Emotional memories of traumatic life events such as accidents, war experiences or serious illnesses are stored in a particularly robust way by the brain. This renders effective treatment very difficult. Researchers at ETH Zurich and the University of Zurich have now successfully tracked down the molecular bases of these strong, very persistent memories.

The expression “post-traumatic stress disorder” is once again constantly on everyone’s lips in relation to those returning from the Iraq war or survivors of catastrophes such as the tsunami. This is not a new development, since it always occurs when people experience extreme situations. It is known that emotional memories of both a positive and a negative kind are stored by our brain in a particularly robust way.

Consequently they have a very large effect on our behaviour and, in the case of adverse memories, they can place considerable restrictions on the way we go about our lives. As a result, we avoid places, smells or objects that remind us of the traumatic experience, because they may trigger severe anxieties. Isabelle Mansuy, Professor of Cellular Neurobiology at ETH Zurich and of Molecular and Cognitive Neurosciences at the University of Zurich, and her research group have now shown that the enzyme calcineurin and the gene regulation factor Zif268 decisively determine the intensity of emotional memories. For the first time, this has enabled the regulatory processes at the synapse, which are important for emotional memories, to be linked to the processes in the cell nucleus.

Mice as an ideal model system

The generation of very persistent memories in the shortest possible time needs molecules in the brain that are not only activated rapidly but which also efficiently control the signalling pathways of long-term information storage in the brain. This is why the protein phosphatase calcineurin, which was already known to have a negative regulatory effect on learning and memory, was a very promising candidate for the Zurich researchers. The researchers used mice as the model system because their learning processes are very similar to those in humans, and established behavioural tests already exist. In their experiments, the researchers conditioned the mice to associate a sugar solution with nausea. This association persists for many months. The mice avoid the sugar solution during this period.

However, their aversion can be overcome slowly through intensive training. Mansuy explains that “Emotional memories are not simply erased. Oppressive negative memories need to be actively replaced by positive memories.” She says it is important at the same time to understand that the negative memories do not disappear, they merely slide down in a kind of priority list and are outweighed by the newly learned positive memories. Mansuy says “This process is not final and absolute, since the priority list can change again.” Karsten Baumgärtel, a post-doctoral researcher in Mansuy’s group, stresses that this is a big difference between emotional memories and learned knowledge. “It is entirely possible for facts to vanish completely from the memory, whereas in extreme cases emotional recollections remain stored for a whole lifetime. Active intervention is necessary to reduce the priority level of negative memories.”

Reduced calcineurin activity

Studies of the amygdala, that part of the brain which is important for emotional perception, showed reduced activity of the enzyme calcineurin in conditioned mice compared to mice in which no association with nausea had been generated. Because calcineurin is a negative regulator of learning and memory, its activity needs to be reduced to enable strong memorisation. To gain more evidence about the role of calcineurin in the memory process, the researchers used transgenic mice in which they were able to selectively activate or deactivate the enzyme in nerve cells of the brain. Mansuy explains that “This selective activation and inactivation in nerve cells is important because calcineurin is an enzyme that occurs in many cells.

For example it also plays an important part in the immune defence system.” As the researchers expected, inactivating calcineurin strengthened the memory of the association between sugar solution and nausea, whereas the memory was weakened by increased calcineurin activity. The researchers were also able to demonstrate that the period of time needed to suppress the negative memory by a purely positive memory could be prolonged or shortened respectively by this intervention.

Regulation processes in synapses and the cell nucleus

Inactivating calcineurin also causes increased expression of the gene regulator Zif268 in the amygdala. Zif268 is responsible for regulating a wide variety of important genes that play a role in the signal processing of memories and learning. Simulating this increased expression of Zif268 in transgenic mice intensified memory in a similar way to the inactivation of calcineurin. This is the first occasion on which it has been possible to demonstrate this magnitude of functional relationship between the activity of an enzyme in the synapse and that of a gene regulation factor in the cell nucleus.

Mansuy and Baumgärtel stress that the purpose of their research is to gain a fundamental understanding of the molecular relationships, but that it is not associated in any way with a direct clinical application in the near future. However, Mansuy explains that: “In the past, the origin of many diseases was unknown and they were regarded as a punishment from God, and at that time those who were affected went to the priest. Nowadays we understand the mechanisms underlying them and can treat these illnesses. We hope that our research has made a small contribution to enabling the same situation also to apply in the future to psychological traumas or brain diseases with memory weakness such as Alzheimer’s, Parkinson’s and strokes.”