科研之友
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摘要
The prefrontal cortex is highly vulnerable to traumatic brain injury (TBI) and its structural and/or functional alterations as a result of TBI can give rise to persistent working memory (WM) dysfunction. Using a rodent model of TBI, we have described profound WM deficits following TBI that are associated with increases in prefrontal catecholamine (both dopamine and norepinephrine) content. In this study, we examined if enhanced norepinephrine signaling contributes to TBI-associated WM dysfunction. We demonstrate that administration of alpha 1 adrenoceptor antagonists, but not alpha 2A agonist, at 14 days post-injury significantly improved WM performance. mRNA analysis revealed increased levels of alpha 1A, but not alpha 1B or alpha 1D, adrenoceptor in the medial prefrontal cortex (mPFC) of brain-injured rats. As alpha 1A and 1B adrenoceptor promoters contain putative cAMP response element (CRE) sequences, we therefore examined if CRE-binding protein (CREB) actively engages these sequences in order to increase receptor gene transcription following TBI. Our results show that the phosphorylation of CREB is enhanced in the mPFC at time points during which increased alpha 1A mRNA expression was observed. Chromatin immuno-precipitation (ChIP) assays using mPFC tissue from injured animals indicated increased phospho-CREB binding to the CRE sites of alpha 1A, but not alpha 1B, promoter compared to that observed in uninjured controls. To address the translatability of our findings, we tested the efficacy of the FDA-approved alpha 1 antagonist Prazosin and observed that this drug improves WM in injured animals. Taken together, these studies suggest that enhanced CREB-mediated expression of alpha 1 adrenoceptor contributes to TBI-associated WM dysfunction, and therapies aimed at reducing alpha 1 signaling may be useful in the treatment of TBI-associated WM deficits in humans.
- 出版日期2011-1-13
