The aim of this thesis was to identify the neural mechanisms that enable a person to adaptively respond to, and recover from stress, which was studied in healthy controls, in people with increased... Show moreThe aim of this thesis was to identify the neural mechanisms that enable a person to adaptively respond to, and recover from stress, which was studied in healthy controls, in people with increased vulnerability or resilience to stress-related disorders, and in people with depression or PTSD, using magnetic resonance imaging (MRI). In most of the studies, a specific MRI method was employed, with which it is possible to assess how different brain regions communicate with each other (i.e., functional connectivity) when the brain is initiating or regulating stress responses. Structure, activity, and connectivity of the amygdala, a small brain region important for stress reactivity, was of main interest. The results show how stress influences information processing, and causes changes in the communication between brain areas, even long after the stressful event ended. Furthermore, personality dimensions associated with increased vulnerability or resilience to affective disorders were associated with changes in brain networks involved in emotion processing and regulation. Finally, smaller amygdala volumes were found in women with PTSD, while reduced integrity of affective brain networks was demonstrated in depression. Together, these results open important new avenues for future research into the short and long term effects of stress on the brain. 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
Schizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate... Show moreSchizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate if a hyperactive dopaminergic genotype interacts with adverse life experiences that activate the stress system. To examine this gene-by-environment interaction, we exposed rats genetically-selected for enhanced apomorphine susceptibility to two stress-provoking life events, poor maternal care early-in-life, and isolation rearing later-in-life. This promoted the development of schizophrenia endophenotypes. Our experiments involved two complementary steps: First, we focused on the immediate endocrine adaptations to maternal separation in common rats. It is known that a single episode of prolonged maternal separation slowly increases corticosterone levels in the neonate rat. We discovered that if the pups had been previously exposed to maternal separation, this rise in corticosterone was abolished, suggesting that the pups had learned to predict the return of the dam. While readily adapting to repeated maternal absence, the pups, surprisingly, stayed alert and displayed a rapid response to an acute stressor. We then investigated whether pup__s stress responsiveness was influenced by the context of maternal separation. It appeared that the experience of being kept in isolation in a novel environment during repeated maternal separation, rather than the maternal absence per se, caused priming of the amygdala fear pathway, with lasting consequences for the responsiveness of the neuroendocrine and behavioral stress system. These endocrine and behavioral alterations, caused by early-life stress experience, consisted of schizophrenia-like phenotypes. Second, we sought to investigate the interplay of such early-life stress experience with schizophrenia genetic predisposition and/or later-life social stress experience. Thus, we were able to test the three-hit (cumulative stress) and the developmental mismatch hypotheses. The former states that exposure to earlylife adversity and later-life psychosocial stressors, superimposed on genetic susceptibility, result in a severe schizophrenia-like phenotype. The latter proposes that experiences early-in-life program the developing brain in preparation for the future. In the case of genetically-predisposed apomorphine susceptible rats (schizophrenia-susceptible), we provide strong evidence for the three-hit hypothesis. In the case of the nongenetically selected Wistar rats, the mismatch hypothesis is supported since the outcome of early-life stress often negatively interacted with the pre-puberty social context. In agreement with the three-hit hypothesis of schizophrenia, we conclude from the current experiments that early-life stress experience in interaction with highly reactive dopaminergic alleles, leads to amygdala priming that, together with additional stressors, precipitate schizophrenia. Show less
