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How postmortem brain samples could hold the key mental health.

Major psychiatric disorders affect more than 350 million people worldwide. It is thought that a combination of genetic and environmental factors make some people more susceptible to psychiatric disorders than others, but to what extent?

A molecular neurobiologist, Dr Natalie Matosin studies the genetic and molecular basis of severe psychiatric conditions, using postmortem brain samples of individuals who were living with psychiatric disorders.

“When anyone asks what I do for work, it always ends up being an interesting conversation,” she says.

The molecules Dr Matosin works with come from brain tissues donated by people who lived with a psychiatric disorder. These tiny pieces are stored inside freezers in human ‘brain banks’, with the tissue quality checked thoroughly before they are used for research.

Dr Matosin studied a Bachelor of Medical Science and went on to study a Doctor of Philosophy, completing both at UOW. She is currently undertaking research at the Max Planck Institute of Psychiatry in Munich, Germany, under a National Health and Medical Research Council (NHMRC) Fellowship.

“Once we know tissue quality is good, we then want to match psychiatric cases as closely as possible with the brains of healthy people (the experimental controls),” she says. “It is important that the cases and controls are matched as closely as possible for age, sex, and whether the samples were taken from the left or the right side of the brain.

“These are factors that influence our brain chemistry and molecular makeup, and can therefore impact on our results. Postmortem human brain studies allow us to look at molecules like DNA, RNA and proteins directly in the brain – something that can’t be done in living people through any current imaging processes.”

Dr Matosin focuses her efforts on the prefrontal cortex (higher order thinking, emotional control), the hippocampus (learning and memory) and amygdala (regulation of the response to fear). Her ultimate research goal: to understand how stress or trauma can be the catalyst for developing a mental health condition like depression, bipolar disorder, schizophrenia or Post Traumatic Stress Disorder (PTSD) and in doing so, reduce the burden of mental health issues on society.

“Mental illness affects basically everyone, either directly or indirectly,” she says. “We are all exposed to stress in our life, but only a proportion of us go on to develop mental health conditions.”

The trigger point

Dr Matosin says certain genes carried by some people can increase the risk of developing a mental health condition. “Mental illness can run in families, but it’s not always the case that there’s a history of it in the family,” she says.

Environmental risk factors can include long-term stress or traumas, particularly those occurring early in life. “During that time, the brain is vulnerable to the effects of stress, which can set the individual on the path to mental illness.”

According to the Australian Bureau of Statistics, one in five Australians aged 16 to 85 will experience a mental disorder each year. Almost half will experience a mental disorder in their lifetime.

“People living with mental illness, particularly those with severe conditions, are more likely to experience a range of adverse health outcomes than the general population,” says Dr Vida Bliokas from UOW’s School of Psychology.

Dr Bliokas agrees that certain environmental conditions may serve to increase a person’s vulnerability to developing a mental disorder. “Psychological trauma from physical, emotional or sexual abuse, neglect or a significant early loss – such as the death of a parent, and substance abuse can all trigger the onset of disorder,” she says.

“In general, individuals with mental disorders experience a range of associated social, economic and health consequences, with stigma being a major contributor to disadvantage. Understanding the complexities of mental illness requires a broad ranging collaborative research approach.”

The molecular switch

In her current line of research, Dr Matosin is focusing on a gene called FKBP5, a key internal regulator of the stress response that is strongly linked to the development of many psychiatric disorders.

“Work from our laboratory indicates that FKBP5 can increase psychiatric risk in individuals exposed to childhood trauma, due to higher levels of FKBP5 throughout the brain,” she says. “This leads to long-term changes in the stress response on the cellular and systemic level, which over time, may increase the individual’s risk of developing a psychiatric disorder.”

FKBP5 has been described as a ‘molecular switch’ that not only back-regulates the stress response, but also forward-regulates many other critical cellular pathways – including cell division, cell migration and cell fate.

“Alterations to FKBP5 might therefore have extensive consequences for cellular function, explaining at least partially why FKBP5 increases the risk to psychiatric disorders in a subset of patients,” Dr Matosin says.

By characterising molecular alterations – changes to gene expression and proteins – that occur in their brains and identifying how they are different, Dr Matosin is hoping to find new targets for drugs that could potentially correct some of the detrimental molecular effects.

“The goal of my research is to be able to find molecular ‘signatures’ that can be used to identify patient groups that will benefit from similar treatment strategies,” she says. The types of samples Dr Matosin explores are often no bigger than the size of a pea, yet the information they provide can give a clear picture of molecular processes that contribute to adverse mental health.

“I find it intriguing that we can examine the makeup of molecules inside the brains of people, and get an understanding of what molecular processes were contributing to their illness. We can also investigate how the differences in a person’s DNA or their life experiences influence the molecules that make up their brain,” she says.

“By doing this type of research, we can find better ways to prevent and treat these illnesses in the future.  Until it becomes possible to do this in living human beings, postmortem human brain studies remain essential.”

Dr Matosin’s fascination with the brain started long before her time at university, but it wasn’t until her Honours degree at UOW that she was able to study the brain directly.

“As part of my Honours project, I studied little pieces of cortex from the brains of individuals who had schizophrenia,” she says. “This interest was only further ignited when my lab partners and I visited our local Brain Bank where we got to learn about how the brains were processed, dissected, anatomically verified and stored.”

The Road to Munich

At the Max Planck Institute Dr Matosin is surrounded by some of the world’s leading psychiatry experts. She relocated to Munich to further her research and experience a European adventure. “I love Munich,” she muses. “Having come here twice as a PhD student for internships, I knew this is where I wanted to be.”

Her desire to undertake research overseas stemmed from an early career workshop as a second year student. “I had been listening to early career researchers talk all day, and the theme that kept coming through was to go overseas to get some international experience, as that would make me more competitive,” she reflects.

“I went home that day and said to my husband, “I think we need to go overseas”. He paused for a moment then he replied, “OK, if that’s what we need to do”. He’s always been super supportive of me and my career.”

Her fearlessness as a millennial scientist led to recognition in the prestigious Forbes 30 Under 30 Europe list, announced earlier this year. Dr Matosin was the only Australian to be nominated in any of the Forbes categories for the Class of 2017.

“It is an incredible feeling, I’m so honoured and proud to be included in the list alongside so many inspiring and interesting young leaders,” she says.

Photo: Natalie Matosin

Hailing from a family of blue-collar workers, Dr Matosin says the work ethic of both of her parents inspired her to pursue her dreams.

“I can honestly say that Dad was the reason I became interested in science. He’s so passionate about animals and the environment, we spent many nights watching documentaries together with my brother,” she says.

“His excitement was contagious, and so I already had a natural curiosity for science before I started to learn it at school.” Through her blog, Dr Matosin is hoping to inspire the next generation of researchers in their transition from PhD to postdoc.

“Just go for it,” she writes in a blog post to early career researchers. “While you should be aware that the future of a researcher is unstable, don’t succumb to paralysis by analysis. Talk to your mentors and do your research to figure out exactly what you need to do to set yourself apart from the rest – then work at making it happen.”

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