Zurich, Switzerland. Post-traumatic Stress Disorder (PTSD) has returned to public awareness. This typically occurs when people experience extreme situations, such as accidents, natural catastrophes, serious illnesses, war, or other singular events. Our brain stores both positive and negative emotional memories, whether copnnected to traumatic life events or not, in a particularly robust manner. Consequently, the retention of such memories can have a very large effect on our behavior.

 

In the case of adverse memories, retention can place considerable restrictions on the way we go about our lives. As a result, we may avoid places, smells or objects that remind us of the traumatic experience, because they may trigger severe anxieties.

 

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Control of the establishment of aversive memory by calcineurin and Zif268. Karsten Baumgärte, David Genoux, Hans Welz, Ry Y Tweedie-Cullen, Kyoko Koshibu, Magdalena Livingstone-Zatchej, Céline Mamie & Isabelle M Mansuy. Nature Neuroscience 11(5):572-8. doi: 10.1038 / nn.2113

 

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.

 

This is an example of stand-by capabilitiy and dual-use in a biological system.

 

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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.  

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The association persisted and mice avoid the sugar solution for many months. However, their aversion can be overcome through slow and 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.”

 

Control of the establishment of aversive memory by calcineurin and Zif268. Karsten Baumgärte, David Genoux, Hans Welz, Ry Y Tweedie-Cullen, Kyoko Koshibu, Magdalena Livingstone-Zatchej, Céline Mamie & Isabelle M Mansuy. Nature Neuroscience 11(5):572-8. doi: 10.1038 / nn.2113

Abstract. Emotional memory is a rapidly acquired and persistent form of memory, and its robustness is in part determined by the initial strength of the memory. Here, we provide new evidence that the protein phosphatase calcineurin (CaN), a potent negative regulator of neuronal signaling that is known to constrain learning and memory, critically regulates the establishment of emotional memory through mechanisms involving the immediate early gene Zif268 (also known as Egr1). We found that CaN is inhibited in the amygdala during the establishment of aversive memory, but Zif268 is activated. Using inducible transgenesis in mice, we further saw that CaN inhibition and Zif268 overexpression during memory establishment strengthen the memory trace and enhance its resistance to extinction. We found that CaN inhibition correlates with increased Zif268 expression and that a common pool of proteins is regulated in the amygdala after CaN inhibition and Zif268 overexpression. Together, these findings reveal a previously unknown mechanism for the control of emotional memory that depends on CaN and Zif268.

 

 

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