Neuroscience Honours Projects – 2008 Effects of Cannabinoid agonists on ppi in patients with Schizophrenia

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Neuroscience Honours Projects – 2008

Effects of Cannabinoid agonists on PPI in patients with Schizophrenia

A/Prof Mathew Martin-Iverson, School of Medicine and Pharmacology

There is currently a great deal of interest and controversy regarding the relationship between cannabis use and schizophrenia. We are studying the effects of cannabis use on a biological marker of schizophrenia, prepulse inhibition of the startle reflex, in patients with schizophrenia and in otherwise healthy people using cannabis (Kedzior and Martin-Iverson, 2006; Kedzior et al., 2006; Kedzior and Martin-Iverson, 2007). This research is carried out at the Neurophysiology Unit of Graylands Hospital.

Overseas (Canada) honours project on cannabinoid heterodimers in rat cognition

A/Prof Mathew Martin-Iverson, School of Medicine and Pharmacology and Prof Richard J Beninger, Queen's University, Canada

A new Neuroscience Honours exchange programme between UWA and Queen’s University in Kingston, Ontario, Canada will be operating in 2008. This programme will cover travel costs and perhaps some additional expenses. My colleague, Prof Richard J Beninger at Queen’s University and I wish to collaborate on a project involving the possible role of cannabinoid receptors and CB1:D2 heterodimers in reward-related learning in rats. Prof Beninger will be visiting Perth in November, 2007. If you have a desire to travel overseas for an honours project on this topic, please email me to arrange a meeting this November with Prof Beninger.

Effects of d-amphetamine on PPI in healthy volunteers

A/Prof Mathew Martin-Iverson and Dr Kyle Dyer, School of Medicine and Pharmacology

Prepulse inhibition of the startle response (PPI) has been reported to be decreased in people with schizophrenia and in rats treated with (+)-amphetamine (dextroamphetamine or d- amphetamine). However, the effects of amphetamine on PPI in healthy people is controversial (Hutchison and Swift, 1999; Swerdlow et al., 2003; Swerdlow et al., 2002). In this project, the effects of amphetamine on PPI in people will be investigated, using an improved PPI methodology.

Effects of d-amphetamine on emotional modulation of the startle reflex in healthy volunteers

A/Prof Mathew Martin-Iverson and Dr Kyle Dyer, School of Medicine and Pharmacology

A number of major theories of the motivational substrates underlying substance use posit that the mesolimbic dopamine system is central to addictive processes. However, theories differ in the way in which dopamine may be involved. Some theories posit that dopamine is a so-called “pleasure” neurotransmitter, with hedonic aspects of stimuli mediated by dopamine release in the nucleus accumbens. Other theorists disagree, arguing that dopamine is involved in “incentive” effects; that is, dopamine subserves “wanting”, not “liking”. Yet other theorists argue that dopamine mediates effects of both hedonic and aversive stimuli, and its actions are better characterised as being “arousal-like”. Hedonic stimuli decrease the effect of startling stimuli on the startle reflex, whereas aversive stimuli increase the effect of startling stimuli. Arousal potentiates the effects of both. Thus, the effect of amphetamine on the modulation of the startle response can differentiate between.

Cannabinoid and stress interactions in Schizophrenia

A/Prof Mathew Martin-Iverson, School of Medicine and Pharmacology

There is much current controversy concerning the relationship between cannabis use and schizophrenia. We are examining this relationship in both people and animal models, using the endophenotype of schizophrenia known as reductions in prepulse inhibition of the startle reflex (PPI). Conflicting reports of the effects of cannabinoid agonists on prepulse inhibition exist, some claiming that cannabinoids increase PPI and some claiming that they decrease PPI (Kedzior and Martin-Iverson 2005; Schneider and Koch 2002; Stanley-Cary et al. 2002). We have evidence that the effects of cannabinoids on PPI depends on the level of activation of glucocorticoid hormone receptors in rats. That is, the effects of cannabis on schizophrenia may alter with stress levels. This honours project will explore this relationship between stress hormone receptors and cannabinoid receptors further in a rodent model of Schizophrenia.

Medicinal uses of Ecstasy (MDMA)

A/Prof Mathew Martin-Iverson, School of Medicine and Pharmacology

There have been recent anecdotal reports the Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) can treat the L-DOPA induced dyskinesias in patients with Parkinson’s disease. This study examines the behavioural (Goni-Allo et al. 2006; Hegadoren et al. 1995; Kamien et al. 1986)and drug discrimination effects of various analogues of MDMA to investigate possible therapeutic and subjective effects of these analogues (synthesised by Dr Matthew Piggott, a medicinal chemist at UWA). It is hoped to find a therapeutic analogue without the neurotoxic or abuse liability effects of the parent compound.

Axonal transport following partial optic nerve injury in a model of secondary degeneration: the effects of lomerizine

Dr Lindy Fitzgerald, Professor Sarah Dunlop, School of Animal Biology

Secondary degeneration following head and spinal cord injury means that any surviving intact tissue is highly compromised; as a result function is severely reduced. Rescuing such intact but vulnerable tissue is currently the only feasible way to optimize function following neurotrauma. Evidence suggests that one possible way to limit secondary degeneration is to maintain axonal transport. Impaired axonal transport is already implicated in numerous pathological conditions including transient ischaemia, glaucoma and diffuse axonal injury. In this project, we will use the visual system as a model to study and potentially improve axonal transport following partial injury to the optic nerve. We generate an incomplete optic nerve injury in which the dorsal side of the optic nerve is severed and the remainder (ventral side) is left intact. Several recently reported lines of evidence have led us to deduce that calcium channel blockers are excellent candidates for improving axonal transport. We will assess the effects of the calcium channel blocker lomerizine in our model of secondary degeneration and monitor axonal transport following intraocular injection of anterograde tracers. We may also assess the effects of lomerizine on an in vitro model of secondary degeneration currently being developed. This project has the potential to deliver findings of considerable clinical relevance and is part of a multi-faceted study on secondary degeneration. As such, some flexibility in experimental scheduling and a prompt start in 2008 would be required. In addition the project requires that the student is comfortable working with animals.

Cortical control of voluntary movement

Professor Geoff Hammond ,School of Psychology

My lab is using transcranial magnetic stimulation (TMS) to study the function of motor cortex in controlling voluntary movement in conscious behaving humans. Brief high-intensity magnetic pulses delivered through a coil positioned on a subject’s scalp over the motor cortex excite underlying neurons and evoke a burst of electromyographic activity in the corresponding muscles (the motor-evoked potential , or MEP). The size of the MEP reflects the excitability of the corticospinal system. A variant of this procedure, using paired TMS pulses, shows the activity of inhibitory and excitatory circuits within motor cortex. These intracortical circuits control the output of motor cortex (and so shape and refine the movement that is produced) and are instrumental in the capacity of the motor cortex to reorganize with experience. Studies are in progress on the motor cortical mechanisms of manual dexterity and handedness (the asymmetry of manual dexterity) and on use-dependent reorganization of motor cortex.

The Neural Basis of Phantom Sounds (Tinnitus)

Professor Don Robertson and Dr Helmy Mulders, School of Biomedical, Biomolecular and Chemical Sciences

Tinnitus, defined as the presence of an auditory sensation without externally-delivered acoustic stimulation, is a very common problem in humans. It has been estimated that between 6-20% of the population suffer from chronic, persistent tinnitus with about 25% of these experiencing tinnitus that is so severe that it has a major impact on quality of life. Our understanding of the basic physiological mechanisms responsible for tinnitus and therefore the basis for treatments is still at an early stage. We have recently developed a simple animal model of tinnitus in which prior exposure to a loud sound that causes partial deafness, results in markedly raised action potential discharge rates in neurons in the auditory midbrain. So far we have only measured this central neural “tinnitus” after 3 weeks recovery from the initiating loud sound exposure, but it is of great interest to know the time course over which this abnormal central activity develops and what the relationship is to the time course of changes in peripheral (cochlear) sensitivity. In this project we will use groups of experimental animals at different time points after exposure, measure the changes in cochlear sensitivity using gross electrical recordings and record the firing rates of single neurons in the auditory midbrain of the same animals, using metal microelectrodes. The results will provide information that will help differentiate between central and peripheral sites of origin of tinnitus.

Mapping connections of an efferent control system in the auditory nervous system

Dr Helmy Mulders and Professor Don Robertson, School of Biomedical, Biomolecular and Chemical Sciences

The auditory nervous system consists of ascending (afferent) components that carry information from the periphery to the higher centres, and descending (or efferent) pathways by which the brain exerts synaptic control over the flow of incoming information. The efferent system is thought to play a number of roles in auditory processing, but its detailed connectivity with afferent subsystems is poorly understood. In this project, we will label selected populations of afferent neurons using retrograde tracers injected into the brainstem of experimental animals and then anatomically map the synaptic connections that the efferent systems make with these labeled neurons by using anterograde tracers injected into the sites of origin of the efferent pathways.

Binaural effects on responses of auditory midbrain neurons

Professor Don Robertson and Dr Helmy Mulders, School of Biomedical, Biomolecular and Chemical Sciences

In the auditory midbrain of mammals, neurons are known to have a diversity of responses to sound when controlled acoustic stimuli are presented to the ear that supplies the dominant synaptic drive to those neurons. However, there is no good investigation in the literature of how these diverse “monaural” responses patterns may be shaped by two possible factors 1) spontaneous afferent input from the opposite ear converging onto the same neurons and 2) acoustically-driven input from the opposite ear when sound presented to one ear is loud enough to physically leak across the head. Such information is vital to a proper interpretation of the responses seen in the auditory midbrain, both in normal animals and in animals with various peripheral auditory pathologies. In this project, students will use metal microelectrodes to record the activity of single neurons in the auditory midbrain of anaesthetized animals and will study the effects on response patterns caused by experimental elimination of inputs from the non-dominant ear.

Regulation of cochlear function by ATP receptors

Professor Don Robertson, School of Biomedical, Biomolecular and Chemical Sciences

Hearing sensitivity is determined by a number of variables in the peripheral receptor organ. One of these is the steady voltage in the scala media, the fluid compartment into which the stereocilia of the hair cells project. This voltage is a vital element in the total driving force on ions through the hair cell transduction channels. Disturbances of this voltage could underly a variety of hearing pathologies including tinnitus and hence it is interesting to study the mechanism by which it is regulated. We have consistently found that perfusion of the cochlea with agonists of receptors for ATP (so-called purinergic receptors) causes a marked rise in the voltage in the scala media (endocochlear potential). Three possible hypotheses of the mechanism of this increase are 1) that there is a change in activity in an efferent feedback loop regulating the voltage, 2) that there is activation of P2 receptors in the stria vascularis (the transporting epithelium that is responsible for generating the voltage) and 3) that there is a reduction in the current drain on the scala media voltage by closure of ion channels in hair cells and/or supporting cells lining the scala media. These hypotheses will be tested by a series of experiments using intracochlear perfusion and intracochlear electrical measurements.

Effects of partial hearing loss on the brain’s control of inner ear function

Professor Don Robertson and Dr Helmy Mulders, School of Biomedical, Biomolecular and Chemical Sciences

Higher centres in the brain have been shown to modulate the function of the inner ear via descending (efferent) control systems. For example, we have demonstrated that electrical stimulation of the inferior colliculus causes a change in cochlear neural and hair cell activity that is consistent with activation of these efferent pathways. Various roles for efferent descending control in normal hearing have been postulated, ranging from homeostatic regulation of hair cell and nerve fibre function to enhancement of the detection of signals of interest in background noise. However, it is not known whether the action of descending pathways is altered by a pre-existing hearing loss, even though it is well known that peripheral hearing loss induces plasticity in central circuitry and levels of neurotransmitter expression. If such changes occur then they indicate that the effects of hearing loss have to include not just direct effects on auditory sensitivity, but changes in efferent modulation as well. This project will address this question by quantifying the effects of electrical stimulation of the inferior colliculus in normal animals and in animals with a partial hearing loss created by prior loud noise exposure.

Axon regeneration induced by genetically modified Schwann cells

Prof Alan Harvey, Dr Giles W. Plant, Dr. Marc J. Ruitenberg, Red’s Spinal Cord Research Laboratory, School of Anatomy and Human Biology

Using lentiviral vectors it is possible to introduce growth factor genes into adult Schwann cells. We have shown previously that these genetically modified cells can be incorporated into peripheral nerve sheaths and, when grafted onto the injured optic nerve, they promote increased regeneration of adult retinal ganglion cell (RGC) axons (Hu et al., Molecular Therapy, 2005). In this project we will examine whether similar types of graft also promote the regeneration of RGC axons when the injury occurs in the brain, at a significant distance from the eye. The study address a critical issue in neural repair - the extent to which the site of axon injury affects the regenerative capability of an injured nerve cell.

Carbonyl scavenging agents and their effects in neuronal viability and axonal growth after exposure to Acrolein or carbonyl stress

Dr Giles Plant and Dr Philip Burcham Anatomy and Human Biology and School of Medicine & Pharmacology

The broad hypothesis underlying this work is that carbonyl-scavenging compounds that block cell damage by acrolein and related electrophilic carbonyls will protect against spinal neurodegeneration following traumatic spinal cord injury (SCI). This hypothesis is based on a growing body of literature showing a role for acrolein, a reactive & highly toxic endogenous electrophile, as well as other reactive carbonyls in SCI pathogenesis. A subsidiary hypothesis is that exposure to mixtures of reactive carbonyl compounds, as occurs in the damaged spinal cord, is more toxic to neuronal cells than exposure to individual compounds. These hypotheses will be tested using a combination of in vitro approaches:

Aim: Using primary neuronal cells comprising dorsal root ganglia from rat embryos or adults, to explore the effect of acrolein and “carbonyl stress” on neuronal viability and axonal growth, and establish whether carbonyl-scavenging agents attenuate any disruption of axon extension.

The use of anti –angiogenic peptides such as ang001 and their role in spinal cord injury recovery

Dr Giles Plant, Dr Stuart Hodgetts and Dr Dharmarajan Anatomy and Human Biology

Interest in angiogenesis research remains strong in recent years: many laboratories worldwide are actively involved in the study of several aspects of this field and the literature on angiogenesis increases exponentially.

The growth of new microvessels from resting vessels is the outcome of a fine balance between molecules that are either positive or negative regulators of angiogenesis (the so called "angiogenic switch"). The explosion of clinical research in angiogenesis is a result of the realization that in many diseases characterized by persistent, unregulated angiogenesis, as cancer, atherosclerosis, rheumatoid arthritis, diabetic neuropathy, and wound healing a common underlying pathogenetic aspect is a derangement in angiogenesis. Suppressors of angiogenesis have potential clinical applications in conditions where abnormal proliferation of blood vessels is related to the disease progression. Several laboratories report new findings about anti-angiogenesis in chronic inflammation. Investigating the vasculature targeting strategies for the treatment of chronic inflammatory diseases has considerable clinical implications. In this study we will explore the role of a novel anti-angiogenic protein, Ang001 in wound healing after a spinal cord injury. These studies will be carried out in collaboration with Professor Dharmarajan who isolated this novel antiangiogenic protein. Both in vitro and in vivo studies have clearly demonstrated a low does such as 250pg is able to significantly reduce wound healing and new blood vessel formation.

Specifically we will:

  1. Determine the ability of Ang001 administered after 12mm contusion injury (24 hours) to increase axonal regeneration, tissue sparing and behavioural recovery using BBB open field testing and Catwalk.

The role of neurotrophins, cAMP or ATP agonists on the formation of myelin in central glia

Dr Giles Plant and Dr Alan Harvey Anatomy and Human Biology

The proposed studies will address the issue of OEG myelination by examining the inherent capacity for OEG to remyelinate axons using defined in vitro co-culture systems, molecular analyses and viral vector technology. This proposal will clarify whether the size or age of the axon is an important factor in triggering myelin formation in OEG. Lastly, extrinsic factors will also be tested to ascertain whether external agents are the trigger for OEG myelin formation. Adult derived SC cultures will be used in parallel control experiments. The findings will have important implications for the future use of OEG not only for spinal cord injury, which has both primary and secondary demyelination events, but also perhaps for promoting remyelination in diseases such as multiple sclerosis. These are important particularly with the ongoing clinical trials in Portugal, Australia and China.

To determine in OEG/neuronal co-cultures whether membrane bound neuregulinß1-Type III, or factors such as brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), CPT-cAMP or ATP agonists stimulate compact myelin formation by adult OEG.

Organisation of corticotectal projections in ephrin-A-/- mice

Dr Jenny Rodger, School of Animal Biology and Prof Alan Harvey, Anatomy and Human Biology

Genetically modified mice that lack one or more ephrin-As, key axon guidance proteins required for the establishment of topographic connections between the retina and visual targets in the brain, have disordered visual system circuitry. We will use this model to address the relationship between brain structure and function. Developmental disruption of the topographic map alters the subsequent alignment of SC maps for other sensory modalities, but the impact on the pattern of visual corticotectal projections has not been addressed in ephrin-A knockout mice. We will inject tracers into different parts of primary visual cortex in ephrin-A2, A5 and A2/A5 mice and examine the pattern of termination of corticotectal axons in the SC, relating any errors to known errors in retinotectal targeting. Methods: Anterograde tracing in different visuotopic parts of the visual cortex. Cryosectioning, immunohistochemistry. Electrophysiological recording.

RGC dendritic morphology in ephrin-A-/- mice

Dr Jenny Rodger, School of Animal Biology and Prof Alan Harvey, Anatomy and Human Biology

Ephrin-As are expressed in retinal ganglion cells and have been detected in their dendrites as well as their axons. This project will investigate whether ephrin-As are involved in regulating the morphology of RGC dendrites and their connections within the retina. Single RGCs from normal and ephrin-A-/- mice will be filled with dye to reveal their dendritic processes and axon trajectories within the retina. Methods: Single cell injection with fluorescent dye, immunohistochemistry, image analysis and neurolucida software.

Neurogenesis in CX3CR1 deficient mice

Dr Marc Ruitenberg, School of Animal Biology and Prof Alan Harvey, Anatomy and Human Biology

The birth of new neurons continues postnatally in a select number of areas in the mammalian brain. Because of its therapeutic potential, the discovery that nerve cells can be successfully added and/or replaced within the adult brain from endogenous stem or precursor cells has caused much excitement in the scientific community. Brain microglia are actively involved in the clearance of dying cells from nervous tissue. However, the molecular signals that govern the activation of these phagocytic cells while maintaining a favourable environment for neuronal replacement are less clear. In this project, we will study the role of the chemokine receptor CX3CR1 in controlled clearance of compromised cells from the brain using experimentally induced neuronal death in normal and CX3CR1 knock-out mice. Understanding the mechanisms of adult neurogenesis at the cellular and molecular level is important to predict how this process might be affected in neurodegenerative conditions in the brain or inflammation as well as for potential therapeutic applications.

Depending on the student's interest, the project can involve a wide variety of techniques, i.e. from rodent neurosurgery, histology to molecular biology (RNA / DNA extraction, PCR etc.).

If you want to know more about this project or others, please feel free to come and see us in the lab! Marc Ruitenberg (phone: 6488 7513 or email:

Microglia turnover in neurogenic areas of the nervous system

Dr Marc Ruitenberg, School of Animal Biology and Prof Alan Harvey, Anatomy and Human Biology

New neurons are continuously added to three select areas of the adult nervous system, i.e. the olfactory neuroepithelium, the olfactory bulb and the hippocampus. In our research, we are particularly interested in cross-talk between the immune and nervous system in those neurogenic areas. Microglia are important in the phagocytosis of dying cells from the brain. Chronic inflammation of the brain and neurodegenerative diseases impair the neurogenesis process. Thus, to maintain a favourable environment for neuronal replacement, inflammation needs to be prevented upon microglia activation. In the lab, we use a transgenic mouse line in which the marker gene green fluorescent protein (GFP) is selectively expressed in all cells derived from the monocytic lineage, including brain microglia. Using GFP as a marker for brain microglia, this project aims to study activation dynamics and turnover of monocytic cells in neurogenic brain areas where cell death and replacement are naturally occurring.

To study microglia turnover, we are using mouse chimaeras in which the bone marrow of lethally-irradiated mice was reconstituted with that of CX3CR1+/GFP mice, i.e. all monocytic cells derived from the donor bone marrow will express GFP. A comparative analysis of the number of GFP-positive cells within the olfactory epithelium, bulb, subventricular zone and hippocampus will be performed at various time points after transplantation.

Techniques include: Genotyping, tissue processing, immunohistochemistry, image acquisition and analysis, etc.


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