Studying The Interaction Of Reelin Deficiency And Environmental Factors In The Development Of Schizophrenia Using Animal Behavioural Models
Funder
National Health and Medical Research Council
Funding Amount
$438,695.00
Summary
Schizophrenia is caused by an interaction of genetic predisposition and environmental risk factors such as stress or drug abuse. Reelin is a protein involved in the normal development of the brain but its levels are markedly reduced in schizophrenia. We will use mice with low levels of reelin in their brain and assess the effect of environmental stress and drugs of abuse. These studies could elucidate gene-environment interaction in schizophrenia and lead to new treatment strategies.
Neurodevelopmental Mechanisms And Early Intervention In Psychiatric Illness
Funder
National Health and Medical Research Council
Funding Amount
$652,765.00
Summary
Schizophrenia and depression are devastating mental illnesses and a huge burden to society. Drug treatments can be beneficial, but many patients are either treatment-resistant or show severe side-effects. There is an urgent need for truly novel treatment strategies which should ideally prevent symptoms. The main aim of this project is to elucidate brain mechanisms involved in schizophrenia and depression development to inform clinical research about improved preventative treatment strategies.
The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE120101311
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Role of intrinsic versus extrinsic cues in cell type determination during development and regeneration. During development all of the different cell types are generated by the action of genes and also signals from the embryo that read out which cell types are present or missing. This project studies how much environmental signals affect cell type generation developmentally and if they can be used to regenerate only the types missing in different diseases.
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less
Targeting Central Inflammation To Combat Obesity And Obesity-related Cognitive Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$470,144.00
Summary
The current obesity epidemic means many of us will suffer from overweight or obesity for at least some of our lives. My findings show obesity can cause inflammation throughout the brain including in regions related to learning and memory. Here I hypothesize that obesity induces long-term changes in the brain’s immune cells, that this can explain why we see susceptibility to cognitive decline in obese individuals, and that we can reverse these negative effects by targeting these immune cells.
The Role Of Reelin-signalling On Cortical Neuron Migration
Funder
National Health and Medical Research Council
Funding Amount
$716,196.00
Summary
Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of d ....Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of development neurons are generated in one part of the brain and migrate great distances to a final destination. It is therefore necessary during development to have a well-orchestrated, controlled series of events that lead to the correct positioning and association of neurons. The precise functions of many gene products involved in this process are not known. One major advancement in the development of the cortex is the discovery of the protein Reelin which is found in the outermost region of the developing cortex. Mutations in Reelin, in humans, have been implicated in the causation of schizophrenia and mood disorders. These disease states are the result of altered migration of neurons in the cortex. The research proposed in this application is designed to understand the precise process of how two types of neurons migrate and assemble in the cortex. Technology today allows us to visualize, in culture, neurons as they migrate in real-time. This is referred to real time-lapse imaging and allows the researcher the ability to examine how external factors, affect migration of cortical neurons. We will determine how Reelin is involved in this process and our research will elucidate the fundamental process of cortical brain development.Read moreRead less
The Functional Role Of Slit-Robo Signaling In Interneuron Migration.
Funder
National Health and Medical Research Council
Funding Amount
$172,500.00
Summary
In the developing brain of vertebrates interneurons undergo directed migration to form complex networks that result in the regulation of neuronal processes. Failure or imbalance of these neuronal networks is known to cause pilepsy and mental retardation. The aim of this project is to investigate the guidance cues, specifically Slit-Robo signalling, that direct the migration of interneurons within the brain.
Understanding Cortical Circuitry Underlying Sensory Integration And The Consequence Of Its Developmental Disruption
Funder
National Health and Medical Research Council
Funding Amount
$527,395.00
Summary
The mammalian neocortex is organised into six layers with a systematic pattern of wiring that relies on normal development and balanced activity of neurons. This project combines developmental, electrophysiological, optogenetic behavioural, and computational methods to establish how the properties of the precise structure of cortical circuits impact their function and how disruptions in the balanced activity during development affect circuit formation and function in the mature brain.