ALTERED BRAIN MORPHOLOGY AND FUNCTIONAL CONNECTIVITY REFLECT A VULNERABLE AFFECTIVE STATE AFTER CUMULATIVE MULTIGENERATIONAL STRESS IN RATS
NEUROSCIENCE
Authors: Mccreary, J. Keiko; Truica, L. Sorina; Friesen, Becky; Yao, Youli; Olson, David M.; Kovalchuk, Igor; Cross, Albert R.; Metz, Gerlinde A. S.
Abstract
Prenatal stress is a risk factor for abnormal neuroanatomical, cognitive, behavioral and mental health outcomes with potentially transgenerational consequences. Females in general seem more resilient to the effects of prenatal stress than males. Here, we examined if repeated stress across generations may diminish stress resiliency and cumulatively enhance the susceptibility for adverse health outcomes in females. Pregnant female rats of three successive generations were exposed to stress from gestational days 12-18 to generate multigenerational prenatal stress (MPS) in the maternal lineage. Stress response was measured by plasma corticosterone levels and open-field exploration in each generation. Neuromorphological consequences of MPS were investigated in the F3 generation using in vivo manganese-enhanced magnetic resonance imaging (MEMRI), T-2-relaxometry, and cytoarchitectonics in relation to candidate gene expression involved in brain plasticity and mental health. Each additional generation of prenatal stress incrementally elevated hypothalamic-pituitary-adrenal axis activation, anxiety-like and aversive behaviors in adult female offspring. Elevated stress responses in the MPS F3 generation were accompanied by reduced neural density in prefrontal cortex, hippocampus and whole brain along with altered brain activation patterns in in vivo MEMRI. MPS increased ephrin receptor A5 (Epha5), neuronal growth regulator (Negr1) and synaptosomal-associated protein 25 (Snap25) gene expression and reduced fibroblast growth factor 12 (Fgf12) in prefrontal cortex. These genes regulate neuronal maturation, arborization and synaptic plasticity and may explain altered brain cytoarchitectonics and connectivity. These findings emphasize that recurrent stress across generations may cumulatively increase stress vulnerability and the risk of adverse health outcomes through perinatal programing in females. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Evaluation of 12 Novel Molecular Markers for Degenerated Nucleus Pulposus in a Chinese Population
SPINE
Authors: Chen, Shuai; Hu, Zhi-Jun; Zhou, Zhi-Jie; Lin, Xian-Feng; Zhao, Feng-Dong; Ma, Jian-Jun; Zhang, Jian-Feng; Wang, Ji-Ying; Qin, An; Fan, Shun-Wu
Abstract
Study Design. A transcriptional expression assessment of human samples. Objective. To evaluate 12 new candidate nucleus pulposus (NP) markers in degenerative disc disease in a Chinese population. Summary of Background Data. Disc degeneration is a major contributor of low back pain. However, no specific and reliable markers of degeneration of NP are available. Methods. Specimens of NP were collected from 81 patients and grouped into the degenerated disc group (undergoing discectomy and fusion with significant signs of disc degeneration) and the trauma control group (undergoing anterior vertebral body and disc excision and fusion without signs of disc degeneration). Lumbar spine magnetic resonance imaging, hematoxylin-eosin staining, and safranin O staining of sections of NP tissues were conducted to evaluate the severity of the disc degeneration in all samples. Quantitative reverse transcription polymerase chain reaction was performed to investigate the levels of mRNA expression of these genes, as well as those of aggrecan, type II collagen, and SRY-box 9 (SOX-9). Degenerated samples were also divided into groups according to Pfirrmann grading system to elucidate the association of severity of degeneration and gene transcriptional levels. We also tested the relationship between mRNA levels of these genes and clinical characteristics such as hypertension and diabetes mellitus. Results. We demonstrated that 11 of the 12 candidates showed significant differential expression in degenerated discs. Changes in the expression of these 11 genes were determined to be risk factors in degenerative disc diseases. The expression of neurochondrin (NCDN), keratin 8 (KRT8), and matrix Gla protein (MGP) even showed signifi cant changes among subgroups of patients with degenerative disc disease stratified according to the Pfirrmann grading system. The expression of keratin 18 (KRT18), cadherin 2 (CDH2), synaptosomal-associated protein 25 (SNAP25), KRT8, and NCDN was significantly decreased in patients with hypertension. In contrast, the expression of MGP and cartilage oligomeric matrix protein was significantly upregulated in patients with diabetes mellitus. Conclusion. Overall, we demonstrated the clinical utility of 11 novel NP markers for degenerative disc disease. Among them, the expression of NCDN, KRT8, and MGP may indicate the severity of disc degeneration.