Brain Matters Summer 2023–24

Brain Matters Your source of neuroscience and mental health insights from The Florey Summer 2023/24

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Mental health One of the biggest health challenges facing our society today Over 2 in 5 Australians aged 16–85 are now estimated to have experienced a mental health condition at some time in their life, with 1 in 5 having experienced a mental health condition in the previous 12 months according to the Australian Institute of Health and Welfare (AIHW).

There is a clear and pressing need to accelerate research to improve the lives of people that live with them.

The Florey’s neuroscientists are working globally with research collaborators, clinical partners and hospitals to create a better quality of life for people living with mental health conditions.

Anxiety, depression and environmental factors Professor Anthony Hannan “I think a strength of The Florey is our research aimed at understanding the causes of, and thus moving towards effective treatments for, major psychiatric disorders, which constitute a large and growing health challenge.”

A program of research in Professor Anthony Hannan’s team suggests that environmental influence on health starts prior to conception, including through the paternal line. Discoveries using preclinical models suggest that what a father experiences before conception (including stress, exercise and diet) can change the epigenetics of his sperm and change what happens in the early embryo.

This may also affect the later brain development and function of the offspring.

The pioneering epigenetic inheritance research at The Florey found not only that the father’s environmental exposures could affect the development of the offspring, but also brain maturation and function. Negative paternal experiences (such as chronically high stress levels prior to conception) might make the offspring more vulnerable and affect specific aspects of brain development relevant to depression and anxiety disorders.

Professor Hannan said: “Our work at The Florey is contributing to new approaches to prevent and treat specific brain disorders, including psychiatric disorders, to improve mental health. This new research has major implications in the context of what is known as the 'Developmental Origins of Health and Disease'."

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"Understanding the developmental origins of brain health and disease can lead to new approaches for prevention and treatment of mental health conditions.”

Find out more about a related project from Professor Hannan on page 7.

Schizophrenia and depression Associate Professor Jess Nithianantharajah Research by Associate Professor Jess Nithianantharajah is focused on developing new therapies that better target cognitive and mood symptoms in mental health conditions like schizophrenia and depression, especially for those that are treatment-resistant.

“We need improved treatment options that are safe, have fewer side effects, are effective, and can be tailored for individuals with mental health conditions based on their specific symptoms. To deliver this, we need greater biological understanding of the processes that change in the brain in mental ill-health, as well as advanced pre-clinical models and tools to measure and refine the efficacy of novel therapies,” Associate Professor Jess Nithianantharajah said.

Her research focuses on our understanding how changes in the molecular machinery that control connectivity and communication in our brains can create either vulnerability or resilience to mental ill-health.

The research team are taking a translation-focused approach to investigate how disruptions in the balance of excitatory-inhibitory connectivity in the brain leads to specific deficits in cognitive processing and regulation of mood.

As part of this, her team use innovative tools they have established to identify brain signatures that underlie disrupted behaviours, and measure real-time changes in neural activity in preclinical models of schizophrenia and depression. The ability to measure and control behaviour in preclinical models, using sophisticated behavioural and neural imaging systems, provides advanced experimental approaches to deliver novel outcomes. Additionally, her team have combined these approaches with deep learning-based tools to enhance tracking of behaviour.

“Our approach allows us to objectively quantify a range of complex behavioural measures, identify how these behaviours may be disrupted in mental ill-health and, importantly, investigate how well treatments restore these behavioural and neural changes,” said Associate Professor Nithianantharajah.

“This work has enormous significance for the development of next-generation therapies and, critically, informing treatment selection and management for those living with mental health conditions like schizophrenia and depression.”

Addiction and alcohol use disorder Professor Andrew Lawrence Professor Lawrence’s Addiction Neuroscience Group is looking at new treatment targets for alcohol use disorder.

AIHW analysis of the National Hospital Morbidity Database showed that alcohol accounted for nearly 3 in 5 drug-related hospitalisations in 2020–21 (57 per cent or 86,400 hospitalisations).

The group has a project that focuses on the brain’s acetylcholine system. This chemical carries messages between nerve cells and specifically the M4 receptor, which modulates dopamine release in a part of the brain called the striatum (composed of four regions responsible for executive function, affective processing, motivation, and motor functions). Researchers say after long-term drinking and abstinence there is a reduction in the expression of the M4 receptor in the striatum and believe that this could be part of the reason why people might still have a propensity to relapse.

Professor Lawrence and his team are now doing mechanistic experiments looking at circuits in the brain where this receptor is implicated in the motivation to obtain and consume alcohol, or relapse to alcohol seeking.

They can also then see what the timeframe of recovery is and if the expression of the receptor does recover, it could mean that it is less susceptible to relapsing.

The researchers say that this approach could possibly be fast-tracked via a novel antipsychotic drug for schizophrenia that, once approved, could be repurposed for alcohol use disorders as it targets the same receptor.

The compound activates the receptor thereby restoring impaired signaling between nerve cells to reduce the desire to consume alcohol.

“We think that the diminished signaling is contributing towards the desire to consume alcohol and relapse. When we boost that signaling artificially with the drug in the animal models, we reduce alcohol use and relapse, and we ultimately want to do that in humans. It’s something that we’re actively pursuing and have made some important discoveries.”

Read our full World Mental Health Day feature here:

Stroke

International experts push for innovation to improve stroke recovery Scientists from The Florey are among the world’s leading stroke experts who have mapped out how researchers and clinicians can improve outcomes for people who have survived a stroke.

The third Stroke Recovery and Rehabilitation Roundtable, an initiative of the International Stroke Recovery and Rehabilitation Alliance, has made a series of key recommendations about managing fatigue, measuring mobility, harnessing non-invasive brain stimulation technologies and improving how trials are designed.

Associate Professor Kate Hayward from The Florey and University of Melbourne co-chaired and convened the roundtable, established by fellow Florey stroke expert Professor Julie Bernhardt in 2016.

“The roundtables aim to address gaps that are hampering progress across the field of stroke recovery and rehabilitation. Momentum is gathering in stroke recovery and it’s so important that we work together, pulling in the right direction, for the benefit of the millions of people globally who are affected by stroke,” Associate Professor Hayward said.

Professor Bernhardt added: “It is through these collective actions that we can accelerate progress towards effective treatments that enhance the lives of the millions of people affected by stroke each year.”

The Florey’s Professor Bernhardt said the roundtable’s recommendations are essential reading for clinicians and researchers in the field of stroke recovery and rehabilitation.

Read the full story here:

Brain Matters Summer 2023/24

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Surviving sepsis his body has undergone through his amputations.

‘Remarkable’ treatment for sepsis

Pictured (L–R) Professor Clive May, sepsis survivor John Davey and Associate Professor Yugeesh Lankadeva.

In the week of his 55th birthday, Mr John Davey contracted meningococcal disease, and was put into an induced coma to be treated with drugs at Knox Hospital in Melbourne’s east.

Within another week or so, he contracted sepsis while in his induced coma.

“My first introduction to septicaemia was when I awoke from the coma and realised that my extremities: my feet, legs and hands were black and dead,” Mr Davey said.

“As I was told they were literally dead weight.”

A few years later, Mr Davey, a quadruple amputee, has gone through rigorous physiotherapy to allow him to adjust to his new body.

Sepsis and septic shock Associate Professor Yugeesh Lankadeva, who leads the Translational Cardiovascular and Renal Research Group and the Systems Neuroscience Theme at The Florey, said sepsis is notoriously difficult to treat and is often deadly.

“Sepsis accounts for 35–50 per cent of all hospital deaths. It occurs when the immune system fails to fight off an underlying infection, causing excessive inflammation, lifethreatening falls in blood pressure, 4

Brain Matters Summer 2023/24

multiple organ failure, and death,” Associate Professor Lankadeva said.

According to the Australian Commission on Safety and Quality in Healthcare, 55,000 Australians are diagnosed with sepsis each year and more than 8,700 lose their lives.

Professor Rinaldo Bellomo, Austin Hospital’s Director of Intensive Care Research, said that sepsis is the biggest killer in intensive care units in Australia and worldwide.

“It often develops so quickly that patients are already critically ill by the time they reach us,” he said.

In many ways, Mr Davey could be considered lucky to be alive, despite the radical transformation

Currently, there aren’t any treatments that reverse the detrimental effects of sepsis on the vital organs.

Two of the main detrimental effects of sepsis are delirium and acute kidney injury, and frequently cognitive impairment and chronic kidney injury in survivors of sepsis. Over the years, Florey researchers have demonstrated that there are large decreases in the levels of oxygen in the brain and kidneys during sepsis and they believe these changes are the causes of the failure of these vital organs.

Associate Professor Lankadeva, Professors Clive May and Rinaldo Bellomo are now developing a new treatment, which is the first ever to actually improve multiple organ health and restore normal physiological functions.

Interestingly, they found that intravenous sodium ascorbate normalised the oxygen levels in the brain and kidneys and reduced requirements for blood pressure maintaining drugs in their preclinical model of sepsis. The organs then started to work again and within 3–4 hours the clinical state dramatically improved.

“We have studied many drugs over the last 20 years to try and develop new better treatments for sepsis, none of which have had much benefit,” Professor Clive May, from The Florey’s Preclinical Critical Care Unit, said.

Watch the video online here:

Professor Rinaldo Bellomo

Florey Society news “The beneficial effect of sodium ascorbate is quite remarkable.”

“We’ve seen quite promising signals translate from bench to bedside, which really puts us at the vanguard to advance this treatment into larger multi-centre clinical trials across mainland Australia to see how effectively this drug works in patients with septic shock,” Associate Professor Lankadeva added.

A potentially ‘worldchanging’ infusion “What John has described is what happens to so many patients with sepsis. The state-of-the-art drugs that are currently given to septic patients really aim just to keep you alive with the hope that eventually your body will recover. They do not reverse the effect of sepsis,” Professor Clive May said.

“This is what’s so exciting about this dose of sodium ascorbate. We believe that it will cure sepsis that is induced by bacteria and by viruses.”

Mr Davey recalls: “My wife watched it all. The five heart attacks, calling my children, flying them over to say goodbye to dad.”

“I thought that was the end of it, but what I learned was that the septicaemia hadn’t actually stopped.

And [the doctors] kept talking about demarcation.”

This is when the body is still deciding what is ‘dead’ and what is going to live and to indicate to doctors when and where on the body the amputation should take place.

Although it is now too late for Mr Davey to have the infusion, he says what the Florey researchers are doing is going to have a serious impact.

“It’s not just life-changing, it’s world-changing, and wow - that’s just incredible,” Mr Davey said.

“It’s heartening to see all those years of painstaking research pay off with a treatment now within reach for patients,” Professor Clive May said.

The researchers also say that sodium ascorbate is affordable and readily available, leading to more rapid clinical uptake in low-income countries which bear the largest burden of sepsis.

Lunch with Professor Ross Bathgate Guests at the second annual Florey Society lunch for Gift in Will supporters enjoyed a talk by Professor Ross Bathgate, leader of The Florey’s Neurotherapeutics Theme. Professor Bathgate, who is the Carl and Wendy Dowd Professorial Fellow, spoke about early-stage target-based, as opposed to disease-focused pharmaceutical drug development.

“Developing drug treatments for brain and mind disorders is extremely challenging and far more expensive than for nonneurological diseases,” Professor Bathgate said. He aims to translate basic drug development research into better medicines for treating anxiety, depression and other neurological disorders.

An exciting development was last year's launch of the start-up LASEREDD Therapeutics to facilitate the development and commercialisation of this research.

Professor Bathgate thanked donors for their vital contributions in support of The Florey’s work.

Bequestor boardroom briefing with Associate Professor Yugeesh Lankadeva Gift in Will supporters were welcomed to a boardroom research briefing with Associate Professor Yugeesh Lankadeva, Head of the Systems Neuroscience Theme and of Translational Cardiovascular and Renal Group. Associate Professor Lankadeva and his team work to improve brain health outcomes after heart surgery. Up to 80 per cent of patients who undergo heart surgery where a heart-lung machine was used develop cognitive dysfunction. Associate Professor Lankadeva is investigating therapeutic strategies to prevent neuroinflammation and mitigate postoperative cognitive dysfunction following cardiopulmonary bypass.

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Detecting Parkinson’s disease decades before symptoms appear Researchers at The Florey and Austin Health have shown it is possible to detect tell-tale signs of Parkinson’s disease 20–30 years before symptoms appear. Their work opens the door to screening programs and preventative treatments long before irreversible damage is done.

Florey Professor Kevin Barnham said Parkinson’s disease, a debilitating neurodegenerative condition, is often thought of as an illness of old age, when in fact it starts in midlife and can go undetected for decades.

“Parkinson’s disease is very hard to diagnose until symptoms are obvious, by which time up to 85 per cent of the brain’s neurons that control motor coordination have been destroyed. At that point, many treatments are likely to be ineffective,” Professor Barnham said.

“Our long-term goal is to find a way to detect the disease much earlier and treat people before the damage is done.”

In a study published recently in Neurology, lead researcher Professor Barnham and colleagues describe how a known biomarker called FAV-133 can be used with positron emission tomography (PET) scans to

diagnose Parkinson’s disease and accurately track neurodegeneration.

In the Melbourne study, Florey Professor Chris Rowe and his team at Austin Health scanned 26 patients with Parkinson’s disease, a control group of 12 people, and 11 people with rapid eye movement sleep behaviour disorder (RBD), which is a strong indicator of the disease.

Each person undertook two PET

PET scans of four brains: a healthy control, a person with REM behaviour disorder, a person with dementia with Lewy bodies, and a person with Parkinson’s disease. Image courtesy of Austin Health.

Supporting research into multiple systems atrophy A Melbourne family has raised more than $90,000 to support vital research at The Florey into the incurable brain condition that claimed the life of Tania Barrot.

Tania was a much-loved mother, wife, daughter and friend when she sadly lost her battle with multiple system atrophy (MSA) in early 2021.

After she fell ill, Tania and all her loved ones had to cope and adapt to her progressively declining health without a clear understanding of how her disease would progress.

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scans two years apart. Key findings include: • No significant changes in clinical symptoms in any of the participants according to currently available assessments for Parkinson’s disease.

• By contrast, the PET scans showed 'significant neuronal loss' in three key regions of the brain in individuals with the disease, suggesting F-AV-133 is a more sensitive means of monitoring neurodegeneration than what is now available.

Tania’s husband Trevor said not having a definitive diagnosis early was very difficult for the family.

“Tania had multiple hospital admissions, ongoing diagnostic testing, constant changes to her medication and saw many different clinicians. If we’d had a definitive diagnosis early in her disease this would have changed how we responded to the illness. It wouldn’t have saved Tania, but it might have made the time we had left with her easier.”

Tania left behind Trevor, son Cambo, daughter Georgie, stepdaughter Mikahla and four sisters who all loved her very much.

In March 2023, two years after Tania’s death, her family organised ‘One More Night for Tania’, a fundraising event. “’One more night’ was one of Tania’s favourite songs,” said Trevor.

Tania Barrot

Males’ immune response to a virus-like challenge alters their offspring’s behaviour

Professor Kevin Barnham

Further mathematical modelling calculated: • an approximate total of 33 years’ slow neuronal loss in Parkinson’s disease • this loss occurs for about 10.5 years before the disease is detectable on a PET scan • once a PET scan is able to detect the disease, it will be a further sixand-a-half years before the onset of physical symptoms • after onset of physical symptoms, there are about a further three years until clinical diagnosis is confirmed • this equates to neuronal loss occurring for about 22.5 years before clinical symptoms are sufficient for diagnosis.

Professor Barnham said the findings open pathways to developing screening protocols for diagnosing and treating Parkinson’s disease up to 10 years earlier than is currently possible.

Researchers at The Florey have discovered that a model of viral infections in males shows impacts on their sperm, affecting their offspring’s brain function and behaviour.

The researchers are calling urgently for more studies to explore what this might mean to human development and brain health in the wake of widespread COVID-19 and flu infections.

Building on their knowledge that sperm epigenetics and offspring brain function and behaviour are affected by paternal stress and diet, preconception, the research team used mouse models to learn what impact a virus might have.

The results have been published in the scientific journal Brain, Behavior and Immunity, with The Florey’s Elizabeth Kleeman and Professor Anthony Hannan as the lead and senior authors.

“We found that a virus-like infection in males before conception had a significant impact on the development and behaviour of their offspring and their grand-offspring.”

“Offspring showed increased depression-like behaviour, a heightened stress response and changes in the messenger RNA molecules which transcribe genetic information expressed in the brain. In male offspring, we saw altered immune responsivity and in their grand-offspring we found reduced early-life bodyweight and anxiety-like behaviour in the males.”

Though solely involving mice, thus far, this research shows that the 'epigenetic cargo' that sperm deliver to an egg at fertilisation can be affected by a virus-like challenge, suggesting potential future implications for men and couples trying to conceive, Professor Hannan said.

“The detrimental pro-depressive behavioural outcomes that arise from this paternal virus-like immune challenge may have implications for human public health.

“With many men of child-bearing age having been infected with viruses such as COVID-19 and the flu, further research examining how virus-related immune activation might affect the human sperm epigenome and offspring health is urgently needed.”

About multiple system atrophy (MSA) MSA is a rare Parkinsonian condition which affects movement, breathing, blood pressure and other body functions. About 3000 people in Australia currently live with MSA.

Tania Barrot’s family

“We wanted to honour our beautiful Tania, but we also wanted to do something practical to support the Victorian Brain Bank at The Florey, which stores MSA brain tissue and provides samples to scientists,

allowing further research into diagnosis, treatment and one day hopefully a cure.”

The family and their supporters raised more than $45,000, which The Florey has matched, resulting in a funding boost of more than $90,000 to support research integral to better understanding MSA. Florey Director Professor Trevor Kilpatrick thanked everyone who

supported the event.

“We are so very grateful for the family’s generosity in Tania’s memory.

The Florey depends on external funding to be able to continue with our world-leading research in neuroscience and mental health.

“The Victorian Brain Bank is integral to The Florey, and their substantial gift will make genuine difference to our work,” Professor Kilpatrick said.

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The bittersweet brain chemical clue that could help women stop binge drinking Scientists at The Florey have discovered a chemical in the brain that may explain the different drinking habits of men and women.

It comes down to how our brains detect bitter tastes, and could be harnessed to help women stop binge drinking.

Dr Leigh Walker led a study that showed that when a certain chemical is removed from the brain, males drink more and females drink less. But when the alcoholic drinks are sweetened, female consumption goes up.

Dr Walker, an expert in the neurobiology of anxiety and alcohol use disorders, said the findings could pave the way for treatments designed to help women stop binge drinking.

“The taste of alcohol is an important and often overlooked factor that drives alcohol preference, intake and use,” Dr Walker said.

“We have identified a chemical in the brain that makes alcohol taste bitter to females, unless the drink is sweetened.”

Dr Leigh Walker

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Email: philanthropy@florey.edu.au Phone: 1800 063 693 Find out more: www.florey.edu.au/donate

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Dr Walker said science has primarily focused on examining how male brains work. Her study, published in Neuropsychopharmacology, looked at how female brains might differ from male brains and identified differences in response to taste. The research centered on ‘CART’, a neuropeptide present in all species and associated with energy balance, depression, anxiety, and reward-related behaviour, including those around drinking alcohol.

Dr Walker, working closely with graduate researcher Xavier Maddern and other Florey researchers, studied the effect of inhibiting CART in mice that were trained to drink alcohol.

“Alcohol has an underlying bitter taste,” Dr Walker said. “When we inhibited CART in male mice their drinking increased. And when we knocked out the same brain chemical in female mice, they drank less. But when the alcohol was sweetened, the female mice drank more.

This tells us that without CART, alcohol is unpalatable to females.”

Alcohol use contributes to about 3 million global deaths each year with alcohol misuse accounting for 5.1 per cent of the global disease burden, while rates of risky drinking and alcohol use disorders are rising in women much faster than in men.* “If we can find a way in future research to target the CART neuropeptide system, we may be able to create treatments to help women curb excessive alcohol use. And if we can work out how male and female brains differ it will open unprecedented opportunity to treat disorders of the brain in women, including alcohol use disorders,” Dr Walker said. * Global status report on alcohol and health 2018, World Health Organization; and Jama Psychiatry.