Memory cue for depression treatment

18 September 2019

Does the way we remember negative events affect our likelihood of experiencing depression? Dr Tak Pan Wong of McGill University in Montreal, Canada, might be able to answer this.

In their recent publication in the Journal for Neuroscience, Dr Tak Pan Wong (Croucher Scholarship 1997) and his team showed that animals that present with depression-like behaviours have increased encoding of memories related to negative events. These results advance our understanding of the molecular basis underlying depression and shed light on the little-known role that memory plays in the disorder.

Named the most debilitating disorder by the World Health Organisation, depression affects more than 300 million individuals around the globe. Despite the fairly common use of antidepressant medications, such as Prozac or Zoloft, approximately 67 per cent of patients fail to achieve remission when relying on initial treatment. This suggests that there are more molecular players involved in depression than those currently targeted by medication.

Memory is an interesting process to study in depression as it can be easily altered in patients. A common finding among clinicians is the expression of a negative memory bias in depressed individuals, who will remember and describe negative life events better than positive or neutral experiences. This focus on the negative aspects of life can then act to promote the development and maintenance of a depressive episode.

One part of the brain associated with forming memories of the episodes of our lives is the hippocampus. It is well established that this area is extremely active when depressed individuals are presented with negative stimuli. However, little is known about how memories might be differentially formed between a depressed versus healthy individual and how memory formation processes might be altered when a memory is of a negative versus positive event.

To begin answering these questions, Wong, associate professor in the Department of Psychiatry at McGill, and his team initiated the study of an animal model of depression. By exposing mice to a chronic social stressor, they were able to elicit social avoidance, among other symptoms of depression, in the animals. Strikingly, when genetically similar mice were exposed to a social stressor, only a subset of these animals expressed behaviours in line with depression.

This mirrors what is seen in humans, as it is known that some individuals are more vulnerable to developing depression than others. If a group of individuals experience a traumatic event, some may fall into a depression, while others remain unaffected in the long term.

The same phenomenon is seen in Wong’s animal model of depression, presenting scientists with the opportunity to characterise the differences that might exist in the brains of the animals that have withstood the same stressors. In other words, why are some more vulnerable to developing depression?

In their recent publication, Wong and his team demonstrated that the answer partly lies in how memories are encoded. He showed that mice that are more susceptible to expressing depression-like behaviours have a greater memory for the social stressor that they experienced, when compared with non-vulnerable or “resilient” animals. Moreover, this enhanced memory formation was found to be specific to the stressor and not seen in relation to neutral events.

“Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression,” Wong and his co-authors explained in their paper. “Given the crucial roles of hippocampal engrams (memory traces) in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.”

Taking this one step further, the Wong lab used a novel neuroscience technique called optogenetics to control memory activation. With this technique, cells that hold memory for the stressor can be turned on or off through the delivery of light to the brain. When the social stress memory was activated, the animals showed more depression-related behaviours and the opposite was seen when the memory was inhibited. In other words, preventing the recall of a stressor temporarily ameliorated symptoms of depression.

Continuing from these findings, Wong is now leading a study of how memory of a stressor is formed over time in animals that later develop depression-like behaviours. This could further advance our knowledge of a devastatingly common condition whose basis is biologically obscure, and advocate for the importance of research in the science behind it.

Only with an understanding of the mechanisms of depression will science be able to better treat those affected.

Dr Tak Pan Wong is an Associate Professor at McGill University and researcher at the Douglas Mental Health University Institute. He moved from Hong Kong to Montreal in 1995 to pursue his PhD study under the supervision of Dr Claudio Cuello and Dr Yves De Koninck at McGill. His postdoctoral training in the laboratory of Dr Yu Tian Wang at University of British Columbia examined the molecular mechanism of synaptic plasticity. Dr Wong received a Croucher Scholarship in 1997.

To view Dr Wong’s Croucher profile, please click here

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