Prenatal Stress Alters Hippocampal Neuroglia and Increases Anxiety in Childhood

Bennett, Greer A.; Palliser, Hannah K.; Shaw, Julia C.; Walker, David W.; Hirst, Jonathan J.

doi:10.1159/000437302

Cited by 36 publications

(38 citation statements)

References 60 publications

(79 reference statements)

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“…There were no data on prenatal status, dietary deficiency (e.g., iron deficiency), or stressful life events during pregnancy, which have also been associated with hippocampal development [62,63]. This is a common limitation in studies on children who were removed from the care of their birth parents, because the medical history of the birth family or the pregnancy cannot always be retrieved.…”

Section: Discussionmentioning

confidence: 99%

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Dahmen¹,

Puetz

Scharke

et al. 2017

Dev Neurosci

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Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life.

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Section: Discussionmentioning

confidence: 99%

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Dahmen¹,

Puetz

Scharke

et al. 2017

Dev Neurosci

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“…The open-field test measured anxiety and locomotion and was performed as previously described (38). Guinea pig pups were allowed to explore the arena (40 × 40 cm) for 10 min, with entries into the inner zone (an area 20 × 20 cm in the centre of the arena) recorded.…”

Section: Open Field and Environment Exploration Testmentioning

confidence: 99%

“…The environment exploration test measured the animals' exploratory behavior and anxiety (38). Following the open-field test, the animal was removed from the arena and two identical objects were placed in the center of the top two quadrants of the arena.…”

Section: Open Field and Environment Exploration Testmentioning

confidence: 99%

Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig

et al. 2016

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Background: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly understood and relevant animal models are required. Methods: Ex-preterm (delivered at 62 d gestation) and term (spontaneously delivered) juvenile guinea pigs underwent behavioral testing at 25 d corrected postnatal age, with tissues collected at 28 d. Neurodevelopmental markers (myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)) were analyzed in the hippocampus and subcortical white matter by immunohistochemistry. Gamma-aminobutyric acid A (GABA A ) receptor subunit mRNA levels were quantified by reverse transcription polymerase chain reaction (RT-PCR), and salivary cortisol measured by enzyme-linked immunosorbent assay. results: Preterm males travelled greater distances, were mobile for longer, spent more time investigating objects, and approached or interacted with familiar animals more than controls. Myelination and reactive astrocyte coverage was lower in the hippocampus and the subcortical white matter in preterm males. Hippocampal levels of the α5 subunit were also lower in the preterm male brain. Baseline salivary cortisol was higher for preterm males compared to controls. conclusion: We conclude that juvenile ex-preterm male guinea pigs exhibit a hyperactive phenotype and feature impaired neurodevelopment, making this a suitable model for future therapeutic studies. c hildren born preterm (birth at <37 wk gestation) have an increased risk of developing a long-term neurodevelopmental disability (1,2). Importantly, this risk exists even in those thought to be "well" at the time of discharge from neonatal care and in those with no evidence of the structural brain injuries known to be associated with adverse neurodevelopmental outcomes (e.g., intraventricular hemorrhage or periventricular leukomalacia) (3,4). Thus, although intraventricular hemorrhage and, or, periventricular leukomalacia explain neurodevelopmental problems in a subset of high-risk infants, they do not account for the overall burden of neurodisability seen in the ex-preterm population.Although major neurodevelopmental problems are usually picked up early, subtle behavioral or psychiatric disorders may not become apparent until school age, at a time distant from the causative insult (5,6). Anxiety disorder and attention deficit hyperactivity disorder are the most commonly diagnosed disorders in school-aged ex-preterm children (7,8). Attention deficit hyperactivity disorder has a male preponderance and is characterized by a deficit in behavioral inhibition, inattention, impulsivity and social difficulties, whereas anxiety disorder is more commonly diagnosed in ex-preterm females (7,8). Thus, the behavioral outcomes of preterm birth occur in a sex-dependent manner. Other neuropathologies, including depression, and impaired cognitive performance are also increased in those born preterm compared to children and adolescents born at term (5,9-11). Hypo-m...

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“…Pups were maintained with dams in normal housing conditions until testing. On postnatal day (PND) 21 all juveniles (prenatal vehicle treatment n = 18, males = 9, females = 9; prenatal finasteride treatment, n = 15, males = 8, females = 7) were weighed and measured before euthanasia via carbon dioxide inhalation, with plasma and brain collection for analysis as previously described (Shaw et al, 2015; Bennett et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

Increased anxiety‐like phenotype in female guinea pigs following reduced neurosteroid exposure in utero

Cumberland¹,

Palliser

Crombie

et al. 2017

Intl J of Devlp Neuroscience

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Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders. The objective of this study was to assess if changes in concentrations of the neurosteroid, allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2-hydroxypropyl)-β-cyclodextrin) or the 5α-reductase inhibitor, finasteride (25mg/kg maternal weight) from gestational age 60 until spontaneous delivery (∼71days gestation). Male and female offspring from vehicle and finasteride treated dams were tested at postnatal day 20 (juvenile-equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and GABA production pathways 24h later. Females with reduced allopregnanolone exposure in utero displayed increased neophobic-like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of allopregnanolone programs vulnerability of female offspring to anxiety-like disorders in juvenility without impacting long term allopregnanolone concentrations.

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Prenatal Stress Alters Hippocampal Neuroglia and Increases Anxiety in Childhood

Cited by 36 publications

References 60 publications

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig

Increased anxiety‐like phenotype in female guinea pigs following reduced neurosteroid exposure in utero

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