NEUROSCIENCE

Memories: the corners of our mind

Dr Ana M M Oliveira is a researcher interested in understanding a variety of processes that occur in the brain. She discusses her journey so far, some of her most exciting findings to date and the potential impact of her research

Could you begin by telling us how you became that is activated in which gene expression and we re-established Dnmt3a2, the mice could interested in cognitive function? protein synthesis is triggered. The synthesis perform memory tests in the same way as of new proteins is thought to modulate the young adult, cognitively normal mice. My interest in – and fascination for – the strength of the connections between neurons – study of the molecular mechanisms that a critical step in long-term memory formation. What challenges have you encountered during underlie cognitive function began during the course of your research and how have you my undergraduate studies, when I was first How did you come to discover that ageing- overcome these? exposed to the topic of synaptic plasticity. associated memory loss is linked to a The brain’s ability to change with experience decrease in the expression of the DNA In scientific research we are always facing is believed to be intrinsic to both learning methyltransferase Dnmt3a2? challenges that need to be overcome! Technical and memory. At the moment I was presented challenges and experimental troubleshooting with this idea I knew it was what I wanted There were already some findings showing routinely occur in the daily life of a scientist. to study. This initial motivation to find out that ageing is accompanied by a loss of DNA This is when the interaction, collaboration and more developed to the point that it informed methylation in many tissues, including the sharing of knowledge between researchers my search for a topic and laboratory for my brain. However, a causal relationship between plays a particularly important role. In doctoral research, which I ended up doing this hypomethylation and age-related cognitive Heidelberg we are in a privileged position at the University of Pennsylvania under the decline had never been investigated. because we are immersed in an outstanding tutelage of Dr Ted Abel. research environment where we can find We decided to look at the levels of DNA expertise in almost every field. This obviously You subsequently went on to conduct research methylation writers in the hippocampus of (and thankfully) enables us to overcome the on long-term memory. What did you find? aged mice. The hippocampus is a brain region majority of challenges we face! with a critical role in memory formation and During my doctoral research I focused on also one of the first areas to be affected by Could you reveal what impact you hope your studying how long-term memory is formed – a ageing and neurodegenerative disorders. We research will have over the course of the next topic I pursued further during my postdoctoral were excited to find that levels of Dnmt3a2 decade or so? work at the University of Heidelberg in were significantly reduced. We also found that Dr Hilmar Bading’s group. My research this enzyme is activated by neuronal activity in We hope that in 10 years we will have made a identified molecules involved in regulating the young adult mice. significant contribution to the advancement of permissiveness of DNA for the activation of knowledge on the mechanisms that underlie transcription and, consequently, the synthesis We established a connection between reduced both memory formation and persistence. of new proteins. When we receive new levels of Dnmt3a2 in the aged hippocampus and information, there will be a subset of neurons cognitive decline by demonstrating that when

1 INTERNATIONAL INNOVATION Extinguishing fear, enhancing memory

Researchers from the University of Heidelberg, Germany, are working to understand epigenetic mechanisms and how they contribute to cognition and long-term memory formation. Their findings could identify new targets for treatments seeking to abate fear and anxiety disorders

Upon exposure to a new environment, a subset MEMORY IS A broad term denoting both the of Dnmt3a2 – a finding that has significantly of neurons is activated triggering the expression structures and processes associated with the advanced ageing research. In identifying the of proteins important for memory formation. The storing and subsequent retrieval of information. specific mechanism associated with particular figure shows immunohistochemical detection of Arc It is difficult to overstate the important and pathological conditions such as memory loss, (a memory relevant protein) in the hippocampus of essential role it plays in our everyday function. the research group has identified a new target mice that have been exposed to a new environment. Indeed, our memory enables us to operate in for therapeutic developments. the present, envisage a future and process a vast amount of information on a daily basis. OF MICE AND MAN The importance of memory can perhaps best Perhaps more fascinatingly, the team has gone be evidenced through what happens to those on to administer Dnmt3a2 to young, cognitively ANALYSIS OF THE DISTINCT REGULATORY who experience a loss of it. In the progressive, normal mice and examined the results. They FUNCTIONS OF DNA METHYLATION IN MEMORY- degenerative brain disease Alzheimer’s, for discovered that increasing levels of Dnmt3a2 RELATED GENES example, memory is slowly eroded to the enhances memory, thereby providing an exciting point where even the simplest tasks cannot be route of enquiry for targeted therapies in the OBJECTIVES performed by those affected. future. In addition to this, Oliveira and her team • To identify key processes and molecules that are found that there was an enhanced extinction activated when learning new things and storing new While much research has been conducted of fear memories: “Extinction experiments information for long periods of time to discover how memory is formed and mimic the procedure that is effectively used • To investigate how DNA methylation, an epigenetic maintained, there is a grey area in our during exposure therapy in human patients of mark, and the molecules that establish this mark understanding of the mechanisms involved anxiety and fear disorders,” explains Oliveira. in the cells are regulated by learning and their in memory function. In shedding light on the “Exposure therapy procedures are aimed at requirement and function in memory formation mechanisms underlying some of the more inhibiting the previously established association complex examples of memory, researchers will between the cue and the aversive experience, by KEY COLLABORATOR facilitate new understandings that will have forming a new memory that severs the link.” Professor Hilmar Bading dramatically positive implications, especially University of Heidelberg, Germany regarding the onset of pathological conditions. Their experiments have shown that when FUNDING young, cognitively normal mice are given German Research Foundation (DFG) MEMORY LOSS FINDINGS Dnmt3a2, they form a new memory of safety in With that in mind, researchers from the a location that an aversive experience occurred CONTACT University of Heidelberg are attempting to within. Thus, Oliveira’s work contributes to Dr Ana M M Oliveira identify key processes and molecules that are the development of new treatment strategies Group Leader activated whenever we learn new things and for anxiety and fear disorders, such as post- Department of Neurobiology are responsible for storing new information traumatic stress disorder. Indeed, combining Heidelberg University for long periods of time. Dr Ana M M Oliveira pharmacological treatments with cognitive Im Neuenheimer Feld 364 and her research team hope to elucidate new behavioural therapy appears to have the effect Heidelberg, 69120 understandings of epigenetic mechanisms that of improving treatment efficacy. Germany contribute to cognition. “We focus on epigenetic mechanisms because they are involved BEING MINDFUL OF THE IMPORTANCE E [email protected] in regulating the permissiveness of gene Presenting findings on the subtle workings http://bit.ly/Ana_Oliveira transcription – a critical step in the formation of memory is fascinating in itself, especially of memory,” explains Oliveira. “Moreover, it has considering there are still so many knowledge http://bit.ly/Oliveira_2012 the potential for being long lasting and is of gaps to fill. But Oliveira and her team’s http://bit.ly/Oliveira_2015 particular importance, given the persistence research has the additional benefit of of memory.” identifying potential targets for treatment ANA M M OLIVEIRA studied of neurodegenerative diseases as well as biochemistry in Coimbra, Portugal, Oliveira, during her postdoctoral work in the fear and anxiety disorders. Truly, these are and gained a PhD in 2008 from the laboratory of Professor Hilmar Bading, honed exciting times for research into memory and University of Coimbra in collaboration in on the DNA methyltransferase Dnmt3a2 cognitive function. with the University of Pennsylvania, and discovered that its decreased levels in the USA. From 2008 to 2014, Oliveira worked as a postdoc brain were linked to age-related memory loss. at Heidelberg University, Germany. In 2014 she was Yet, subsequent research discovered that older awarded a Emmy Noether grant from DFG and since mice perform just as well as younger mice then has been an independent Group Leader at in memory tests when given extra amounts Heidelberg University.

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