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Neuromodulatory control of complex behaviour and memory by relaxin-3/RXFP3 networks

A major research interest of our laboratory is elucidating the role of neuropeptide signalling in the control of complex modalities such as arousal, stress, mood, and sensory integration, and the associated cognitive processes, under both normal and neuropathological conditions. We have extensively researched the neurobiology of the relaxin-3/RXFP3 (peptide/receptor) system in brain, as well as the role of an associated neural network driven by neurons in the nucleus incertus. These studies employ a range of biomolecular tools, including receptor-selective peptides and viral-vector delivered- neural tracing molecules, receptor-targeting peptides, and designer receptors (DREADDs), in rodent models, including ligand and receptor knockout and floxed-RXFP3 transgenic mice.

Aims

1. Determine the neurochemical phenotype of relaxin-3 neurons, and neurons directly influenced by relaxin-3 in key brain regions, by mapping the co-expression of RXFP3 mRNA with other mRNA species that reflect neuronal function and responsiveness.
2. Determine the effects of neuropathology on this expression profile, including correlative changes in identified trophic factor and signalling pathway components, in brains from mice subjected to stress, high-fat diets, Alzheimer’s disease toxicity, and chronic pain.
3. Explore the effect of virally (AAV)-mediated changes in relaxin-3 neuron activity, and levels of RXFP3 activation in affective and cognitive networks, on behaviour and brain function. Current studies are focused on effects of n. incertus modulation on arousal, and deletion and activation of RXFP3 on learning and memory, anxiety and social interaction, and sensory integration.
4. Determine effects of RXFP3 agonist and antagonist peptides on neuron activity in hippocampus, amygdala and prefrontal cortex, by measuring neurophysiological responses in brain slices from wildtype and transgenic mice. Data can be correlated with the behavioural effects and changes in identified target neuron activity observed in the in vivo functional studies.

Experimental data suggest relaxin/RXFP3 signalling regulates networks that contribute to arousal, attention, memory, and sensory processing; and key characteristics of brainstem relaxin-3 neurons and their RXFP3-positive target neurons have been documented. In rat and mouse brain, relaxin-3 is expressed by long-projecting GABAergic neurons, which we have shown undergo neurochemical plasticity in response to specific neural inputs and stimuli. Rxfp3 is expressed by topographically-distributed inhibitory (and excitatory) neurons throughout the forebrain, but the nature and function of relaxin-3/RXFP3 signalling is many of these circuits remains largely uncharacterised. Areas of interest include prefrontal cortex, septum, hippocampus, amygdala, hypothalamus and periaqueductal grey
 

Thus, this multidisciplinary project is investigating the role of relaxin-3 neurons and their target neurons that express the neural membrane receptor, RXFP3. We aim to determine the gene/protein expression profile of relaxin-3 and RXFP3-positive neurons in mouse brain, and assess the impact of different behavioural and physiological perturbations and brain pathology on this profile. We have established a series of approaches to explore the functional role of this peptide system, including studies to determine the effect of AAV-mediated: (i) knockdown of relaxin-3 expression in, and DREADD-mediated activation and inhibition of, nucleus incertus neurons; (ii) deletion of RXFP3 from specific relaxin-3 target circuits; and (iii) chronic RXFP3 activation in affective and cognitive networks, on behaviour and brain function. Current studies are focused on effects of n. incertus modulation on arousal, and deletion and activation of RXFP3 in septum and hippocampus, on learning and memory, in amygdala on anxiety and social interaction, and in prefrontal cortex on sensory integration.
We will also explore if and precisely how relaxin-3/RXFP3 signalling alters the activity of RXFP3-positive neurons in different circuits in brain slices. Studies will reveal the therapeutic potential of a peptide-receptor system for alleviating cognitive and emotional symptoms in neurological and psychiatric disorders.

RXFP3 mRNA is widely expressed in forebrain regions, including the anterior cingulate cortex (aCC), bed nucleus of stria terminalis (BNST), central amygdala (CeA) and periaqueductal grey (PAG). In these areas, RXFP3 mRNA (green) is expressed by different types of neurons, including somatostatin (SOM) interneurons (red) in the anterior cingulate cortex.

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