I am a Neuroscientist by training, focusing on (early) stress in relation to brain plasticity and disease, with a focus on adult hippocampus neurogenesis and dementia.
In this perspective article, we reflect on the recent debate about the existence of human neuroge... more In this perspective article, we reflect on the recent debate about the existence of human neurogenesis and discuss direct, and also indirect, support for the ongoing formation, and functional relevance, of new neurons in the adult and aged human hippocampus. To explain the discrepancies between several prominently published human studies, we discuss critical methodological aspects and highlight the importance of optimal tissue preservation and processing for histological examination. We further discuss novel approaches, like single-cell/nucleus sequencing and magnetic resonance spectroscopy, that will help advance the study of human neurogenesis to its fullest potential-understanding its contribution to human hippocampal functions and related disorders like depression and dementia.
Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorti... more Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological co...
In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (... more In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in the control of access of cortisol and corticosterone to the mouse and human brain. [ 3 H]Cortisol poorly penetrated the brain of adrenalectomized wildtype mice, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a Ϫ/Ϫ mice. In sharp contrast, treatment with [ 3 H]corticosterone revealed high labeling of brain tissue without difference between both genotypes. Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementary DNA showed polar transport of [ 3 H]cortisol that could be blocked by a specific Pgp blocker, whereas [ 3 H]corticosterone transport did not differ between transfected and host cells. Determination of the concentration of both steroids in extracts of human postmortem brain tissue using liquid chromatography mass spectrometry revealed that the ratio of corticosterone over cortisol in the brain was significantly increased relative to plasma. In conclusion, the data demonstrate that in both mouse and human brain the penetration of cortisol is less than that of corticosterone. This finding suggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.
Recent studies on apolipoprotein E (apoE) have stressed the importance of this protein in neurona... more Recent studies on apolipoprotein E (apoE) have stressed the importance of this protein in neuronal viability, especially in the hippocampal area. In the present study, we used the Morris water maze to assess spatial learning and memory in 6-month-old homozygous apoE-deficient and heterozygous control mice. The apoE status was checked by genotyping and immunocytochemistry. ApoE-knockout mice were not able to learn the task at all, developed neither spatial nor other strategies to locate the platform, but rather an unusual repetitive behavioral pattern of 'wall bumping'. Heterozygous control mice did not experience any difficulty with the task. Swimming ability and general locomotor activity of both groups were comparable. These results indicate that absence of apoE in these animals might be critical for spatial learning and memory abilities.
broad definition of pathology, we here review the "neuropathology of stress" and focus on structu... more broad definition of pathology, we here review the "neuropathology of stress" and focus on structural consequences of stress exposure for different regions of the rodent, primate and human brain. We discuss cytoarchitectural, neuropathological and structural plasticity measures as well as more recent neuroimaging techniques that allow direct monitoring of the spatiotemporal effects of stress and the role of different CNS structures in the regulation of the hypothalamic-pituitary-adrenal axis in human brain. We focus on the hypothalamus, hippocampus, amygdala, nucleus accumbens, prefrontal and orbitofrontal cortex, key brain regions that not only modulate emotions and cognition but also the response to stress itself, and discuss disorders like Abstract 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 system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Using a
Background: Environmental factors like stress affect age-related cognitive deficits and promote A... more Background: Environmental factors like stress affect age-related cognitive deficits and promote Alzheimer's disease (AD)-related pathology in mice. Excess glutamate has been proposed as a possible mediator underlying these effects in the hippocampus, a vulnerable brain region implicated in learning and memory. Methods: Here, we examined a) whether stress applied during a sensitive developmental period early in life affects later synaptic plasticity, learning and memory and plaque load in the APPswe/PS1dE9 mouse model for Alzheimer's disease and b) whether these effects could be rescued using long-term treatment with the glutamate modulator riluzole. Results: Our results demonstrate that ELS impairs synaptic plasticity in 6-month-old mice and increases plaque load in 12-month-old APPswe/PS1dE9 mice, while impairing flexible spatial learning in the Barnes maze at this age. Notably, spatial learning correlated well with hippocampal expression of the transporter EAAT2, which is important for extracellular glutamate uptake. The changes in LTP, plaque load and cognition after ELS were all prevented by riluzole treatment that started from post-weaning. Conclusion: These results suggest that normalising glutamate signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing stress-aggravated AD, particularly in relation to adverse early life experiences.
The brain of many species including humans, harbors stem cells that continue to generate new neur... more The brain of many species including humans, harbors stem cells that continue to generate new neurons up into adulthood. This form of structural plasticity occurs in a limited number of brain regions, i.e. the subventricular zone and the hippocampal dentate gyrus and is regulated by environmental and hormonal factors. In this minireview, we provide an overview of the effects of stress and glucocorticoid hormones on adult hippocampal neurogenesis and discuss how these effects may be relevant for cognitive function and possibly, brain disease. While its exact functional role remains elusive, adult neurogenesis has been implicated in learning and memory, fear and mood regulation and recently, adult-born neurons were found to be involved in specific cognitive functions such as pattern separation (i.e. the ability to form unique memory representations) and cognitive flexibility. The process of adult neurogenesis is influenced by several factors; whereas e.g. exercise stimulates, exposure to stress and stress hormones generally inhibit neurogenesis. Effects of acute, mild stress are generally short-lasting and recover quickly, but chronic or severe forms of stress can induce lasting reductions in adult neurogenesis. Some of the inhibitory effects of stress can be rescued by exercise, by allowing a period of recovery from stress, by drugs that target the stress system, or by some, but not all, antidepressants. Stress may, partly through its effects on adult neurogenesis, alter structure and plasticity of the hippocampal circuit. This can lead to subsequent changes in stress responsivity and aspects of memory processing, which may be particularly relevant for stress related psychopathology or brain diseases that involve perturbed memory processing.
We tested the effect of early-life stress (ELS)-24 h maternal deprivation (MD) at postnatal day (... more We tested the effect of early-life stress (ELS)-24 h maternal deprivation (MD) at postnatal day (PND) 3-on cognitive performance and hippocampal structure in 12-17-week-old female rats. Behavioral performance was examined in: the Elevated Plus Maze, as an index for general anxiety; the rodent Iowa gambling test, probing reward-based decision making; and the object recognition and object-in-location task, to assess non-stressful contextual memory performance. We further determined hippocampal dentate gyrus (DG) volume and cell density as well as adult proliferation and neurogenesis rates. Half of the rats was treated with the glucocorticoid receptor antagonist mifepristone during a critical pre-pubertal developmental window (PNDs 26-28), in an attempt to ameliorate the potentially adverse behavioral consequences of ELS. Neither MD nor treatment with the glucocorticoid antagonist affected behavioral performance of the females in any of the tasks. Also, DG structure, proliferation and neurogenesis were not different between the groups. Lack of structural differences and a behavioral phenotype in non-stressful hippocampus dependent learning tasks fits with the lack of phenotype generally reported after ELS in female but less so in male rodents. As evident from an extensive literature review, female and male animals appear to respond more similarly to early-life adversity when tested in anxiety-related tasks. This agrees with recent findings in humans suggesting that females may be relatively resilient to the structural/hippocampal effects of childhood maltreatment, but not to the anxiety and mood-related psychopathology for which childhood maltreatment is considered a risk factor. This article is part of a Special Issue entitled: Early Adversity.
Neuroinflammation and neurogenesis have both been the subject of intensive investigation over the... more Neuroinflammation and neurogenesis have both been the subject of intensive investigation over the past 20 years. The sheer complexity of their regulation and their ubiquity in various states of health and disease have sometimes obscured the progress that has been made in unraveling their mechanisms and regulation. A recent study by Kozareva et al. (Neuronal Signaling (2019) 3), provides evidence that the orphan nuclear receptor TLX is central to communication between microglia and neural precursor cells and could help us understand how inflammation, mediated by microglia, influences the development of new neurons in the adult hippocampus. Here, we put recent studies on TLX into the context of what is known about adult neurogenesis and microglial activation in the brain, along with the many hints that these processes must be inter-related.
Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit ch... more Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit characteristics, and can be modeled in mice by administration of kainic acid (KA). Adult neurogenesis in the dentate gyrus (DG) contributes to hippocampal functions and has been reported to contribute to the development of TLE. Some of the phenotypical changes include neural stem and precursor cells (NPSC) apoptosis, shortly after their birth, before they produce hippocampal neurons. Here we explored these early phenotypical changes in the DG 3 days after a systemic injection of KA inducing status epilepticus (KA-SE), in mice. We performed a multi-omics experimental setup and analyzed DG tissue samples using proteomics, transcriptomics and microRNA profiling techniques, detecting the expression of 2327 proteins, 13401 mRNAs and 311 microRNAs. We here present a description of how these data were obtained and make them available for further analysis and validation. Our data may help to furth...
This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the mo... more This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.
Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressa... more Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the serotonin re-uptake inhibitor (SSRI) fluoxetine (Prozac) enhances neurogenesis, the new dual serotonin/noradrenaline reuptake inhibitor (SNRI) duloxetine has not been evaluated in this context. In addition, it is unclear whether effects of antidepressants and running on cell genesis and behavior are of similar magnitude in mice. Here,we assessed neurogenesis and open field behavior in 2 month old female C57Bl/6 mice after 28 days of treatment with either fluoxetine (18 mg/kg), duloxetine (2, 6 or 18 mg/kg) or exercise. New cell survival, as measured by 5-bromo-2´-deoxyuridine (BrdU) labeled cells, was enhanced by 200% in the running group only. Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data not only show that the neurogenic response to exercise is much stronger than to antidepressants, but also imply a low likelihood that reported effects of these two drugs on anxiety are mediated by adult neurogenesis in C57Bl/6 mice.
Many lines of independent research have provided convergent evidence regarding oxidative stress, ... more Many lines of independent research have provided convergent evidence regarding oxidative stress, cerebrovascular disease, dementia, and Alzheimer's disease (AD). Clinical studies spurred by these findings engage basic and clinical communities with tangible results regarding molecular targets and patient outcomes. Focusing on recent progress in characterizing age-related diseases specifically highlights oxidative stress and mechanisms for therapeutic action in AD. Oxidative stress has been investigated independently for its relationship with aging and cardiovascular and neurodegenerative diseases and provides evidence of shared pathophysiology across these conditions. The mechanisms by which oxidative stress impacts the cerebrovasculature and bloodbrain barrier are of critical importance for evaluating antioxidant therapies. Clinical research has identified homocysteine as a relevant risk factor for AD and dementia; basic research into molecular mechanisms associated with homocysteine metabolism has revealed important findings. Oxidative stress has direct implications in the pathogenesis of age-related neurodegenerative diseases and careful scrutiny of oxidative stress in the CNS has therapeutic implications for future clinical trials. These mechanisms of dysfunction, acting independently or in concert, through oxidative stress may provide the research community with concise working concepts and promising new directions to yield new methods for evaluation and treatment of dementia and AD.
In this chapter, we will review changes in structural plasticity of the adult hippocampus during ... more In this chapter, we will review changes in structural plasticity of the adult hippocampus during stress and exposure to glucocorticoids (GCs). We further discuss the protective and normalizing role of glucocorticoid receptor (GR) antagonist treatment under these conditions and its implications for disorders such as depression and diabetes mellitus. 6.1 The Stress Response Stress represents an old, yet essential alarm system for an organism. Whenever a discrepancy occurs between an organism's expectations and the reality it encounters, stress systems are activated; particularly when it involves a threat to, or disturbance of its homeostasis, well being, or health. Loss of control, or unpredictability when faced with predator threat in animals, or psychosocial demands in humans, can all produce stress signals. The same holds true for perturbations of a more physical or biological nature, such as energy crises, injury, or inflammation. Upon exposure to a stressor, various sensory and cognitive signals converge to activate a stress response that triggers several adaptive processes in the body and brain which aim to promote restoration of homeostasis. In mammals, Selye [1] noted that the effect of stressors develops in a stereotypic manner. The first phase largely involves activation of the sympathoadrenal system through the rapid release of epinephrine and norepinephrine from the adrenal medulla; these hormones elevate basal metabolic rate and increase blood flow to vital organs like the heart and muscles. At a later stage, the limbic hypothalamo-pituitary-adrenal (HPA) system is activated as well, a classic neuroendocrine circuit in which limbic and hypothalamic brain structures integrate emotional, cognitive, neuroendocrine, and autonomic inputs, that together determine the magnitude and duration of the organism's behavioral, neural, and hormonal response to a stressor.
Early-life stress (ES) exposure increases the risk of developing obesity. Breastfeeding can marke... more Early-life stress (ES) exposure increases the risk of developing obesity. Breastfeeding can markedly decrease this risk, and it is thought that the physical properties of the lipid droplets in human milk contribute to this benefit. A concept infant milk formula (IMF) has been developed that mimics these physical properties of human milk (Nuturis®, N-IMF). Previously, we have shown that N-IMF reduces, while ES increases, western-style diet (WSD)-induced fat accumulation in mice. Peripheral and central inflammation are considered to be important for obesity development. We therefore set out to test the effects of ES, Nuturis® and WSD on adipose tissue inflammatory gene expression and microglia in the arcuate nucleus of the hypothalamus. ES was induced in mice by limiting the nesting and bedding material from postnatal day (P) 2 to P9. Mice were fed a standard IMF (S-IMF) or N-IMF from P16 to P42, followed by a standard diet (STD) or WSD until P230. ES modulated adipose tissue inflamma...
Early life stress (ES) increases the risk to develop metabolic and brain disorders in adulthood. ... more Early life stress (ES) increases the risk to develop metabolic and brain disorders in adulthood. Breastfeeding (exclusivity and duration) is associated with improved metabolic and neurocognitive health outcomes, and the physical properties of the dietary lipids may contribute to this. Here, we tested whether early life exposure to dietary lipids mimicking some physical characteristics of breastmilk (i.e., large, phospholipid-coated lipid droplets; Concept Nuturis® infant milk formula (N-IMF)), could protect against ES-induced metabolic and brain abnormalities under standard circumstances, and in response to prolonged Western-style diet (WSD) in adulthood. ES was induced by exposing mice to limited nesting material from postnatal day (P) 2 to P9. From P16 to P42, male offspring were fed a standard IMF (S-IMF) or N-IMF, followed by either standard rodent diet (SD) or WSD until P230. We then assessed body composition development, fat mass, metabolic hormones, hippocampus-dependent cogn...
In this perspective article, we reflect on the recent debate about the existence of human neuroge... more In this perspective article, we reflect on the recent debate about the existence of human neurogenesis and discuss direct, and also indirect, support for the ongoing formation, and functional relevance, of new neurons in the adult and aged human hippocampus. To explain the discrepancies between several prominently published human studies, we discuss critical methodological aspects and highlight the importance of optimal tissue preservation and processing for histological examination. We further discuss novel approaches, like single-cell/nucleus sequencing and magnetic resonance spectroscopy, that will help advance the study of human neurogenesis to its fullest potential-understanding its contribution to human hippocampal functions and related disorders like depression and dementia.
Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorti... more Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological co...
In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (... more In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in the control of access of cortisol and corticosterone to the mouse and human brain. [ 3 H]Cortisol poorly penetrated the brain of adrenalectomized wildtype mice, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a Ϫ/Ϫ mice. In sharp contrast, treatment with [ 3 H]corticosterone revealed high labeling of brain tissue without difference between both genotypes. Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementary DNA showed polar transport of [ 3 H]cortisol that could be blocked by a specific Pgp blocker, whereas [ 3 H]corticosterone transport did not differ between transfected and host cells. Determination of the concentration of both steroids in extracts of human postmortem brain tissue using liquid chromatography mass spectrometry revealed that the ratio of corticosterone over cortisol in the brain was significantly increased relative to plasma. In conclusion, the data demonstrate that in both mouse and human brain the penetration of cortisol is less than that of corticosterone. This finding suggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.
Recent studies on apolipoprotein E (apoE) have stressed the importance of this protein in neurona... more Recent studies on apolipoprotein E (apoE) have stressed the importance of this protein in neuronal viability, especially in the hippocampal area. In the present study, we used the Morris water maze to assess spatial learning and memory in 6-month-old homozygous apoE-deficient and heterozygous control mice. The apoE status was checked by genotyping and immunocytochemistry. ApoE-knockout mice were not able to learn the task at all, developed neither spatial nor other strategies to locate the platform, but rather an unusual repetitive behavioral pattern of 'wall bumping'. Heterozygous control mice did not experience any difficulty with the task. Swimming ability and general locomotor activity of both groups were comparable. These results indicate that absence of apoE in these animals might be critical for spatial learning and memory abilities.
broad definition of pathology, we here review the "neuropathology of stress" and focus on structu... more broad definition of pathology, we here review the "neuropathology of stress" and focus on structural consequences of stress exposure for different regions of the rodent, primate and human brain. We discuss cytoarchitectural, neuropathological and structural plasticity measures as well as more recent neuroimaging techniques that allow direct monitoring of the spatiotemporal effects of stress and the role of different CNS structures in the regulation of the hypothalamic-pituitary-adrenal axis in human brain. We focus on the hypothalamus, hippocampus, amygdala, nucleus accumbens, prefrontal and orbitofrontal cortex, key brain regions that not only modulate emotions and cognition but also the response to stress itself, and discuss disorders like Abstract 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 system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Using a
Background: Environmental factors like stress affect age-related cognitive deficits and promote A... more Background: Environmental factors like stress affect age-related cognitive deficits and promote Alzheimer's disease (AD)-related pathology in mice. Excess glutamate has been proposed as a possible mediator underlying these effects in the hippocampus, a vulnerable brain region implicated in learning and memory. Methods: Here, we examined a) whether stress applied during a sensitive developmental period early in life affects later synaptic plasticity, learning and memory and plaque load in the APPswe/PS1dE9 mouse model for Alzheimer's disease and b) whether these effects could be rescued using long-term treatment with the glutamate modulator riluzole. Results: Our results demonstrate that ELS impairs synaptic plasticity in 6-month-old mice and increases plaque load in 12-month-old APPswe/PS1dE9 mice, while impairing flexible spatial learning in the Barnes maze at this age. Notably, spatial learning correlated well with hippocampal expression of the transporter EAAT2, which is important for extracellular glutamate uptake. The changes in LTP, plaque load and cognition after ELS were all prevented by riluzole treatment that started from post-weaning. Conclusion: These results suggest that normalising glutamate signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing stress-aggravated AD, particularly in relation to adverse early life experiences.
The brain of many species including humans, harbors stem cells that continue to generate new neur... more The brain of many species including humans, harbors stem cells that continue to generate new neurons up into adulthood. This form of structural plasticity occurs in a limited number of brain regions, i.e. the subventricular zone and the hippocampal dentate gyrus and is regulated by environmental and hormonal factors. In this minireview, we provide an overview of the effects of stress and glucocorticoid hormones on adult hippocampal neurogenesis and discuss how these effects may be relevant for cognitive function and possibly, brain disease. While its exact functional role remains elusive, adult neurogenesis has been implicated in learning and memory, fear and mood regulation and recently, adult-born neurons were found to be involved in specific cognitive functions such as pattern separation (i.e. the ability to form unique memory representations) and cognitive flexibility. The process of adult neurogenesis is influenced by several factors; whereas e.g. exercise stimulates, exposure to stress and stress hormones generally inhibit neurogenesis. Effects of acute, mild stress are generally short-lasting and recover quickly, but chronic or severe forms of stress can induce lasting reductions in adult neurogenesis. Some of the inhibitory effects of stress can be rescued by exercise, by allowing a period of recovery from stress, by drugs that target the stress system, or by some, but not all, antidepressants. Stress may, partly through its effects on adult neurogenesis, alter structure and plasticity of the hippocampal circuit. This can lead to subsequent changes in stress responsivity and aspects of memory processing, which may be particularly relevant for stress related psychopathology or brain diseases that involve perturbed memory processing.
We tested the effect of early-life stress (ELS)-24 h maternal deprivation (MD) at postnatal day (... more We tested the effect of early-life stress (ELS)-24 h maternal deprivation (MD) at postnatal day (PND) 3-on cognitive performance and hippocampal structure in 12-17-week-old female rats. Behavioral performance was examined in: the Elevated Plus Maze, as an index for general anxiety; the rodent Iowa gambling test, probing reward-based decision making; and the object recognition and object-in-location task, to assess non-stressful contextual memory performance. We further determined hippocampal dentate gyrus (DG) volume and cell density as well as adult proliferation and neurogenesis rates. Half of the rats was treated with the glucocorticoid receptor antagonist mifepristone during a critical pre-pubertal developmental window (PNDs 26-28), in an attempt to ameliorate the potentially adverse behavioral consequences of ELS. Neither MD nor treatment with the glucocorticoid antagonist affected behavioral performance of the females in any of the tasks. Also, DG structure, proliferation and neurogenesis were not different between the groups. Lack of structural differences and a behavioral phenotype in non-stressful hippocampus dependent learning tasks fits with the lack of phenotype generally reported after ELS in female but less so in male rodents. As evident from an extensive literature review, female and male animals appear to respond more similarly to early-life adversity when tested in anxiety-related tasks. This agrees with recent findings in humans suggesting that females may be relatively resilient to the structural/hippocampal effects of childhood maltreatment, but not to the anxiety and mood-related psychopathology for which childhood maltreatment is considered a risk factor. This article is part of a Special Issue entitled: Early Adversity.
Neuroinflammation and neurogenesis have both been the subject of intensive investigation over the... more Neuroinflammation and neurogenesis have both been the subject of intensive investigation over the past 20 years. The sheer complexity of their regulation and their ubiquity in various states of health and disease have sometimes obscured the progress that has been made in unraveling their mechanisms and regulation. A recent study by Kozareva et al. (Neuronal Signaling (2019) 3), provides evidence that the orphan nuclear receptor TLX is central to communication between microglia and neural precursor cells and could help us understand how inflammation, mediated by microglia, influences the development of new neurons in the adult hippocampus. Here, we put recent studies on TLX into the context of what is known about adult neurogenesis and microglial activation in the brain, along with the many hints that these processes must be inter-related.
Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit ch... more Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit characteristics, and can be modeled in mice by administration of kainic acid (KA). Adult neurogenesis in the dentate gyrus (DG) contributes to hippocampal functions and has been reported to contribute to the development of TLE. Some of the phenotypical changes include neural stem and precursor cells (NPSC) apoptosis, shortly after their birth, before they produce hippocampal neurons. Here we explored these early phenotypical changes in the DG 3 days after a systemic injection of KA inducing status epilepticus (KA-SE), in mice. We performed a multi-omics experimental setup and analyzed DG tissue samples using proteomics, transcriptomics and microRNA profiling techniques, detecting the expression of 2327 proteins, 13401 mRNAs and 311 microRNAs. We here present a description of how these data were obtained and make them available for further analysis and validation. Our data may help to furth...
This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the mo... more This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.
Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressa... more Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the serotonin re-uptake inhibitor (SSRI) fluoxetine (Prozac) enhances neurogenesis, the new dual serotonin/noradrenaline reuptake inhibitor (SNRI) duloxetine has not been evaluated in this context. In addition, it is unclear whether effects of antidepressants and running on cell genesis and behavior are of similar magnitude in mice. Here,we assessed neurogenesis and open field behavior in 2 month old female C57Bl/6 mice after 28 days of treatment with either fluoxetine (18 mg/kg), duloxetine (2, 6 or 18 mg/kg) or exercise. New cell survival, as measured by 5-bromo-2´-deoxyuridine (BrdU) labeled cells, was enhanced by 200% in the running group only. Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data not only show that the neurogenic response to exercise is much stronger than to antidepressants, but also imply a low likelihood that reported effects of these two drugs on anxiety are mediated by adult neurogenesis in C57Bl/6 mice.
Many lines of independent research have provided convergent evidence regarding oxidative stress, ... more Many lines of independent research have provided convergent evidence regarding oxidative stress, cerebrovascular disease, dementia, and Alzheimer's disease (AD). Clinical studies spurred by these findings engage basic and clinical communities with tangible results regarding molecular targets and patient outcomes. Focusing on recent progress in characterizing age-related diseases specifically highlights oxidative stress and mechanisms for therapeutic action in AD. Oxidative stress has been investigated independently for its relationship with aging and cardiovascular and neurodegenerative diseases and provides evidence of shared pathophysiology across these conditions. The mechanisms by which oxidative stress impacts the cerebrovasculature and bloodbrain barrier are of critical importance for evaluating antioxidant therapies. Clinical research has identified homocysteine as a relevant risk factor for AD and dementia; basic research into molecular mechanisms associated with homocysteine metabolism has revealed important findings. Oxidative stress has direct implications in the pathogenesis of age-related neurodegenerative diseases and careful scrutiny of oxidative stress in the CNS has therapeutic implications for future clinical trials. These mechanisms of dysfunction, acting independently or in concert, through oxidative stress may provide the research community with concise working concepts and promising new directions to yield new methods for evaluation and treatment of dementia and AD.
In this chapter, we will review changes in structural plasticity of the adult hippocampus during ... more In this chapter, we will review changes in structural plasticity of the adult hippocampus during stress and exposure to glucocorticoids (GCs). We further discuss the protective and normalizing role of glucocorticoid receptor (GR) antagonist treatment under these conditions and its implications for disorders such as depression and diabetes mellitus. 6.1 The Stress Response Stress represents an old, yet essential alarm system for an organism. Whenever a discrepancy occurs between an organism's expectations and the reality it encounters, stress systems are activated; particularly when it involves a threat to, or disturbance of its homeostasis, well being, or health. Loss of control, or unpredictability when faced with predator threat in animals, or psychosocial demands in humans, can all produce stress signals. The same holds true for perturbations of a more physical or biological nature, such as energy crises, injury, or inflammation. Upon exposure to a stressor, various sensory and cognitive signals converge to activate a stress response that triggers several adaptive processes in the body and brain which aim to promote restoration of homeostasis. In mammals, Selye [1] noted that the effect of stressors develops in a stereotypic manner. The first phase largely involves activation of the sympathoadrenal system through the rapid release of epinephrine and norepinephrine from the adrenal medulla; these hormones elevate basal metabolic rate and increase blood flow to vital organs like the heart and muscles. At a later stage, the limbic hypothalamo-pituitary-adrenal (HPA) system is activated as well, a classic neuroendocrine circuit in which limbic and hypothalamic brain structures integrate emotional, cognitive, neuroendocrine, and autonomic inputs, that together determine the magnitude and duration of the organism's behavioral, neural, and hormonal response to a stressor.
Early-life stress (ES) exposure increases the risk of developing obesity. Breastfeeding can marke... more Early-life stress (ES) exposure increases the risk of developing obesity. Breastfeeding can markedly decrease this risk, and it is thought that the physical properties of the lipid droplets in human milk contribute to this benefit. A concept infant milk formula (IMF) has been developed that mimics these physical properties of human milk (Nuturis®, N-IMF). Previously, we have shown that N-IMF reduces, while ES increases, western-style diet (WSD)-induced fat accumulation in mice. Peripheral and central inflammation are considered to be important for obesity development. We therefore set out to test the effects of ES, Nuturis® and WSD on adipose tissue inflammatory gene expression and microglia in the arcuate nucleus of the hypothalamus. ES was induced in mice by limiting the nesting and bedding material from postnatal day (P) 2 to P9. Mice were fed a standard IMF (S-IMF) or N-IMF from P16 to P42, followed by a standard diet (STD) or WSD until P230. ES modulated adipose tissue inflamma...
Early life stress (ES) increases the risk to develop metabolic and brain disorders in adulthood. ... more Early life stress (ES) increases the risk to develop metabolic and brain disorders in adulthood. Breastfeeding (exclusivity and duration) is associated with improved metabolic and neurocognitive health outcomes, and the physical properties of the dietary lipids may contribute to this. Here, we tested whether early life exposure to dietary lipids mimicking some physical characteristics of breastmilk (i.e., large, phospholipid-coated lipid droplets; Concept Nuturis® infant milk formula (N-IMF)), could protect against ES-induced metabolic and brain abnormalities under standard circumstances, and in response to prolonged Western-style diet (WSD) in adulthood. ES was induced by exposing mice to limited nesting material from postnatal day (P) 2 to P9. From P16 to P42, male offspring were fed a standard IMF (S-IMF) or N-IMF, followed by either standard rodent diet (SD) or WSD until P230. We then assessed body composition development, fat mass, metabolic hormones, hippocampus-dependent cogn...
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Papers by Paul Lucassen