PhD Fly, mouse and computational modelling of the effect of Alzheimer disease on clock neuron excitability

Closing Date

23 Nov 2018

Address

School of Physiology and Pharmacology, University of Bristol

Duration

3.5 years

Project Description

Dementia has 800,000 UK sufferers, with care costs of >£26billion per year. The most common form of dementia is AD which is characterized by extensive neurodegeneration associated with accumulation of amyloid Beta (AB) plaques and tau tangles in the hippocampus and cortex. There is no cure and only a few symptomatic treatments available that are only partially effective and do not treat or reverse the underlying causes of AD. Hence, there is an unmet need for new treatments requiring us to better understand the underlying molecular mechanisms of AD. Behavioural changes such as memory, circadian rhythm and sleep loss are the earliest clinically evident symptoms ahead of progression into dementia. Targeting this “watershed” is of the utmost importance to stop or at least ameliorate progressive dementia. The molecular mechanism of the intracellular clock generating circadian rhythms is conserved from flies to mice to humans. This consists of clock genes (e.g. per) that are rhythmically expressed in clock neurons of the fly brain and mammalian suprachiasmatic nuclei (SCN). In fly and mouse clock neurons, the molecular clock drives changes in clock neuron excitability, which feeds-back and shapes the activity of the molecular clock. We and others have shown: 1) the daily pattern of clock neuron excitability is similar in flies and mice, increased during the day and lowered at night; 2) many of the ionic mechanisms regulating clock neuron excitability and the identity of the ion channels involved are conserved between flies and mammals, and we are modelling these computationally; 3) expression of human AD genes in fly or mouse (e.g. hippocampal) neurons can cause changes in excitability (which we have modelled) and AD relevant phenotypes such as neurodegeneration and memory loss. However, the exact mechanisms underlying this pathology is poorly understood preventing discovery of effective treatments.

Aim and experimental design: We propose a mixed model approach to study the effect of AD-related pathology on circadian rhythms and sleep using flies, mice and computational modelling. We capitalize on the genetic tractability, rapid senescence and powerful circadian assays in Drosophila to determine the mechanisms underlying clock neuron AB pathology. To achieve this, we will measure age-dependent changes in clock neuron electrophysiology, molecular rhythms, neurodegeneration, circadian rhythms and sleep. We will generate computational models of the changes in clock neuron excitability identifying the key ion channels and molecular clock changes. These will then be targeted to rectify the pathology using genetic rescue, optogenetic stimulation and channel specific pharmacology. The results of these experiments and our computational models will guide measurements of the similar circadian changes in SCN Per expressing neurons with or without human AB. We will then test the effective treatments screened in flies to reverse AD pathology in mice. 

Funding Notes

Apply: You will need to complete both an application to the GW4 BioMed MRC DTP for an ‘offer of funding’ and to University of Bristol for an ‘offer to study’. Please see: View Website 

Funding is for 3.5 years and to be eligible for a full award (fees and stipend) from a Research Council, a UK or EU student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship. For further details on eligibility: View Website

References

1. Smith P, Ronald Arias, Ismael Santa-Maria, Shilpa Sonti, Brian D. McCabe, Krasimira Tsaneva-Atanasova, Elan D. Louis, Hodge JJL*, Clark LA. A Drosophila Model of Essential Tremor. Scientific Reports 8(1):7664 

2. Julienne H, Buhl E, Leslie DS, Hodge JJL (2017) Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson’s disease phenotypes. Neurobiol Dis 104:15-23 

3. Buhl E, Bradlaugh A, Ogueta M, Chen K-F, Stanewsky R, Hodge JJL (2016) Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability. PNAS 113:13486-13491 

4. Booth CA, Witton J, Nowacki J, Tsaneva-Atanasova K, Jones MW, Randall AD Brown JT, (2016) Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy. J Neuroscience 36: 350-363 

5. Tamagnini F, Novelia J, Kerrigan TL, Brown JT, Tsaneva-Atanasova K, Randall AD (2015) Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice, Frontiers in Cellular Neuroscience 9: 372 

6. Belle MD, Diekman CO, Forger DB, Piggins HD (2009) Daily electrical silencing in the mammalian circadian clock. Science 326: 281-284

To apply, click here