Effects of early life adversity on immediate early gene expression:Systematic review and 3-level meta-analysis of rodent studies

Early-life adversity (ELA) causes long-lasting structural and functional changes to the brain, rendering affected individuals vulnerable to the development of psychopathologies later in life. Immediate-early genes (IEGs) provide a potential marker for the observed alterations, bridging the gap between activity-regulated transcription and long-lasting effects on brain structure and function. Several heterogeneous studies have used IEGs to identify differences in cellular activity after ELA; systematically investigating the literature is therefore crucial for comprehensive conclusions. Here, we performed a systematic review on 39 pre-clinical studies in rodents to study the effects of ELA (alteration of maternal care) on IEG expression. Females and IEGs other than cFos were investigated in only a handful of publications. We meta-analyzed publications investigating specifically cFos expression. ELA increased cFos expression after an acute stressor only if the animals (control and ELA) had experienced additional hits. At rest, ELA increased cFos expression irrespective of other life events, suggesting that ELA creates a phenotype similar to naïve, acutely stressed animals. We present a conceptual theoretical framework to interpret the unexpected results. Overall, ELA likely alters IEG expression across the brain, especially in interaction with other negative life events. The present review highlights current knowledge gaps and provides guidance to aid the design of future studies

The mouse brain after foot shock in four dimensions:Temporal dynamics at a single-cell resolution

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes’ expression—as proxy for cellular activity—after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others—like the dentate gyrus—dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this “strategy” changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal

Establishing a Mental Health Surveillance in Germany: Development of a framework concept and indicator set

In the course of the recognition of mental health as an essential component of population health, the Robert Koch Institute has begun developing a Mental Health Surveillance (MHS) system for Germany. MHS aims to continuously report data for relevant mental health indicators, thus creating a basis for evidence-based planning and evaluation of public health measures. In order to develop a set of indicators for the adult population, potential indicators were identified through a systematic literature review and selected in a consensus process by international and national experts and stakeholders. The final set comprises 60 indicators which, together, represent a multidimensional public health framework for mental health across four fields of action. For the fifth field of action ‘Mental health promotion and prevention’ indicators still need to be developed. The methodology piloted proved to be practicable. Strengths and limitations will be discussed regarding the search and definition of indicators, the scope of the indicator set as well as the participatory decision-making process. Next steps in setting up the MHS will be the operationalisation of the single indicators and their extension to also cover children and adolescents. Given assured data availability, the MHS will contribute to broadening our knowledge on population mental health, supporting a targeted promotion of mental health and reducing the disease burden in persons with mental disorders

Aufbau einer Mental Health Surveillance in Deutschland: Entwicklung von Rahmenkonzept und Indikatorenset

Im Zuge der Anerkennung psychischer Gesundheit als wesentlicher Bestandteil der Bevölkerungsgesundheit wird am Robert Koch-Institut eine Mental Health Surveillance (MHS) für Deutschland aufgebaut. Ziel der MHS ist die kontinuierliche Berichterstattung relevanter Kennwerte zum Zweck einer evidenzbasierten Planung und Evaluation von Public-Health- Maßnahmen. Zur Entwicklung eines Indikatorensets für die erwachsene Bevölkerung wurden potenzielle Indikatoren durch eine systematische Literaturrecherche identifiziert und in einem strukturierten Konsentierungsprozess durch internationale und nationale Expertinnen und Experten beziehungsweise Stakeholder ausgewählt. Das finale Set enthält 60 Indikatoren, die ein mehrdimensionales Public-Health-Rahmenkonzept psychischer Gesundheit in vier Handlungsfeldern abbilden. Im fünften Handlungsfeld „Gesundheitsförderung und Prävention“ besteht Bedarf der Indikatorenentwicklung. Die pilotierte Methodik erwies sich als praktikabel. Diskutiert werden Stärken und Limitationen der Recherche und Definition von Indikatoren, der Umfang des Indikatorensets sowie die partizipative Entscheidungsfindung. Nächste Schritte zur Etablierung der MHS bestehen in der Operationalisierung von Indikatoren und der Erweiterung unter anderem auf das Kindes- und Jugendalter. Bei gesicherter Datenverfügbarkeit wird die MHS zum Wissen über die Gesundheit der Bevölkerung beitragen und die gezielte Förderung psychischer Gesundheit sowie die Verringerung der Krankheitslast psychischer Störungen unterstützen

Data

Temporary and final datasets for: Schuler, H.*, Bonapersona, V.*, Joëls, M., Sarabdjitsingh, R.A. (2021). Effects of early life adversity on immediate early gene expression: A systematic review and meta-analysis. In Preparation. *Contributed equally

Supplementary Videos

Supplementary results' videos accompanying the paper

The mouse brain after footshock in 4D: temporal dynamics at a single cell resolution

Acute stress leads to sequential activation of functional brain networks. The challenge is to get insight in whole brain activity at multiple scales, beyond the level of (networks of) nuclei. We developed a novel pre-processing and analytical pipeline to chart whole-brain immediate early genes’ expression – as proxy for cellular activity – after a single stressful foot-shock, in 4 dimensions; that is, from functional networks up to 3D single-cell resolution, and over time. The pipeline is available as R-package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot-shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal and finally thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others –like the dentate gyrus– dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this ‘strategy’ changed after foot-shock in half of the brain areas. The strength of our approach is that single-cell data were simultaneously examined across all of 90 brain areas and can be visualized in 3D in our interactive web-portal