Fear extinction

Two signals converging into fear acquisition

It is a general observation in animals that a cue (conditioned stimulus (CS)) comes to induce fear response when it is repeatedly paired with a noxious stimulus (unconditioned stimulus (US)), such as foot shock.

However, it is also known for some time that, if animals are exposed only to the CS without pairing with US, the previously acquired responses will gradually decrease, a phenomenon referred to as fear extinction (R1)

Experiments performed by various laboratories using different animal models indicated that long-term memory formation involved activation of the protein kinases such as calcium/calmodulin kinase II, cAMP-dependent protein kinase (PKA), and mitogen-activated protein kinase (MAPK).

Once stimulated, these kinases could translocate to the nucleus and subsequently activate transcription factors to promote gene transcription and new protein synthesis. (R1)

Fear Extinction requires NMDA receptor activation, MAPK Kinase, CB1R and protein phosphatase 1

Much less is known about the cellular mechanisms leading to memory extinction. Previous studies have shown that experimental extinction was blocked by NMDA receptor antagonists and MAPK kinase (MEK) inhibitors and facilitated byd-cycloserine, a partial NMDA agonist.

Recently, it was found that extinction of fear conditioning was impaired in cannabinoid receptor 1-deficient or protein phosphatase 1-inhibited mice. (R1)

Fear acquisition is associated with activation of PI3K and Akt

This laboratory showed recently that acquisition of fear was associated with an activation of phosphatidylinositol 3-kinase (PI-3 kinase) and its downstream target Akt in the rat amygdala.

PI-3 kinase and Akt were also activated in response to long-term potentiation (LTP)-inducing tetanic stimulation (TS). In parallel, PI-3 kinase inhibitors interfered with TS-induced LTP as well as long-term fear memory formation (R1)

In parallel, PI-3 kinase inhibitors interfered with TS-induced LTP as well as long-term fear memory formation.

Therefore, it is of particular interest to see whether extinction trials affect phosphorylated state of this protein kinase. Here we show for the first time that fear training-induced phosphorylation of Akt in the rat amygdala is reduced after extinction training and is accompanied by an increase in the protein level and enzymatic activity of calcineurin. (R1)

Fear conditioning affects phosphorylation of Akt, but not the expression of Akt

shows that conditioned rats exhibited an increase in Akt phosphorylation after test compared with those of naive and unpaired controls.

The increase was transient and significant from 60 to 120 min after testing but not at other time points (F(6,35) = 24.32; p < 0.001). Post hoc comparisons (Newman–Keuls) revealed the differences between control and 60, 90, and 120 min time points (p < 0.01). No change was observed when blotted membrane was reprobed with an antibody that recognized Akt independently of its phosphorylated state. (R1)

Calcineurin facilitates fear extinction

In combination with behavioral and biochemical experiments, we show here that activation of calcineurin contributes to the extinction of fear memory. The identification of calcineurin as a molecular signal in memory liability suggests a potential new target for the treatment of anxiety and posttraumatic stress disorders. (R1)

MAPK-dependent cascade plays a role in fear extinction

Here we show that the MAPK pathway is also involved in extinction. Specifically, intra-amygdala infusion of the MAPK inhibitor PD98059 blocked the extinction of conditioned fear as assessed with fear-potentiated startle.

This could not be attributed either to lasting damage to the amygdala (because conditioned fear did extinguish in animals previously given PD98059 when the extinction procedure was repeated without drug) or to state-dependent drug effects. Moreover, the effects were anatomically specific. Intrahippocampal infusions did not disrupt extinction. (R3)

MAPK

The mammalian MAPK family of kinases includes three subfamilies:

1. Extracellular signal-regulated kinases (ERKs)
2. c-Jun N-terminal kinases (JNKs)
3. p38 mitogen-activated protein kinases (p38s)

Generally, ERKs are activated by growth factors and mitogens, whereas cellular stresses and inflammatory cytokines activate JNKs and p38s. (Wikipedia)