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Maladaptive Alterations of Defensive Response Following Developmental Complex Stress in Rats.

ABSTRACT: Objective:Despite the etiological significance of complex developmental trauma in adult personality disorders and treatment-resistant depression, neurobiological studies have been rare due to the lack of useful animal models. As a first step, we devised an animal model to investigate the effects of multiple trauma-like stress during different developmental periods. Methods:Twenty-one male Sprague-Dawley rats were classified into 3 groups based on the stress protocol: fear conditioning control (FCC, n = 6), complex stress (ComS, n = 9), and control (n = 6). While the ComS experienced three types of stress (maternal separation, juvenile isolation, electric foot shock), the FCC only experienced an electric foot shock stress and the control never experienced any. We compared fear responses at postnatal day (PND) 29 and PND 56 through freezing time per episode (FTpE), total freezing time (TFT), total freezing episodes (TFE), and ultrasonic vocalization (USV). Results:ComS showed the longest FTpE in the conditioned fear response test. ComS and FCC exhibited the longer TFT and these two groups only displayed USV. ComS show difference TFE between PND 29 and PND 56. Conclusion:The results of this investigation show that complex stress may affect not quantity of fear response but characteristics of fear response. Longer FTpE may be associated with tonic immobility which could be considered as a failed self-protective reaction and might be analogous to a sign of inappropriate coping strategy and self-dysregulation in complex trauma patients.

SUBMITTER: Kim J

PROVIDER: S-EPMC7383007 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Maladaptive Alterations of Defensive Response Following Developmental Complex Stress in Rats.

Kim Junhyung J Park Minkyung M Lee Chiheon C Ha Jung Jin JJ Choi June-Seek JS Kim Chul Hoon CH Seok Jeong-Ho JH

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 20200801 3

<h4>Objective</h4>Despite the etiological significance of complex developmental trauma in adult personality disorders and treatment-resistant depression, neurobiological studies have been rare due to the lack of useful animal models. As a first step, we devised an animal model to investigate the effects of multiple trauma-like stress during different developmental periods.<h4>Methods</h4>Twenty-one male Sprague-Dawley rats were classified into 3 groups based on the stress protocol: fear conditio ...[more]

PMID: 32702220

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Project description:BackgroundPrevious studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment.ObjectivesA complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes.MethodsMale neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 ?g?BPA/kg?BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS).ResultsThe lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 ?g/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses.ConclusionsDevelopmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050.

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Maladaptive Alterations of Defensive Response Following Developmental Complex Stress in Rats.

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Maladaptive Alterations of Defensive Response Following Developmental Complex Stress in Rats.

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