NEUROSCIENCE RESEARCH CLUSTER
Lauren Poppi, Tom Wellings, Mark Bigland, Michael Geaghan, Adelle Liebenberg
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.
- RHD student Lauren Poppi received Best Student Prize at the Kioloa Neuroscience Colloquium – Feb. 2015
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.
Abula Yusupjiang, Ye-Win Oo, Lyvia Petiz
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.
Evgeny Bondarenko, Alireza Mazloumi
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 commenced a collaborative project with the Defence cluster addressing biomarkers of resilience to psychological stresses, and have created a Bio-Analytics Research Strategy Group affiliated with the Defence and Security hub of the University of Newcastle.
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.
In 2014, Associate Professor Tooney began the development of a new project in collaboration with Dr Phillip Jobling and Dr Brett Graham to investigate why people with schizophrenia have more inhibitory interneurons in the white matter underneath the cortex of brain regions known to be affected in schizophrenia.
Of particular interest is the functional consequences these interneurons might have on normal brain functions. In collaboration with Professor Deborah Hodgson and Emeritus Professor Patricia Michie the laboratory is investigating whether maternal infection (a risk factor for the development of schizophrenia) has a role in the changes to neurons in the white matter of their offspring.
Sarah Beynon, Lin Kooi Ong
Giovanni Pietrogrande, Murielle Kluge, Ratchaniporn Kongsui, Madeliene Patience, Kim Jones, Zidan Zhao, Jordan Turley
The group’s primary objective is to understand the relationship between psychological stress, neuroinflammation and alterations in glia. The group interfaces with a number of disease processes including; stroke, Alzheimer’s, and depression. The research makes uses of a large variety of techniques spanning from the analysis of individual genes of interest through to the behavioural level. The research laboratories, situated at with the School of Biomedical Sciences and Pharmacy, are ideally equipped with state of the art equipment to undertake these multilevel investigations.
In 2014 the laboratory began working in earnest on a project that was supported in the previous year by the NHMRC. Specifically, the project aims to examine how glia can contribute to the regulation of complex behaviours.
Previously, the group had identified that microglia play an active role in modulating cognitive functions such as working memory and that targeting microglia can restore working memory deficits. Across the course of the year the group have focused on developing a new approach known as in vitro real time imaging to help the group further explore this issue. It is now hoped that this work will assist in the development of significantly more efficacious treatments for mood disturbances such as depression.
Sonia Oliveira, Jasmine Lee
Co-Supervised PhD Students
Ryan Duchatel, Kelly Smith, Abula Yusufujiang
The laboratory studies the autonomic motor and primary sensory neurones that control peripheral tissues and use a combination of anatomical, electrophysiological and molecular techniques to study populations of neurons that communicate with a wide range of organs and cells.
Ongoing projects include:
Tumour innervation and Trophic Factors in Ovarian Cancer
This project investigates the relationship between peripheral nerves and ovarian tumours. The laboratory has found evidence that ovarian cancers are invaded by nerves from surrounding normal tissue. In addition many tumours make a protein called “Nerve Growth Factor” that may be responsible for the invasion of tumours by nerves. Experiments to identify the specific types of nerves that invade tumours and the neurochemical that they release onto cancer cells are ongoing.
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. The laboratory first quantified the distribution of nerves in normal mouse mammary gland. Both sympathetic and sensory nerves innervate the gland. Mammary gland tumours from some mice were invaded by nerve fibres. Some of these were sympathetic axons that release noradrenaline. The impact of this neurotransmitter on the invasiveness of breast cancer cells is currently being investigated. This establishes the PYMT mouse model of breast cancer as suitable.
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).
Effects of Hypoxia on Uterine Function
This projects investigates the effects of hypoxia and ischemia on uterine motility in the mouse. Specifically the impact that the natural compound resveratrol has on modulating uterine function in normal and hypoxic conditions. This data will be used to predict the cellular consequences of deceases in blood flow to the uterus.
Ethan Cresswell, Ellise Roper
Gemma Parkinson, Mark Bigland, Daniel McIlroy, Jack Mayhew
The main aim of the laboratory's research is to better understand the effects of ageing on nervous system function.
Our society is rapidly ageing and soon there will be more people over the age of 65 than there are children 15 years old or younger. Many of these elderly will develop dementia and by understanding how ageing impacts the nervous system the group hope to be able to reduce the burden of this debilitating age-related disease.
The 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 the group have characterised age-related changes in both the nuclear and mitochondrial genomes.
It is not known whether age-related genomic 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 state-of-the-art, laser based microdissection.
For instance, midbrain dopamine neurons are collected, which play an important role in motor control as can be appreciated from Parkinson's disease, at different ages and determine changes in mitochondrial DNA and the expression level of various genes. Similar approaches are being used for CNS blood vessel associated cells, spinal cord motor neurons, & inner ear vestibular hair cells.
The group’s genomics studies in rats and mice have both indicated cholesterol homeostasis is markedly changed in the ageing CNS. The group introduced lipidomics into their battery of approaches to obtain a more comprehensive understanding of how ageing impacts the way the CNS processes lipids, in particular cholesterol, an essential lipid for myelin.
Myelin is the “white substance” in white matter (WM) tracts, and these tracts are very susceptible to the influences of ageing. It is argued that ageing actually has a greater and more deleterious impact on WM compared to grey matter (GM; cell bodies, dendrites, synapses). The majority of the spinal cord is WM, and through the group’s genomics and lipidomics approaches they hope to better understand how ageing affects information processing and propagation between the brain and the periphery.
An important aspect of the study relates to the broader and important issue of whether the course of ageing can be modified. For example, environmental enrichment, which includes improved physical, social and cognitive activities, is thought to be beneficial to health span and the group are finding out whether enrichment can alter age-related genomic and lipidomic changes in various regions of the nervous system