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Postnatal Stress Induced by Injection with Valproate Leads to Developing Emotional Disorders Along with Molecular and
Chih-Yen Wang1, Chien-Wen Cheng1, Wei-Hua Wang1
1Institute of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Insights
Early life stress, simulated by valproic acid (VPA) in rat pups, disrupts brain development, leading to anxiety, depression, and social deficits. These effects highlight early stress as a risk factor for emotional disorders.
Area of Science:
- Neuroscience
- Developmental Psychology
- Psychiatry
Background:
- Adverse early-life experiences can significantly impact brain development and increase the risk of psychiatric disorders.
- Understanding the specific mechanisms linking early-life stress to behavioral outcomes is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the effects of a single early-life stressor, valproic acid (VPA) administration, on neurodevelopment and behavior in a rat model.
- To explore the molecular and cellular changes in the brain following VPA exposure during a critical developmental window.
Main Methods:
- Valproic acid (VPA), a histone deacetylation inhibitor (HDACi), was administered intraperitoneally to male rat pups at postnatal day 7 (P7).
- Gene expression (DCX, NeuroD1), cell proliferation, neuronal populations (DCX+, NeuN+), and microglial morphology were assessed in the hippocampus and amygdala.
- Behavioral tests were conducted at later postnatal ages to evaluate anxiety-like, depressive-like, and social interaction behaviors.
Main Results:
- VPA injection downregulated neuronal differentiation genes (DCX, NeuroD1) and decreased neuronal populations in the hippocampus and dentate gyrus.
- Increased cell proliferation was observed in the dentate gyrus and amygdala, alongside rapid microglial morphological changes.
- VPA-treated rats exhibited depressive-like and anxiety-like behaviors, along with impaired social interaction at 8 weeks of age.
Conclusions:
- A single VPA administration during early development disrupts neural differentiation, alters neuron-glia interactions, and induces long-lasting behavioral deficits.
- Early-life stress, even a single exposure, poses a significant risk for developing emotional and social disorders, potentially due to persistent molecular and cellular alterations.
- Findings underscore the critical role of the early-life environment in shaping brain development and long-term mental health outcomes.
Abstract:
Stress derived from an adverse environment during brain development could contribute to psychiatric disorders. To study the influence of stress occurring at birth on behavior development in human, we performed an intraperitoneal injection (i.p.) of valproic acid (VPA; 200 mg/kg), a histone deacetylation inhibitor (HDACi), into male rat pups at the age of postnatal day 7 (P7) that is equivalent to an infant at 36-40 weeks gestation. Our results showed that neuronal differentiation genes, doublecortin (DCX) and NeuroD1, were downregulated in the hippocampus at 24 h post VPA injection. In addition, the cell proliferation was increased in the dentate gyrus and amygdala of rats receiving VPA injection. DCX+ and NeuN+ cell population was decreased in the dentate gyrus at 24 h post VPA injection. Moreover, microglial morphological changes in the hippocampus and amygdala were rapidly induced at 24 h after VPA injection. Through a series of behavior tests, we found that rats receiving VPA injection displayed depressive and anxiety-like behaviors at the late postnatal ages, and had impaired social interaction at 8 weeks old. In summary, a single postnatal administration of VPA not only disrupted neural cell differentiation program but also induced anxious, depressive, and impaired social behaviors. Our findings also shed light on early life stress to infants as a significant risk factor with regard to developing emotional disorders in youth, and that these effects may continue into adulthood, possibly due to altered gene expression and neuron-glia interaction occurring in the hippocampus and amygdala at an early age.
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