Direct and indirect activation effects on reconsolidation in amygdala

Debiec, J., Doyere, V., Nader, K., LeDoux, J.E. (February 28, 2006). Directly reactivated, but not indirectly reactivated, memories undergo reconsolidation in the amygdala. PNAS, Volume 103, Number 9, 3428-3433.

The first experiment of the paper used second-order fear conditioning (SOFC) to create an associative memory network in rat brain. To do this, a conditioned stimulus (CS1) is paired with an unconditioned stimulus (US), which naturally elicits a response. After pairing, now CS1 elicits the response (such as freezing in fear). This is the first-order conditioning. Now, a second conditioned stimulus (CS2) is paired with CS1, and by association elicits the response transitively. When extinction of CS1 responding does not affect the responding of CS2, CS2 is considered independent of the first-order fear memory. But if CS2 responding decreases with CS1 extinction, then we have an associative chain (CS2 --> CS1 --> US).

The second experiment, building on such a conditioning chain, discovered that extinction of freezing responses to the first-order stimulus (CS1) leads to responding impairments in CS2. Extinction of the second-order stimulus (CS2), does not have any effect on CS1. This builds a case for a hierarchical, uni-directional chain.

The last experiment examined the effect of activation (memory retrieval) on such an associative chain. (In another paper, Nader and LeDoux showed that reactivation of a memory places it in a labile state -- that is, susceptible to disruption -- until again reconsolidated.) Results demonstrated that protein synthesis inhibition after exposure to a single CS1 impairs responses to both CS1 and CS2. But protein synthesis inhibition after exposure to a single CS2, only disrupts CS2 and leaves CS1 freezing intact. Therefore, it is believed that when the first-order association is directly activated, it is placed into a labile state, which may have an impact on dependent associations. However, when the first-order association is only indirectly activated (through an associative chain), it appears that there is not sufficient stimulation to kick off cellular processes which would place it in a labile state, so it remains fixed.

Clinical applications of such research may be in the areas of PTSD, where victims suffer not only from fearful memories, but also from everyday stimuli somehow associated with the initial trauma. This study shows that disrupting associated reactions will only alleviate the sufferer from these quirky stress reactions, while breaking associative chains at the root cause may provide cascading relief.