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Notch developmental pathway regulates fear memory formation.

Nature is thrifty. The same signals that embryonic cells use to decide whether to become nerves, skin or bone come into play again when adult animals are learning whether to become afraid. Researchers at Emory University, have learned that the molecule Notch, critical in many processes during embryonic development, is also involved in fear memory formation. Understanding fear memory formation is critical to developing more effective treatments and preventions for anxiety disorders such as post-traumatic stress disorder (PTSD).  The results are published in the journal Neuron.

The team have found that developmental pathways that appear to be quiescent during adulthood are transiently reactivated to allow new memory formation to occur.

The Notch signalling pathway, present in insects, worms and vertebrates, is involved in embryonic patterning as well as nervous system and cardiovascular development. It’s a way for cells to communicate and coordinate which cells are going to become what types of tissues.

The team probed the Notch pathway because they were examining many genes that are activated in the brains of mice after they learn to become afraid of a sound paired with a mild foot-shock. They were looking for changes in the amygdala, a region of the brain known to regulate fear learning.

The researchers were particularly interested in micro RNAs. MicroRNAs do not encode proteins but can inhibit other genes, often several at once in a coordinated way. The researchers found that levels of miRNA-34a are increased in the amygdala after fear learning occurs. A day after fear training, animals whose brains were injected with a virus engineered to carry a ‘sponge’ against miRNA-34a froze less often than control animals.

The researchers found that miRNA-34a regulated several genes that encode components of the Notch pathway. They believe their study is the first to link miRNA-34a and Notch signalling to a role in memory consolidation.  Notch is under investigation as a target in the treatment of various cancers and some drugs that target Notch have been well-tolerated by humans.

From a therapeutic perspective, the team state that their data suggests that relevant drugs that regulate Notch signalling could potentially be a starting point for preventing or treating PTSD.

Source:  Yerkes National Primate Research Center, Emory University

Working Model of miR-34a-Mediated Regulation of Notch Signaling as Being Permissive to Fear Memory Consolidation.  (A) Baseline levels of Notch signaling in the BLA as a consequence of ligand (Jag1 and Dll1) and receptor (Notch 1 and Notch 2) interaction maintains status quo and the baseline state. (B) After training, miR-34a upregulation in the amygdala results in downregulation of components of the Notch pathway and a decrease in Notch signaling, thereby creating a molecular and cellular environment that is permissive to the consolidation of cued fear memory. Green: Inhibiting miR-34a action in the BLA by expressing miR-34a sponges via lentiviruses impairs fear memory consolidation, as does overexpressing Hes1 in the BLA and consequently increasing Notch signaling. Yellow: In contrast, inhibiting Notch signaling by suppressing the activity of g-secretase using systemic DAPT administration or using Anti-Jag1-Fc antibody in the BLA enhances fear memory consolidation.  Ressler et al 2014.
Working Model of miR-34a-Mediated Regulation of Notch Signalling as Being Permissive to Fear Memory Consolidation. (A) Baseline levels of Notch signalling in the BLA as a consequence of ligand (Jag1 and Dll1) and receptor (Notch 1 and Notch 2) interaction maintains status quo and the baseline state.
(B) After training, miR-34a upregulation in the amygdala results in downregulation of components of the Notch pathway and a decrease in Notch signalling, thereby creating a molecular and cellular environment that is permissive to the consolidation of cued fear memory. Green: Inhibiting miR-34a action in the BLA by expressing miR-34a sponges via lentiviruses impairs fear memory consolidation, as does overexpressing Hes1 in the BLA and consequently increasing Notch signalling. Yellow: In contrast, inhibiting Notch signalling by suppressing the activity of g-secretase using systemic DAPT administration
or using Anti-Jag1-Fc antibody in the BLA enhances fear memory consolidation. Ressler et al 2014.

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