- Vacancy Reference Number
- CLS-NPB Forsythe
- Closing Date
- 17 Aug 2018
- Salary
- Stipend at RCUK level
- Address
- Department of Neuroscience, Psychology & Behaviour
University of Leicester
Leicester
LE2 7RH
- Duration
- 36 months
Project Description
The brain uses vast metabolic resources to maintain electrical excitability and to integrate sensory information. This activity-dependent metabolic demand is the basis of the BOLD signal of raised brain activity in fMRI and is postulated to correlate with the increased activity of the neurones and synapses. However, the fundamental mechanisms by which brain activity can influence metabolic rate or how compromised metabolism may influence information transmission are unresolved.
My laboratory has extensive experience in the study of synaptic transmission and neuronal excitability. These studies would be conducted in the auditory brainstem since this region has a high metabolic rate. We have a well-established in vitro brain-slice preparation from which we can conduct whole-cell patch recording, western blotting, imaging and immunohistochemistry; and we have recently established that presynaptic ATP depletion during synaptic activity compromises synaptic transmission (Lucas et al., 2018).
The project will explore how ATP availability or metabolic constraint, undermines brain function. For example, sustained exposure to sensory input means that high rates of nerve activity are passing into the brain. This project will examine how these high rates of information transmission influence downstream synapses in the brain, and will explore the adaptations to ATP depletion, AMP kinase activation and the functional consequences of metabolic limitation.
The successful candidate will join a team of neuroscientists (see web site for further information) studying neuronal activity and synaptic transmission. This scholarship will use electrophysiological and imaging techniques to study metabolic demand at the calyx of Held giant synapse. Whole cell patch and imaging methods will be used to monitor presynaptic ATP concentrations during high rates of synaptic transmission and when metabolic substrates are in limited supply. This knowledge will contribute to understanding mechanisms of brain damage associated with ischaemic stroke and would determine the extent of the metabolic support and signalling between neurons and glia as postulated in the astroglia-neuron lactate shuttle (ANLS) hypothesis (Barros & Weber, 2018; Bak & Walls, 2018).
Key methods in which the student will receive training:
In vitro brain slice preparation
Patch recording from neurons and glial
Calcium and ATP imaging
Voltage-clamp
Western blotting
Immunohistochemistry
References:
Bak LK, Walls AB. CrossTalk opposing view: lack of evidence supporting an astrocyte-to-neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain. J Physiol. 2018; 596(3):351-353.
Barros LF, Weber B. CrossTalk proposal: an important astrocyte-to-neuron lactate shuttle couples neuronal activity to glucose utilisation in the brain. J Physiol. 2018; 596(3):347-350.
Lucas SJ, Michel CB, Marra V, Smalley JL, Hennig MH, Graham BP, Forsythe ID. Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse. J Physiol. 2018, 596(9):1699-1721.
Further Information
https://www2.le.ac.uk/departments/npb/people/professor-ian-forsythe-1
Contact Details
Professor I Forsythe
Department of Neuroscience, Psychology & Behaviour
University of Leicester
email: idf@leicester.ac.uk
