Corticostriatal dopamine and the inhibitory modulation of associative learning

 

Lab rotation project description

The rotation will interface with an ongoing project funded by the BBSRC, so there will be help and support at all times in the lab. Academic supervisions will be scheduled weekly. In practical terms, the rotation will cover techniques relevant to the available PhD project, for example, intra-cerebral drug administration and behavioural testing.

The rotation will deliver skills in the following areas:

  • behavioural experiments in rats: behavioural procedures are fundamental to the project and provide the most appropriate introduction. You will receive hands-on training in animal handling and welfare, experimental design and scheduling. Some behavioural testing of previously treated animals is permissible under delegated Home Office Licence authority. In line with Home Office requirements, the specific experiments available will depend on the ongoing research in progress at the time of the rotation.
  • surgical procedures: you will observe regulated procedures ongoing in our laboratories. There will also be opportunities to assist, under continuous supervision, with health monitoring post-operatively and with intra-cerebral drug administration via indwelling cannulae
  • data analysis: you will be trained in the statistical analysis of behavioural data. There may also be opportunities to assist with the histology procedures used to verify the placement of the cannulae or electrodes (used for intra-cerebral drug administration or to record neural activity).
  • seminars and meetings: you will be expected to attend the group lab meetings and will be directed to relevant seminars and journal clubs across the university.

The ethical and legal framework and the principles of the 3Rs will be embedded in the training provided within the rotation. You will either conduct, assist with or observe the in vivo aspects of the research, depending on whether s/he already has a Home Office personal licence. Experiments of this kind rely on team work and it will usually be possible to assist in some way.

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MCO

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BBSRC Doctoral Training Partnerships
 

Linked PhD Project Outline

Conditioned inhibition is a form of learning seen when an otherwise expected event does not occur in the presence of the inhibitor. Such inhibitory modulation is fundamental to many aspects of normal psychological function, such as the control of food intake, while impairments in this process underpin a wide variety of mental health conditions. We have found that this kind of inhibitory learning is impaired in humans with schizophrenia (as well as those with particular personality profiles). We have therefore adapted the experimental design for use in rats, with a refined appetitive procedure, to investigate the role of the dopamine (DA) system and interconnected cortical structures, specifically medial prefrontal cortex (mPFC). We will use this translational task to analyse the role of corticostriatal DA in inhibitory modulation, with a view to developing novel therapeutic strategies. The mPFC and DA systems have been independently identified as being involved in aspects of inhibition. The proposed plan of work will advance on these findings by testing for dissociable effects in mPFC sub-regions. Moreover, the mPFC projects topographically to nucleus accumbens (NAc) in the striatum, which is also a functionally heterogenous structure. 

We will compare the effects of regional inactivation and electrophysiological profiles in NAc and the corresponding sub-regions in mPFC, to identify functional interactions between the two structures. We will go on to investigate the role of particular DA receptor sub-types in a series of micro-infusion studies at the coordinates identified in the regional inactivation studies. This will allow us to examine the modulatory role of DA in the key brain regions of interest. The proposed use of a translational task in a rat model allows for localised intervention (including disconnection) studies to establish cause and effect, combined with co-relational studies of interconnectivity of small sub-regions.

This project involves in vivo neuroscience and behavioural techniques to determine the substrates of inhibitory learning. The aims of this project are to define the components of corticostriatal circuitry necessary for the inhibitory modulation of appetitive associative learning and investigate the role of different dopamine receptor sub-types in the corticostriatal circuitry.

This project addresses a number of hypotheses and specific predictions. For example, based on the hypothesised functional interplay between pre-frontal cortex and striatum, inactivation of the prelimbic part of pre-frontal cortex or nucleus accumbens core is predicted to impair acquisition of conditioned inhibition. Based on your literature review of the cognitive processes underlying inhibition and their neuropharmacological substrates, you will be encouraged to formulate your own hypotheses and specific experimental predictions.

The project sits within the brain science, mental health and lifelong health and wellbeing cross-research council transdisciplinary programmes. Moreover, we address two BBSRC responsive mode priorities: Food, Nutrition and Health, because food intake is often triggered by external cues and identified inhibitory cues provide us with cognitive-behavioural strategies to keep body mass index in a healthy range; and Healthy Ageing across the Lifecourse as the loss of cognitive inhibition in ageing populations is well documented.

 

Biotechnology and Biological Sciences Doctoral Training Programme

The University of Nottingham
University Park
Nottingham, NG7 2RD

Tel: +44 (0) 115 8466946
Email: bbdtp@nottingham.ac.uk