Effects of prenatal stress on behavioural and neurodevelopmental outcomes are altered by maternal separation in the neonatal period

Crombie, Gabrielle K.; Palliser, Hannah K.; Shaw, Julia C.; Hodgson, Deborah M.; Walker, David W.; Hirst, Jonathan J.

doi:10.1016/j.psyneuen.2020.105060

Cited by 29 publications

(32 citation statements)

References 51 publications

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“…Frozen hippocampal tissue was prepared for PCR as previously described ( Shaw et al, 2016 ; Shaw et al, 2019 ; Crombie et al, 2021 ). Briefly, tissue was homogenised in RLT Plus Buffer (Qiagen RNeasy Plus Mini Kit, Qiagen Pty Ltd, Chadstone, Australia) using a Precellys 24 dual-tissue homogenizer (Bertin Technologies, France).…”

Section: Methodsmentioning

confidence: 99%

Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment

et al. 2022

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Background: Preterm birth can lead to brain injury and currently there are no targeted therapies to promote postnatal brain development and protect these vulnerable neonates. We have previously shown that the neurosteroid-analogue ganaxolone promotes white matter development and improves behavioural outcomes in male juvenile guinea pigs born preterm. Adverse side effects in this previous study necessitated this current follow-up dosing study, where a focus was placed upon physical wellbeing during the treatment administration and markers of neurodevelopment at the completion of the treatment period.Methods: Time-mated guinea pigs delivered preterm (d62) by induction of labour or spontaneously at term (d69). Preterm pups were randomized to receive no treatment (Prem-CON) or ganaxolone at one of three doses [0.5 mg/kg ganaxolone (low dose; LOW-GNX), 1.0 mg/kg ganaxolone (mid dose; MID-GNX), or 2.5 mg/kg ganaxolone (high dose; HIGH-GNX) in vehicle (45% β-cyclodextrin)] daily until term equivalence age. Physical parameters including weight gain, ponderal index, supplemental feeding, and wellbeing (a score based on respiration, activity, and posture) were recorded throughout the preterm period. At term equivalence, brain tissue was collected, and analysis of hippocampal neurodevelopment was undertaken by immunohistochemistry and RT-PCR.Results: Low and mid dose ganaxolone had some impacts on early weight gain, supplemental feeding, and wellbeing, whereas high dose ganaxolone significantly affected all physical parameters for multiple days during the postnatal period when compared to the preterm control neonates. Deficits in the preterm hippocampus were identified using neurodevelopmental markers including mRNA expression of oligodendrocyte lineage cells (CSPG4, MBP), neuronal growth (INA, VEGFA), and the GABAergic/glutamatergic system (SLC32A1, SLC1A2, GRIN1, GRIN2C, DLG4). These deficits were not affected by ganaxolone at the doses used at the equivalent of normal term.Conclusion: This is the first study to investigate the effects of a range of doses of ganaxolone to improve preterm brain development. We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.

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Section: Methodsmentioning

confidence: 99%

Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment

et al. 2022

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“…The effects of prenatal stress on neurosteroid synthesis have also been examined in guinea pigs, which have a steroid profile during pregnancy and parturition more similar to humans than that in rats [ 33 ]. Maternal stress using strobe light exposure in late pregnancy results in anxiety-like behaviour and impaired myelination in the juvenile offspring [ 34 – 36 ]. In this model, 5α-reductase protein expression was not altered in the hippocampus [ 34 ]; however, 5α-reductase gene expression was elevated in the cerebellum [ 37 ].…”

Section: Role Of Neurosteroids In Mediating Early Life Programming Ef...mentioning

confidence: 99%

“…In this model, 5α-reductase protein expression was not altered in the hippocampus [ 34 ]; however, 5α-reductase gene expression was elevated in the cerebellum [ 37 ]. Moreover, while brain allopregnanolone concentrations were evidently not affected in juvenile PNS offspring [ 34 ], a decrease in circulating allopregnanolone was reported in some studies [ 36 ], but not in others [ 37 ]. Lower-plasma allopregnanolone concentrations in juvenile offspring are also observed when maternal stress exposure occurs for longer and earlier in pregnancy [ 35 ], suggesting that alterations in circulatory allopregnanolone in adulthood is dependent on the timing and duration of the maternal stressor.…”

Section: Role Of Neurosteroids In Mediating Early Life Programming Ef...mentioning

confidence: 99%

“…Interestingly, one study reported that many of the gene expression changes in oligodendrocyte and GABA-related markers (i.e. GABA receptor subunits, GABA synthesis enzymes and cotransporters) in the offspring’s brain induced by prenatal stress are absent when prenatal stress is combined with postnatal stress [ 36 ], perhaps indicating a predictive adaptive response [ 38 ]. Together, these studies indicate a consistent deficit in GABA-mediated processes in PNS guinea pig offspring.…”

Section: Role Of Neurosteroids In Mediating Early Life Programming Ef...mentioning

confidence: 99%

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Neurosteroids and early-life programming: An updated perspective

Sze

Brunton²

2022

Current Opinion in Endocrine and Metabolic Research

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“…In the number of mature neurons in the prefrontal cortex in rats, NMS24 hours could cause a reduction in prefrontal cortex thickness (Crombie et al, 2021). Fabricius et al (2008) found that mice undergoing MS on PND9, the dentate gyrus neurons signi cant reduction.…”

Section: Introductionmentioning

confidence: 99%

Effects of early intermittent maternal separation on cognitive development of the prefrontal cortex in piglets

Cheng

Zhou

Zhang

et al. 2022

Preprint

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In actual production, because increase of sows litter size, the management of piglets in split-suckling leads to intermittent neonatal maternal separation (NMS). Early lactation is a critical period of cognitive development in the piglets' brain. The experiment hypothesizes that intermittent NMS may affect piglets' neurological development and cognitive ability. To determine the extent of effects of NMS on the piglets' prefrontal cortex cognitive development, the control group (Con group, n=53) was set up with no NMS, the experimental group (MS group, n=53) was set up with MS for 4 h/day, and the piglets were milk supplemented during the separation period and weaned until 35d. Twelve piglets at postnatal day (PND) 35 were selected from each group for cognitive assessment. Three PND35 piglets from each group were slaughtered, and collected prefrontal cortex samples for reference transcriptome sequencing. Following bioinformatics analysis, GO enrichment and KEGG enrichment analysis as well as candidate gene screening were performed for differentially expressed genes. Finally, quantitative reverse transcription PCR (qRT-PCR) was used to verify the sequencing data were accurate. The results showed that, in the spatial holeboard discrimination task, the working memory and reference memory of piglets in the MS group were significantly lower than those in the Con group (P < 0.01). In the new object recognition task, the MS group was significantly lower than the Con group in the number of exposure to new objects and discrimination index (P < 0.01). In the prefrontal cortex of the MS group, 349 up-regulated, 151 down-regulated differential genes, and 584 significant GO entries were discovered. Screening for 9 genes associated with cognition at large differential multiples. qPCR validation results showed that MC4R, GRP, CYFIP2, NMB, CPEB1, ADCYAP1 were significantly downregulated and MAG, PLP1, CPEB4 were significantly upregulated. Light microscopy results showed changes in the morphological structure of neuronal cells and microglia. In summary, intermittent NMS may impair partial cognitive function in piglets by damaging the structure of the prefrontal cortex.

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Effects of prenatal stress on behavioural and neurodevelopmental outcomes are altered by maternal separation in the neonatal period

Cited by 29 publications

References 51 publications

Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment

Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment

Neurosteroids and early-life programming: An updated perspective

Effects of early intermittent maternal separation on cognitive development of the prefrontal cortex in piglets

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