Research Studentship: Evaluation of the contribution of astrocyte function to neurovascular coupling
Reference : MED238
Closing Date : Open until filled
Several authors have suggested that astrocytes provide an important functional link between the metabolic demand generated by neuronal activity and metabolite supply delivered by the vasculature (e.g. (Koehler et al. 2006). This parallels the anatomical position of astrocyte end feet – interposed between the vascular endothelium and neuronal processes. Neurovascular coupling is not only essential for efficient brain function, but is also the basis for functional magnetic resonance imaging (fMRI), which works by imaging the local increase in oxygenated haemoglobin seen in active brain areas.
Although this functional role for astrocytes is a reasonable hypothesis, there are alternative ways by which a local increase in neuronal demand could lead to locally increased blood flow without astrocytic involvement – such as via increased extracellular adenosine, decreased pH, or via diffusion of neuronal nitric oxide.
It is not practicable to use gene-knock-out approaches to study the importance of astrocytes in neurovascular coupling (by looking at the consequences of removing them), since they are also required for normal brain development and for the maintenance of a normal blood-brain barrier. Acute pharmacological manipulations of aspects of astrocyte function have produced equivocal evidence to date. The alternative approach to be used in this project is to rapidly and selectively eliminate astrocyte function with a gliotoxic chemical 3-chloropropionate (Cavanagh et al. 1993;Willis et al. 2004). This will be done in rats, in which 3-chloropropionate does only kills astrocytes in certain brain regions (Cavanagh and Nolan 1993). The largest of these is the inferior colliculus, in which the level of metabolic demand can readily be manipulated by graded auditory stimulation (Holton et al. 1997), enabling a quantitative evaluation of the link between neuronal function and blood flow.
Regional brain blood flow in the inferior colliculus will be quantified by inert tracer washout using inhaled hydrogen gas as the tracer and polarography as the detection method (Ray 1982). The corresponding neuronal response will be quantified via the brainstem auditory evoked response (Mulheran et al. 1999) using the same implanted electrode as for blood flow. The cerebellar cortex will be used as a reference area that is non-responsive to sound and in which the astrocytes are not damaged by 3-chlorohydrin to correct for non-specific changes in blood flow.
The project will address a question (the mechanism of neurovascular coupling) at the forefront of current neuroscience, as well as providing training in whole animal work, in auditory electrophysiology, blood brain flow measurement, and in neuropathology.
The successful student will be registered for a PhD (MPhil in the first instance) and will be affiliated with the Institute of Neuroscience.
This studentship is available for a period of four years and provides a postgraduate stipend.
Informal enquiries may be addressed to Dr D Ray, Email: David.Ray@Nottingham.ac.uk. Please note that certain eligibility conditions apply, therefore, this studentship is only available to UK/EU citizens ordinarily resident in the UK.
Applications, with a detailed CV and the names and addresses of three referees, should be sent to Dr D Ray, School of Biomedical Sciences, Queen’s Medical Centre, Nottingham, NG7 2UH. Email: David.Ray@Nottingham.ac.uk.
References:
Cavanagh J B and Nolan C C (1993) The neurotoxicity of alpha-chlorohydrin in rats and mice: II. Lesion topography and factors in selective vulnerability in acute energy deprivation syndromes. Neuropathol. Appl. Neurobiol. 19, 471-479.
Cavanagh J B, Nolan C C and Seville M P (1993) The neurotoxicity of alpha-chlorohydrin in rats and mice: I. Evolution of the cellular changes. Neuropathol. Appl. Neurobiol. 19, 240-252.
Holton J L, Nolan C C, Burr S A, Ray D E and Cavanagh J B (1997) Increasing or decreasing nervous activity modulates the severity of the glio-vascular lesions of 1,3-dinitrobenzene in the rat: effects of the tremorgenic pyrethroid, Bifenthrin, and of anaesthesia. Acta Neuropathol. (Berl) 93, 159-165.
Koehler R C, Gebremedhin D and Harder D R (2006) Role of astrocytes in cerebrovascular regulation. J Appl. Physiol 100, 307-317.
Mulheran M, Ray D E, Lister T and Nolan C C (1999) The effect of 1,3-dinitrobenzene on the functioning of the auditory pathway in the rat. Neurotoxicol. 20, 27-39.
Ray D E (1982) Changes in brain blood flow associated with deltamethrin-induced choreoathetosis in the rat. Exp. Brain Res. 45, 269-276.
Willis C L, Nolan C C, Reith S N, Lister T, Prior M J W, Guerin C J, Mavroudis G and Ray D E (2004) Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 45, 325-337.
Closing Date : Open until filled
Several authors have suggested that astrocytes provide an important functional link between the metabolic demand generated by neuronal activity and metabolite supply delivered by the vasculature (e.g. (Koehler et al. 2006). This parallels the anatomical position of astrocyte end feet – interposed between the vascular endothelium and neuronal processes. Neurovascular coupling is not only essential for efficient brain function, but is also the basis for functional magnetic resonance imaging (fMRI), which works by imaging the local increase in oxygenated haemoglobin seen in active brain areas.
Although this functional role for astrocytes is a reasonable hypothesis, there are alternative ways by which a local increase in neuronal demand could lead to locally increased blood flow without astrocytic involvement – such as via increased extracellular adenosine, decreased pH, or via diffusion of neuronal nitric oxide.
It is not practicable to use gene-knock-out approaches to study the importance of astrocytes in neurovascular coupling (by looking at the consequences of removing them), since they are also required for normal brain development and for the maintenance of a normal blood-brain barrier. Acute pharmacological manipulations of aspects of astrocyte function have produced equivocal evidence to date. The alternative approach to be used in this project is to rapidly and selectively eliminate astrocyte function with a gliotoxic chemical 3-chloropropionate (Cavanagh et al. 1993;Willis et al. 2004). This will be done in rats, in which 3-chloropropionate does only kills astrocytes in certain brain regions (Cavanagh and Nolan 1993). The largest of these is the inferior colliculus, in which the level of metabolic demand can readily be manipulated by graded auditory stimulation (Holton et al. 1997), enabling a quantitative evaluation of the link between neuronal function and blood flow.
Regional brain blood flow in the inferior colliculus will be quantified by inert tracer washout using inhaled hydrogen gas as the tracer and polarography as the detection method (Ray 1982). The corresponding neuronal response will be quantified via the brainstem auditory evoked response (Mulheran et al. 1999) using the same implanted electrode as for blood flow. The cerebellar cortex will be used as a reference area that is non-responsive to sound and in which the astrocytes are not damaged by 3-chlorohydrin to correct for non-specific changes in blood flow.
The project will address a question (the mechanism of neurovascular coupling) at the forefront of current neuroscience, as well as providing training in whole animal work, in auditory electrophysiology, blood brain flow measurement, and in neuropathology.
The successful student will be registered for a PhD (MPhil in the first instance) and will be affiliated with the Institute of Neuroscience.
This studentship is available for a period of four years and provides a postgraduate stipend.
Informal enquiries may be addressed to Dr D Ray, Email: David.Ray@Nottingham.ac.uk. Please note that certain eligibility conditions apply, therefore, this studentship is only available to UK/EU citizens ordinarily resident in the UK.
Applications, with a detailed CV and the names and addresses of three referees, should be sent to Dr D Ray, School of Biomedical Sciences, Queen’s Medical Centre, Nottingham, NG7 2UH. Email: David.Ray@Nottingham.ac.uk.
References:
Cavanagh J B and Nolan C C (1993) The neurotoxicity of alpha-chlorohydrin in rats and mice: II. Lesion topography and factors in selective vulnerability in acute energy deprivation syndromes. Neuropathol. Appl. Neurobiol. 19, 471-479.
Cavanagh J B, Nolan C C and Seville M P (1993) The neurotoxicity of alpha-chlorohydrin in rats and mice: I. Evolution of the cellular changes. Neuropathol. Appl. Neurobiol. 19, 240-252.
Holton J L, Nolan C C, Burr S A, Ray D E and Cavanagh J B (1997) Increasing or decreasing nervous activity modulates the severity of the glio-vascular lesions of 1,3-dinitrobenzene in the rat: effects of the tremorgenic pyrethroid, Bifenthrin, and of anaesthesia. Acta Neuropathol. (Berl) 93, 159-165.
Koehler R C, Gebremedhin D and Harder D R (2006) Role of astrocytes in cerebrovascular regulation. J Appl. Physiol 100, 307-317.
Mulheran M, Ray D E, Lister T and Nolan C C (1999) The effect of 1,3-dinitrobenzene on the functioning of the auditory pathway in the rat. Neurotoxicol. 20, 27-39.
Ray D E (1982) Changes in brain blood flow associated with deltamethrin-induced choreoathetosis in the rat. Exp. Brain Res. 45, 269-276.
Willis C L, Nolan C C, Reith S N, Lister T, Prior M J W, Guerin C J, Mavroudis G and Ray D E (2004) Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 45, 325-337.
