Glucocorticoids regulate memory consolidation, facilitating long-term storage of relevant information to adequately respond to future stressors in similar conditions. This effect of glucocorticoids... Show moreGlucocorticoids 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. Show less
Daskalakis, N.P.; Meijer, O.C.; Kloet, E.R. de 2022
'You can't roll the clock back and reverse the effects of experiences' Bruce McEwen used to say when explaining how allostasis labels the adaptive process. Here we will for once roll the clock back... Show more'You can't roll the clock back and reverse the effects of experiences' Bruce McEwen used to say when explaining how allostasis labels the adaptive process. Here we will for once roll the clock back to the times that the science of the glucocorticoid hormone was honored with a Nobel prize and highlight the discovery of their receptors in the hippocampus as inroad to its current status as master regulator in control of stress coping and adaptation. Glucocorticoids operate in concert with numerous neurotransmitters, neuropeptides, and other hormones with the aim to facilitate processing of information in the neurocircuitry of stress, from anticipation and perception of a novel experience to behavioral adaptation and memory storage. This action, exerted by the glucocorticoids, is guided by two complementary receptor systems, mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), that need to be balanced for a healthy stress response pattern. Here we discuss the cellular, neuroendocrine, and behavioral studies underlying the MR:GR balance concept, highlight the relevance of hypothalamic pituitary-adrenal (HPA)-axis patterns and note the limited understanding yet of sexual dimorphism in glucocorticoid actions. We conclude with the prospect that (i) genetically and epigenetically regulated receptor variants dictate cell-type-specific transcriptome signatures of stress-related neuropsychiatric symptoms and (ii) selective receptor modulators are becoming available for more targeted treatment. These two new developments to 'restart the clock' with the to resilience. Show less
In this thesis, the consequences of Parkinson’s disease (PD) are studied using advanced approaches in neuroimaging, including structural as well as functional connectivity networks, examination of... Show moreIn this thesis, the consequences of Parkinson’s disease (PD) are studied using advanced approaches in neuroimaging, including structural as well as functional connectivity networks, examination of the role of aging in white matter degeneration in PD, and the use of machine learning classification models. Brain MRI features of PD patients are compared with healthy control subjects, and the relations between these features and patient characteristics, such as age, dopaminergic medication, motor and predominantly non-dopaminergic impairment, are described. Furthermore, brain features that may contribute to the differentiation of PD and Dementia with Lewy body dementia are described. Show less
Johnson, B.V.; Kumar, R.; Oishi, S.; Alexander, S.; Kasherman, M.; Vega, M.S.; ... ; S 2020
BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and... Show moreBACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function. Show less
Blood-brain barrier (BBB) leakage is considered an important underlying process in both cerebral small vessel disease (cSVD) and Alzheimer's disease (AD). The objective of this study was to examine... Show moreBlood-brain barrier (BBB) leakage is considered an important underlying process in both cerebral small vessel disease (cSVD) and Alzheimer's disease (AD). The objective of this study was to examine associations between BBB leakage, cSVD, neurodegeneration, and cognitive performance across the spectrum from normal cognition to dementia. Leakage was measured with dynamic contrast-enhanced magnetic resonance imaging in 80 older participants (normal cognition, n = 32; mild cognitive impairment, n 34; clinical AD-type dementia, n = 14). Associations between leakage and white matter hyperintensity (WMH) volume, hippocampal volume, and cognition (information processing speed and memory performance) were examined with multivariable linear regression and mediation analyses. Leakage within the gray and white matter was positively associated with WMH volume (gray matter, p = 0.03; white matter, p = 0.01). A negative association was found between white matter BBB leakage and information processing speed performance, which was mediated by WMH volume. Leakage was not associated with hippocampal volume. WMH pathology is suggested to form a link between leakage and decline of information processing speed in older individuals with and without cognitive impairment. (C) 2019 Elsevier Inc. All rights reserved. Show less
Detailed descriptions of the development of the hippocampus promise to shed light on the neural foundation of development of memory and other cognitive functions, as well as the emergence of major... Show moreDetailed descriptions of the development of the hippocampus promise to shed light on the neural foundation of development of memory and other cognitive functions, as well as the emergence of major mental disorders. Hippocampus is a heterogeneous structure with a well characterized internal complexity, but development of its distinct subregions in humans has remained poorly described. We analyzed magnetic resonance imaging (MRI) data from a large longitudinal sample (270 participants, 678 scans) using an automated segmentation tool and mixed models to delineate the development of hippocampal subregion volumes from childhood to adulthood. We also examined sex differences in subregion volumes and their development, and associations between hippocampal subregions and general cognitive ability. Nonlinear developmental trajectories with early volume increases were observed for subiculum, cornu ammonis (CA) 1, molecular layer (ML) and fimbria. In contrast, parasubiculum, presubiculum, CA2/3, CA4 and the granule cell layer of the dentate gyrus (GC-DG) showed linear volume decreases. No sex differences were found in hippocampal subregion development. Finally, general cognitive ability was positively associated with CA2/3 and CA4 volumes, as well as with ML development. In conclusion, hippocampal subregions appear to develop in diversified ways across adolescence, and specific subregions may link to general cognitive level. Show less
During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory... Show more During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory processes. To investigate this further we aimed to answer the question:""What are the primary genomic binding sites of the by stress and thus cortisol stimulated protein receptors MR and GR in the hippocampus?" To answer this question, new methods have been applied to determine where exactly MR and GR bind to the DNA, to find out which genes are potentially involved during stress management. As a result we have identified thousands of GR-binding sites at the DNA of which we have analyzed a selection in further detail. One of the identified pathways that have been found to be sensitive for activated GR and corticosteroids is the mTOR pathway. This pathway is involved in neuronal plasticity, which is the fundament for resilience. We have found that expression of the mTOR protein is decreased after exposure to acute stress when the organism has a history of chronic stress. Our results indicate that the reduced resilience after experiencing chronic stress is likely to be mediated by mTOR. Show less
Opmeer, E.M.; Tol, M.J. van; Kortekaas, R.; Wee, N.J.A. van der; Woudstra, S.; Buchem, M.A. van; ... ; Aleman, A. 2015
The results in this thesis showed for the first time doublecortin-like (DCL)-specific expression in the adult mouse brain. Besides the expected regions with the capacity to generate new neurons ... Show moreThe results in this thesis showed for the first time doublecortin-like (DCL)-specific expression in the adult mouse brain. Besides the expected regions with the capacity to generate new neurons (hippocampus and olfactory forebrain), DCL expression was found in three novel brain areas namely hypothalamic tanycytes, suprachiasmatic nucleus and Islands of Calleja. A state of the art conditional shRNA expressing mouse model was used to target DCL mRNA. The analysis of these DCL knockdown animals using qPCR and Western blot revealed strong reduction of DCL protein expression. Subsequent stereological analysis using BrdU and several stem cell and neuronal markers revealed increased progenitor proliferation, but impaired neurogenesis in the hippocampus. This impaired neurogenesis was associated, however, with an apparent normal spatial and contextual fear memory formation in circular hole board and in a contextual fear conditioning paradigm. Therefore, DCL-regulated adult neurogenesis seems not crucial for hippocampus-dependent learning. However, more subtle functions like pattern separation and context distinction might be regulated by DCL. DCL knockdown also increased D2 activity within the hypothalamus. Altogether, the DCL-KD mouse seems a good working model to study adult neurogenesis and the role of DCL in this process. Show less
Schizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was... Show moreSchizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was to identify novel susceptibility genes and pathways for psychosis in a psychostimulant mouse model which is considered a model for psychosis. Genome-wide analysis of transcripts in the hippocampal CA1, driving mesocortical dopaminergic activity, which has a prominent role in schizophrenia, revealed differential expression of target genes of Myocyte Enhancer Factor 2 (MEF2) and Glucocorticoid Receptor (GR). This suggest that this gene network is involved in sensitivity to amphetamine. In primary hippocampal neurons, knockdown of MEF2 reduced the expression of c-Jun and abolished its regulation by GR. Moreover, activation of MEF2 by neuronal depolarization was attenuated by glucocorticoids, suggesting a mutual feedback regulation of these transcription factors. Finally, in vivo MEF2 and GR appeared to be active in the induction phase of amphetamine sensitization. Overall, the findings suggest that in the hippocampus activation of GR can modulate the role of MEF2 target genes in induction of behavioral sensitization. This finding points to the hippocampus as an exciting target for further studies on the role of MEF2 and GR in the precipitation of psychosis susceptibility. Show less
Stress induces a switch in learning strategies of male C57BL/6J mice from predominantly spatial to more stimulus-response learning. To study generalization of these findings over sex, we... Show moreStress induces a switch in learning strategies of male C57BL/6J mice from predominantly spatial to more stimulus-response learning. To study generalization of these findings over sex, we investigated female C57BL/6J mice at three phases of the estrous cycle under non stress and acute (10 mm) restraint stress conditions. On a circular hole board (CHB) task, about half of the naive female mice used spatial and stimulus-response strategies to solve the task. Under stress, female mice favored spatial over stimulus-response strategies, with 100% of female mice in the estrus phase. Performance expressed as latency to solve the task is only improved in stressed female mice in the estrus phase. We conclude that the use of learning strategies is influenced by sex and this difference between sexes is aggravated by acute stress. (C) 2012 Elsevier B.V. All rights reserved. Show less