z

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.

https://pubmed.ncbi.nlm.nih.gov/36481769/

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.

https://pubmed.ncbi.nlm.nih.gov/34503674/