Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus.
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 5' untranslated exons (I-IV) with unique promoters, and a common 3' 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.
Nair
Amrita
A
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Vadodaria
Krishna C
KC
Banerjee
Sunayana B
SB
Benekareddy
Madhurima
M
Dias
Brian G
BG
Duman
Ronald S
RS
Vaidya
Vidita A
VA
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism*; D008297:Male; D008426:Maternal Deprivation; D009434:Neural Pathways / Q000254:growth & development / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger