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.

Acceleration of GABA-switch after early life stress changes mouse prefrontal glutamatergic transmission.

Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model.

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.

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.

The rodent object-in-context task: A systematic review and meta-analysis of important variables.

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.

Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5.

Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus.

Increasing the statistical power of animal experiments with historical control data.

Low statistical power reduces the reliability of animal research; yet, increasing sample sizes to increase statistical power is problematic for both ethical and practical reasons. We present an alternative solution using Bayesian priors based on historical control data, which capitalizes on the observation that control groups in general are expected to be similar to each other. In a simulation study, we show that including data from control groups of previous studies could halve the minimum sample size required to reach the canonical 80% power or increase power when using the same number of animals.

Age-dependent shift in spontaneous excitation-inhibition balance of infralimbic prefrontal layer II/III neurons is accelerated by early life stress, independent of forebrain mineralocorticoid receptor expression.

In this study we tested the hypothesis i) that age-dependent shifts in the excitation-inhibition balance of prefrontal neurons are accelerated by early life stress, a risk factor for the etiology of many psychiatric disorders; and if so, ii) that this process is exacerbated by genetic forebrain-specific downregulation of the mineralocorticoid receptor, a receptor that was earlier found to be a protective factor for negative effects of early life stress in both rodents and humans. In agreement with the literature, an age-dependent downregulation of the excitation-inhibition balance was found both with regard to spontaneous and evoked synaptic currents. The age-dependent shift in spontaneous excitatory relative to inhibitory currents was significantly accelerated by early life stress, but this was not exacerbated by reduction in mineralocorticoid receptor expression.

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 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.

Sex-Dependent Modulation of Acute Stress Reactivity After Early Life Stress in Mice: Relevance of Mineralocorticoid Receptor Expression.

Early life stress (ELS) is considered a major risk factor for developing psychopathology. Increasing evidence points towards sex-dependent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as a contributing mechanism. Additionally, clinical studies suggest that the mineralocorticoid receptor (MR) may further confer genetic vulnerability/resilience on a background of ELS.

Identification of mineralocorticoid receptor target genes in the mouse hippocampus.

Brain mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respond to the same glucocorticoid hormones but can have differential effects on cellular function. Several lines of evidence suggest that MR-specific target genes must exist and might underlie the distinct effects of the receptors. The present study aimed to identify MR-specific target genes in the hippocampus, a brain region where MR and GR are co-localised and play a role in the stress response.

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

Altered cognitive performance is considered an intermediate phenotype mediating early life adversity (ELA) effects on later-life development of mental disorders, e.g. depression.

Mechanistic Insights in NeuroD Potentiation of Mineralocorticoid Receptor Signaling.

Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR.

The Role of Stressful Parenting and Mineralocorticoid Receptor Haplotypes on Social Development During Adolescence and Young Adulthood.

The development of social behavior could be affected by stressful parenting. The mineralocorticoid receptor, one of the two main receptors for the stress hormone cortisol, plays a vital role in adequate responses to stress. Therefore, the effects of stressful parenting on social development (i.

Hyperthermia-induced seizures followed by repetitive stress are associated with age-dependent changes in specific aspects of the mouse stress system.

Stress is among the most frequently self-reported factors provoking epileptic seizures in children and adults. It is still unclear, however, why some people display stress-sensitive seizures and others do not. Recently, we showed that young epilepsy patients with stress-sensitive seizures exhibit a dysregulated hypothalamic-pituitary-adrenal (HPA)-axis.

Effects of early life stress on biochemical indicators of the dopaminergic system: A 3 level meta-analysis of rodent studies.

Adverse early life events are a well-established risk factor for the precipitation of behavioral disorders characterized by anomalies in the dopaminergic system, such as schizophrenia and addiction. The correlation between early life conditions and the dopaminergic system has been causally investigated in more than 90 rodent publications. Here, we tested the validity of the hypothesis that early life stress (ELS) alters dopamine signaling by performing an extensive 3-level mixed effect meta-analysis.

The stressed brain of humans and rodents.

After stress, the brain is exposed to waves of stress mediators, including corticosterone (in rodents) and cortisol (in humans). Corticosteroid hormones affect neuronal physiology in two time-domains: rapid, non-genomic actions primarily via mineralocorticoid receptors; and delayed genomic effects via glucocorticoid receptors. In parallel, cognitive processing is affected by stress hormones.

Diffusion MRI-based cortical connectome reconstruction: dependency on tractography procedures and neuroanatomical characteristics.

Diffusion MRI (dMRI)-based tractography offers unique abilities to map whole-brain structural connections in human and animal brains. However, dMRI-based tractography indirectly measures white matter tracts, with suboptimal accuracy and reliability. Recently, sophisticated methods including constrained spherical deconvolution (CSD) and global tractography have been developed to improve tract reconstructions through modeling of more complex fiber orientations.

Circadian and ultradian patterns of HPA-axis activity in rodents: Significance for brain functionality.

The hypothalamo-pituitary-adrenal (HPA) axis comprises interactions between the hypothalamus, the pituitary and the adrenal glands and its activation results in the release of corticosteroid hormones. Corticosteroids are secreted from the adrenal gland in a distinct 24-h circadian rhythm overarching an ultradian rhythm, which consists of hourly corticosteroid pulses exposing target tissues to rapidly changing steroid levels. On top of these rhythms surges can take place after stress.

Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation.

Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [postnatal days (PND)26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood.

Early life stress-induced alterations in rat brain structures measured with high resolution MRI.

Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excitability and microstructure. Detailed information on the effects of ELS on rodent brain structural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses.

Hippocampal Fast Glutamatergic Transmission Is Transiently Regulated by Corticosterone Pulsatility.

In recent years it has become clear that corticosteroid hormones (such as corticosterone) are released in ultradian pulses as a natural consequence of pituitary-adrenal interactions. All organs, including the brain, are thus exposed to pulsatile changes in corticosteroid hormone level, important to ensure full genomic responsiveness to stress-induced surges. However, corticosterone also changes neuronal excitability through rapid non-genomic pathways, particularly in the hippocampus.

Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity.

The rodent adrenal hormone corticosterone (CORT) reaches the brain in hourly ultradian pulses, with a steep rise in amplitude before awakening. The impact of a single CORT pulse on glutamatergic transmission is well documented, but it remains poorly understood how consecutive pulses impact on glutamate receptor trafficking and synaptic plasticity. By using high-resolution imaging and electrophysiological approaches, we report that a single pulse of CORT to hippocampal networks causes synaptic enrichment of glutamate receptors and increased responses to spontaneously released glutamatergic vesicles, collectively abrogating the ability to subsequently induce synaptic long-term potentiation.

Rapid corticosteroid actions on synaptic plasticity in the mouse basolateral amygdala: relevance of recent stress history and β-adrenergic signaling.

The rodent stress hormone corticosterone rapidly enhances long-term potentiation in the CA1 hippocampal area, but leads to a suppression when acting in a more delayed fashion. Both actions are thought to contribute to stress effects on emotional memory. Emotional memory formation also involves the basolateral amygdala, an important target area for corticosteroid actions.