The ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve... Show moreThe ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve the mesocortical circuitry. Coping with stress increases VTA-DA excitability, but when the stressor becomes chronic the VTA-DA circuit is less active, which may lead to degeneration and local microglial activation. This switch between activation and inhibition of VTA-DA neurons is modulated by e.g. corticotropin-releasing hormone (CRH), opioids, brain-derived neurotrophic factor (BDNF), and the adrenal glucocorticoids. These actions are coordinated with energy-demanding stress-coping styles to promote behavioral adaptation. The VTA circuits show sexual dimorphism that is programmed by sex hormones during perinatal life in a manner that can be affected by glucocorticoid exposure. We conclude that insight in the role of stress in VTA-DA plasticity and connectivity, during reward processing and stress-coping, will be helpful to better understand the mechanism of resilience to breakdown of adaptation. Show less
When a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood... Show moreWhen a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood emotional maltreatment (CEM). CEM is the most common form of child abuse, however, CEM is also the most hidden, underreported and least studied form of child abuse. An important reason for this may be because that the consequences of CEM are underestimated (e.g. __Sticks and Stones may break bones, but words will never hurt me__). However, this thesis shows that CEM is related with a persistent negative impact on cognition and the brain. We discovered that individuals that report CEM show differential structure and function of a brain area (the medial prefrontal cortex) that is crucial for role in responding to stress and thinking about yourself. Individuals with CEM also showed more activity in an area that signals threat (the amygdala) which may represent a persistent vigilance towards the detection of threat from others. These brain changes may underlie our other findings that individuals with CEM think more negatively about themselves and others. Negative thoughts can evoke negative thoughts and in new situations, which reinforces more negative memories. Due to this process, emotionally abused individuals may be more vulnerable to develop a depressive and/or anxiety disorder. Our findings warrant scientific and policital investments to increase societal awareness about the detrimental impact of CEM on cognition and the brain. Increased societal knowledge will hopefully lead to better awareness, reports, and subsequent interventions for individuals with CEM. Show less
Claessens, S.E.F.; Daskalakis, N.P.; Oitzl, M.S.; Kloet, E.R. de 2012
Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous... Show moreSynthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1-21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1-3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype. (C) 2012 Elsevier Inc. All rights reserved. Show less
Synthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and... Show moreSynthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and lung maturation, early glucocorticoid exposure has been shown to adversely affect neurodevelopmental processes. Both human and animal studies have reported acute and long-lasting impairments, including shortening of the lifespan in rodents. Therefore, the objective of the studies described in this thesis was to investigate, using an animal model: 1) the short- and long-term consequences of neonatal dexamethasone treatment and 2) the possibility to prevent these effects using pharmacological and behavioural intervention strategies. We reported that systemic dexamethasone treatment acutely affects brain development by suppressing cell proliferation and glial activity. These acute effects on the brain can be partially prevented by central glucocorticoid receptor antagonist pre-treatment, which might serve as a protective strategy against the adverse effects of dexamethasone treatment on the developing brain. Although neonatal dexamethasone exposure clearly affects the developmental trajectory, we did not observe the frequently described detrimental long-lasting consequences of this treatment. We showed that daily handling of the neonate, which was an inevitable component of our experimental design and leads to enhanced levels of maternal care towards the offspring, may compensate for some of the adverse effects of dexamethasone treatment. We conclude that the impact of neonatal glucocorticoid exposure highly depends on interactions with other components of the early environment and is therefore susceptible to pharmacological and behavioural intervention strategies. Show less
Een emotionele gebeurtenis zoals een auto-ongeluk of eerste kus wordt goed onthouden. Stresshormonen spelen een grote rol bij deze link tussen emotie en cognitie. Onder normale omstandigheden... Show moreEen emotionele gebeurtenis zoals een auto-ongeluk of eerste kus wordt goed onthouden. Stresshormonen spelen een grote rol bij deze link tussen emotie en cognitie. Onder normale omstandigheden worden emotionele en cognitieve processen bevorderd door stresshormonen zoals adrenaline en corticostero_den. Echter, te veel of juist te weinig stresshormonen, of een te lange periode van stress kan emotie en cognitie zo be_nvloeden dat sommige mensen stressgerelateerde ziekten zoals posttraumatische stressstoornis (PTSS) ontwikkelen. Waarom de een wel en de ander niet ziek wordt van stress is niet bekend. Men denkt dat de corticostero_den hiervoor van belang zijn. Vera Brinks richtte zich in haar onderzoek op de rol van corticostero_den in de integratie van emotionele en cognitieve processen, en dus stressgerelateerde fysiologie en psychopathologie. De focus lag hierbij op de rol van de corticostero_d receptoren in de hersenen; de mineralo- (MR) en glucocortico_d receptoren (GR). Dit onderzoek verrichte zij bij muizen. De experimenten lieten zien dat emotie een flinke verbetering van cognitieve prestaties gaf bij de muizen. Hierbij bleek dat activering van de GR - in vergelijking met MR activatie - belangrijk is in de integratie van emotie en cognitie. GR activatie met hoeveelheden van het stress hormoon corticosteron die ook vrij komen bij milde stress, resulteert in een optimale prestatie wanneer het dier ook een emotionele ervaring had. Een te lage of te hoge activatie van deze receptor (de GR) verstoorde de integratie van emotie en cognitie. Die GR werkt dus optimaal binnen nauwe grenzen. Wanneer de MR genetisch wordt 'uitgeschakeld'(knockout), dan worden bepaalde negatieve ervaringen niet uitgedoofd (vergeten). Een belangrijke vinding was ook dat corticostero_dbehandeling de herinnering aan een traumatische gebeurtenis zowel kan verminderen als verbeteren afhankelijk van de genetische achtergrond van de muizen Deze kennis kan gebruikt worden bij de behandeling van het veel te sterke geheugen voor traumatische en angstige PTSS-pati_nten. Bovendien is het een basis om de genetische factoren te onderzoeken die bij kunnen dragen aan het ontstaan en de vermindering van het sterke angstgeheugen bij PTSS-pati_nten. Onze experimenten hebben laten zien dat de MR een uitstekende kandidaat is als target voor een geheel nieuw soort geneesmiddelen. Show less
