The role of astrocytes in experience-dependent plasticity
Lead Research Organisation:
Keele University
Department Name: Inst for Science and Tech in Medicine
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Changing the whisker complement in rodents induces experience-dependent plastic changes in neurones of the somatosensory cortex. Much is known about the mechanisms for experience-dependent plasticity (EDP), but very little about the potential role of astrocytes in this phenomenon. The potential role of astrocytes may be significant since it has recently been demonstrated that astrocytes regulate synaptic plasticity induced in vitro and in the somatosensory system can undergo plastic changes themselves, as well as modulating neuronal activity. We will therefore evaluate the degree of the contribution astrocytes might make to neuronal EDP. We will use the single-whisker experience (SWE) model to ask whether our recently discovered plasticity of astrocytic glutamate release, known as long-term enhancement (LTE) is experience-dependent, whether astrocytes are necessary for the induction and the maintenance of EDP, and finally whether concurrent whisker and astrocytic stimulation are sufficient to induce EDP. The study will comprise of in vitro, in vivo and ex vivo experiments. The magnitude of LTE will be determined using patch-clamp recordings from neurones and Calcium imaging from astrocytes. The magnitude of EDP will be determined by single-unit recordings, and use of FosGFP transgenic mice. The experiments delineating the role of astrocytes in EDP will employ genetically modified animals, in which astrocytic signalling is down-regulated (IP3-R2 KO) or up-regulated by lentiviral expression of the OPTO-XR fusion gene under a GFAP promoter into the barrel cortex and optical stimulation. Should we find that astrocytes and/or astrocytic plasticity are involved in EDP, then this will promise major advances in our understanding of basic brain function and may offer new mechanisms by which brain damage due to sensory function loss, epilepsy, or memory deficits, can be therapeutically targetted.
Planned Impact
The immediate direct beneficiaries of this project will be the two research assistants that will take part in the project. They will receive training in the rapidly advancing field of astrocyte - neuron interactions and the cutting edge techniques of electrophysiology, calcium imaging and optogenetics, and so will acquire a highly relevant skill set. They will also gain from being part of a multi level collaboration between the two laboratories, which will provide them with a firm foundation for their future careers. The academic research communities at Aston and Keele will benefit with the interaction with those involved in this exciting proposal. In addition, undergraduate and postgraduate students that we teach in both Aston and Keele will benefit, as our teaching of neuroscience is directly informed by our research. Such content inspires students and increases their awareness of the limitless possibilities of scientific research and development.
The interested general public will also gain. We still do not know precisely how the healthy cerebral cortex operates and how it responds to changes in the environment. There is currently a resurgence of interest in science, notable by the success of large science festivals such as The Cheltenham and British Science festivals and the growth in popular science programmes and celebrity scientists on television. There is a special interest in brain function and increasing brain plasticity through "brain training" games which is coming to the attention of neuroscientists (Herculano-Houzel S. (2003) What does the public want to know about the brain Nat. Neurosci., 6:325). We believe the public and non-neuroscientists will be fascinated by our research and findings as it will increase knowledge of brain function and shed light on new mechanisms of learning.
Equipment that we will purchase for the selective light activation of OPTO-XR has been developed by CAIRN Research, which is based in the UK, in Kent. We have had a good rapport with this leading British concern for a number of years and so apart from the initial purchase of the system, CAIRN will benefit from our feedback on specific light activation strategies of astrocytic signalling, and from this be able to produce tailor made systems in the future to address such questions. This will feed forward to benefit future researchers entering the astrocyte signalling field.
The proposal is directed towards a previously unexplored area of research that we expect to reveal new mechanism of plasticity that could be therapeutically targeted. Our proposal to test the malleability of plasticity by light activation of astrocytes, therefore has many potential applications - to increase plasticity where there are deficits such as increasing cognition, or even in disease states. We believe that we could understand eventually how to reduce plasticity in other distressing states such as phantom limb syndrome.
Benefits to the research assistants will range from the time of commencement of the project, right through their long term careers. Undergraduate students and the general public will also benefit during the project lifetime as well as following the project when work is being published and promoted. Companies such as CAIRN will benefit immediately from our communication and may be expected to benefit commercially in a few years. Through the next decade, we expect this proposal to contribute to clinical interventions, as well as the field of neurological research.
The interested general public will also gain. We still do not know precisely how the healthy cerebral cortex operates and how it responds to changes in the environment. There is currently a resurgence of interest in science, notable by the success of large science festivals such as The Cheltenham and British Science festivals and the growth in popular science programmes and celebrity scientists on television. There is a special interest in brain function and increasing brain plasticity through "brain training" games which is coming to the attention of neuroscientists (Herculano-Houzel S. (2003) What does the public want to know about the brain Nat. Neurosci., 6:325). We believe the public and non-neuroscientists will be fascinated by our research and findings as it will increase knowledge of brain function and shed light on new mechanisms of learning.
Equipment that we will purchase for the selective light activation of OPTO-XR has been developed by CAIRN Research, which is based in the UK, in Kent. We have had a good rapport with this leading British concern for a number of years and so apart from the initial purchase of the system, CAIRN will benefit from our feedback on specific light activation strategies of astrocytic signalling, and from this be able to produce tailor made systems in the future to address such questions. This will feed forward to benefit future researchers entering the astrocyte signalling field.
The proposal is directed towards a previously unexplored area of research that we expect to reveal new mechanism of plasticity that could be therapeutically targeted. Our proposal to test the malleability of plasticity by light activation of astrocytes, therefore has many potential applications - to increase plasticity where there are deficits such as increasing cognition, or even in disease states. We believe that we could understand eventually how to reduce plasticity in other distressing states such as phantom limb syndrome.
Benefits to the research assistants will range from the time of commencement of the project, right through their long term careers. Undergraduate students and the general public will also benefit during the project lifetime as well as following the project when work is being published and promoted. Companies such as CAIRN will benefit immediately from our communication and may be expected to benefit commercially in a few years. Through the next decade, we expect this proposal to contribute to clinical interventions, as well as the field of neurological research.
People |
ORCID iD |
Stanislaw Glazewski (Principal Investigator) |
Publications
Butcher JB
(2022)
A requirement for astrocyte IP3R2 signaling for whisker experience-dependent depression and homeostatic upregulation in the mouse barrel cortex.
in Frontiers in cellular neuroscience
Glazewski S
(2017)
Time-course and mechanisms of homeostatic plasticity in layers 2/3 and 5 of the barrel cortex.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Description | The main results last year: GuR1 KO animals that exhibit diminished experience-dependent depression (EDD) induced by all whisker deprivation, exhibit also diminished homeostatic plasticity (HP). This results supports the view that EDD regulates HP in this system. Also , collected more controls to the Nature Communications paper that is still unpublished |
Exploitation Route | The outcome contributes to basic knowledge on HP and the role of astrocytes in this process. The gliotransmitter involved is unknown. This could also lead to some clnically orientated follow up. |
Sectors | Education Healthcare Pharmaceuticals and Medical Biotechnology |
Description | The data have been communicated to the students and staff in frame of Erasmus exchange in Poland and Armenia and also at Keele University in frame of popular lectures for students and staff and also in frame of the teachning programme |
First Year Of Impact | 2013 |
Sector | Education |
Impact Types | Societal |
Description | BBSRC International Scientific Interchange Scheme |
Amount | £3,520 (GBP) |
Funding ID | BB/M025675/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2014 |
Description | Ethovision and Observer video systems for research and teaching. |
Amount | £33,060 (GBP) |
Organisation | Keele University |
Department | School of Life Sciences |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2016 |
End | 03/2016 |
Description | Keele University Travel Award |
Amount | £500 (GBP) |
Organisation | Keele University |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2016 |
End | 07/2016 |
Description | Physiological Society Travel Fund |
Amount | £365 (GBP) |
Organisation | Physiological Society |
Sector | Charity/Non Profit |
Country | Global |
Start | 05/2015 |
End | 07/2015 |
Description | Physiological Society Travel Fund |
Amount | £700 (GBP) |
Organisation | Physiological Society |
Sector | Charity/Non Profit |
Country | Global |
Start | 05/2013 |
End | 06/2013 |
Description | Physiological Society Travel Fund |
Amount | £700 (GBP) |
Organisation | Physiological Society |
Sector | Charity/Non Profit |
Country | Global |
Start | 06/2014 |
End | 07/2014 |
Description | Travel Grant |
Amount | £694 (GBP) |
Organisation | Physiological Society |
Sector | Charity/Non Profit |
Country | Global |
Start | 03/2017 |
End | 04/2017 |
Description | travel support to attend SFN meeting in Chicago 2015 |
Amount | £500 (GBP) |
Organisation | Keele University |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2015 |
End | 10/2015 |
Title | new method of stimulating astrocytes via IP3R using opto - and chemogenetics |
Description | optogenetic via Gq coupled melanopsin (OPN-GFAP-CNP) and a chemo-genetic via "Designer Receptor Exclusively Activated by Designer Drug" with GFAP promoter (GFAP-Gq-DREADD) can be used to target astrocyte Gq-IP3 signalling |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | using these methods one can drive astrocytes via their major known pathways |
Description | Impact of astrocytes on experience-dependent plasticity in the barrel cortex |
Organisation | Aston University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Recordings from mice somatosensory cortex in vivo, including genetically modified animals |
Collaborator Contribution | Recordings from slices cut from mouse somatosensory cortex, including genetically modified animals |
Impact | 2 papers published (3 in preparation) and also 5 meeting papers |
Start Year | 2013 |
Description | Mechanisms of plasticity in mouse barrel cortex |
Organisation | Carnegie Mellon University |
Country | United States |
Sector | Academic/University |
PI Contribution | Electrophysiological recordings from mouse brains in vivo, travel money |
Collaborator Contribution | logistics, animals, set up, consumables, writing |
Impact | Journal papers: Glazewski, S. and Barth A.L. Stimulus-intensity determines experience-dependent modifications in neocortical neuron firing rates. Eur. J. Neurosci. In last stages of acceptance Benedetti B.L., Glazewski S. and Barth A. (2009) Reliable and precise neuronal firing during sensory plasticity in superficial layers of somatosensory cortex. J. Neurosci. 29: 11817-11827. Glazewski S., Benedetti B.L. and Barth A. (2007) Ipsilateral whiskers suppress experience-dependent plasticity in the barrel cortex. J. Neurosci., 27: 3019-3920. Meeting papers: Glazewski S., Benedetti B. and Barth A.L. Ipsilateral whisker deprivation enhances spared whisker plasticity in the murine barrel cortex. Society for Neuroscience Annual Meeting, Washington D.C., 2005. Glazewski S., Benedetti B.L. and Barth A. Ipsilateral whiskers modulate spared whisker evoked plasticity in the murine barrel cortex. Physiological Society Meeting, London, 2006. Glazewski S., Benedetti B.L. and Barth A. Ipsilateral whiskers enhances spared whisker plasticity in the murine barrel cortex. Forum of European Neuroscience, Vienna, Austria, 2006. Jasinska M, Siucinska, Glazewski S., Pyza E. and Kossut M. Short-lasting classical conditioning with use of whiskers leads to formation of GABA-ergic synapses in the affected barrels of adult mouse. Forum of European Neuroscience, Vienna, Austria, 2006. Benedetti B.L., Glazewski S., and Barth A. Rapid spared whisker potentiation in the absence of ipsilateral whisker activity. Society for Neuroscience Annual Meeting, Atlanta, 2006. |
Start Year | 2006 |
Description | Mechanisms of plasticity in the mouse barrel cortex |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Electrophysiological recordings from wt and genetically modified mice in vivo, travel money, consumables, lab work |
Collaborator Contribution | genetically modified and wt mice, some recordings, travel and accommodation money |
Impact | Journal Papers Fox K. Wright N., Wallace H. and Glazewski S. (2003) The origin of cortical surround receptive fields studied in the barrel cortex. J. Neurosci. 23: 8380-8391. *Hardingham N.R., *Glazewski S., *Pakhotin P., Giese K.P., Chapman P. and Fox K. (2003) The effect of a CaMKII T286A point mutation on experience-dependent plasticity and LTP in mouse barrel cortex. J. Neurosci., 23: 4428-4436.*shared first authorship. Wright N., Glazewski S. Hardingham N., Philips K., Pervolaraki E. and Fox K. (2008) Laminar analysis of the role of GluR1 in experience-dependent and synaptic depression in barrel cortex. Nature Neurosci. 11: 1140-1142. Dachtler J., Hardingham N., Glazewski S., Wright N., Blain E., Fox K. (2011) Experience-dependent plasticity acts via GluR1 and a novel NOS1-dependent synaptic mechanism in adult cortex. J. Neurosci. 31: 11220-11230. Meeting papers: Glazewski S., Sprengel R. and Fox K. The effect of deleting AMPA receptor subunit GluR A on experience-dependent plasticity in mouse barrel cortex. Society for Neuroscience Annual Meeting, Orlando 2002. Fox K, Wright N., Wallace H and Glazewski S. The origin of cortical surround receptive fields studied in the barrel field. Barrel Meeting, Lausanne, 2004. Dachtler, J.; Wright, N. F.; Glazewski, S.; Fox, K. D. The role of neuronal nitric oxide in experience-dependent plasticity in the mouse barrel cortex. Society for Neuroscience Annual Meeting, Washington D.C, 2008. Dachtler J., Hardingham N. R., Glazewski S.; Fox K. D. Gender differences in neuronal nitric oxide synthase-dependent neocortical plasticity. Society for Neuroscience Annual Meeting, Chicago, 2009. Dachtler, J.; Wright, N. F.; Glazewski, S.; Fox, K. D. The role of neuronal nitric oxide in experience-dependent plasticity in the mouse barrel cortex. Society for Neuroscience Annual Meeting, Washington D.C, 2008. Glazewski, S., Greenhill, S., Fox, K. Experience-dependent Homeostatic plasticity in the barrel cortex. Society for Neuroscience Annual Meeting, San Diego, 2013. Glazewski, S., Greenhill, S., Butcher, J., Fox, K. Experience-dependent Homeostatic plasticity in the barrel cortex. Forum of European Neuroscience, Milan, Italy, 2014. |
Start Year | 2006 |
Description | Brain Awareness Week in Krakow and Lublin, Poland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Brain Awareness Week in Krakow and Lublin. Individual lectures in frame of this event in Krakow with media attendance and broad spectrum of the public (well over 500 participants in each case). The purpose was to familiarise the public with recent achievements in chosen areas of neuroscience, including the newest technology, prospects, impact on society and medicine. This was followed by the discussion and media interview. |
Year(s) Of Engagement Activity | 2007,2009,2015 |
Description | Erasmus teaching in Yerevan |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Undergraduate students |
Results and Impact | 8 hours of lecturing , including on astrocyte modulation of neuronal transmission and plasticity |
Year(s) Of Engagement Activity | 2019 |
Description | Open and Visit days at Keele |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | I participate in average in 4 such event a week. The aim is to present our teaching offer for new entrants and their parents. |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016 |
Description | School open/Visit days |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | meeting with parents and the candidates (done 4 times a year) |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019 |
Description | School visit (topic: Baby it is cold outside) |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Talk about physiology of cold |
Year(s) Of Engagement Activity | 2019 |
Description | School visits (two schools..one comprehensive and one grammar) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Different forms of activities. Mostly lecturing followed by the discussion, questions and answers. Sometimes demonstrations. The aim is to popularise neuroscience. not measurable |
Year(s) Of Engagement Activity | 2012,2013,2014,2015,2016 |
Description | Speaker in frame of 13th Electrophysiological Conference, Warsaw , Poland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Formal talk to professionals including the data collected during both grants |
Year(s) Of Engagement Activity | 2018 |
Description | Teaching Mobility Lublin |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Undergraduate students |
Results and Impact | 8h of lecturing (neuroscience, including the role of astrocytes in various processes in the CNS)...50-70 people attending each of them |
Year(s) Of Engagement Activity | 2016 |
Description | Teaching Mobility Lublin |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Undergraduate students |
Results and Impact | 8 hours of lecturing delivered in frame of Erasmus Teaching Mobility with discussion afterwards plus exchange on research and teaching |
Year(s) Of Engagement Activity | 2010,2011,2012,2013,2014,2015,2016,2017,2018 |
Description | University visit in frame of Teaching Mobility (Krakow and Lublin, Poland) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Undergraduate students |
Results and Impact | Series of lectures concerning different aspects of neuroscience (each year the different set) and in many cases linked to the understanding every day human activities. The lectures also includes large technological components, including their possible impact ion every day life. There is always long discussion at the end of each lectures followed by private talks. The main purpose is to popularise neuroscience , which is a rarity in Poland not measurable |
Year(s) Of Engagement Activity | 2008,2009,2010,2011,2012,2013,2014,2015,2016 |