Chronic stressor induces the release of glucocorticoid from the adrenal glands, the subsequent decrease of hippocampal volume, and the development of depression. Brain-derived neurotrophic factor (BDNF), composed of mature BDNF (mBDNF) and proBDNF, plays opposite roles in the structural integrity of the brain. However, the underlying mechanism of glucocorticoid-induced hippocampal atrophy remains unclear. Using the open field test, sucrose preference test, elevated plus maze test, and forced swimming test, we observed that the chronic (3 w) administration of corticosterone (CORT) (50 μg/ml) induced depressive-like behaviors in rats. Next, using Western blot assay, we showed that CORT exposure increased the proBDNF level in the ventral hippocampal dentate gyrus (DG), decreased the mBDNF level in the dorsal and ventral DG, and decreased the mBDNF/proBDNF ratio in the hippocampal DG. Furthermore, CORT administration differentially altered the expression of 11 Bdnf mRNA transcripts in the dorsal and ventral hippocampal DG. Our findings suggest an essential role for the mBDNF-proBDNF system in regulating the hippocampus of CORT-treated rats and present a new therapeutic mechanism for antidepressant treatments by targeting the Bdnf mRNA transcripts.
Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.
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