期刊
NEUROPSYCHOPHARMACOLOGY
卷 32, 期 7, 页码 1504-1519出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.npp.1301276
关键词
maternal separation; immobilization stress; neurogenesis; BDNF exon; dentate gyrus; progenitor
资金
- FIC NIH HHS [1R03 TW 006257-01] Funding Source: Medline
Stress regulation of brain-derived neurotrophic factor ( BDNF) is implicated in the hippocampal damage observed in depression. BDNF has a complex gene structure with four 50 untranslated exons (I-IV) with unique promoters, and a common 30 coding exon (V). To better understand the stress regulation of BDNF, we addressed whether distinct stressors differentially regulate exon-specific BDNF transcripts in the postnatal and adult hippocampus. The early life stress of maternal separation (MS) resulted in a time point-dependent differential upregulation of BDNF transcripts restricted to early postnatal life (P14-BDNF II, P21-BDNF IV, V). In adulthood, distinct stressors regulated BDNF transcripts in a signature manner. Immobilization stress, administered once, decreased all BDNF splice variants but had differing effects on BDNF I/II (increase) and III/IV (decrease) when administered chronically. Although immobilization stress reduced BDNF (V) mRNA, chronic unpredictable stress did not influence total BDNF despite altering specific BDNF transcripts. Furthermore, a prior history of MS altered the signature pattern in which adult-onset stress regulated specific BDNF transcripts. We also examined the expression of cyclic AMP response element-binding protein ( CREB), an upstream transcriptional activator of BDNF, and observed a CREB induction in the postnatal hippocampus following MS. As a possible consequence of enhanced CREB and BDNF expression following MS, we examined hippocampal progenitor proliferation and observed a significant increase restricted to early life. These results suggest that alterations in CREB/BDNF may contribute to the generation of individual differences in stress neurocircuitry, providing a substrate for altered vulnerability to depressive disorders.
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