Using brain imaging to understand cognitive deficits in neurodevelopmental disorders.

Supervisors: Dr. Tim Silk, Prof. Alasdair Vance

Childhood neurodevelopmental disorders including Attention Deficit Hyperactivity Disorder (ADHD), Dysthymic Disorder (DD) and Obsessive Compulsive Disorder (OCD), are associated with cognitive deficits in addition to the clinical symptoms and behaviours. While clinically distinct disorders, they are highly comorbid with each other as well as other psychiatric problems, and overlap lies in the neuropsychological profile of executive function. This project will use Magnetic Resonance Imaging to examine both the functional and structural similarities or differences in children with ADHD, DD and OCD.

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Using genetically-modified mice to study neurodevelopmental and neuropharmacological mechanisms in schizophrenia

Schizophrenia and other mental illnesses are likely to be caused by an interaction of genetic and early neurodevelopmental factors, leading to altered expression of trophic factors in the brain and changes in synaptic density and neuronal activity. We use mice with reduced brain expression of trophic factors such as BDNF (brain-derived neurotrophic factors) and Reelin. These mice are tested in behavioural animal models for aspects of schizophrenia, including locomotor hyperactivity, prepulse inhibition, social behaviour and cognitive deficits (short-term and long-term memory, avoidance memory). These studies may be complemented with assessment of protein levels in the brain by Western Blot or immunohistochemistry, or with receptor autoradiography. This project is aimed at students who are interested in obtaining experience with animal models of schizophrenia, genetically-modified mice, pre-clinical psychopharmacology and behavioural neuroscience. The project will be done at the Behavioural Neuroscience Laboratory, Mental Health Research Institute, in Parkville, Victoria.

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Using Next Generation Sequencing to Discover Novel Genes that cause Mitochondrial Disease.

Co-supervisors: Dr Alison Compton

Mitochondria are the powerhouses of the cell, generating cellular energy through the oxidative phosphorylation (OXPHOS) system. Pathogenic mutations in genes required for correct assembly of the OXPHOS protein complexes result in a variety of neurodegenerative disorders collectively known as mitochondrial diseases. Nearly 100 (nuclear and mitochondrial) genes are known causes of mitochondrial disease, however ~50% of patients still do not have a molecular diagnosis with many more novel disease genes awaiting discovery. Recently, we used a pooled high-throughput sequencing strategy to screen 103 genes encoding complex I subunits and proteins putatively involved in complex I biogenesis in a cohort of 103 complex I deficient patients. Our patient cohort included 43 patients with known mutations, allowing us to demonstrate a sensitivity of 83% for detecting nuclear DNA mutations. We identified a new genetic diagnosis in 22% of the remaining 60 patients, including mutations in known subunit and complex I assembly factor genes.

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Using recombinant adeno-associated viruses to modulate neuropeptide function in the brain

Co-Supervisor: A/Prof Andrew Gundlach

PhD and Honours projects are available to study the modulation of neuropeptide and neuropeptide receptor (GPCR) expression using recombinant adeno-associated viruses. Candidates will undergo training in various techniques including molecular cloning, cell biology, confocal microscopy, viral expression and animal behavioural phenotyping.

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Using replication deficient viruses to modulate neuronal activity.

Replication-deficient viruses represent a novel and highly effective method for inducing gene expression in selected sub-groups of neurons in vivo (7). Using this approach we can cause expression of novel activators, or inhibitors of neuronal activity and then observe the functional relevance of a particular group of neurons. This project involves the introduction of a novel insect receptor into specific neurons of the brain. We can then inhibit the activity of those neurons specifically in order to understand their function. The project will employ surgical methods for microinjection, physiological recording and various approaches to examine gene expression.

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