The project will investigate cognitive control and its underlying neural substrates in a new Sts (steroid sulfatase) deletion ‘knockout’ mouse model generated via the MRC Harwell Genome Editing Mice for Medicine (GEMM) programme; its findings will be of direct relevance to the 7.5million individuals worldwide affected by STS deficiency, and will inform our understanding of different Attention Deficit Hyperactivity Disorder (ADHD) subtypes.
ADHD is a common neurodevelopmental condition characterised by age-inappropriate inattention, impulsivity and hyperactivity. In DSM-5, three ADHD presentations are recognised: ‘predominantly inattentive’, ‘predominantly hyperactive-impulsive’, and ‘combined’, but the neurobiology distinguishing these is unclear [1].
In man, deletion of the STS gene (associated with the dermatological condition X-linked ichthyosis, XLI) is associated with a substantially-increased risk of ADHD, particularly of the inattentive subtype [2-4]; however, deletion carriers exhibit reduced motor impulsivity [5,6]. Consistent with this, genetic variation within STS is associated with attentive, but not impulsive, traits in boys with ADHD [7] and healthy men [8].
STS is expressed in the developing human basal ganglia [7], and adult deletion carriers exhibit lower volumes of the globus pallidus, nucleus accumbens and putamen [9]. Chromosomal-mutant male 39,XY*O mice lacking Sts, and wildtype mice in which the STS enzyme is acutely inhibited, also exhibit attention deficits [10] but enhanced motor response inhibition [11]; the former group exhibit increased basal ganglia tissue serotonin (5-HT) levels [12]. Unlike the 39,XY*O model, the Sts-deletion mouse only has the Sts gene disrupted and can be easily bred; Sts-deficient mice show no overt skin pathology.
In Cardiff:
- Sts-deletion and wildtype control mice will be subject to a battery of touchscreen-based cognitive tasks taxing attention and/or impulsivity to specify any between-group cognitive differences
- a new task taxing behavioural flexibility (reversal learning) not previously assayed in Sts-deficient mice will also be developed, specified, and used to characterise Sts-deletion mice
- the sensitivity of any significant effects to pharmacological modulation (e.g. of the 5-HT system) will be investigated
- the effects of administering the STS inhibitor STX-64, or the STS substrate dehydroepiandrosterone sulfate (DHEAS), acutely to wildtype mice on relevant measures will also be examined as previously [9,10]; this will allow us to dissociate between adult cognitive effects arising from developmental and/or ongoing STS activity
In Bristol:
- the neuroanatomy and electrophysiology of the basal ganglia of behaviourally-tested and behaviourally-naïve mice with genetic/pharmacological manipulations of the STS axis will be investigated [13], with a focus on the 5-HT system and subthalamic nucleus-globus pallidus connectivity previously implicated in distractibility, over-rigidity and motor response inhibition [14].
The project will identify neuroanatomical/neurochemical correlates of inattention and reduced motor impulsivity which may be: a) experimentally manipulated in future animal work to demonstrate causality, and b) focussed upon in future human e.g. neuroimaging work. The work will be conducted in parallel with ongoing PhD work within Dr Davies’ group on the behavioural/neuropsychological profile of XLI, will feed into world-leading clinical research into the presentation of ADHD being conducted across Cardiff and Bristol, and will be disseminated via our established links to relevant skin and ADHD charities and support groups (e.g. Ichthyosis Support Group).
Supervisory team will be Dr William Davies, Dr Trevor Humby, Professor Lawrence Wilkinson, Dr Laura Westacott and Dr Paul Dodson (Bristol)
The GW4 BioMed2 MRC DTP is offering up to 20 funded studentships across a range of biomedical disciplines, with a start date of October 2022
These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK, EU and International students.
About the GW4 BioMed2 Doctoral Training Partnership
The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'.
The DTP already has over 90 studentships over 6 cohorts in it’s first phase.
The 80 projects available for application, are aligned to the following themes;
• Infection, Immunity, Antimicrobial Resistance and Repair
• Neuroscience and Mental Health
• Population Health Sciences
Applications open on 11st October 2021 and close at 5.00pm on 26th November 2021.
Residency: The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international. The GW4 partners have all agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded, but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD. All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).
How to Apply
A list of all the projects and how to apply is available on our website at gw4biomed.ac.uk. You may apply for up to 2 projects.
Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’. You may also need to make an 'offer to study' to your chosen institution(s) – further details are on the website.
Please complete the online application form by 5.00pm on 26th November 2021. If you are shortlisted for interview, you will be notified by 28th January 2022. Interviews will be held virtually on 16th and 17th February 2022.
Further Information
For informal enquiries, please contact [Email Address Removed]
For project related queries, please contact the respective supervisors listed on the projects.
Continue with Facebook
