Fear Memories and PTSD
Learning and memory represent fundamental processes that allow us to acquire information about the world around us. Integration of memories from past experiences with sensory information from the surrounding environment allows animals to alter their behavior to avoid danger and ensure survival. Fear memories are of particular importance, as learning to associate sensory cues with dangerous situations are key in maintaining behaviors that promote survival. Although the formation of strong fear memories is evolutionarily advantageous, over-generalization of fear can lead to debilitating disorders such as post-traumatic stress disorder (PTSD) and generalized anxiety disorders. Because of this, fully understanding the molecular mechanisms underlying memory storage is critical for the development of effective treatments for generalized fear disorders.
Laurel Drane, a Neuroscience PhD candidate working in the laboratory of Leon Reijmers, has focused her studies on trying to better understand the role of protein translation during the process of memory formation. Local protein translation, specifically in dendrites (the processes of neurons that receive information), is fundamentally important in understanding the molecular mechanisms of memory formation and storage. To study this problem, she has worked with two transgenic mouse models.
In order to conduct a screen looking at dendritically translated mRNAs immediately following fear conditioning, Laurel and Joshua Ainsley, a former postdoc in the Reijmers lab, have used the Camk2a-TRAP mouse, which tags ribosomes within Camk2a expressing cells. Camk2a is a kinase that, within the hippocampus, is expressed exclusively in excitatory pyramidal cells, which allows for the specific tagging and manipulation of one particular cell type from tissue that contains a heterogeneous cell population. Using this model they identified ribosome-bound mRNA from hippocampal pyramidal cell dendrites. This screen showed that activation of the hippocampus by fear conditioning increased the amount of mRNA bound to ribosomes in pyramidal cell dendrites. In addition, multiple mRNAs were found to be translated within dendrites that had not been known to function outside of the nucleus.
Laurel is also using the TetTag-TRAP mouse model that allows for the extraction of ribosome-bound mRNA specifically from neurons activated during the creation of a fear memory. The TetTag-TRAP mouse conditionally expresses its molecular tag under the activity-dependent Fos promoter, so that only neurons that have been activated (through fear memory formation) become tagged. This system will enable Laurel to extract mRNA from excitatory hippocampal pyramidal neurons that were activated during the creation of a fear memory, thus honing in on what genes are translated in neurons activated during fear memory formation.
By using the list of genes found to be dendritically translated after fear conditioning, Laurel has moved the focus of her studies onto characterizing the function of one of these genes. Through her experiments, Laurel has discovered a novel function for her protein of interest within neurons, and is currently pursuing this function in greater detail.
Drane L, Ainsley JA, Mayford MR, Reijmers LG. 2014. A transgenic mouse line for collecting ribosome-bound mRNA using the tetracycline transactivator system. Front Mol Neurosci. 7: 82.
Ainsley JA, Drane L, Jacobs J, Kittelberger KA, Reijmers LG. 2014. Functionally diverse dendritic mRNAs rapidly associate with ribosomes following a novel experience. Nat Commun. 5: 4510.