NEUROSCIENCE RESEARCH CLUSTER
Dr Rikki Quinn
The group study how the inner ear vestibular organs generate the basic neural signals that provide us with a sense of balance.
The group’s attempts to study balance in humans has been hampered by the lack of suitable mammalian models for direct investigation.
Much of what the group know has come from the indirect experimental studies of vestibular nerve fibres in whole animals.
In addition, previous studies have emphasised the properties of individual components, (eg. receptor cells or vestibular nerve fibres) but not how these components interact with each other to function as a sensory unit.
This wide gap in knowledge is being addressed in a new series of experiments in the laboratory aimed at understanding the intrinsic function of human and non-human vestibular organs.
The group’s current research and the focus of recent funding is the feedback pathway that goes from the central nervous system back to the inner ear balance organs.
This feedback circuit or Efferent Vestibular System (EVS) is thought to modulate the output of balance organs, but it is not known how the EVS works.
The group have assembled an international group of scientists (London, UK, Rochester, Salt Lake City, and Chicago, USA) to study the EVS and determine how it might be used as therapeutic target in cases of disabling dizziness and vertigo, as a result of disease, trauma, or ageing.
Maurice (Dillwyn) Bartholomeusz (P/T)
Shannon Casinto (P/T)
The aim of the Head and Neck Sensory System laboratory is to better understand the role and influence of the head and neck sensory systems on normal activities of daily living and in circumstances involving dysfunction and or injury to the head and neck.
Sensory receptors in the head and neck are very important in our daily activities of living. Injury of the head and neck, even following a minor whiplash event, can cause significant clinical problems such as headache, neck pain, dizziness, visual disturbances and disorientation.
In instances of severe injury to the head and neck, the brain and spinal cord can also be damaged resulting in very significant clinical problems. In either circumstance when these symptoms persist and become chronic they can be very disabling for the individual and very costly to the community.
The laboratory is particularly interested in better understanding the role of signals arising from the musculoskeletal system of the neck and the balance (vestibular) system in the head with the intent of identifying ways to reduce both pain and suffering associated with dysfunction and injury to the head and neck.
Professor Robert Callister
(Deputy Head Of Faculty)
Professor Callister's current research can be broadly classified as neurophysiology with emphasis on nerve cell excitability and synaptic mechanisms in spinal cord and brainstem neurons.
Techniques used include patch clamp recording, applied to both in vitro (spinal cord or brainstem slices) and in vivo (deeply anaesthetised) preparations, as well as immunohistochemical and cell-labelling techniques.
The group studies the mechanisms involved in processing sensory signals in both the peripheral and central nervous system under normal and pathological conditions. Focus is on sensory systems and injuries that are important clinically: pain, balance and spinal cord injury.
The mouse is used because this species allows researchers to make use of recent advances in molecular genetics.
For example, various naturally occurring and transgenic mouse lines are used to better understand the role of ligand-gated ion channels (particularly, glycine receptors) in the processing of sensory signals under normal and pathological conditions
Simon Harries, Rebecca Williams, Craig Richards
The group investigate the effects of exercise and related influences on human health, performance and physiology.
Particular projects in 2015 were finalising a study on the effects of a home-based exercise and diet intervention on prevention of type 2 diabetes in men, the effects of an individualised home or community-based exercise program for stroke survivors, and the effects of a supervised exercise program for the treatment of clinical depression in young people.
The group also examine respiratory health in athletes in collaboration with the Australian Institute of Sport, as well as cooling strategies to improve exercise performance in the heat in endurance athletes, and a study to determine whether there are differences in injury rates in runners depending on choice of running shoes.
This research involves substantial collaboration with scientists and health professionals from a wide range of backgrounds.
A new project is investigating the effects of exercise on recovery of upper limb function after stroke.
Investigations are being made on cellular rhythms including those in lymphatics, blood vessels, gastrointestinal tract, female reproductive tract, heart and specific mood-associated brain nuclei.
The group have discovered a new mechanism that is driven by intracellular Ca2+ stores that allow groups of cells to self pace and hence become rhythmic.
The group are now exploring the relevance of this mechanism in a range of tissues and are also interested in specific proteins involved in the pacemaker mechanism including inositol 1,4,5-trisphosphate receptors, ryanodine receptors (RyR), store operated calcium channels and TRP family proteins.
These studies may influence future therapies to control lymphedema, digestive disorders, heart arrhythmias and brain mood states. Further to this the group are investigating the role of mitochondria in neurodegeneration.
In this regard the group have uncovered a putative cytoskeletal link between mitochondria and a common membrane calcium channel finding that this mechanism is specialised to specific neurons such as those of the Locus coeruleus, cells that are badly damaged in Parkinson’s disease.
The group aim to determine whether this link is damaged in Parkinson’s disease using an animal model.
Ms Rikki Quinn, Ms Erin Campbell, Mr Cameron Adams, Ms Caitlin Mitchell
This laboratory focuses on the brain pathways that are involved in motivated behaviours and stress.
The group study the basic wiring of circuits controlling the activity of specific cell types in the hypothalamus and other nodes of the brain reward-seeking pathway.
The group’s aim is to dissect the maladaptive rewiring that occurs in the brain which promote pathological motivational states that can manifest as addictions, obesity and mood disorders.
Research projects centre around two major themes:
- Understanding the hypothalamic circuit remodelling that occurs in response to physical, chemical or emotional challenges.
- Determine the cellular and molecular basis for why some individuals are more prone to pathologies of motivational state e.g. addiction or stress than others.
Kelly Smith, Mark Gradwell, Jack Mayhew
The spinal cord is much like a telephone exchange, receiving information from a multitude of channels, which must be preserved and processed before they can be directed to appropriate destinations. In spinal cord injury those lines of communication are severed, halting the transmission of vital information and causing a loss of sensation and movement below the injury site. In chronic pain, these communication lines can become crossed and information is redirected to inappropriate destinations with the potential to make a gentle touch cause excruciating pain. Similarly, many movement disorders can be likened to a situation where communication lines are either crossed or broken with the consequence being a loss of smooth, efficient, coordinated movement.
The group’s goal is to understand and treat this range of spinally-based conditions, by studying how information from the outside world is relayed to our brains through connections in the spinal cord. This is a task that has long been considered too immense given the sheer number of different nerve cell types interconnected in spinal cord networks, and the lack of anatomical organisation – ie, unlike a telephone exchange where wires and cables are organised in a ordered manner, the connections of the spinal cord are intermingled in a chaotic and disorganised mosaic. Fortunately, a number of recent scientific breakthroughs have now given us tools to understand how spinal networks are connected and disconnected by disease and injury.
The group have been using a number of these technologies to study specific populations of spinal cord nerve cells. They use transgenic mice where various nerve cells have been labelled with green fluorescent protein (GFP) to: compare different populations; identify unique properties that could be targeted with drugs; and assess how different nerve cell types contribute to chronic pain and sensory dysfunction. In addition, the group have established transgenic mouse lines that allow optogenetic stimulation of nerve cells. This means nerve cell activity can be controlled by light stimulation, allowing us to study how nerve cell are connected into spinal pain circuits using our newly installed Laser Stimulating and Uncaging (LASU) microscope. The optogenetic animals also allow the group to stimulate specific nerve cells in awake behaving animals and determine how they contribute to sensory experiences including pain.
Post doctoral Fellow
Amir Ashna, YeWin Oo, Yury Nikolaev
The research group aims to better understand how the properties of calcium release channels of the heart (RyR2) are linked to contraction and rhythmicity in the heart. To this end, they have developed the first 3D computer model of the cardiac dyad that reproduces the time-course of localized Ca2+ release events in heart cells (Ca2+ sparks).
This work has identified the first plausible negative-regulation mechanism for SR calcium release that counters the inherently regenerative process of calcium induced calcium release. Thus providing an explanation for the control of cardiac Ca2+ release by the surface membrane.
The group also carry out experiments to understand how mal-regulation of RyR2 by intracellular Ca2+ and Mg2+ give rise to cardiac arrhythmias and how inhibitors of RyR2 can restore normal heart rhythm. They have identified mutations in CaM (a binding partner of RyR2) that cause excess activity of RyR2 which lead to cardiac sudden death in humans. The group discovered that the association of calmodulin with the RyR is essential for the RyR inhibiting action of muscle relaxing/anti-arrhythmic drugs such as dantrolene and a modifier of potency of the anti-arrhythmic drug flecainide.
Dr Alireza Mazloumi Gavgani
The research has two directions: neurobiology of nausea and resilience to psychological stress.
The group continued their research into the neurobiology of nausea, and expanded it now to human studies where they explore the consequences of cybersickness – a subtype of motion sickness provoked by an immersion into the virtual environment.
The group is a part of the newly created Centre for Advanced Training Systems that is affiliated with the Defence and Security hub of the University of Newcastle. We are involved in several Defence-funded projects addressing biomarkers of resilience to psychological stresses and and biomarkers of cognitive overload.
Senior Research Fellow
Jason Woods, Ritambhara Aryal
Research in the laboratory is focused on using cultured cells and mouse models to understand the role of protein phosphatase 2A (PP2A) in signal transduction and Alzheimer disease pathogenesis.
Over the years, the group have uncovered many functions of this major Ser/Thr phosphatase in cell signalling, adhesion and transformation (e.g. Cell 1993; EMBO J 1997; J Cell Biol. 2002), and established its role in the regulation of tau and cytoskeletal dynamics (J Cell Biol 1995; Neuron, 1996; J. Biol. Chem. 1999, 2012, 2013).
The group have undertaken pioneering work showing that PP2A methylation becomes downregulated in Alzheimer disease, and following alterations in folate and homocysteine metabolism in several mouse models (JNEN 2004; J. Neurosci. 2007, 2008, 2012; Frontiers in Aging Neurosci. 2014).
In collaboration with Drs. Russell Nicholls and Ottavio Arancio, and Nobel Laureate Eric Kandel (Columbia University, NY, USA), the group are currently studying how deregulation of PP2A methylation in transgenic mice plays a key role in the neurotoxic cascade of Alzheimer disease.
The group are also working on further elucidating the mechanisms of regulation of PP2A (methylation, phosphorylation) and assessing their functional significance for neuronal and epithelial cell homeostasis.
This work is performed in collaboration with several national and international laboratories (USA, Austria)
This team's current research into the use of body cooling to reduce the spread of brain injury in stroke victims has led to a breakthrough finding that could make the treatment more viable for a much wider range of patients. Cooling the body to 32-33 degrees Celsius for between 12 and 24 hours – effectively putting it into a state of hibernation – can stall the progression of brain injury and buy time for a blood clot to break up.
The procedure is potentially lifesaving, but putting the body into a prolonged state of hypothermia can produce severe side effects, including pneumonia or disruption to heart rhythm. As well, pressure within the skull (intracranial pressure) tends to rise sharply in stroke victims within 72 hours of the incident, and while cooling will reduce this pressure, it may return or go even higher once the patient's body is warmed up again.
Fortunately, recent work in the laboratory has shown that short duration (2 hours) and mild cooling (35 degrees) can completely prevent this rise in intracranial pressure while avoiding most side effects, potentially making it a more widely applicable therapy for stroke. Recent findings from the lab have also highlighted the importance of preventing intracranial pressure rise.
An increase in intracranial pressure causes a dramatic reduction in residual (“bypass”) blood supply to the brain. This may then lead to more brain cell death and result in stroke patients being left with severe neurological impartment and disability.
The ongoing work in this laboratory is aiming to:
- Understand the mechanism of short duration body cooling in preventing intracranial pressure elevation.
- Identify the best method of body cooling.
- Translate these findings into the clinic as a way of preventing intracranial pressure elevation, reducing brain cell death and ultimately reducing disability in stroke patients.
Neil Spratt is a neurology specialist at the John Hunter Hospital and is a key member of the Hunter Medical Research Institute Stroke Research Group.
The group have a keen interest in understanding the cellular and molecular mechanisms of diseases, so that better diagnoses and treatment strategies can be developed.
The research from 1998 to date has focused on the neurobiology and genetics underpinning schizophrenia.
The laboratory have conducted and collaborated on world-class studies detailing the changes to gene expression in the brain and also the blood from patients with schizophrenia.
Interestingly many of these studies suggest changes in genes that have roles in the immune system and inflammatory processes.
Postdoctoral Research Fellows
Dr Marina Ilicic
Dr Rebecca Hood
Dr Prajwal Gyawali
Ms Kristy Martin
Sonia Sanchez Bezanilla
Wei Zhen Chow
The group’s primary objective is to investigate how the environment shapes the brain during both wellness and disease. Professor Walker’s research group investigates brain cell inflammation as a primary cause of psychological disorders and homeostatic changes after injury, particularly stroke.
The group’s research activities span across a wide range of pre-clinical and human research projects, continuously striving towards implementing cutting edge technology and highly translatable therapeutic avenues, such as high altitude training and growth hormone use in stroke recovery.
On a fundamental level, the group’s research looks at the role of microglia cells, a key part of the immune defence of the central nervous system, and how those cells can be manipulated to mediate the effects of chronic stress, mood disorders and the recovery processes after brain injury.
Co-Supervised PhD Students
Nathan Griffin, Xiang Li, Aysha Ferdoushi, Fangfang Gao
Renee Baldwin (co supervised with immunology and microbiology)
Our laboratory studies the autonomic nervous system and endocrine control of peripheral tissues to better understand human and animal diseases. We use a combination of anatomical, electrophysiological and molecular techniques to study how internal organs are regulated with a focus on reproductive tract and solid tumours. Ongoing projects include:
Nerve infiltration and Neurotransmitters in Breast Cancer
This project investigates the relationship between nerves and mammary gland tumours in a mouse model of breast cancer that resembles human HER2-positive tumors. We first quantified the distribution of nerves in normal mouse mammary gland. We then used immunohistochemistry to quantify nerve fibres and receptors for neurotransmitters in mammary gland tumours. We found that this preclinical model mirrors the innervation patterns seen in human disease allowing us to trial targeted interventions to reduce tumour growth.
Effect of infections on motility of the female reproductive tract
Infertility subsequent to inflammation of the reproductive tract (eg, Pelvic inflammatory disease - PID) is an increasing clinical problem. In this project a well-defined model is used of genital tract infection and subsequent PID to investigate changes in motility of the female reproductive tract. Both in vivo and in vitro physiological recording techniques are used and detailed knowledge is acquired on cellular changes that occur after Chlamydia infection. In addition the laboratory will investigate the best strategies to deliver therapies directly to the female reproductive tract (FRT).
Effect of Chytrid Fungus (Batrachochytrium dendrobatidis) on the reproductive physiology of endangered Bell frogs.
The Chytrid fungus is a pathogen that is responsible for the global extinction of one third of amphibian species. We are establishing a conservation physiology project in collaboration with the conservation biology group to assess reproductive status of frogs in Chytrid affected environments. We hope to establish a non-invasive assay to better monitor and protect these animals.
Using optogenetics to study autonomic nerve function:
In this project we used optogenetics to investigate autonomic control of the pancreas using a transgenic mouse where channelrhodopsin 2 (ChR2) is expressed in neurons containing the enzyme for acetylcholine synthesis. We found neuroanatomical and functional evidence that ChR2 is expressed in the peripheral nervous system in these mice and focal stimulation with blue light can activate action potentials in the vagus nerve. This finding will allow us to gain detailed knowledge about the autonomic control of visceral organs by allowing selective activation in vivo and in vitro of specific neural circuits.
The main aim of our research is to better understand the effects of ageing on the nervous system and in particular how ageing makes the brain susceptible to Alzheimer’s disease.
Our society is rapidly ageing and soon there will be more people over the age of 65 than there are children. Many elderly will develop dementia and by understanding how ageing impacts the nervous system our long term goal is to be able to reduce the burden of this debilitating age-related disease.
Our group primarily use genomics (RNA-Seq, microarray, qPCR), lipidomics (LC and GC/MS), protein, electrophysiological, and behavioural approaches to determine how ageing changes central (brain and spinal cord) and peripheral (inner ear vestibular apparatus) nervous system structure and function. For example, in the genomics studies we have analysed how ageing changes the brain’s transcriptome - all ~20,000 expressed genes. Using state of the art next generation sequencing technology (RNA-seq) we characterized the effects of ageing on different CNS regions that are important for cognition and sensorimotor control.
Our protein work is investigating how ageing increases the levels of dysfunctional proteins in the CNS. One of the major challenges to the nervous system is maintaining the function of its complement of proteins (called the ‘proteome”). This is a huge task as there are about 200 billion cells in the human brain and each of these has several billion protein molecules that must be kept at a precise concentration and in a precise conformation, otherwise they can precipitate out and form aggregates – then we have a problem! For reasons that are not understood, which is why we are studying this topic, ageing is associated with an increase in damaged and misfolded proteins that tend to aggregate. If this gets out of control it can become a proteinopathy, which is what Alzheimer’s disease is. Critically, this protein aggregation and other disease processes are occurring decades before there are symptoms, so we need to understand what is happening early on in the disease and ageing process. Understanding these early changes is a major focus of our group.
It is not known whether age-related genomic, lipid and protein changes are common across all cell types of the CNS, or whether they occur in a cell-specific manner. This is particularly important for the nervous system given it has a highly heterogeneous cell population. To address this issue, the group are characterising the genomic changes in specific populations of cells using single cell and single nucleus sequencing and qPCR, and also laser-based microdissection. It is hoped by teasing out how the different cell types function across the adult lifespan, we will have a more complete picture of what potentially goes wrong.
One of the group’s more intriguing recent findings is the impairment in cholesterol homeostasis in the ageing CNS. It has been known for many years that cholesterol is somehow involved in Alzheimer’s disease, but the exact mechanism has remained elusive. This cholesterol finding may be one piece of a very complex neurobiological puzzle, and it may be part of the early stages in the ageing CNS that, left unresolved, may end up resulting in full blown Alzheimer’s disease.
An obvious and important question is whether the course of ageing can be modified. The short answer is yes it can! For example, the fact there are many elderly individuals that are highly functional, they are called ‘successful’ or ‘healthy’ agers, indicates the effects of ageing are not necessarily inevitable (within reason). So, the goal is to increase our health span and interventions such as environmental enrichment, which includes improved physical, social and cognitive activities, and dietary modifications (e.g. intermittent fasting and calorie restriction) are thought to be beneficial to health span. A challenge though, given detrimental cellular changes may start relatively early in adult life, is these types of intervention need to begin early and be sustained.