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Combined Effect of Maternal Separation and Early-Life Immune Activation on Brain and Behaviour of Rat Offspring
Bharti Biswas1,2, Valsamma Eapen1, Margaret J Morris2
1School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW 2052, Australia.
Insights
Early life stress, like maternal separation (MS) and immune challenges (LPS), impacts brain development and behavior. Combining MS and LPS synergistically altered anxiety, activity, and brain gene expression in rats.
Area of Science:
- Neuroscience
- Developmental Psychology
- Toxicology
Background:
- Early life adversity significantly impacts brain development and behavior.
- Long-term effects of cumulative early-life stressors remain poorly understood.
- A two-hit rat model combining maternal separation and immune activation was used to investigate these effects.
Purpose of the Study:
- To investigate the long-term effects of cumulative early-life stressors on brain and behavior in a rat model.
- To examine the impact of maternal separation (MS) and lipopolysaccharide (LPS) administration on offspring.
- To analyze sex-specific behavioral and molecular outcomes.
Main Methods:
- Rat pups were exposed to varying durations of maternal separation (MS) from postnatal day 2-14.
- Pups received saline or lipopolysaccharide (LPS) on postnatal day 3.
- Behavioral tests (open-field, object-place recognition) and prefrontal cortex/hippocampus mRNA expression analysis were conducted.
Main Results:
- Maternal separation (MS) induced anxiety-like behavior in males and reduced locomotor activity in both sexes.
- Lipopolysaccharide (LPS) caused a minor memory decline in males.
- MS increased GFAP and BDNF in the PFC and Iba1 in the male hippocampus; MS and LPS synergistically affected anxiety, activity, and GFAP expression.
Conclusions:
- Early life adversity, particularly the combination of MS and LPS, has significant, sex-specific effects on brain and behavior.
- The two-hit model reveals synergistic impacts on anxiety-like behavior, locomotor activity, and specific gene expression.
- Findings highlight the lasting neurobiological consequences of early-life stress paradigms.
Abstract:
Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2-14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33-35 and P42-50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52-55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes.
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