Altered DNA Methylation in the Developing Brains of Rats Genetically Prone to High versus Low Anxiety

被引:19
作者
McCoy, Echelsea R. [1 ]
Glover, Matthew E. [1 ]
Flynn, Leigh T. [1 ]
Simmons, Rebecca K. [3 ]
Cohen, Joshua L. [4 ]
Ptacek, Travis [5 ]
Lefkowitz, Elliot J. [5 ]
Jackson, Nateka L. [6 ]
Akil, Huda [7 ]
Wu, Xiaowei [2 ]
Clinton, Carah M. [1 ]
机构
[1] Virginia Polytech Inst & State Univ, Sch Neurosci, Blacksburg, VA 24061 USA
[2] Virginia Polytech Inst & State Univ, Dept Stat, Blacksburg, VA 24061 USA
[3] Univ Western Australia, Harry Perkins Inst Med Res, Crawley, WA 6009, Australia
[4] Univ Alabama Birmingham, MD PhD Med Scientist Training Program, Birmingham, AL 35233 USA
[5] Univ Alabama Birmingham, Ctr Clin & Translat Sci, Dept Microbiol, Birmingham, AL 35233 USA
[6] Univ Alabama Birmingham, Dept Cellular Dev & Integrat Biol, Birmingham, AL 35233 USA
[7] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院;
关键词
amygdala; anxiety; depression; DNA methylation; neurodevelopment; NOVELTY-SEEKING; BEHAVIORAL-INHIBITION; INDIVIDUAL-DIFFERENCES; GENE-EXPRESSION; EPIGENETIC REGULATION; PRENATAL STRESS; SEX-DIFFERENCES; DEPRESSION; RISK; HIPPOCAMPUS;
D O I
10.1523/JNEUROSCI.1157-15.2019
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder [LR]) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats. Prior work revealed distinct limbic brain development in HR versus LR rats, including altered expression of genes involved in DNA methylation. This led us to hypothesize that DNA methylation differences in the developing brain drive the disparate HR/LR neurobehavioral phenotypes. Here we report altered DNA methylation markers (altered DNA methyltransferase protein levels and increased global DNA methylation levels) in the early postnatal amygdala of LR versus HR male rats. Next-generation sequencing methylome profiling identified numerous differentially methylated regions across the genome in the early postnatal HR/LR amygdala. We also contrasted methylat ion profiles of male HRs and LRs with a control rat strain that displays an intermediate behavioral phenotype relative to the HR/LR extremes; this revealed that the LR amygdalar methylome was abnormal, with the HR profile more closely resembling that of the control group. Finally, through two methylation manipulations in early life, we found that decreasing DNA methylation in the developing male and female amygdala improves adult anxiety- and depression-like behavior. These findings suggest that inborn DNA methylation differences play important roles in shaping brain development and lifelong emotional behavior.
引用
收藏
页码:3144 / 3158
页数:15
相关论文
共 74 条
[1]   Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility [J].
Bagot, Rosemary C. ;
Cates, Hannah M. ;
Purushothaman, Immanuel ;
Lorsch, Zachary S. ;
Walker, Deena M. ;
Wang, Junshi ;
Huang, Xiaojie ;
Schluter, Oliver M. ;
Maze, Ian ;
Pena, Catherine J. ;
Heller, Elizabeth A. ;
Issler, Orna ;
Wang, Minghui ;
Song, Won-min ;
Stein, Jason. L. ;
Liu, Xiaochuan ;
Doyle, Marie A. ;
Scobie, Kimberly N. ;
Sun, Hao Sheng ;
Neve, Rachael L. ;
Geschwind, Daniel ;
Dong, Yan ;
Shen, Li ;
Zhang, Bin ;
Nestler, Eric J. .
NEURON, 2016, 90 (05) :969-983
[2]   Early life experience drives structural variation of neural genomes in mice [J].
Bedrosian, Tracy A. ;
Quayle, Carolina ;
Novaresi, Nicole ;
Gage, Fred. H. .
SCIENCE, 2018, 359 (6382) :1395-+
[3]   Neuronal changes in the basolateral complex during development of the amygdala of the rat [J].
Berdel, B ;
Morys, J ;
Maciejewska, B .
INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, 1997, 15 (06) :755-765
[4]   Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain [J].
Berger, MA ;
Barros, VG ;
Sarchi, MI ;
Tarazi, FI ;
Antonelli, MC .
NEUROCHEMICAL RESEARCH, 2002, 27 (11) :1525-1533
[5]   The NIH Roadmap Epigenomics Mapping Consortium [J].
Bernstein, Bradley E. ;
Stamatoyannopoulos, John A. ;
Costello, Joseph F. ;
Ren, Bing ;
Milosavljevic, Aleksandar ;
Meissner, Alexander ;
Kellis, Manolis ;
Marra, Marco A. ;
Beaudet, Arthur L. ;
Ecker, Joseph R. ;
Farnham, Peggy J. ;
Hirst, Martin ;
Lander, Eric S. ;
Mikkelsen, Tarjei S. ;
Thomson, James A. .
NATURE BIOTECHNOLOGY, 2010, 28 (10) :1045-1048
[6]   Further evidence of association between behavioral inhibition and social anxiety in children [J].
Biederman, J ;
Hirshfeld-Becker, DR ;
Rosenbaum, JF ;
Hérot, C ;
Friedman, D ;
Snidman, N ;
Kagan, J ;
Faraone, SV .
AMERICAN JOURNAL OF PSYCHIATRY, 2001, 158 (10) :1673-1679
[7]  
Blankenberg Daniel, 2010, Curr Protoc Mol Biol, VChapter 19, DOI 10.1002/0471142727.mb1910s89
[8]   Inter-individual variation of DNA methylation and its implications for large-scale epigenome mapping [J].
Bock, Christoph ;
Walter, Joern ;
Paulsen, Martina ;
Lengauer, Thomas .
NUCLEIC ACIDS RESEARCH, 2008, 36 (10)
[9]   Neonatal development of projections to the basolateral amygdala from prefrontal and thalamic structures in rat [J].
Bouwmeester, H ;
Smits, K ;
Van Ree, JM .
JOURNAL OF COMPARATIVE NEUROLOGY, 2002, 450 (03) :241-255
[10]   Whole-genome DNA methylation profiling using MethylCap-seq [J].
Brinkman, Arie B. ;
Simmer, Femke ;
Ma, Kelong ;
Kaan, Anita ;
Zhu, Jingde ;
Stunnenberg, Hendrik G. .
METHODS, 2010, 52 (03) :232-236