Chronic Stress Effects on Hippocampal Structure and Synaptic Function: Relevance for Depression and Normalization by Anti-Glucocorticoid Treatment

Exposure of an organism to environmental challenges activates two hormonal systems that help the organism to adapt. As part of this adaptational process, brain processes are changed such that appropriate behavioral strategies are selected that allow optimal performance at the short term, while relevant information is stored for the future. Over the past years it has become evident that chronic uncontrollable and unpredictable stress also exerts profound effects on structure and function of limbic neurons, but the impact of chronic stress is not a mere accumulation of repeated episodes of acute stress exposure. Dendritic trees are reduced in some regions but expanded in others, and cells are generally exposed to a higher calcium load upon depolarization. Synaptic strengthening is largely impaired. Neurotransmitter responses are also changed, e.g., responses to serotonin. We here discuss: (a) the main cellular effects after chronic stress with emphasis on the hippocampus, (b) how such effects could contribute to the development of psychopathology in genetically vulnerable individuals, and (c) their normalization by brief treatment with anti-glucocorticoids

Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance

One of the core reactions in response to a stressful situation is the activation of the hypothalamus–pituitary–adrenal axis which increases the release of glucocorticoid hormones from the adrenal glands. In concert with other neuro-modulators, such as (nor)adrenaline, these hormones enable and promote cognitive adaptation to stressful events. Recent studies have demonstrated that glucocorticoid hormones and noradrenaline, via their receptors, can both rapidly and persistently regulate the function of excitatory synapses which are critical for storage of information. Here we will review how glucocorticoids and noradrenaline alone and in synergy dynamically tune these synapses in the hippocampus and amygdala, and discuss how these hormones interact to promote behavioral adaptation to stressful situations

Individual differences in the encoding of contextual details following acute stress:An explorative study

Information processing under stressful circumstances depends on many experimental conditions, like the information valence or the point in time at which brain function is probed. This also holds true for memorizing contextual details (or 'memory contextualization'). Moreover, large interindividual differences appear to exist in (context-dependent) memory formation after stress, but it is mostly unknown which individual characteristics are essential. Various characteristics were explored from a theory-driven and data-driven perspective, in 120 healthy men. In the theory-driven model, we postulated that life adversity and trait anxiety shape the stress response, which impacts memory contextualization following acute stress. This was indeed largely supported by linear regression analyses, showing significant interactions depending on valence and time point after stress. Thus, during the acute phase of the stress response, reduced neutral memory contextualization was related to salivary cortisol level; moreover, certain individual characteristics correlated with memory contextualization of negatively valenced material: (a) life adversity, (b) alpha-amylase reactivity in those with low life adversity and (c) cortisol reactivity in those with low trait anxiety. Better neutral memory contextualization during the recovery phase of the stress response was associated with (a) cortisol in individuals with low life adversity and (b) alpha-amylase in individuals with high life adversity. The data-driven Random Forest-based variable selection also pointed to (early) life adversity-during the acute phase-and (moderate) alpha-amylase reactivity-during the recovery phase-as individual characteristics related to better memory contextualization. Newly identified characteristics sparked novel hypotheses about non-anxious personality traits, age, mood and states during retrieval of context-related information

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 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. 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 on sex, strain, prior arousal, context (size, walls, shape, etc.) and timing (habituation, learning, and memory phase) 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

Maternal care of heterozygous dopamine receptorD4knockout mice:Differential susceptibility to early-life rearing conditions

The differential susceptibility hypothesis proposes that individuals who are more susceptible to the negative effects of adverse rearing conditions may also benefit more from enriched environments. Evidence derived from human experiments suggests the lower efficacy dopamine receptor D4 (DRD4) 7-repeat as a main factor in exhibiting these for better and for worse characteristics. However, human studies lack the genetic and environmental control offered by animal experiments, complicating assessment of causal relations. To study differential susceptibility in an animal model, we exposed Drd4+/− mice and control litter mates to a limited nesting/bedding (LN), standard nesting (SN) or communal nesting (CN) rearing environment from postnatal day (P) 2-14. Puberty onset was examined from P24 to P36 and adult females were assessed on maternal care towards their own offspring. In both males and females, LN reared mice showed a delay in puberty onset that was partly mediated by a reduction in body weight at weaning, irrespective of Drd4 genotype. During adulthood, LN reared females exhibited characteristics of poor maternal care, whereas dams reared in CN environments showed lower rates of unpredictability towards their own offspring. Differential susceptibility was observed only for licking/grooming levels of female offspring towards their litter; LN reared Drd4+/− mice exhibited the lowest and CN reared Drd4+/− mice the highest levels of licking/grooming. These results indicate that both genetic and early-environmental factors play an important role in shaping maternal care of the offspring for better and for worse

Time-dependent effects of psychosocial stress on the contextualization of neutral memories

Memories about stressful experiences need to be both specific and generalizable to adequately guide future behavior. Memory strength is influenced by emotional significance, and contextualization (i.e., encoding experiences with their contextual details) enables selective context-dependent retrieval and protects against overgeneralization. The current randomized-controlled study investigated how the early and late phase of the endogenous stress response affects the contextualization of neutral and negative information. One hundred healthy male participants were randomly divided into three experimental groups that performed encoding either 1) without stress (control), 2) immediately after acute stress (early) or 3) two hours after acute stress (late). Stress was induced via the Trier Social Stress Test and salivary alpha-amylase and cortisol levels were measured throughout the experiment. In the Memory Contextualization Task, neutral and angry faces (items) were depicted against unique context pictures during encoding. During testing 24 h later, context-dependent recognition memory of the items was assessed by presenting these in either congruent or incongruent contexts (relative to encoding). Multilevel analyses revealed that neutral information was more contextualized when encoding took place two hours after psychosocial stress, than immediately after the stressor. Results suggest that the late effects in the unique, time-dependent sequence of a healthy endogenous stress response, could complement reduced contextualization immediately after stress. The contextualization of negative information was not influenced by psychosocial stress, as opposed to earlier reported effects of exogenous hydrocortisone administration. An imbalance between the early and late effects of the endogenous stress response could increase vulnerability for stress-related psychopathology.</p

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 pre-frontal 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. The age-dependent changes in the excitation-inhibition balance were mirrored by similar changes in receptor subunit expression and morphological alterations, particularly in spine density, which could thus potentially contribute to the functional changes. However, none of these parameters displayed acceleration by early life stress, nor depended on mineralocorticoid receptor expression. We conclude that, in agreement with the hypothesis, early life stress accelerates the developmental shift of the excitation-inhibition balance but, contrary to expectation, there is no evidence for a putative protective role of the mineralocorticoid receptor in this system. In view of the modest effect of early life stress on the excitation-inhibition balance, alternative mechanisms potentially underlying the development of psychiatric disorders should be further explored

Non-genomic steroid signaling through the mineralocorticoid receptor:Involvement of a membrane-associated receptor?

Corticosteroid receptors in the mammalian brain mediate genomic as well as non-genomic actions. Although receptors mediating genomic actions were already cloned 35 years ago, it remains unclear whether the same molecules are responsible for the non-genomic actions or that the latter involve a separate class of receptors. Here we focus on one type of corticosteroid receptors, i.e. the mineralocorticoid receptor (MR). We summarize some of the known properties and the current insight in the localization of the MR in peripheral cells and neurons, especially in relation to non-genomic signaling. Previous studies from our own and other labs provided evidence that MRs mediating non-genomic actions are identical to the ones involved in genomic signaling, but may be translocated to the plasma cell membrane instead of the nucleus. With fixed cell imaging and live cell imaging techniques we tried to visualize these presumed membrane-associated MRs, using antibodies or overexpression of MR-GFP in COS7 and hippocampal cultured neurons. Despite the physiological evidence for MR location in or close to the cell membrane, we could not convincingly visualize membrane localization of endogenous MRs or GFP-MR molecules. However, we did find punctae of labeled antibodies intracellularly, which might indicate transactivating spots of MR near the membrane. We also found some evidence for trafficking of MR via beta-arrestins. In beta-arrestin knockout mice, we didn't observe metaplasticity in the basolateral amygdala anymore, indicating that internalization of MRs could play a role during corticosterone activation. Furthermore, we speculate that membrane-associated MRs could act indirectly via activating other membrane located structures like e.g. GPER and/or receptor tyrosine kinases

Pro-social preference in an automated operant two-choice reward task under different housing conditions:Exploratory studies on pro-social decision making

In this study, we aimed to develop a behavioral task that measures pro-social decision making in rats. A fully automated, operant pro-social two-choice task is introduced that quantifies pro-social preferences for a mutual food reward in a set-up with tightly controlled task contingencies. Pairs of same-sex adult Wistar rats were placed in an operant chamber divided into two compartments (one rat per compartment), separated by a transparent barrier with holes that allowed the rats to see, hear, smell, but not touch each other. Test rats could earn a sucrose pellet either for themselves (own reward) or for themselves and the partner (both reward) by means of lever pressing. On average, male rats showed a 60 % preference for the lever that yielded a food reward for both themselves and their partner. In contrast, females did not show lever preference, regardless of the estrous cycle phase. Next, the impact of juvenile environmental factors on male rat social decision making was studied. Males were group-housed from postnatal day 26 onwards in complex housing Marlau™ cages that provided social and physical enrichment and stimulation in the form of novelty. Complex housed males did not show a preference for the pro-social lever