Supervisor 1:
Professor Kevin Fone
Supervisor 2:
Dr Madeleine King
Funding Status: we will select the right option (competition funded studentships; Home and EU
student eligibility)
Application deadline: 16th January 2015
Project Title: Combined maternal immune activation and post-weaning social isolation of rats as an
improved model of schizophrenia, to understand the neurobiology of the disorder and test potential
new treatments.
Project Description:
The Universities of Nottingham and Monash have launched a joint PhD programme at the cutting
edge of molecular pharmacology and drug discovery and are recruiting exceptional calibre
applicants of any EU nationality for a 4-year research programme including a full year of study at
Monash University, Australia. Upon admission to the programme students would undertake 3
rotations from a bank of available projects prior to selecting a final project.
Schizophrenia is ranked as the third most disabling condition with a life-time risk of 0.5 to 1.0% and
an estimated cost per patient to UK society in 1999 of £23K. Rearing rats in social isolation from
weaning (to mimic early life social neglect) produces a robust set of lasting behavioural,
neurochemical and neurostructural changes resembling many core symptoms seen in schizophrenia
making this a very useful neurodevelopmental model to determine the neurobiology of, and
potential new therapeutic treatments for, this disorder. A diverse array of evidence suggests that
maternal exposure to infections during pregnancy is associated with a higher incidence of
schizophrenia in resultant offspring. One hypothesis is that activation of the foetal immune system
by elevated maternal cytokines may be the epidemiological link. In the rodent a similar maternal
immune activation (MIA) can be evoked by the cytokine inducer polyriboinosinic–polyribocytidylic
acid (Poly I:C), which mimics the acute response seen with a viral infection by inducing interferons
and up-regulating pro-inflammatory cytokines in the dam and foetus. Poly I:C produces long-lasting
changes in offspring behaviour which also resemble symptoms seen in schizophrenia. This study will
combine MIA with subsequent isolation rearing as a ‘dual-hit’ to attempt to produce even more
robust changes in behaviour which may have even higher translational relevance to changes
reported in man.
Following MIA and isolation rearing or saline and group housing (controls) subjects will undergo a
battery of behaviours (open field, novel object recognition, social interaction and reversal learning in
visual touch screens). Particular focus will be paid to tasks having relevance to negative and
cognitive symptoms of schizophrenia as these are the least responsive to antipsychotic medication.
Deficits in social interaction (a paradigm thought to reflect negative symptoms in schizophrenia) are
limited following isolation rearing alone and this study will also examine whether MIA causes more
robust changes in this behaviour which would enhance the utility of the model for drug discovery.
Western blots on selected post-mortem brain regions will measure marker of neurotransmission and
cytokine levels will be detected by reverse-phase protein microarray and correlated with behaviour.
Studies in second and third years will attempt to reverse changes by treatment with an existing
antipsychotic, aripiprazole, and novel drugs under development.
This project will provide training in rodent behaviour, surgery, neurochemical analysis and benefit
from a synergistic projects being undertaken by other postgraduates and post-doctoral fellows
working in the group. The student would monitor changes in brain function during behaviour and
following drug treatment; including measurement of core body temperature change by
radiotelemetry and measurement of post mortem brain cytokine levels. This combination of
techniques allows us to simultaneously relate changes in neuronal function to ongoing behaviours
available to few research groups within academia in the UK. The project involves collaborate with a
Monash laboratory involved in rodent neuropharmacology or drug discovery research where the
molecular mechanisms of modulation of the dopamine D2 receptor by the drugs tested will be
evaluated.
Interviews will take place in Nottingham in person or via Skype as appropriate.
Funding Notes: Students of UK and other EU nationalities are eligible to apply. Study fees and a
tax-free stipend of at least £13,863 (subject to confirmation) for 4-years (3 years in Nottingham plus
1 year at Monash) is provided. Travel expenses associated with the year of study in Australia will be
paid.
References: GASKIN P.L.R., ALEXANDER S.P.H. & FONE K.C.F. (2014) Neonatal phencyclidine
administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’
behaviour in the rat. Psychopharmacology 231, 2533-2545.
JONES C.A., WATSON D.J.G. & FONE K.C.F. (2011) Animal models of schizophrenia. British Journal of
Pharmacology 164, 1162–1194.
MEFFRE J., CHAUMONT-DUBEL S., MANNOURY LA COUR C., LOISEAU F., WATSON D., DEKEYENE A.,
SEVENO M., RIVET J-M., GAVEN, F., HERVE D., FONE K.C.F., BOCKAERT J., MILLAN M.J. & MARIN P.
(2012) mTOR recruitment by 5-HT6 receptors as a potential mechanism for cognitive deficits of
schizophrenia. EMBO Molecular Medicine 4, 1043-1056.
Project classification: Neuropharmacology; neuroscience and animal behaviour.
Application Enquiries:
Name: Professor Kevin F one
Email: kevin.fone@nottingham.ac.uk
Applications: Applications consisting of a CV and covering letter should be sent to Professor Steve
Hill (stephen.hill@nottingham.ac.uk) or Dr Ian Kerr (ian.kerr@nottingham.ac.uk).