Shaping Memories via Stress: A Synaptic Engram Perspective.

Stress modulates the activity of various memory systems and can thereby guide behavioral interaction with the environment in an adaptive or maladaptive manner. At the cellular level, a large body of evidence indicates that (nor)adrenaline and glucocorticoid release induced by acute stress exposure affects synapse function and synaptic plasticity, which are critical substrates for learning and memory. Recent evidence suggests that memories are supported in the brain by sparsely distributed neurons within networks, termed engram cell ensembles. While the physiological and molecular effects of stress on the synapse are increasingly well characterized, how these synaptic modifications shape the multiscale dynamics of engram cell ensembles is still poorly understood. In this review, we discuss and integrate recent information on how acute stress affects synapse function and how this may alter engram cell ensembles and their synaptic connectivity to shape memory strength and memory precision. We provide a mechanistic framework of a synaptic engram under stress and put forward outstanding questions that address knowledge gaps in our understanding of the mechanisms that underlie stress-induced memory modulation.

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism.

INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aß) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear. METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence. RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins. DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

Early Life Stress Enhances Cognitive Decline and Alters Synapse Function and Interneuron Numbers in Young Male APP/PS1 Mice.

BACKGROUND: Exposure to stress early in life increases the susceptibility to Alzheimer's disease (AD) pathology in aged AD mouse models. So far, the underlying mechanisms have remained elusive. OBJECTIVE: To investigate 1) effects of early life stress (ELS) on early functional signs that precede the advanced neuropathological changes, and 2) correlate synaptosomal protein content with cognition to identify neural correlates of AD. METHODS: APPswe/PS1dE9 mice and littermates were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days 2-9. At 3 months of age, an age where no cognitive loss or amyloid-ß (Aß) pathology is typically reported in this model, we assessed hippocampal Aß pathology, synaptic strength and synapse composition and interneuron populations. Moreover, cognitive flexibility was assessed and correlated with synaptosomal protein content. RESULTS: While ELS did not affect Aß pathology, it increased synaptic strength and decreased the number of calretinin+ interneurons in the hippocampal dentate gyrus. Both genotype and condition further affected the level of postsynaptic glutamatergic protein content. Finally, APP/PS1 mice were significantly impaired in cognitive flexibility at 3 months of age, and ELS exacerbated this impairment, but only at relatively high learning criteria. CONCLUSIONS: ELS reduced cognitive flexibility in young APP/PS1 mice and altered markers for synapse and network function. These findings at an early disease stage provide novel insights in AD etiology and in how ELS could increase AD susceptibility.

Early life stress lastingly alters the function and AMPA-receptor composition of glutamatergic synapses in the hippocampus of male mice.

Early postnatal life is a sensitive period of development that shapes brain structure and function later in life. Exposure to stress during this critical time window can alter brain development and may enhance the susceptibility to psychopathology and neurodegenerative disorders later in life. The developmental effects of early life stress (ELS) on synaptic function are not fully understood, but could provide mechanistic insights into how ELS modifies later brain function and disease risk. We here assessed the effects of ELS on synaptic function and composition in the hippocampus of male mice. Mice were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days (P) 2-9. Synaptic strength was measured in terms of miniature excitatory postsynaptic currents (mEPSCs) in the hippocampal dentate gyrus at three different developmental stages: the early postnatal phase (P9), preadolescence (P21, at weaning) and adulthood at 3 months of age (3MO). Hippocampal synaptosome fractions were isolated from P9 and 3MO tissue and analyzed for protein content to assess postsynaptic composition. Finally, dendritic spine density was assessed in the DG at 3MO. At P9, ELS increased mEPSC frequency and amplitude. In parallel, synaptic composition was altered as PSD-95, GluA3 and GluN2B content were significantly decreased. The increased mEPSC frequency was sustained up to 3MO, at which age, GluA3 content was significantly increased. No differences were found in dendritic spine density. These findings highlight how ELS affects the development of hippocampal synapses, which could provide valuable insight into mechanisms how ELS alters brain function later in life.

Corrigendum: The interplay between quality of life and resilience factors in later life: a network analysis.

[This corrects the article DOI: 10.3389/fpsyg.2021.752564.].

Improving goal striving and resilience in older adults through a personalized metacognitive self-help intervention: a protocol paper.

BACKGROUND: Successful aging is often linked to individual's ability to demonstrate resilience: the maintenance or quick recovery of functional ability, well-being, and quality of life despite losses or adversity. A crucial element of resilience is behavioral adaptability, which refers to the adaptive changes in behavior in accordance with internal or external demands. Age-related degradation of executive functions can, however, lead to volition problems that compromise flexible adjustment of behavior. In contrast, the reliance on habitual control has been shown to remain relatively intact in later life and may therefore provide an expedient route to goal attainment among older adults. In the current study, we examine whether a metacognitive self-help intervention (MCSI), aimed at facilitating goal striving through the gradual automatization of efficient routines, could effectively support behavioral adaptability in favor of resilience among older adults with and without (sub-clinical) mental health problems. METHODS: This metacognitive strategy draws on principles from health and social psychology, as well as clinical psychology, and incorporates elements of established behavioral change and activation techniques from both fields. Additionally, the intervention will be tailored to personal needs and challenges, recognizing the significant diversity that exist among aging individuals. DISCUSSION: Despite some challenges that may limit the generalizability of the results, our MCSI program offers a promising means to empower older adults with tools and strategies to take control of their goals and challenges. This can promote autonomy and independent functioning, and thereby contribute to adaptability and resilience in later life. TRIAL REGISTRATION: Pre-registered, partly retrospectively. This study was pre-registered before the major part of the data was collected, created, and realized. Only a small part of the data of some participants (comprising the baseline and other pre-intervention measures), and the full dataset of the first few participants, was collected prior to registration, but it was not accessed yet. See: https://osf.io/5b9xz.

Elevated corticosterone after fear learning impairs remote auditory memory retrieval and alters brain network connectivity.

Glucocorticoids are potent memory modulators that can modify behavior in an adaptive or maladaptive manner. Elevated glucocorticoid levels after learning promote memory consolidation at recent time points, but their effects on remote time points are not well established. Here we set out to assess whether corticosterone (CORT) given after learning modifies remote fear memory. To that end, mice were exposed to a mild auditory fear conditioning paradigm followed by a single 2 mg/kg CORT injection, and after 28 d, auditory memory was assessed. Neuronal activation was investigated using immunohistochemistry for the immediate early gene c-Fos, and coactivation of brain regions was determined using a correlation matrix analysis. CORT-treated mice displayed significantly less remote auditory memory retrieval. While the net activity of studied brain regions was similar compared with the control condition, CORT-induced remote memory impairment was associated with altered correlated activity between brain regions. Specifically, connectivity of the lateral amygdala with the basal amygdala and the dorsal dentate gyrus was significantly reduced in CORT-treated mice, suggesting disrupted network connectivity that may underlie diminished remote memory retrieval. Elucidating the pathways underlying these effects could help provide mechanistic insight into the effects of stress on memory and possibly provide therapeutic targets for psychopathology.

Assessing the degree of urbanisation using a single-item self-report measure: a validation study.

The differential impact of rural versus urban residence on mental health remains a controversial topic that requires more in-depth investigations. This calls for a valid and easy measure to assess the degree of urbanisation. The purpose of the present study was to determine the utility of a single-item self-report measure (SIDU) as a tool to classify areas along the rural-urban continuum. The validity of the SIDU was assessed by comparing its scores (1-7) to a commonly used objective surrogate measure of the degree of urbanisation (i.e. surrounding address density, SAD) in two independent older adult samples (A: N = 36, 65+; B: N = 121, 55+). SIDU scores approximated SAD scores, with r = .77 to 0.82, (A), and r = .79 to 0.83 (B). A SIDU threshold score of 6 most accurately distinguished extremely urbanised areas from other areas. Altogether, our findings suggest that SIDU scores could be used as proxy of SAD. Since self-report leaves room for the consideration of additional aspects that confer an urban settlement, this single-item scale may be even more comprehensive, and circumvents the collection and handling of highly sensitive location data when the primary goal is solely to distinguish urbanisation subgroups.

The Subjective Experience of Ageism: The Perceived Ageism Questionnaire (PAQ).

Ageism as perceived by older individuals has been recognized as a potential risk factor for physical and mental health. We aimed to develop a comprehensive scale that can quantify perceived ageism among aging individuals (55+), including both positive and negative stereotypes, prejudices, and discriminations. This effort resulted in an 8-item Perceived Ageism Questionnaire (PAQ-8), with good psychometric properties and a two-factor structure distinguishing a positive (3 items) and negative (5 items) subscale (Analysis 1; n = 500). This dimensionality was confirmed in a separate cross-validation sample (Analysis 2; n = 500). The subscales' correlation patterns with individuals' self-perceptions of aging and mental health variables (i.e., quality of life, mental well-being, depression, anxiety, loneliness and perceived stress) accorded with theoretical hypotheses and existing knowledge of the concept of ageism. The PAQ-8 can help to gather more standardized data of the level, role and impact of perceived ageism.

Horizons in Human Aging Neuroscience: From Normal Neural Aging to Mental (Fr)Agility.

While aging is an important risk factor for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, age-related cognitive decline can also manifest without apparent neurodegenerative changes. In this review, we discuss molecular, cellular, and network changes that occur during normal aging in the absence of neurodegenerative disease. Emerging findings reveal that these changes include metabolic alterations, oxidative stress, DNA damage, inflammation, calcium dyshomeostasis, and several other hallmarks of age-related neural changes that do not act on their own, but are often interconnected and together may underlie age-related alterations in brain plasticity and cognitive function. Importantly, age-related cognitive decline may not be reduced to a single neurobiological cause, but should instead be considered in terms of a densely connected system that underlies age-related cognitive alterations. We speculate that a decline in one hallmark of neural aging may trigger a decline in other, otherwise thus far stable subsystems, thereby triggering a cascade that may at some point also incur a decline of cognitive functions and mental well-being. Beyond studying the effects of these factors in isolation, considerable insight may be gained by studying the larger picture that entails a representative collection of such factors and their interactions, ranging from molecules to neural networks. Finally, we discuss some potential interventions that may help to prevent these alterations, thereby reducing cognitive decline and mental fragility, and enhancing mental well-being, and healthy aging.

Application of a pharmacological transcriptome filter identifies a shortlist of mouse glucocorticoid receptor target genes associated with memory consolidation.

Glucocorticoids regulate memory consolidation, facilitating long-term storage of relevant information to adequately respond to future stressors in similar conditions. This effect of glucocorticoids is well-established and is observed in multiple types of behaviour that depend on various brain regions. By and large, higher glucocorticoid levels strengthen event-related memory, while inhibition of glucocorticoid signalling impairs consolidation. The mechanism underlying this glucocorticoid effect remains unclear, but it likely involves the transcriptional effects of the glucocorticoid receptor (GR). We here used a powerful paradigm to investigate the transcriptional effects of GR in the dorsal hippocampus of mice after training in an auditory fear conditioning task, aiming to identify a shortlist of GR target genes associated to memory consolidation. Therefore, we utilized in an explorative study the properties of selective GR modulators (CORT108297 and CORT118335), alongside the endogenous agonist corticosterone and the classical GR antagonist RU486, to pinpoint GR-dependent transcriptional changes. First, we confirmed that glucocorticoids can modulate memory strength via GR activation. Subsequently, by assessing the specific effects of the available GR-ligands on memory strength, we established a pharmacological filter which we imposed on the hippocampal transcriptome data. This identified a manageable shortlist of eight genes by which glucocorticoids may modulate memory consolidation, warranting in-depth follow-up. Overall, we showcase the strength of the concept of pharmacological transcriptome filtering, which can be readily applied to other research topics with an established role of glucocorticoids.

Psychological Coping and Behavioral Adjustment Among Older Adults in Times of COVID-19: Exploring the Protective Role of Working Memory and Habit Propensity.

The impact of the COVID-19 pandemic on mental health, well-being, and behavior is likely influenced by individual characteristics that determine one's capacity for resilience. In this exploratory study, we examined whether individual differences in working memory (WM) capacity and habit propensity (HP), measured before the outbreak, could predict variation in subsequent psychological coping efficacy (as operationalized by measures of depression, mental well-being, perceived stress, and loneliness) and behavioral adjustment (by evaluating compliance and self-reported automaticity of four COVID-19 guidelines) among Dutch older adults (n = 36) during the pandemic (measured April 25 to May 6, 2020). While we found elevated levels of depression and emotional loneliness, overall mental well-being, and perceived stress were not affected by the pandemic. Contrary to our expectations, we found no robust evidence for a protective role of WM in predicting these outcomes, although our findings hint at a positive relationship with perceived change in mental well-being. Interestingly, WM and HP were found to affect the self-reported automaticity levels of adherence to behavioral COVID-19 guidelines (i.e., washing hands, physical distancing), where a strong HP appeared beneficial when deliberate resources were less available (e.g., low WM capacity). These novel and preliminary findings offer new potential avenues for investigating individual differences in resilience in times of major life events or challenges. Supplementary Information: The online version contains supplementary material available at 10.1007/s10804-022-09404-9.

An emerging role for microglia in stress-effects on memory.

Stressful experiences evoke, among others, a rapid increase in brain (nor)epinephrine (NE) levels and a slower increase in glucocorticoid hormones (GCs) in the brain. Microglia are key regulators of neuronal function and contain receptors for NE and GCs. These brain cells may therefore potentially be involved in modulating stress effects on neuronal function and learning and memory. In this review, we discuss that stress induces (1) an increase in microglial numbers as well as (2) a shift toward a pro-inflammatory profile. These microglia have (3) impaired crosstalk with neurons and (4) disrupted glutamate signaling. Moreover, microglial immune responses after stress (5) alter the kynurenine pathway through metabolites that impair glutamatergic transmission. All these effects could be involved in the impairments in memory and in synaptic plasticity caused by (prolonged) stress, implicating microglia as a potential novel target in stress-related memory impairments.

The Interplay Between Quality of Life and Resilience Factors in Later Life: A Network Analysis.

Age-related challenges and transitions can have considerable social, psychological, and physical consequences that may lead to significant changes in quality of life (QoL). As such, maintaining high levels of QoL in later life may crucially depend on the ability to demonstrate resilience (i.e., successful adaptation to late-life challenges). The current study set out to explore the interplay between several resilience factors, and how these contribute to the realization and maintenance of (different facets of) QoL. Based on the previous work, we identified behavioral coping, positive appraisal, self-management ability, and physical activity as key resilience factors. Their interplay with (various facets of) QoL, as measured with the WHOQOL-OLD, was established through network analysis. In a sample of community-dwelling older adults (55+; N=1,392), we found that QoL was most strongly (and directly) related to positive appraisal style and self-management ability. Among those, taking care of multifunctional resources (i.e., yielding various benefits at the same time) seemed to be crucial. It connected directly to "satisfaction with past, present, and future activities," a key facet of QoL with strong interconnections to other QoL facets. Our analysis also identified resilience factor(s) with the potential to promote QoL when targeted by training, intervention, or other experimental manipulation. The appropriate set of resilience factors to manipulate may depend on the goal and/or facet of QoL that one aims to improve.

Glucocorticoids Promote Fear Generalization by Increasing the Size of a Dentate Gyrus Engram Cell Population.

BACKGROUND: Traumatic experiences, such as conditioned threat, are coded as enduring memories that are frequently subject to generalization, which is characterized by (re-) expression of fear in safe environments. However, the neurobiological mechanisms underlying threat generalization after a traumatic experience and the role of stress hormones in this process remain poorly understood. METHODS: 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. RESULTS: We found 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, while leaving expression of auditory fear memory unaffected. CONCLUSIONS: These results implicate the sparse ensemble of DG engram cells as a critical cellular substrate underlying fear generalization induced by glucocorticoid stress hormones.

Ketamine treatment upon memory retrieval reduces fear memory in marmoset monkeys.

Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p<0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p<0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD.

Early life stress amplifies fear responses and hippocampal synaptic potentiation in the APPswe/PS1dE9 Alzheimer mouse model.

Cognitive deficits and alterations in emotional behaviour are typical features of Alzheimer's disease (AD). Moreover, exposure to stress or adversity during the early life period has been associated with an acceleration of cognitive deficits and increased AD pathology in transgenic AD mouse models. Whether and how early life adversity affects fear memory in AD mice remains elusive. We therefore investigated whether exposure to early life stress (ELS) alters fear learning in APPswe/PS1dE9 mice, a classic mouse model for AD, and whether this is accompanied by alterations in hippocampal synaptic potentiation, an important cellular substrate for learning and memory. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing the dams and her pups with limited nesting and bedding material from postnatal days 2-9. Following a fear conditioning paradigm, 12-month-old ELS-exposed APPswe/PS1dE9 mice displayed enhanced contextual freezing behaviour, both in the conditioning context and in a novel context. ELS-exposed APPswe/PS1dE9 mice also displayed enhanced hippocampal synaptic potentiation, even in the presence of the GluN2B antagonist Ro25-6981 (which prevented synaptic potentiation in control mice). No differences in the level of PSD-95 or synaptophysin were observed between the groups. We conclude that in APPswe/PS1dE9 mice, ELS increases fear memory in the conditioning context as well as a novel context, which is accompanied by aberrant hippocampal synaptic potentiation. These results may help to understand how individual differences in the vulnerability to develop AD arise and emphasise the importance of the early postnatal time window in these differences. This article is part of Special Issue entitled: Lifestyle and Brain Metaplasticity.

How the COVID-19 pandemic highlights the necessity of animal research.

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.

Glucocorticoid and ß-adrenergic regulation of hippocampal dendritic spines.

Glucocorticoid hormones are particularly potent with respect to enhancing memory formation. Notably, this occurs in close synergy with arousal (i.e., when norepinephrine levels are enhanced). In the present study, we examined whether glucocorticoid and norepinephrine hormones regulate the number of spines in hippocampal primary neurons. We report that brief administration of corticosterone or the ß-adrenergic receptor agonist isoproterenol alone increases spine number. This effect becomes particularly prominent when corticosterone and isoproterenol are administered together. In parallel, corticosterone and isoproterenol alone increased the amplitude of miniature excitatory postsynaptic currents, an effect that is not amplified when both hormones are administered together. The effects of co-application of corticosterone and isoproterenol on spines could be prevented by blocking the glucocorticoid receptor antagonist RU486. Taken together, both corticosterone and ß-adrenergic receptor activation increase spine number, and they exert additive effects on spine number for which activation of glucocorticoid receptors is permissive.