Project title Does PAR2 activation induce depression-like behaviour? Project typ

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Project title Does PAR2 activation induce depression-like behaviour?
Project type: Computer based projectSupervisor: Dr Trevor BushellBackground Four proteinase-activated receptors (PARs1-4) have been cloned to date and they have been implicated in various inflammation-related diseases in both the periphery and central nervous system (CNS)1.  We have previously investigated the role of one PAR subtype, PAR2, in CNS function revealing that its activation modulates neuronal excitability2, is neuroprotective3 and plays a role in sickness behaviour4.  However, whilst we have shown that PAR2 activation induces certain aspects of depression-like behaviour5 including reduced locomotor activity and induction of anhedonia, we do not know whether it induces another core symptom of depression, namely apathy.  Given the link between PAR2 and depression-like behaviour, we hypothesise that PAR2 activation will induce apathy-like activity when examined in mice using the splash test. Aim: Thus the aim of this project is to test this hypothesis by examining the following research aims:
1.      Confirm, using machine learning, that the PAR2 activator, AC264613, reduces locomotor activity.
2.      Determine whether AC264613 induces apathy-like behaviour in mice.
Answers to these questions will improve our understanding of how PAR2 activation induces depression-like behaviour core symptoms that are observed in people living with depression.
Techniques: Data analysis of videos using machine learning and hand scoring techniques.Refs: 1. Bushell, T.J. et al., (2016). Proteinase-activated receptor 2: Are common functions in glial and immune cells linked to inflammation-related CNS disorders? Curr Drug Targets 17, 1861-1870.
2.      Gan, J. et al., (2011).  Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2. British Journal of Pharmacology. 163, 984-94.
3.      Greenwood, S.M. & Bushell, T.J. (2010). Astrocytic activation and an inhibition of MAP kinases are required for proteinase-activated receptor-2-mediated protection from neurotoxicity. J Neurochem. 113, 1471-80.
4.      Abulkassim, R. et al., (2016). Proteinase-activated receptor 2 is involved in the behavioural changes associated with sickness behaviour.  J  Neuroimmunol, 295-296, 139-147.
5.      Moudio et al., (2022). Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines. Psychopharmacology (Berl). 239:229-242.
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