Research Fellow (104297 – 0821) . Job Reference: 1878425
University Of Warwick
To undertake research to:
• Provide genetic evidence that Cx26 hemichannels underlie the CO2-sensitivity of VTA GABA neurons and determine the proportion and location of Cx26 expressing GABA neurons in VTA.
• Determine the effect of Cx26-mediated CO2-sensitivity of VTA neurons on the arousal response to hypercapnia.
• Defining the projections of Cx26 expressing VTA GABA neurons, showing their role in arousal and the location of the CX26 hemichannels (soma and terminals).
DUTIES AND RESPONSIBLITIES
• To undertake experimental work under the instruction and supervision of the Principal Investigator.
• To contribute to the design of experiments in relation to the project.
• To correctly execute the experiments, ensuring that experiments are appropriately powered, recorded, analysed and documented both electronically and by maintaining a lab book that will serve as a permanent record of the methodologies used and the experiments performed.
• To collect and analyse data.
• To prepare and present findings of research activities to colleagues and learned societies.
• To contribute to the writing, submission and revision of papers to be published in appropriate peer-reviewed journals, or progress reports for funding bodies, collaborating with others as necessary.
• To contribute to the preparation of results for presentation by the Principal Investigator.
• To contribute to the preparation and drafting of research proposals.
• May present information on research progress and outcomes to bodies supervising research, e.g., steering groups.
• To contribute to the induction and direction of other research staff and students if so, requested by the Principal Investigator.
• To work flexibly when required. As duties and responsibilities change, the job description will be reviewed and be subject to amendment in consultation with the post holder.
• To contribute to the overall activities of the research team and the Department (including teaching) as appropriate.
• To carry out other duties, as are within the scope, spirit and purpose of the job, as requested by the Principal Investigator or Head of Department.
• To continually update own knowledge and understanding in field or specialism.
TEACHING AND LEARNING SUPPORT
• Could be expected to contribute to the teaching and learning programmes in the department.
• Assist in the supervision of student projects and the development of student research skills.
• May be involved in the assessment of student knowledge and supervision of projects.
The post is funded by the BBSRC and the successful candidate will report to Dr M. J Wall in the School of Life Sciences. The overall role is to define the role of CO2-sensitive connexin 26 hemichannels expressed by VTA GABA neurons in the hypercapnic arousal response and define the novel neural circuit that underlies this response.
An essential life preserving reflex is hypercapnic stimulation of arousal and wakefulness an extreme example of this is sleep apnea, where the cessation of breathing produces hypercapnia leading to rapid waking and then the conscious control of breathing. While here are several pathways that contribute to hypercapnic arousal, we have recently discovered a novel pathway that includes the VTA. The VTA is an important component of the sleep/wake circuitry, with for example activation of VTA GABA neurons leading to sleep/sedation 1. We have recently shown that these VTA GABA neurons express CO2 sensitive Cx26 hemichannels 2. Opening of Cx26 hemichannels in response to raised CO2 levels causes a fall in the input resistance of these GABA neurons 2, effectively switching them, which we hypothesize will lead to arousal. This direct CO2-sensing via Cx26 could provide a very rapid arousal response to hypercapnia, which may be faster than other mechanisms that rely on much slower pH changes (acidification).
To achieve the aims of the project the CO2 sensitive Cx26 hemichannels expressed by VTA GABA neurons will be targeted with a dominant negative (dn) dnCx26 viral construct. This reduces CO2 sensitivity of the Cx26 hemichannels without changing their expression and has successfully been used to define the role of medullary glial Cx26 hemichannels in breathing 3. Using this construct, we will investigate changes in the state of arousal and vigilance when this novel pathway is inhibited.
Our data suggest that Cx26 hemichannels are expressed by VTA GABA neurons and this gives them CO2 sensitivity 2. However, there is considerable complexity within the population of GABA neurons in the VTA with some projecting locally (for example to dopaminergic neurons) and some projecting to a variety of other brain areas including dorsal raphe and lateral habenula 4. To begin defining the neural circuit underlying VTA hypercapnic arousal, we will first identify where the Cx26- expressing VTA GABA neurons project to. As an initial starting point, we will investigate those pathways that are known to be involved in arousal.
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31 Aug 2021