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Correlation between early childhood trauma scores and subjective stress during PET. A trendlevel association between early childhood trauma scores (0-11) and decreased reactivity to the stress task in HV, but not NAPD. Association in HV p = 0.07.
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Context 1
... association between early trauma score and subjective stress scores during the MIST para- digm was not significantly different for NAPD and HV (b = .7, t(1, 23) = 1.18, p = .26). How- ever, when testing within-group main effect of childhood trauma on subjective experience of stress, a trend for a negative association between early childhood trauma and the subjective stress response was detected in HV (b = -.7, t(11) = -2, p = .07), with higher early childhood trauma being associated with lower subjective stress responses to the task (Fig 3). No main effect of childhood trauma on the subjective stress response to the task was present in NAPD (b = .004, t(11) = .01, p = .99; Fig 3). There was no interaction or main effect between late child- hood trauma and the subjective stress response to the task (all p-values>.05) and there was no association between the two childhood trauma scores and psychotic symptoms during the scan in ...
Context 2
... association between early trauma score and subjective stress scores during the MIST para- digm was not significantly different for NAPD and HV (b = .7, t(1, 23) = 1.18, p = .26). How- ever, when testing within-group main effect of childhood trauma on subjective experience of stress, a trend for a negative association between early childhood trauma and the subjective stress response was detected in HV (b = -.7, t(11) = -2, p = .07), with higher early childhood trauma being associated with lower subjective stress responses to the task (Fig 3). No main effect of childhood trauma on the subjective stress response to the task was present in NAPD (b = .004, t(11) = .01, p = .99; Fig 3). There was no interaction or main effect between late child- hood trauma and the subjective stress response to the task (all p-values>.05) and there was no association between the two childhood trauma scores and psychotic symptoms during the scan in ...
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... Studies have shown that ELS reduces dopamine levels in the PFC of individuals with psychotic disorders. One hypothesis is that the reduction of dopamine levels may be related to an adaptation in brain circuits caused by the psychotic disorder [79]. ...
Early life stress (ELS), characterized as abuse, neglect, and abandonment, can cause several adverse consequences in the lives of affected individuals. ELS experiences can affect an individual’s development in variable ways, persisting in the long term and promoting lasting impacts, considering that early exposure to stressors can be biologically incorporated, as prolonged stimulation of stress response systems affects the development of the brain structure and other body systems, increasing the risk of diseases associated with stress and cognitive impairment. This type of stress increases the risk of developing major depressive disorder (MDD) in a severe form that does not respond adequately to traditional antidepressant treatments. Several alterations are studied as mechanisms that relate ELS with MDD, such as epigenetic alterations, neurotransmitters, and neuronal signaling. This review discusses research that brings evidence about the ELS mechanisms involved in synaptic impairments and MDD. The processes involved in epigenetic changes and the HPA axis are highlighted, as well as changes in neurotransmitters and neuronal signaling mechanisms.
... Prefrontal and striatum volume increases in those exposed to early psychological trauma may be adaptive, as exposure to adverse environments during childhood lead to increased vigilance to threatening stimuli [67] and increased frontal and striatal dopamine activity [68][69][70]. Increased frontal and basal ganglia volumes have been previously reported in transdiagnostic samples [43], healthy individuals and patients with schizophrenia exposed to childhood trauma [38,40], and may reflect premature maturation of these regions [38]. Striatal volume alterations associated with cumulative pre/perinatal risk varied according to PEs group. ...
Psychotic experiences (PEs) occur in 5-10% of the general population and are associated with exposure to childhood trauma and obstetric complications. However, the neurobiological mechanisms underlying these associations are unclear. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 138 young people aged 20 with PEs (n = 49 suspected, n = 53 definite, n = 36 psychotic disorder) and 275 controls. Voxel-based morphometry assessed whether MRI measures of grey matter volume were associated with (i) PEs, (ii) cumulative childhood psychological trauma (weighted summary score of 6 trauma types), (iii) cumulative pre/peri-natal risk factors for psychosis (weighted summary score of 16 risk factors), and (iv) the interaction between PEs and cumulative trauma or pre/peri-natal risk. PEs were associated with smaller left posterior cingulate (pFWE < 0.001, Z = 4.19) and thalamus volumes (pFWE = 0.006, Z = 3.91). Cumulative pre/perinatal risk was associated with smaller left subgenual cingulate volume (pFWE < 0.001, Z = 4.54). A significant interaction between PEs and cumulative pre/perinatal risk found larger striatum (pFWE = 0.04, Z = 3.89) and smaller right insula volume extending into the supramarginal gyrus and superior temporal gyrus (pFWE = 0.002, Z = 4.79), specifically in those with definite PEs and psychotic disorder. Cumulative childhood trauma was associated with larger left dorsal striatum (pFWE = 0.002, Z = 3.65), right prefrontal cortex (pFWE < 0.001, Z = 4.63) and smaller left insula volume in all participants (pFWE = 0.03, Z = 3.60), and there was no interaction with PEs group. In summary, pre/peri-natal risk factors and childhood psychological trauma impact similar brain pathways, namely smaller insula and larger striatum volumes. The effect of pre/perinatal risk was greatest in those with more severe PEs, whereas effects of trauma were seen in all participants. In conclusion, environmental risk factors affect brain networks implicated in schizophrenia, which may increase an individual's propensity to develop later psychotic disorders. Molecular Psychiatry; https://doi.
... Studies in a variety of species have revealed that the development of the dopaminergic system is particularly sensitive towards prenatal stress [61,62] and neonatal stress experience [62][63][64][65][66][67]. Dopamine D1-like receptors in the hippocampus are especially noted for their critical role in spatial memory [27,28], and activating these receptors could enhance spatial learning and memory [25]. ...
Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced spatial learning and memory deficit in male and female rats. Hence, neonatal rats (postnatal day (PND)1 to 21) were exposed to MS (180 min/day). Next, the acquisition of spatial learning and memory (Barnes maze task) and the expression of dopamine D1 receptor, dopamine transporter (DAT), and the neuronal GTPase, RIT2, which binds DAT in the vehicle-treated rats were evaluated in the prefrontal cortex and hippocampus in the adolescent animals. The results show that MS impairs the acquisition of spatial learning and memory in rats, with a more severe effect in females. Moreover, the MS induced upregulation of DAT and dopamine D1 receptors expression in the prefrontal cortex and hippocampus in adolescent rats. Regarding RIT2, the expression was decreased in the hippocampus for both the males and females, however, in the prefrontal cortex, reduction was found only in the females, suggesting that there are region-specific differences in DAT endocytic trafficking. CE-123 ameliorated the behavioral deficits associated with MS. Furthermore, it decreased the MS-induced upregulation of D1 receptor expression level in the hippocampus. These effects were more noted in females. Overall, CE-123, an atypical DAT inhibitor, is able to restore cognitive impairment and dopamine signaling in adolescent rats exposed to MS—with more evident effect in females than males.
... However, other factors can trigger PFC dysfunction. Psychosocial stress and early life adversity, known risk factors for psychosis (76,77), can compromise PFC function, increase dopamine release, and increase dopamine metabolite levels in genetically high-risk individuals (78)(79)(80). Convergent evidence from preclinical models and human postmortem findings indicates that hypofunction of N-methyl-D-aspartate (NMDA) receptors on cortical GABA neurons, which is thought to disinhibit cortical pyramidal cells, augments the activity of glutamatergic projections to the midbrain and ultimately disinhibits dopamine activity (81,82). Pharmacological studies in rodents demonstrate that administration of either ketamine or phencyclidine (PCP), both of which act on NMDA receptors, produce schizophrenia-like behaviors in rodents such as sensorimotor gating disruptions, cognitive deficits, and social impairments (83-86). ...
Dopamine is known to play a role in the pathogenesis of psychotic symptoms, but the mechanisms driving dopaminergic dysfunction in psychosis remain unclear. Considerable attention has focused on the role of corticostriatothalamic (CST) circuits, given that they regulate, and are modulated by, the activity of dopaminergic cells in the midbrain. Preclinical studies have proposed multiple models of CST dysfunction in psychosis, each prioritizing different brain regions and pathophysiological mechanisms. A particular challenge is that CST circuits have undergone considerable evolutionary modification from the rodent to primate and human brains, complicating comparisons across species. Here, we consider preclinical models of CST dysfunction in psychosis and evaluate the degree to which they are supported by evidence from human resting-state fMRI studies conducted across the psychosis continuum, ranging from subclinical schizotypy to established schizophrenia. In partial support of some preclinical models, human studies indicate that dorsal CST and hippocampal-striatal functional dysconnectivity are apparent across the psychosis spectrum and may represent a vulnerability marker for psychosis. In contrast, midbrain dysfunction may emerge when symptoms warrant clinical assistance and may thus be a trigger for illness onset. The major difference between clinical and preclinical findings is the strong involvement of the dorsal CST in the former, consistent with an increasing prominence of this circuitry in the primate brain. We close by underscoring the need for high-resolution characterization of phenotypic heterogeneity in psychosis to develop a refined understanding of how dysfunction of specific circuit elements gives rise to distinct symptom profiles.
... This is due to the fact they too show impaired cognitive ability, marked deficits in attention and motivation, and a tendency for impulsive behavior or poor decision-making skills (Anand and Scalzo, 2000;Capitanio and Mason, 2000;Chugani et al., 2001;Glaser, 2000;Sanchez et al., 2001). Indeed, early life stressors of childhood trauma or adversity have recently been linked to altered dopaminergic functioning in the prefrontal cortex of humans (Boecker et al., 2014;Kasanova et al., 2016). Second, as indicated by its contribution to movement difficulties in Parkinson's disease and Gilles de la Tourette syndrome, DA acting along the nigrostriatal pathway is involved in sensory integration and the control of locomotion (Aquilonius, 1989). ...
Dopamine (DA) is a critical neuromodulator of behavior. With propensities for addiction, hyper-activity, cognitive impairment, aggression, and social subordinance, monkeys enduring early maternal deprivation evoke human disorders involving dopaminergic dysfunction. To examine whether DA system alterations shape the behavioral correlates of adverse rearing, male monkeys (Macaca mulatta) were either mother-reared (MR: N = 6), or separated from their mothers at birth and nursery-reared (NR: N = 6). Behavior was assessed during 20-minute observations of subjects interacting with same-or differently-reared peers. Cerebrospinal fluid (CSF) biogenic amines, and serum testosterone (T), cortisol (CORT), and prolactin (PRL) were collected before and after pharmacologic challenge with saline or the DA receptor-2 (DRD2) antagonist Raclopride (RAC). Neuro-peptide correlations observed in MR were non-existent in NR monkeys. Compared to MR, NR showed reduced DA tone; higher basal serum T; and lower CSF serotonin (5-HT). RAC increased PRL, T and CORT, but the magnitude of responses varied as a function of rearing. Levels of PRL significantly increased following RAC in MR, but not NR. Elevations in T following RAC were only significant among MR. Contrastingly, the net change (RAC CORT-saline CORT) in CORT was greater in NR than MR. Finally, observations conducted during the juvenile phase in a novel play-arena revealed more aggressive, self-injurious, and repetitive behaviors, which negatively correlated with indexes of dopaminergic tone in NR monkeys. In conclusion, early maternal deprivation alters brain DA systems, and thus may be associated with characteristic cognitive, social, and addiction outcomes.
... Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) play a major role in reward and motivation processing as well as in the formation of long-term memory traces (reviewed in Lisman and Grace, 2005;Pignatelli and Bonci, 2015;Salamone et al., 2016). Thus, early life stress-induced disturbances in these processes appear to be related, at least partially, to altered functional connectivity between the VTA and hippocampus (Pruessner et al., 2004;Marusak et al., 2017) as well as to increased stress-related DAergic activity in the cerebral cortex and the ventral striatum of those who experience early childhood trauma (Kasanova et al., 2016). Another well-known effect of early life adversity is disturbed development of the hypothalamic-pituitary-adrenal (HPA) axis that results in altered responsiveness to different types of stressors in individuals who experience childhood maltreatment (Heim et al., 2008). ...
Childhood maltreatment, which can take the form of physical or psychological abuse, is experienced by more than a quarter of all children. Early life stress has substantial and long-term consequences, including an increased risk of drug abuse and psychiatric disorders in adolescence and adulthood, and this risk is higher in women than in men. The neuronal mechanisms underlying the influence of early life adversities on brain functioning remain poorly understood; therefore, in the current study, we used maternal separation (MS), a rodent model of early-life neglect, to verify its influence on the properties of neurons in the ventral tegmental area (VTA), a brain area critically involved in reward and motivation processing. Using whole-cell patch-clamp recordings in brain slices from adolescent female Sprague-Dawley rats, we found an MS-induced increase in the excitability of putative dopaminergic (DAergic) neurons selectively in the medial part of the VTA. We also showed an enhancement of excitatory synaptic transmission in VTA putative DAergic neurons. MS-induced alterations in electrophysiology were accompanied by an increase in the diameter of dendritic spine heads on lateral VTA DAergic neurons, although the overall dendritic spine density remained unchanged. Finally, we reported MS-related increases in basal plasma ACTH and corticosterone levels. These results show the long-term consequences of early life stress and indicate the possible neuronal mechanisms of behavioral disturbances in individuals who experience early life neglect.
... In prefrontal cortex, effects of acute stress exposure interact with childhood trauma and appear to differ between subjects with psychotic disorders and healthy controls: only in healthy controls, stress-induced dopamine release in the medial prefrontal cortex was positively associated with the severity of early and late childhood trauma [87], confirming alterations in prefrontal-striatal neurocircuits in psychosis [77,85]. First-degree relatives of patients with a psychotic disorder also displayed less dopamine release in the ventral medial prefrontal cortex in response to stress [88]. ...
Systematic reviews and meta-analyses suggest that there are increased rates of schizophrenia and related psychoses in first- and second-generation migrants and refugees. Here, we present a meta-analysis on the incidence of non-affective psychotic disorders among first- and second-generation migrants. We found substantial evidence for an increased relative risk of incidence among first- and second-generation migrants compared to the native population. As heterogeneity of included studies was high, effect estimates should be interpreted with caution and as guiding values rather than exact risk estimates. We interpret our findings in the context of social exclusion and isolation stress, and provide an explanatory framework that links cultural differences in verbal communication and experienced discrimination with the emergence of psychotic experiences and their neurobiological correlates. In this context, we discuss studies observing stress-dependent alterations of dopamine neurotransmission in studies among migrants versus non-migrants as well as in subjects with psychotic disorders. We suggest that social stress effects can impair contextualization of the meaning of verbal messages, which can be accounted for in Bayesian terms by a reduced precision of prior beliefs relative to sensory data, causing increased prediction errors and resulting in a shift towards the literal or “concrete” meaning of words. Compensatory alterations in higher-level beliefs, e.g., in the form of generalized interpretations of ambiguous interactions as hostile behavior, may contribute to psychotic experiences in migrants. We thus suggest that experienced discrimination and social exclusion is at the core of increased rates of psychotic experiences in subjects with a migration background.
... An example of early childhood stress is the maternal separation; in humans, it can be related to institutionalization in orphanages [6], which has already been shown to be responsible for long-term behavioral damages, such as increased anxiety [7], and psychopathologies, as schizophrenia [8]. Several reports suggest that early childhood traumas may affect distinct neural circuits, such as those involving the dopaminergic and the noradrenergic systems [9][10][11][12][13], which perform several functions in the brain, including the regulation of cognition, attention, and stress [12,[14][15][16][17]. In addition, neuroimaging studies in humans suggest that early childhood stress interferes in the maturation of the dopaminergic system [18]. ...
... In rodents, maternal deprivation (MD) is a stress model widely used as a paradigm to study early life adverse events [19], as parental abuse or loss [11]. In this model, there is evidence that early-stage stress leads to changes in dopamine neurotransmission, affecting both dopamine (DA) levels [20] and dopaminergic receptor density (D1 and D2) [18]. ...
During the neonatal period, the brain is susceptible to external influences. Exposure to stressful events during this phase of life influences brain development and impacts adult life. In animals, the maternal deprivation (MD) model is effective in mimicking stress in the early stages of development. In contrast, physical exercise seems to be able to prevent deficits in memory consolidation. Although the effects of chronic exercise in cognition are already well established, little is known about the effects of acute aerobic exercise. Here, male Wistar rats divided into deprived (MD) and nondeprived (NMD) rats were submitted to the object recognition (OR) memory test. Immediately after OR training, some of the rats were submitted to a single aerobic exercise session for 30 minutes. Memory consolidation and persistence were evaluated by retention tests performed 24 h and 7, 14, and 21 days after OR training. We show that a single physical exercise session is able to modulate learning by promoting memory consolidation and persistence in rats with cognitive deficits induced by MD. Hippocampal dopamine levels, measured by HPLC, were not altered after OR training in rats that performed and in rats that did not perform an exercise session; on the other hand, while OR training promoted increase of hippocampal norepinephrine in NMD rats, the MD rats did not present this increase, regardless of the practice or not of exercise.
... Our review contains a single study that explored the modification of dopaminergic activity linked to childhood trauma in schizophrenia patients never having received antipsychotic treatments (Kasanova et al., 2016). Kasanova et al. measured dopamine release in the medial PFC during a social stress task in 12 schizophrenia subjects and 12 matched control subjects. ...
... An exposure to acute stress is associated with more important striatal dopamine release in adults exposed to childhood trauma than in non-exposed subjects (Pruessner et al., 2004), striatal dopamine release being associated with positive symptoms in schizophrenia. Childhood trauma is associated with prefrontal cortex dopamine release modifications in acute stress in healthy subjects but not in schizophrenia subjects, and could be an adaptive response to childhood trauma (Kasanova et al., 2016). ...
... Consequently, dysfunctions in the dopaminergic system are implicated in a number of pathologies such as Parkinson's disease, schizophrenia, depression, and ADHD. Studies in a variety of species and stress paradigms revealed that the development of the dopaminergic system is particularly sensitive toward ELA such as prenatal stress [4,25] and neonatal stress experience [26,36,40,43,[82][83][84]. With regard to changes of dopamine receptors, it has been reported in rats that MS (24 h on PND 9) increases the expression of DRD1 (and DRD2) receptors [16,85]. ...
Early-life adversity (ELA) represents a major risk factor for the development of behavioral dysfunctions and mental disorders later in life. On the other hand, dependent on type, time point, and duration, ELA exposure can also induce adaptations, which result in better stress coping and resilience later in life. Guided by the hypothesis that chronic exposure to ELA results in dysfunctional brain and behavior, whereas short exposure to ELA may result in resilience, the behavioral and neurobiological consequences of long-term separation stress (LTSS) and short-term separation stress (STSS) were compared in a mouse model for ELA. In line with our hypothesis, we found that LTSS induced depressive-like behavior, whereas STSS reduced depressive-like behavioral symptoms. We then tested the hypothesis that the opposite behavioral outcomes of the two stress paradigms may be mediated by functional, epigenetically regulated changes of dopaminergic modulation in the hippocampal formation. We found that STSS exposure elevated dopamine receptor D1 (DRD1) gene expression and decreased gene expression of its downstream modulator DARPP-32 (32-kDa dopamine- and cAMP-regulated phosphoprotein), which was paralleled by decreased H3 acetylation at its gene promoter region. In contrast, LTSS elevated DARPP-32 gene expression, which was not paralleled by changes in histone acetylation and DRD1 gene expression. These findings indicate that short- and long-term neonatal exposure to ELA induces changes in dopaminergic molecular pathways, some of which are epigenetically regulated and which either alleviate or aggravate depressive-like symptoms later in life.
