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Rare cortical projection-neurons: function in arousal, sleep and neuropathology

Neurological disorders like Alzheimer's disease and age-related/cerebrovascular dementia, are a huge clinical/economic burden for society, with a major impact on cognitive and mental health of sufferers. Thus, new ‘targets’ for cause and treatment need to be examined, including signalling processes that link neurons to other brain cells, cerebral blood vessels, the surrounding extracellular matrix, and cerebrospinal fluid. Critically, cognitive and emotional problems occur prior to end-stage pathology, so a clear opportunity exists to alleviate symptoms and delay disease progression. This project seeks to identify the role of the relaxin peptide signalling system in brain function, physiology, and behaviour in mice, and to provide insights into potentially novel treatments for multiple neurological disorders.

Aims

1. Map the mRNA expression profile of relaxin neurons in mouse cortex using multiplex in situ hybridisation to reveal their topographic distribution in different layers and regions, and levels of co-expression with mRNA species that reflect their function and responsiveness.
2. Explore the effect of perturbations of cortical function on this profile, including correlative changes in identified trophic factor and signalling pathway components, in brains from mice subjected to sleep deprivation, cortical injury, epilepsy, and Alzheimer’s disease toxicity.
3. Determine the cellular and regional localisation of key peptides and proteins including the relative somatic, axonal and dendritic subcellular localisation, and projection patterns in cortex.
4. Determine effects of relaxin and synthetic RXFP1 agonist and antagonist peptides on cortical neuron activity, by measuring morphological and neurophysiological responses in brain slices from suitable transgenic mice.

Experimental and in silico data suggest relaxin/RXFP1 signalling regulates networks that contribute to arousal, attention, memory, and sensory processing; and key characteristics of cortical relaxin neurons and their RXFP1-positive target cells have been revealed. In mouse cortex, relaxin (not Rxfp1) mRNA is expressed by long-projecting GABA neurons, which we hypothesise are capable of morphological, neurochemical and synaptic plasticity in response to specific neural inputs and to acute and chronic brain injury. In contrast, Rxfp1 mRNA is expressed by topographically-distributed inhibitory and excitatory neurons in outer and deep cortical layers which are likely targeted by adjacent or distant relaxin neurons, but their nature and function are otherwise uncharacterised.
Thus, this multidisciplinary project will investigate the role of the populations of cortical neurons that synthesize the peptide, relaxin, and their target neurons that express the neural membrane receptor RXFP1. We propose relaxin/RXFP1 signalling in areas containing sensory, emotional and cognitive circuits regulates processes, including nerve growth and modification of synapses and the surrounding environment, with links to sleep/wake states, and responses to brain injury.
We will determine the gene/protein expression profile of relaxin- and RXFP1-positive neurons in mouse brain, and assess the impact of perturbations such as sleep deprivation and brain pathology on this profile. We will also explore if and how relaxin alters the activity of RXFP1-positive cortical neurons in mice. Studies will reveal the therapeutic potential of a peptide-receptor system for alleviating cognitive and emotional symptoms in neurological disorders.

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