期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 13, 页码 4056-4064出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5539-08.2009
关键词
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资金
- NATIONAL INSTITUTE OF MENTAL HEALTH [R25MH060478, K08MH068850, P50MH079513] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS052819] Funding Source: NIH RePORTER
- NIMH NIH HHS [R25 MH060478, MH079513, P50 MH079513-01A10001, MH060478, P50 MH079513, MH068850, K08 MH068850] Funding Source: Medline
- NINDS NIH HHS [R01 NS052819-04, R01 NS052819, NS052819] Funding Source: Medline
Brain-derived neurotrophic factor (BDNF) plays important roles in activity- dependent plasticity processes, such as long-term potentiation, learning, and memory. The recently reported human BDNF Val66Met (BDNFMet) polymorphism has been shown to lead to altered hippocampal volume and impaired hippocampal-dependent memory and is associated with a variety of neuropsychiatric disorders. There are few studies, however, that investigate the effect of the BDNFMet polymorphism on hippocampal-independent memory processes. A conditioned taste aversion (CTA) task was used for studying the mechanisms of long-term, hippocampal-independent, nondeclarative memory in the mammalian brain. Using the CTA paradigm, we found a novel impairment in extinction learning, but not acquisition or retention, of aversive memories resulting from the variant BDNFMet. BDNFMet mice were slower to extinguish an aversive CTA memory compared with wild-type counterparts. Moreover, the BDNFMet was associated with smaller volume and decreased neuronal dendritic complexity in the ventromedial prefrontal cortex (vmPFC), which plays a significant role in extinction of CTA. Finally, this delay in extinction learning could be rescued pharmacologically with a cognitive enhancer, D-cycloserine (DCS). To our knowledge, this is the first evidence that the BDNFMet polymorphism contributes to abnormalities in memory extinction. This abnormality in extinction learning may be explained by alterations in neuronal morphology, as well as decreased neural activity in the vmPFC. Importantly, DCS was effective in rescuing this delay in extinction, suggesting that when coupled with behavior therapy, DCS may be an effective treatment option for anxiety disorders in humans with this genetic variant BDNF.
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