Biology subjects

Sarabdjitsingh, R. A.

Publications and source records attributed to Sarabdjitsingh, R. A..

8 recordsLinked to original sources

bioRxiv2022

Structural changes after early life adversity in rodents: a systematic review with meta-analysis

Early life adversity (ELA) is a well-documented risk factor for psychiatric illnesses in humans. This risk may, in part, be conferred by structural changes induced by ELA, lasting into adulthood. We here review the evidence for such lasting structural changes in rodent models for ELA involving altered maternal care during the first two postnatal weeks. In total, we extracted data from 64 studies reporting on 260 comparisons in adult rats or mice which experienced ELA or control treatment. Most of the observations concerned structural changes in the hippocampus of adult male rats earlier exposed to maternal separation. A 3-level meta-analysis revealed that ELA reduced hippocampal volume and the number of dendritic branches as well as dendritic length of principal hippocampal cells. No differences were observed across the hippocampal subfields. In terms of adult neurogenesis in the dentate subgranular zone, both staining for BrdU and the early neuronal marker DCX were significantly reduced, while the general proliferation marker Ki67 remained unchanged. The neuronal growth factor BDNF did not show significant changes, although the unexplained heterogeneity was moderate. Generally, the effect of ELA compared to control on structural markers was not affected by additional stressors experienced in life. Overall, the data available support the notion that ELA, at least in the hippocampus of male rats, lastingly reduces volume, hampers dendritic growth and suppresses adult neurogenesis.

neuroscience↗

bioRxiv2021

Pre-trauma memory contextualization as predictor for PTSD-like behavior in male rats

While many people experience potentially threatening events during their life, only a minority develops posttraumatic stress disorder (PTSD). The identification of individuals at risk among those exposed to trauma is crucial for PTSD prevention in the future. Since re-experiencing trauma elements outside of the original trauma-context is a core feature of PTSD, we investigate if the ability to bind memories to their original encoding context (i.e. memory contextualisation) predicts PTSD vulnerability. We hypothesize that pre-trauma neutral memory contextualization (under stress) negatively relates to PTSD-like behavior, in a prospective design using the cut-off behavioral criteria rat model for PTSD. 72 male Sprague Dawley rats were divided in two experimental groups to assess the predictive value of 1) memory contextualization without acute stress (NS-group) and 2) memory contextualization during the recovery phase of the acute stress-response (S-group) for susceptibility to PTSD-like behavior. A powerful extension to regression analysis-path analysis-was used to test this specific hypothesis, together with secondary research questions. Following traumatic predator scent stress, 19.4% of the rats displayed PTSD-like behavior. Results showed a negative relation between pre-trauma memory contextualization and PTSD-like behavior, but only in the NS-group. Pre-trauma memory contextualization was positively related to fear association in the trauma environment, again only in the NS group. If the predictive value of pre-trauma contextualization of neutral information under non-stressful conditions for PTSD susceptibility is replicated in prospective studies in humans, this factor would supplement already known vulnerability factors for PTSD and improve the identification of individuals at risk among the trauma exposed, especially those at high trauma risk such as soldiers deployed on a mission.

neuroscience↗

bioRxiv2021

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 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 multiple negative life events. At rest, ELA increased cFos expression irrespective of other life events, suggesting that ELA creates a phenotype similar to naive, 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.

neuroscience↗

bioRxiv2021

Pipeline for 4D whole-brain microscopy preprocessing and analysis.

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 dramatically increased c-fos intensity in just a subset of cells; this strategy changed after foot-shock in half of the brain areas. All single-cell data can be visualized for each of the 90 brain areas examined through our interactive web-portal.

neuroscience↗

bioRxiv2021

Measuring context-dependent memory in rodents: a systematic review and meta-analysis of important variables in the object-in-context task.

Environmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as context) and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and - for those who design a new experiment or carry out pilot experiments - the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations to create more consensus in the set-up, procedure and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.

neuroscience↗

bioRxiv2019

RePAIR: a power solution to animal experimentation

Low statistical power challenges the reliability of animal research; yet, increasing sample sizes to the required level raises important ethical and practical issues. We present an alternative solution, RePAIR, which capitalizes on the observation that control groups in general are expected to be similar to each other. As shown in a simulation study, including information of previous control experiments in the statistical analysis using RePAIR reduced the required sample size by 49% or increased power up to 100%. We validated the potential of RePAIR in a unique dataset based on 7 independent experiments across the world, studying cognitive effects of early life adversity in mice. RePAIR comes with an open-source web-based tool and can be widely used to largely improve quality of animal experimentation. One Sentence SummaryPrior studies information can reduce use of animals or increase statistical power, improving animal research reliability

animal behavior and cognition↗

bioRxiv2019

Distinct structure-function relationships across cortical regions and connectivity scales in the rat brain

An improved understanding of the structure-function relationship in the brain is necessary to know to what degree structural connectivity underpins abnormal functional connectivity seen in many disorders. We integrated high-field resting-state fMRI-based functional connectivity with high-resolution macro-scale diffusion-based and meso-scale neuronal tracer-based structural connectivity, to obtain an accurate depiction of the structure-function relationship in the rat brain. Our main goal was to identify to what extent structural and functional connectivity strengths are correlated, macro- and meso-scopically, across the cortex. Correlation analyses revealed a positive correspondence between functional connectivity and macro-scale diffusion-based structural connectivity, but no correspondence between functional connectivity and meso-scale neuronal tracer-based structural connectivity. Locally, strong functional connectivity was found in two well-known resting-state networks: the sensorimotor and default mode network. Strong functional connectivity within these networks coincided with strong short-range intrahemispheric structural connectivity, but with weak heterotopic interhemispheric and long-range intrahemispheric structural connectivity. Our study indicates the importance of combining measures of connectivity at distinct hierarchical levels to accurately determine connectivity across networks in the healthy and diseased brain. Distinct structure-function relationships across the brain can explain the organization of networks and may underlie variations in the impact of structural damage on functional networks and behavior.

neuroscience↗

bioRxiv2019

The behavioral phenotype of early life adversity: a 3-level meta-analysis of rodent studies

1BackgroundAltered cognitive performance has been suggested as an intermediate phenotype mediating the effects of early life adversity (ELA) on later-life development of mental disorders, e.g. depression. Whereas most human studies are limited to correlational conclusions, rodent studies can prospectively investigate how ELA alters cognitive performance in a number of domains. Despite the vast volume of reports, no consensus has yet been reached on the i) behavioral domains being affected by ELA and ii) the extent of these effects.\n\nMethodsTo test how ELA (here: aberrant maternal care) affects specific behavioral domains, we used a 3-level mixed-effect meta-analysis, a flexible model that accounts for the dependency of observations. We thoroughly explored heterogeneity with MetaForest, a machine-learning data-driven analysis never applied before in preclinical literature. We validated the robustness of our findings with substantial sensitivity analyses and bias assessments.\n\nResultsOur results, based on >400 independent experiments, yielded >700 comparisons, involving ~8600 animals. Especially in males, ELA promotes memory formation during stressful learning but impairs non-stressful learning. Furthermore, ELA increases anxiety and decreases social behavior. The ELA phenotype was strongest when i) combined with other negative experiences (\"hits\"); ii) in rats; iii) in ELA models of ~10days duration.\n\nConclusionProspective and well-controlled animal studies demonstrate that ELA durably and differentially impacts distinct behavioral domains. All data is now easily accessible with MaBapp (https://osf.io/ra947/), which allows researchers to run tailor-made meta-analyses on the topic, thereby revealing the optimal choice of experimental protocols and study power.

neuroscience↗