Osborne F.X. Almeida

• PhD
• Max Planck Institute of Psychiatry

This scientific commentary refers to ‘Path integration deficits are associated with phosphorylated tau accumulation in the entorhinal cortex’, by Koike et al. (https://doi.org/10.1093/braincomms/fcad359).

Labels serve as identifiers and convenient descriptors of inanimate and animate objects. In humans, given labels can easily become part of an individual’s self-perceived identity. Negative labels ascribed to a person can result in internalized stigma , a state that will shape the subject’s biography. This can ultimately impact the person’s mental a...

Like other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARγ in the CNS, many reports suggest direct PPARγ-mediated actions in the brain. This study ai...

[This corrects the article DOI: 10.3389/fncel.2019.00239.].

Oestrogens are steroid hormones that act through specific receptors in the brain to influence a variety of functions, including mood and cognition. The best‐known and most potent endogenous oestrogen is 17β‐oestradiol (17β‐E2). Oestrogen actions in the brain include alterations of neuronal excitability, neurotransmitter synthesis and metabolism, ne...

Steroid hormones secreted by the gonads (sex steroids) and adrenal glands (glucocorticoids, GC) are known to influence brain structure and function. While levels of sex steroids wane in late adulthood, corticosteroid levels tend to rise in many individuals due to age-related impairments in their feedback on central mechanisms regulating adrenal fun...

Aim: Since foods with high hedonic value are often consumed in excess of energetic needs, this study was designed to identify the mechanisms that may counter anorexigenic signalling in the presence of hedonic foods in lean animals. Methods: Mice, in different states of satiety (fed/fasted, or fed/fasted and treated with ghrelin or leptin, respec...

Chronic stress is a major risk factor for developing Alzheimer's disease (AD) and promotes the processing of amyloid precursor protein (APP) to β‐amyloid (Aβ). However, the precise relationship of stress and disease‐typical cognitive decline is presently not well understood. The aim of this study was to investigate how early life stress may affect...

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with a complex physiopathology whose initiators are poorly defined. Accumulating clinical and experimental evidence suggests a causal role of lifetime stress in AD. This chapter summarizes current knowledge about how chronic stress and its accompanying high levels of glucocorti...

Environmental enrichment (EE), comprising positive physical (exercise) and cognitive stimuli, influences neuronal structure and usually improves brain function. The promise of EE as a preventative strategy against neuropsychiatric disease is especially high during early postnatal development when the brain is still amenable to reorganization. Despi...

Hippocampal hyperactivity, ascribed to amyloid β (Aβ)-induced imbalances in neural excitation and inhibition, is found in patients with mild cognitive impairment, a prodromal stage of Alzheimer's disease (AD). To better understand the relationship between hippocampal hyperactivity and the molecular triggers of behavioral impairments in AD, we used...

Hippocampal hyperactivity is accentuated during aging. Wildtype mice (C57BL/6 strain), aged 10 (n = 5) or 20–23 (n = 6) months were scanned using MEMRI following placement in a novel environment. Note the reduced ability of the older group to display task-induced deactivation of the hippocampus. **P < 0.01.

Tau depletion does not improve performance in MWM with invisible escape platform. Following training and testing (3 d) with a visible escape platform, WT (n = 9), J20 (n = 9), tau KO (n = 7), and J20/tau KO (n = 8) mice (aged 7–10 months) were then exposed to 5 daily sessions during which the platform was submerged. (A) Acquisition profiles showing...

Tau depletion elevates body weight. Body weight was measured in WT (n = 7), J20 (n = 8), tau KO (n = 7), and J20/tau KO (n = 8) mice (aged 8–11 months) before MEMRI.

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 week...

Supplemental information

We show here that glutamate-activated AMPA and NMDA receptors regulate local translation of tau protein and recruit mechanisms that lead to the accumulation of hyperphosphorylated tau and enhance the neurofibrillary lesions. Glutamate stimulation is thought to cause neurodegeneration in AD; memantine, which relieves the aberrant excitation of gluta...

The hippocampus and prefrontal cortex (PFC) are connected in a reciprocal manner: whereas the hippocampus projects directly to the PFC, a polysynaptic pathway that passes through the nucleus reuniens (RE) of the thalamus relays inputs from the PFC to the hippocampus. The present study demonstrates that lesioning and/or inactivation of the RE reduce...

The dynamic turnover of hippocampal neurons is implicated in the regulation of cognitive and affective behavior. Extending our previous demonstration that administration of dexamethasone (ND) to neonatal rats depletes the resident population of neural precursor cells (NPC) and restrains the size of the neurogenic regions, we now show that the adver...

The state-of-the-art regarding the important role that endogenous opioid peptides and their respective receptors play in the regulation of a variety of physiological and behavioral functions under normal and stressful conditions is presented. This chapter covers the biology, pharmacology, and molecular biology of opioids, as well as the implication...

Background Chronic stress is associated with increased risk of glucose intolerance and cardiovascular diseases, albeit through undefined mechanisms. With the aim of gaining insights into the latter, this study examined the metabolic profile of young adult male rats that were exposed to chronic unpredictable stress. Methods Young adult male rats wer...

Early-stage Alzheimer’s disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific...

Significance Exposure to stressful events is a well-known inducer of neuronal atrophy implicated in the development of neuropsychiatric and neurological pathologies (e.g., depression and Alzheimer’s disease), although the underlying molecular mechanisms remain elusive. The current study demonstrates that absence of the cytoskeletal protein Tau bloc...

Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, a well-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause-effect relationship between these events remains to be established. To test t...

Synaptic dysfunction during early stages of Alzheimer’s disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits...

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclea...

Neurofibrillary tangles, composed of hyperphosphorylated tau fibrils, are a pathological hallmark of Alzheimer's disease; the neurofibrillary tangle load correlates strongly with clinical progression of the disease. A growing body of evidence indicates that tau oligomer formation precedes the appearance of neurofibrillary tangles and contributes to...

Supplementary Figures 1-6, Supplementary Tables 1-2 and Supplementary References

The extreme desert area where live the diurnal fat sand rat (Psammomys obesus), may induce special sensitivity to seasonal variations of physiological and behavioural factors such as reproductive and adrenal cortex activities. The breeding season occurred in autumn and winter which coincided with food availability, favourable temperatures and p...

p>Cognitive reserve (CR) helps explain the mismatch between expected cognitive decline and observed maintenance of cognitive functioning in older age. Factors such as education, literacy, lifestyle, and social networking are usually considered to be proxies of CR and its variability between individuals. A more direct approach to examine CR is throu...

The adrenal cortex exerts a wide range of biological effects, particularly with regard to the stress response and regulation of overall metabolism. The wild sand rat Psammomys obesus,presented seasonal variations of testicular activity in synergy with the adrenal cortex activity. The present study was undertaken to evaluate the effect of testic...

Stress activates the hypothalamic-pituitary-adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule esse...

Endocrine dysfunction is a common effect of traumatic brain injury (TBI). In addition to affecting the regulation of important body functions, the disruption of endocrine physiology can significantly impair mental functions, such as attention, memory, executive function, and mood. This mini-review focuses on alterations in mental functioning that a...

Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a...

The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP...

Eating depends strongly on learning processes which, in turn, depend on motivation. Conditioned learning, where individuals associate environmental cues with receipt of a reward, forms an important part of hedonic mechanisms; the latter contribute to the development of human overweight and obesity by driving excessive eating in what may become a vi...

Eating behavior depends on associations between the sensory and energetic properties of foods. Healthful balance of these factors is a challenge for industrialized societies that have an abundance of food, food choices and food-related cues. Here, we were interested in whether appetitive conditioning changes as a function of age. Operant and pavlov...

The wild sand rat, Psammomys obesus, displays seasonal variations in adrenocortical activity that parallel those of testicular activity, indicating functional cross-talk between the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes. In the present study, we examined androgen receptor (AR)-mediated actions of testicular steroids i...

Tau-mediated neurodegeneration is a central event in Alzheimer's disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers Tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interac...

Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompan...

Clinical and experimental studies suggest a causal role of chronic stress for brain pathology and diseases e.g. depression and Alzheimer´s disease (AD) as stress is strongly associated with neuronal and synaptic atrophy/loss resulting in impaired mood and/or cognition. Indeed, synaptic loss is a key underlying pathomechanism in both disorders while...

Early-life stress (ELS) increases the vulnerability thresholds for stress-related diseases such as major depression and anxiety by inducing alterations in the structure and function of neural circuits and endocrine pathways. We previously demonstrated the contribution of epigenetic mechanisms to the long-term programming of the hypothalamo-pituitar...

Elevated glucocorticoid levels and sign tracking (ST) in Pavlovian conditioning are potential biomarkers of compulsive behaviors such as addiction. As overeating is sometimes viewed as a form of addictive behavior, we hypothesized that murine Pavlovian sign trackers would have a greater propensity to overeat and develop obesity. Using a food reward...

Chronic mild stress (CMS) protocols are widely used to create animal models of depression. Despite this, the inconsistencies in the reported effects may be indicative of crucial differences in methodology. Here, we considered the time of the diurnal cycle in which stressors are applied as a possible relevant temporal variable underlying the associa...

Adelylyl cyclase 8(AC8) is a brain specific cyclase activated only by calcium. Therefore its activity has been associated with plasticity process underlying learning and memory. AC8 knockout(KO) mice show impaired stress-induced anxiety. Here we try to find whether AC8 is involved in hypothalamus-hypophysis-axis(HPA) regulation and if it influences...

Environmental challenges are part of daily life for any individual. In fact, stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous...

Despite numerous descriptions of rapid effects of corticosterone on neuronal function, the intracellular mechanisms responsible for these changes remain elusive. The present comprehensive analysis reveals that signaling from a membrane-located G protein-coupled receptor activates PKC, Akt/PKB, and PKA, which subsequently trigger the phosphorylation...

To consider the evidence that human and animal behaviors are epigenetically programmed by lifetime experiences. Extensive PubMed searches were carried out to gain a broad view of the topic, in particular from the perspective of human psychopathologies such as mood and anxiety disorders. The selected literature cited is complemented by previously un...

There is accumulating evidence that the nucleus accumbens (NAc) has an important role in the pathophysiology of depression. As the NAc is a key component in the neural circuitry of reward, it has been hypothesized that anhedonia, a core symptom of depression, might be related to dysfunction of this brain region. Neuronal morphology and expression o...

Impairment of hippocampal neurogenesis has been associated with the expression of depressive-like symptoms and some studies have suggested neurogenesis as a critical factor in the normalization of behavior by antidepressant (AD) drugs. This study provides robust evidence that ongoing neurogenesis is essential for the maintenance of behavioral homeo...

Maladaptive responses to stress and the associated hypersecretion of glucocorticoids cause psychopathologies ranging from hyperemotional states and mood dysfunction to cognitive impairments. Research in both humans and animal models has begun to identify morphological correlates of these functional changes. These include dendritic and synaptic reor...

Identification of predictors of cognitive trajectories through the establishment of composite or single-parameter dimensional categories of cognition and mood may facilitate development of strategies to improve quality of life in the elderly. Participants (n = 487, aged 50+ years) were representative of the Portuguese population in terms of age, ge...

Alzheimer's disease is a severely debilitating disease of high and growing proportions. Hypercholesterolaemia is a key risk factor in sporadic Alzheimer's disease that links metabolic disorders (diabetes, obesity and atherosclerosis) with this pathology. Hypercholesterolaemia is associated with increased levels of immunoglobulin G against oxidized...

The bed nucleus of the stria terminalis (BNST) is critically implicated in anxiety behavior and control of the hypothalamus-pituitary-adrenal axis. Having previously shown that chronic stress triggers dendritic/synaptic remodeling in specific nuclei of the BNST, we characterised the pattern of activation of neurons within different regions of the B...

Exposure to diet, drugs and early life adversity during sensitive windows of life 1,2 can lead to lasting changes in gene expression that contribute to the display of physiological and behavioural phenotypes. Such environmental programming is likely to increase the susceptibility to metabolic, cardiovascular and mental diseases 3,4. DNA methylation...

Stress is defined as a challenge to the homeostatic equilibrium of the organism. In stressful situations, a cascade of hormonal and behavioral changes is generated in an attempt to maintain homeostasis. However, maladaptation to stress is considered to be an etiological factor in the emergence of mood disorders like depression and anxiety, which ar...

Sex differences in the activity of the hypo-thalamus-pituitary-adrenal (HPA) axis in rats are programmed by neonatal estrogens; expo-sure of female neonates to estradiol (E 2) leads to overt defeminization of endocrine and behavioral functions in adulthood. E 2 activates both estrogen receptor isoforms (ERα and ERβ); these are widely expressed in t...

Stress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the p...

Disorders such as depression and anxiety exhibit strong sex differences in their prevalence and incidence, with women also differing from men in their response to antidepressants. Furthermore, receptors for corticotrophin releasing hormone (CRHR1) and arginine vasopressin receptor subtype 1b (AVPR1b) are known to contribute to the regulation of moo...

Aβ-induced GKAP degradation does not require PI-3K, ERK, Jnk and PKC activity, but depends on proteasome activity. (A) Rat frontal neurons were pretreated with PI-3K inhibitor Wortmannin (2 µM), ERK inhibitor UO126 (10 µM), Jnk inhibitor (AEG 100 µM) or PKC inhibitor Gö6893 (5 µM) before being exposed to Aβ (1 µM, 1 h). All inhibitors were ineffect...

Amyloid-β forms low-N oligomers in culture medium. Amyloid-β 40 was diluted in the culture medium at the concentration used to treat neurons and incubated at 37°C for 1 h. Samples of incubated, diluted Aβ were resolved on polyacrylamide gradient gel under non-denaturating conditions and probed with anti Aβ antibody. Three prominent bands were detec...

Homer1b and Shank1 cluster dispersal by Aβ does not depend upon AMPAR or mGluR activity. (A, B) Cultured fronto-cortical neurons were pre-treated with the AMPAR blocker NQBX (50 µM, 45 min) or the mGluR I/II blocker E4CPG (10 µM) before exposure to Aβ (1 µM, 1 h), after which they were fixed and immunostained for synaptophysin and either Homer1b (p...

In silico analysis identifies kinase candidates for the regulation of GKAP. We interrogated a database containing proteomic data regarding post-translational modifications of synaptic proteins (available at http://www.phosphosite.org/) using the reference sequence of SAPAP1 as query, 38 phospho-peptides were retrieved. The phosphopeptides were anno...

AMPAR, VDCC and tyrosine kinases are not involved in GKAP down-regulation. (A) AMPAR and VDCC are not involved in Aβ-induced degradation of GKAP. Pretreatment of rat cortical neurons with either the AMPAR blocker NQBX (25 µM) or the VDCC blocker Verapamil (50 µM) before exposure to Aβ (1 µM, 1 h) did not prevent GKAP down-regulation in synaptic clu...

Aβ activates the PKB pathway through NMDAR. Rat cortical neurons were starved (see Methods) for 2 h before pre-treatment (45 min) with the NMDAR antagonist MK801 (10 µM), the VDCC blocker verapamil (50 µM) or vehicle before exposure to Aβ (1 µM, 10 min). Cells were fixed and immunostained for p-PKB (Thr308) and synaptophysin. (A) Representative ima...

The early stages of Alzheimer's disease are marked by synaptic dysfunction and loss. This process results from the disassembly and degradation of synaptic components, in particular of scaffolding proteins that compose the post-synaptic density (PSD), namely PSD95, Homer and Shank. Here we investigated in rat frontal cortex dissociated culture the m...

Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC) secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and...

Stressful life experiences are likely etiological factors in sporadic forms of Alzheimer's disease (AD). Many AD patients hypersecrete glucocorticoids (GCs), and their GC levels correlate with the rate of cognitive impairment and extent of neuronal atrophy. Severity of cognitive deficits in AD correlates strongly with levels of hyperphosphorylated...

Alternative splicing serves to increase biological diversity and adaptation. Many genes, including the glucocorticoid receptor (GR), contain multiple 5'-untranslated exons in their promoter regions that can give rise to various mRNA isoforms encoding the same protein. To date, information on the mouse GR promoter remains sparse. Here, we extensivel...

Stress and high levels of glucocorticoids during pre-and early postnatal life seem to alter developmental programs that assure dopaminergic transmission in the mesolimbic, mesocortical, and nigrostriatal systems. The induced changes are likely to be determined by the ontogenetic state of development of these brain regions at the time of stress expo...

Stress and high levels of glucocorticoids during pre- and early postnatal life seem to alter developmental programs that assure dopaminergic transmission in the mesolimbic, mesocortical, and nigrostriatal systems. The induced changes are likely to be determined by the ontogenetic state of development of these brain regions at the time of stress exp...

Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 μM...