Forgetting the fear

There are some memories one would rather forget. This is especially true for people who suffer from phobias or from post-traumatic stress disorder. Some memories can decrease and even disappear through a process called extinction, but the mechanisms that are involved are not known. Tsai and colleagues now show that a molecular pathway in the hippocampus that involves cyclin-dependent kinase 5 (Cdk5) regulates the extinction of contextual fear in mice.

When mice are exposed to an aversive stimulus in a neutral context, they develop fear for that context — this is called conditioned fear. In a subsequent ‘extinction procedure’ that consists of daily 3-minute long re-exposures to the context alone, the animals gradually become less afraid of the environment, as evidenced by reduced freezing.

Read full story here

Source:

Sananbenesi et al. Hippocampal cyclin-dependent kinase 5 regulates the loss of fearful associations. Nature Reviews Neuroscience 8, 651 (September 2007)

Abstract:

Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.