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Early life is a critical and sensitive period during which the developing brain can be ‘programmed’ for life. Several studies have shown that exposure to early-life stress (ES), such as childhood abuse or neglect, leads to a higher vulnerability to develop brain disorders in adulthood. These include for example cognitive impairments, anxiety and depression. Interestingly, these disorders often occur in a sex-speci c manner and, notably, are often comorbid with metabolic diseases, e.g. obesity and diabetes. It is furthermore remarkable that also nutrition-related changes occurring during the early life period, like the Dutch Hunger Winter of 1944, are associated with similar metabolic disorders later in life. This indicates a close interplay between stress and nutrition in programming the adult body and brain. So far, however, it is unclear if and how peripheral metabolic and nutritional factors are involved in the ES-induced programming of the brain. Also, if this is the case, there are currently no e ective nutritional interventions available that may possibly modify or prevent these diseases.
Hence, the main goals of this thesis were to; i) gain insight into the short- and/or long-term sex-specific effects of ES on the brain and metabolism. We focused on the metabolic leptin and ghrelin systems, and also investigated if ES-exposed mice were metabolically more vulnerable when challenged with an early western-style diet. We assessed if ii) ES affects nutritional availability by studying the essential fatty acids centrally and peripherally, and iii) whether nutritional supplementation with a low omega (ω)-6/ω-3 diet during the early life period, might prevent the ES-induced cognitive impairments and later metabolic alterations. We further investigated some of the possible (neuro)biological mechanisms that could underlie the bene cial e ects of diet on cognition; we included the central and peripheral fatty acid compositions, hippocampal neurogenesis, microglial phagocytosis, neuronal plasticity, apoptosis and maternal care.
Increasing numbers of children and adolescents are treated with psychotropic medications for Major Depressive Disorder (MDD) or Attention-Deficit/Hyperactivity Disorder (ADHD). Although these psychotropic medications have been well studied in the adult population, much less is known about their long-term effects on human brain development. However, animal studies illustrated that these medications induce long lasting, possibly permanent, changes in specific systems and regions in the brain when prescribed at a younger age, i.e. when the brain is still developing; a phenomenon known as ‘chemical imprinting’. Here, we conducted a series of clinical studies to investigate whether chemical imprinting also occurs in the human brain. To this purpose, we investigated the age-dependency and long-term effects of both methylphenidate treatment for ADHD and antidepressant treatment for MDD.
The main results of this thesis indicate that also in the human brain the effects of ADHD medications are dependent on age. For instance, early-, but not late exposure to methylphenidate lastingly affected the GABA neurotransmitter system, but methylphenidate also had a lasting positive effect on sleep in children with ADHD. However, we could not replicate these chemical imprinting findings for antidepressants. The work described in this thesis contributes to a better understanding of the effects of psychotropic medications on the developing brain, and illustrates the need for more longitudinal follow-up studies into the long-term effects of psychotropic medications on the human brain.
This thesis specifically focused on the direct regulation of neural stem cells (NSCs); a crucial process for the generation of new neurons throughout life in the mammalian brain. Mammalian species are constantly exposed to environmental challenges for which adaptation of brain function through e.g. neuronal modulation and plasticity is crucial. Adult hippocampal neurogenesis (AHN) constitutes one of the recent, most intensively studied forms of structural plasticity. It has long been proposed that newborn neurons are needed in certain types of hippocampus-dependent memory functions, and therefore would relate to cognitive capacity of mammalian species. While there is evidence for the involvement of newborn granule cells (GCs) in these functions, a unified theoretical framework for adult neurogenesis has not been reached yet and will likely require more experimental data.
The capacity of the adult hippocampal stem cell pool to generate new neurons while maintaining itself is not indefinite, and this capacity decreases with age. To prevent an early exhaustion of the adult hippocampal stem cell pool, AHN must be tightly regulated and several cell intrinsic and extrinsic signaling pathways have been identified that regulate AHN. Deregulation of AHN is a hallmark of many brain pathologies, including epilepsy, although its exact role in these pathologies remains mostly unclear. Here, we aimed to identify new regulatory pathways of AHN in both health and disease, focusing on epigenetic mechanisms.
Glucocorticoid hormones (GCs) are important mediators of the stress response in mammals including humans. GCs are released from the adrenal in response to stress and affect numerous processes in the body and brain. Their levels are controlled via negative feedback exerted by GC binding to brain glucocorticoid receptors (GR). In particular the hypothalamus, hippocampus and amygdala are important brain regions involved in this feedback regulation of the stress response. Whereas the anatomical distribution of brain GR was well known for various animal species, very little was known about GR presence and (subregional) distribution in human brain, nor about possible alterations in stress-related brain disorders.<br/>We here describe the first anatomical distribution of GR protein in key areas of the human brain involved in stress regulation. We next studied changes in GR protein in relation to aging and disorders like major/bipolar depression and Alzheimer’s disease (AD). We found abundant GR-immunoreactivity (GR-ir) to be present in almost all neuronal nuclei of the human hypothalamus, hippocampus and amygdala and in +/-50% of the astrocytes. In major depression, hippocampal GR-ir correlated positively with age, and increased GR-ir was found in depressed women relative to depressed men. In the human amygdala, GR-ir was significantly increased in major, but not bipolar, depression. In AD, higher GR levels were found in female relative to male AD patients, a difference absent in age-matched controls.<br/>These first studies on the human GR may help better understand the molecular mechanisms underlying stress-related disorders and can possibly improve future therapeutic development.
This thesis aims to further characterize the neurobiological origins underlying the pharmacological magnetic resonance imaging (phMRI) signal. phMRI is an MRI technique that measures the hemodynamic response to a psychotropic drug in order to non-invasively visualize neurochemical processes in the brain. Our second aim was to use this knowledge to investigate the effects of methylphenidate (MPH), used in the treatment of attention-deficit/hyperactivity disorder (ADHD), on the developing dopamine (DA) system (i.e. its age-dependency). Our results from studies in amphetamine users and ADHD patients are promising as they show that phMRI can detect DA abnormalities in the human brain. However, further technological improvements are necessary to improve the sensitivity and specificity of the technique and to allow advancement of this field. In addition, we showed for the first time that ADHD medications, such as MPH, have differential effects on the developing compared to the matured brain in humans; in a randomized clinical trial the cerebral blood flow in response to MPH was increased in children, but not adults, treated with MPH for four months. This has important implications with regard to the use (and increased prescription rates) of MPH in the treatment of ADHD, because the brains of children are still developing. Therefore, our findings stress the need for future studies on the long-term effects of MPH in children.
Stressful events are remembered well in general. While this is an important behavioural adaptation to adapt to aversive events it also renders vulnerable individuals sensitive to develop stress-related psychopathology such as seen in post-traumatic stress disorder. It is therefore important to understand why we remember these events so well. Corticosteroid hormones are released during stress-exposure. In the brain, these hormones bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). Hui Xiong examined how these hormones regulate synaptic function, which is a major substrate for learning and memory. He showed that these hormones alter activity-dependent synaptic function within minutes after stress-hormone exposure via activation of MRs, but also that these hormones also have persistent effects on synaptic function via activation of GRs. He showed that slow onset effects of GRs on synaptic function are mediated by trafficking of AMPARs to the membrane and involves membrane insertion as well as synaptic retention of AMPARs. Ultimately showed that this is relevant for consolidation of contextual fear. In addition he showed that not only AMPA receptors, but also mobility and function of NMDA receptors is sensitive for stress (hormones) which may contribute to the effects of stress on consolidation of fear.
Adaptation to behaviourally challenging events requires rapid appropriate behavioural responses but also retention of relevant aspects of those particular stressful experiences. This requires multiple memory systems that allow rapid behavioural adjustments and memory storage. In response to these events, corticosteroid hormones, released from the adrenal glands, bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain. Together, these hormones promote behavioural adaptation to stressful events. In this thesis, Marit Arp examined how these hormones, via their receptors, promote behavioural adaptation. In addition she examined how behavioural adaptation depends on experiences earlier in life and the genetic background. First, MRs appear to be particularly relevant for spatial and stimulus-response learning. In addition, corticosteroid hormones regulate synaptic function in the striatum which is particular relevant for stimulus-response learning. Second, early life experience reduced the ability to discriminate between potentially safe and non-safe environments. These effects could be prevented by targeting GRs at adolescence. Also mice with transgenic overexpression of MRs were less well able to discriminate these contexts. Third, early life adversity differently affected synaptic function in hippocampus and striatum, which may affect the switch between behavioral strategies. These effects on synapses could be targeted by using a GR antagonist at adolescent age. Together, these studies show that stress-hormones and early life experiences interact to regulate different memory systems and synapses in relevant brain areas.
In our daily lives we are regularly exposed to stressful experiences. These events can vary from small hassles to major life events. Many people are well able to cope with these challenging situations, while others are more sensitive to develop pathology such as seen in depression, anxiety disorders and post-traumatic stress-disorders. This emphasises the need to understand how the interaction between genes and environmental factors determines adaptation to stressful experiences, and why some individuals are more resilient than others. In response to stressful events the hypothalamus-adrenal axis is activated which results in the release of corticosteroid hormones. These hormones bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain, which enable adaptation to stress. In this thesis we examined the role of MR as resilience factor. Using mouse models with transgenic overexpression it was shown that overexpression of MRs prevents against the adverse effects of prolonged stress in adulthood and against the effects of stress during the early postnatal period on contextual / declarative memory formation. These effects could partly be attributed to alterations in the generation of newborn cells in the dentate gyrus. These studies help to understand the molecular and cellular basis of vulnerability to stress and may hint to new approaches to prevent or reduce stress-related psychopathology.