Abstract
The medial prefrontal cortex (mPFC) is known to regulate executive decisions and the expression of emotional memories. More specifically, the prelimbic cortex (PL) of the mPFC is implicated in driving emotional responses via downstream targets including the nucleus accumbens and amygdala, but mechanisms are yet to be fully understood. Therefore, we investigated whether prelimbic cortical brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tyrosine kinase receptor B (TrkB) receptor may serve as a molecular mechanism underlying emotional memory encoding. Here, we utilized viral-mediated inducible bdnf deletion within the PL, as well as TrkBF616A mutant mice, wherein TrkB receptor point mutation results in its being highly sensitive to inhibition by small PP1-derivative molecules, serving as a specific TrkB inhibitor. The site-specific TrkB antagonism and viral-mediated bdnf deletion within the PL resulted in deficits in both cocaine-dependent associative learning and fear expression. Deficiencies were rescued by the novel TrkB agonist 7,8-dihydroxyflavone, indicating that PL BDNF expression and downstream signaling through the TrkB receptor are required for memory formation in both appetitive and aversive domains.
Highlights
The formation of aversively and appetitively valenced memories is critical for normal behavior
The prelimbic cortical subregion (PL) bdnf gene deletion here resulted in attenuated fear responses following fear-conditioning, is consistent with the previous work, suggesting PL brain-derived neurotrophic factor (BDNF) is required for consolidation of learned fear.[10]
In these bdnf knockdown mice, there were no effects of bdnf silencing on the acquisition of fear during fear-conditioning, and there were no differences in the extinction of fear, suggesting that PL BDNF is critical for consolidation of learned fear, but not extinction of fear
Summary
The formation of aversively and appetitively valenced memories is critical for normal behavior Such memories can become detrimental to health if they evolve into uncontrolled fear, anxiety or reward seeking. The medial prefrontal cortex (mPFC) is highly implicated in both aversive and appetitive learning.[1] Of particular interest is the prelimbic cortical subregion (PL), which sends robust projections to the basolateral nucleus of the amygdala and nucleus accumbens,[2] providing clear connectivity to fear and reward pathways. A firmer grasp on the neurobiology of the PL is critical for understanding the mechanisms of normal learning and the development of fear and anxiety disorders such as posttraumatic stress disorder, as well as drug addiction and co-morbidities. The molecular mechanisms that regulate fear expression, consolidation and extinction are, still unresolved
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