About the Project
Supervisors: Professor Bettina Platt, Dr Tara Spires-Jones (Edinburgh) and Professor Gernot Riedel
Background:
Ageing affects cognition by reducing neuronal plasticity and altering cellular morphology. It is well established that lifestyle, such as the environment and social factors, strongly impact on these parameters. However, the physiological correlates and cellular / molecular mechanisms underlying these age-related changes are as yet not fully determined. We here hypothesise that specific key proteins sustain neuronal health and their decline triggers the ageing process. Conversely, halting their degradation may halt or slow age-related deterioration. Recent evidence (Pavlopoulos et al., 2013) confirmed the crucial involvement of the histone-binding protein RbAp48 in synaptic function, which declines with age and replenishing it recovers cognition.
The Aim of this studentship would be to conduct in vivo electrophysiological recordings in C57B/L6 mice during cognitive testing followed by data analyses using advanced computational methods to selectively track and categorise behavioural performance during rest and in specific learning strategies. We suggest that physiological changes occur earliest in the ageing process, therefore, respective recordings offer a particularly sensitive approach but also a functional readout for age-related changes, especially when combined with behavioural testing.
These methods would be applied to mice from different age-groups (from 4-24 months) and include the manipulation of synaptic parameters via a) modification of holding conditions and b) viral intervention to up-regulate RbAp48 selectively in cognition-relevant brain regions. Our studies would reveal the contribution of region-specific synaptic and molecular components driving the physiological patterns that bring about learning and memory.
Detailed, state-of-the-art post mortem tissue analysis would investigate cellular and sub-cellular compartments in which specific changes occur (e.g. spines) and determine the roles of histone binding proteins (HBPs) and histone acetyltransferase (HAT) related to synaptic morphology and function.
Overall, we would establish which regional, sub-cellular synaptic components determine local signalling properties as well as network connectivity in a behaviour-specific context, and how these are affected in the age-dependent decline of cognitive function.
Experimental Groups and Training:
We will study in vivo electrophysiology combined with behavioural testing (Aberdeen site) to determine:
(1) The general ageing profile (cognition & physiology):
Electrophysiology would be based on our novel wireless Nat device (4 channels, depth recordings for local field potentials (LFPs) in prefrontal cortex and hippocampus bilaterally). New algorithms using linear and non-linear designs would be applied to study LFPs in a time-resolved and brain-region specific manner. Connectivity analysis will comprise novel approaches (see Sommerlade et al., 2014).
Cognitive testing is based on the Y maze (spatial working memory) and the STFP paradigm (semantic memory; described in Plucinska et al., 2014).
(2) Good and bad learners and their corresponding physiological & synaptic correlates.
(3) Does replenishing RbAp48 (localised viral delivery) improve cognition in aged cohorts?
(4) Does social / environmental isolation vs social / environmental enrichment manipulate synaptic density, neuronal signalling and HBP/HAT profiles?
Postmortem, tissue will be processed in Edinburgh where the student will apply cutting-edge imaging techniques alongside standard biochemical and histological methods to determine:
(1) Structure-function correlations in ageing brain. Neuronal morphology based on Golgi staining in brain regions important for cognition will elucidate whether RbAp48 and improved environmental conditions affect cognition and neuronal signalling through increasing synapse numbers.
(2) Molecular changes at synapses associated with ageing and experimental manipulations – using array tomography (Kay et al., 2013) and biochemical measurement of synaptic fractions.
(3) Non-synaptic molecular changes contributing to age-related cognitive decline: neurogenesis will be examined histologically, histone binding proteins such as RbAp48 (NURFF55) as well as CREB1-dependent CBP and HAT will be examined with microarrays.
Funding Notes
This project is eligible for the EASTBIO Doctoral Training Partnership: http://www.eastscotbiodtp.ac.uk/.
This opportunity is only open to UK nationals (or EU students who have been resident in the UK for at least three years immediately prior to the programme start date) due to restrictions imposed by the funding body.
References
Kay KR, Smith C, Wright AK, Serrano-Pozo A, Pooler AM, Koffie R, Bastin ME, Bak TH, Abrahams S, Kopeikina KJ, McGuone D, Frosch MP, Gillingwater TH, Hyman BT, Spires-Jones TL. 2013. Studying synapses in human brain with array tomography and electron microscopy. Nature Protocols 8(7):1366-1380.
Pavlopoulos E, Jones S, Kosmidis S, Close M, Kim C, Kovalerchik O, Small SA, Kandel ER. Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med. 2013 Aug 28;5(200):200ra115.
Plucińska K, Crouch B, Koss D, Robinson L, Siebrecht M, Riedel G, Platt B. Knock-In of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci, 34(32):10710-28, 2014.
Sommerlade L, Thiel M, Mader M, Mader W, Timmer J, Platt B & Schelter B. Assessing the strength of directed influences among neural signals: An approach to noisy data. J Neurosci Methods, 2014 (in press). DOI: 10.1016/j.jneumeth.2014.09.007.
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