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Long-term effects of neonatal stress on adult conditioned place preference (CPP) and hippocampal neurogenesis
Sarah L Hays1, Ronald J McPherson, Sandra E Juul
1Department of Pediatrics, University of Washington, Seattle, WA 98195, United States.
Insights
Neonatal stress and morphine exposure in mice impact adult behavior and brain development. Early life stress may desensitize animals, reducing stress responsiveness and preparing them for future challenges, supporting the stress inoculation hypothesis.
Area of Science:
- Neuroscience
- Developmental Psychology
- Pharmacology
Background:
- Early life stress and morphine exposure can negatively affect neurodevelopment and behavior in preterm infants.
- Previous studies showed neonatal stress or morphine impaired adult morphine-rewarded conditioned place preference (CPP) and altered hippocampal gene expression in mice.
Purpose of the Study:
- To investigate the short- and long-term effects of neonatal stress and morphine treatment on neurodevelopment and behavior in mice.
- To examine how neonatal interventions influence adult learning, stress responsiveness, and hippocampal neurogenesis.
Main Methods:
- Neonatal C57BL/6 mice received daily stress (maternal separation, gavage feeding, hypoxia/hyperoxia) or morphine injections from postnatal day 5 to 9.
- Short-term effects (postnatal day 9) assessed via neuronal staining and corticosterone levels.
- Long-term effects (adults >P60) evaluated using cocaine-rewarded CPP, kappa opioid receptor (KOR) agonist U50,488, and hippocampal neurogenesis markers.
Main Results:
- Neonatal stress reduced cocaine-CPP learning, an effect reversed by KOR stimulation.
- Both neonatal stress and morphine increased adult hippocampal neurogenesis.
- Reduced learning and increased neurogenesis suggest neonatal stress desensitized mice, lowering arousal and stress response.
Conclusions:
- Neonatal stress and morphine have lasting effects on neurobehavioral outcomes and brain plasticity.
- Early life stress may lead to reduced responsiveness to rewards and altered stress coping mechanisms in adulthood.
- Findings support the stress inoculation hypothesis, suggesting early stressors can enhance resilience to future stress.
Abstract:
Critically ill preterm infants are often exposed to stressors that may affect neurodevelopment and behavior. We reported that exposure of neonatal mice to stressors or morphine produced impairment of adult morphine-rewarded conditioned place preference (CPP) and altered hippocampal gene expression. We now further this line of inquiry by examining both short- and long-term effects of neonatal stress and morphine treatment. Neonatal C57BL/6 mice were treated twice daily from postnatal day (P) 5 to P9 using different combinations of factors. Subsets received saline or morphine injections (2mg/kgs.c.) or were exposed to our neonatal stress protocol (maternal separation 8h/d × 5d+gavage feedings ± hypoxia/hyperoxia). Short-term measures examined on P9 were neuronal fluorojade B and bromodeoxyuridine staining, along with urine corticosterone concentrations. Long-term measures examined in adult mice (>P60) included CPP learning to cocaine reward (± the kappa opioid receptor (KOR) agonist U50,488 injection), and adult hippocampal neurogenesis (PCNA immunolabeling). Neonatal stress (but not morphine) decreased the cocaine-CPP response and this effect was reversed by KOR stimulation. Both neonatal stress or morphine treatment increased hippocampal neurogenesis in adult mice. We conclude that reduced learning and increased hippocampal neurogenesis are both indicators that neonatal stress desensitized mice and reduced their arousal and stress responsiveness during adult CPP testing. Reconciled with other findings, these data collectively support the stress inoculation hypothesis whereby early life stressors prepare animals to tolerate future stress.
