Abstract
Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC) mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC) and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF) protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it’s phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.
Highlights
Prenatal exposure to cocaine in both animals and humans has been associated with changes in brain structure [1,2,3,4,5] and cognitive impairments including deficits in attention and learning [6,7,8,9,10]
We identified decreased mature brain derived neurotrophic factor (BDNF) protein in the medial prefrontal cortex of prenatal cocaine exposed Val66Met mice during extinction training, suggesting this as a possible mechanism mediating the deficit in fear extinction [10]
In this study we observed a deficit in recall of fear extinction in adult prenatal cocaine exposed mice attributable to a decrease in mature form of BDNF (mBDNF) signaling through its tropomyosine receptor kinase B (TrkB) receptor, in the medial prefrontal cortex (mPFC) during consolidation of the extinction memory
Summary
Prenatal exposure to cocaine in both animals and humans has been associated with changes in brain structure [1,2,3,4,5] and cognitive impairments including deficits in attention and learning [6,7,8,9,10]. Utilizing a fear extinction learning paradigm, we recently reported that prenatal cocaine exposed mice, heterozygous for the brain-derived neurotrophic factor (Bdnf) Val66Met allele, exhibit a deficit in recall of an extinguished cue-conditioned fear [10]. We identified decreased mature BDNF protein in the medial prefrontal cortex (mPFC) of prenatal cocaine exposed Val66Met mice during extinction training, suggesting this as a possible mechanism mediating the deficit in fear extinction [10]. Extinction of a cueconditioned fear requires suppression of a conditioned response elicited by a stimulus that no longer predicts reinforcement. This behavior is a well-established learning paradigm that involves several brain regions including the mPFC and hippocampus [11]. Increased BDNF protein within the IL plays an integral role in enabling the recall of the extinction memory [19]
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