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

Abstract

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...

Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth

“…As with myelination, GAD67+ Purkinje cell numbers in lobule IX were also unaffected in the preterm female cohort. Although the mechanism of these differences is unclear, this supports previous findings in the guinea pig that indicate female offspring are less vulnerable to neurological deficits caused by preterm birth (Shaw et al, 2016). The decrease in GAD67+ Purkinje cells numbers identified in lobule X in both the preterm males and females coincided with a reduction in the internal granule cell layer width in both sexes.…”

“…Juvenile ex‐preterm guinea pigs also exhibited behavioural disturbances at the equivalence of childhood, supporting the clinical relevance of the model; specifically, preterm male guinea pigs displayed a hyperactive phenotype (ADHD‐type) compared to male term‐born animals (Shaw et al, 2016). Whilst, preterm female guinea pigs exhibited anxiety‐related symptoms compared to the female term‐born animals (Shaw et al, 2016). The aim of the current study was to determine the effects of preterm birth on the development of the cerebellum in the guinea pig.…”

“…The preterm animals also had significantly decreased myelination (as evidenced by less MBP expression) in the CA1 region of the hippocampus, the adjacent subcortical white matter, and the cerebellum 24 h after delivery and at term equivalent age (Shaw et al, 2015; Kelleher et al, 2013; Palliser et al, 2015). Interestingly, we have also previously identified a long lasting reduction of myelination in the subcortical white matter and CA1 region of the hippocampus in juvenile guinea pigs born preterm (Shaw et al, 2016). Juvenile ex‐preterm guinea pigs also exhibited behavioural disturbances at the equivalence of childhood, supporting the clinical relevance of the model; specifically, preterm male guinea pigs displayed a hyperactive phenotype (ADHD‐type) compared to male term‐born animals (Shaw et al, 2016).…”

“…Interestingly, we have also previously identified a long lasting reduction of myelination in the subcortical white matter and CA1 region of the hippocampus in juvenile guinea pigs born preterm (Shaw et al, 2016). Juvenile ex-preterm guinea pigs also exhibited behavioural disturbances at the equivalence of childhood, supporting the clinical relevance of the model; specifically, preterm male guinea pigs displayed a hyperactive phenotype (ADHD-type) compared to male term-born animals (Shaw et al, 2016). Whilst, preterm female guinea pigs exhibited anxiety-related symptoms compared to the female termborn animals (Shaw et al, 2016).…”

“…These findings suggest that there is impairment of the GABAergic system, and furthermore that an imbalance between inhibitory and excitatory arms of the system may be involved in the development of neuropsychiatric disorders as a decrease in GABA concentration and subsequent action is associated with an increase in glutamate and excitation (Sanacora et al, 2004). In previous studies we have identified an altered expression of GABA A receptors in the preterm guinea pig neonate and juvenile in both the cerebellum and hippocampus (Shaw et al, 2016; Shaw et al, 2015), suggesting that the GABAergic system may also be deregulated following preterm birth in this species, increasing the clinical relevance of the preterm guinea pig model.…”