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Environmental Intervention as a Therapy for Adverse Programming by Ancestral Stress

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ABSTRACT

Ancestral stress can program stress sensitivity and health trajectories across multiple generations. While ancestral stress is uncontrollable to the filial generations, it is critical to identify therapies that overcome transgenerational programming. Here we report that prenatal stress in rats generates a transgenerationally heritable endocrine and epigenetic footprint and elevated stress sensitivity which can be alleviated by beneficial experiences in later life. Ancestral stress led to downregulated glucocorticoid receptor and prefrontal cortex neuronal densities along with precocious development of anxiety-like behaviours. Environmental enrichment (EE) during adolescence mitigated endocrine and neuronal markers of stress and improved miR-182 expression linked to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) regulation in stressed lineages. Thus, EE may serve as a powerful intervention for adverse transgenerational programming through microRNA-mediated regulation of BDNF and NT-3 pathways. The identification of microRNAs that mediate the actions of EE highlights new therapeutic strategies for mental health conditions and psychiatric disease.

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Enriched environment improves dysregulated hypothalamic-pituitary-adrenal axis activity.(A) Illustration of critical components of the HPA axis assessed in this study. (B) Both transgenerational (TPS) and multigenerational (MPS) prenatal stress reduced glucocorticoid receptor markers in the hippocampus compared to the control group. Exposure to enriched environment increased glucocorticoid receptor count. (C) Circulating plasma corticosterone levels were reduced by enriched environment across all groups. Enrichment therapy thus improved HPA axis feedback regulation. Asterisks denote significances due to EE (*p < 0.05, **p < 0.01, ***p < 0.001); #denotes significant difference due to ancestral stress (#p < 0.05).
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f1: Enriched environment improves dysregulated hypothalamic-pituitary-adrenal axis activity.(A) Illustration of critical components of the HPA axis assessed in this study. (B) Both transgenerational (TPS) and multigenerational (MPS) prenatal stress reduced glucocorticoid receptor markers in the hippocampus compared to the control group. Exposure to enriched environment increased glucocorticoid receptor count. (C) Circulating plasma corticosterone levels were reduced by enriched environment across all groups. Enrichment therapy thus improved HPA axis feedback regulation. Asterisks denote significances due to EE (*p < 0.05, **p < 0.01, ***p < 0.001); #denotes significant difference due to ancestral stress (#p < 0.05).

Mentions: A summary of the total hippocampal GR cell count is shown in Fig. 1B and measurements of delineated areas of the hippocampus are shown in Fig. 2. Stereological analysis of total GR-positive cells (markers) counted in the hippocampus revealed a significant decrease due to stress (F(2,34) = 5.570, p < 0.05), and a significant increase due to enrichment (F(1,34) = 57.529, p < 0.0001). Delineated GR measurements included markers counted in the dentate gyrus (DG), CA1-2, and CA3. In the CA1-2 areas of the hippocampus, there was a significant main effect of stress linked to a decrease in total GR markers (F(2,34) = 15.871, p < 0.0001), and a significant effect of enriched environment linked to an increase in total GR markers (F(1,34) = 75.842, p < 0.0001). In the CA3, there was a significant increase in total GR markers due to stress compared to controls (F(2,34) = 8.423, p = 0.001), where enrichment still produced a significant increase in total markers (F(1,34) = 92.016, p < 0.0001). In the DG, there was a significant decrease in GR markers due to TPS compared to controls (p < 0.05), which was significantly improved in the enriched TPS group (p < 0.05).


Environmental Intervention as a Therapy for Adverse Programming by Ancestral Stress
Enriched environment improves dysregulated hypothalamic-pituitary-adrenal axis activity.(A) Illustration of critical components of the HPA axis assessed in this study. (B) Both transgenerational (TPS) and multigenerational (MPS) prenatal stress reduced glucocorticoid receptor markers in the hippocampus compared to the control group. Exposure to enriched environment increased glucocorticoid receptor count. (C) Circulating plasma corticosterone levels were reduced by enriched environment across all groups. Enrichment therapy thus improved HPA axis feedback regulation. Asterisks denote significances due to EE (*p < 0.05, **p < 0.01, ***p < 0.001); #denotes significant difference due to ancestral stress (#p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121646&req=5

f1: Enriched environment improves dysregulated hypothalamic-pituitary-adrenal axis activity.(A) Illustration of critical components of the HPA axis assessed in this study. (B) Both transgenerational (TPS) and multigenerational (MPS) prenatal stress reduced glucocorticoid receptor markers in the hippocampus compared to the control group. Exposure to enriched environment increased glucocorticoid receptor count. (C) Circulating plasma corticosterone levels were reduced by enriched environment across all groups. Enrichment therapy thus improved HPA axis feedback regulation. Asterisks denote significances due to EE (*p < 0.05, **p < 0.01, ***p < 0.001); #denotes significant difference due to ancestral stress (#p < 0.05).
Mentions: A summary of the total hippocampal GR cell count is shown in Fig. 1B and measurements of delineated areas of the hippocampus are shown in Fig. 2. Stereological analysis of total GR-positive cells (markers) counted in the hippocampus revealed a significant decrease due to stress (F(2,34) = 5.570, p < 0.05), and a significant increase due to enrichment (F(1,34) = 57.529, p < 0.0001). Delineated GR measurements included markers counted in the dentate gyrus (DG), CA1-2, and CA3. In the CA1-2 areas of the hippocampus, there was a significant main effect of stress linked to a decrease in total GR markers (F(2,34) = 15.871, p < 0.0001), and a significant effect of enriched environment linked to an increase in total GR markers (F(1,34) = 75.842, p < 0.0001). In the CA3, there was a significant increase in total GR markers due to stress compared to controls (F(2,34) = 8.423, p = 0.001), where enrichment still produced a significant increase in total markers (F(1,34) = 92.016, p < 0.0001). In the DG, there was a significant decrease in GR markers due to TPS compared to controls (p < 0.05), which was significantly improved in the enriched TPS group (p < 0.05).

View Article: PubMed Central - PubMed

ABSTRACT

Ancestral stress can program stress sensitivity and health trajectories across multiple generations. While ancestral stress is uncontrollable to the filial generations, it is critical to identify therapies that overcome transgenerational programming. Here we report that prenatal stress in rats generates a transgenerationally heritable endocrine and epigenetic footprint and elevated stress sensitivity which can be alleviated by beneficial experiences in later life. Ancestral stress led to downregulated glucocorticoid receptor and prefrontal cortex neuronal densities along with precocious development of anxiety-like behaviours. Environmental enrichment (EE) during adolescence mitigated endocrine and neuronal markers of stress and improved miR-182 expression linked to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) regulation in stressed lineages. Thus, EE may serve as a powerful intervention for adverse transgenerational programming through microRNA-mediated regulation of BDNF and NT-3 pathways. The identification of microRNAs that mediate the actions of EE highlights new therapeutic strategies for mental health conditions and psychiatric disease.

No MeSH data available.


Related in: MedlinePlus