Does a Molecular Mechanism Protect against Traumatic Memories?

Neuroscientists identify effect of a protein that controls memories of fear-ridden events at the biological level

The biphasic activity of the protein Npas4 modulates the strength of the memorie
The biphasic activity of the protein Npas4 modulates the strength of the memories linked to a bad experience. | Figure: Janina Kupke

A previously unknown molecular mechanism could protect the brain from traumatic memories and help prevent anxiety disorders at the biological level. A research team led by Dr Ana M. M. Oliveira, a neuroscientist at Heidelberg University and the Central Institute of Mental Health in Mannheim, discovered evidence of such a mechanism in experiments on a mouse model. The consolidation of strong fear memories in long-term memory is linked to the activity of a specific protein. This protein plays a key role in modulating synaptic connections between nerve cells.

Memories of fearful events enable one to respond appropriately to new situations. But traumatic experiences can invoke very strong fear memories that trigger feelings of panic in situations that have nothing to do with the original event, explains Dr Oliveira. The neuroscientist studies the molecular and cellular aspects of memory formation at the Interdisciplinary Center for Neurosciences (IZN) of Heidelberg University and the Department of Molecular and Cellular Cognition Research of the Central Institute of Mental Health. In cooperation with international colleagues, she investigated which biological processes promote or prevent the formation of strong fear memories.

In studies with mice, both pharmacological and genetic approaches were used. The researchers discovered that the activity of a protein called Npas4 had a significant impact on the animals’ memory of bad experiences. Npas4 regulates the transcription of genes that control the contacts and communication between nerve cells. The researchers observed two phases in which the Npas4 levels in the brain were especially high when responding to a strong negative stimulus. The second phase proved decisive. "It appears to modulate the strength of the memories linked to bad experiences," states Ana Oliveira. When the researchers blocked the two-phase activity of Npas4, the fear memories were so strong that the mice exhibited fear reactions in other situations as well. When a second Npas4 interval was artificially induced after a traumatic experience, the fear responses were lower.

In connection with the two Npas4 phases, the researchers were also able to demonstrate the increased activity of a neurotransmitter that suppresses neuronal activity. They suspect that the Npas4 protein influences the strength of fear memories in long-term memory by regulating the activity of this neurotransmitter. "Our research results point to a previously unknown protective mechanism in the brain that controls the memory of traumatic events at the biological level and hence resilience against such experiences," adds Dr Oliveira. It could provide a molecular target for developing new treatment approaches.

In addition to researchers of the IZN, scientists from Heidelberg, Frankfurt, the Netherlands, Portugal, and Russia contributed to the study. The results were published in the journal "Molecular Psychiatry".

D. V. C. Brito, J. Kupke, R. Sokolov, S. Cambridge, M. Both, C. P. Bengtson, A. Rozov, A. M. M. Oliveira: Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice. Molecular Psychiatry (13 February 2024)