Genetic profiling and targeting the modules of the central noradrenergic neuromodulationsystem

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 18 studentships for entry in September/October 2019. The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities.

Neuromodulators, like noradrenaline, exert profound effects on brain function and add contrast, colour and context to the synaptic computations undertaken by networks of neurons. Noradrenaline regulates a broad range of functions including attention, mood,
sensation, motor control and sleep-wake transition. Dysfunctions of noradrenergic control have been implicated in many diseases including depression, chronic pain, dementia and Parkinson’s disease. Many therapeutic approaches use drugs that target the noradrenergicsystem but their efficacy is limited by side effects (often because of noradrenaline’s ubiquity). The major source of noradrenaline is the locus coeruleus (LC) – a small cluster of neurons in the brainstem - which extends huge projections throughout the brain. This organisation led to the idea that noradrenaline globally modulates brain states. However, several independent recent studies (eg Hirschberg 2018 Elife) indicate that it is sub-divided into modules with specific projection patterns and discrete functional roles. This provides a means for sets of noradrenergic neurons to independently modulate brain functions.
Importantly, this also means that it may be possible to therapeutically manipulate a particular noradrenergic function (e.g. analgesia) without detrimentally influencing other cognitive functions (sedation, memory, mood). To achieve this objective we need to know
how this organisational architecture is genetically encoded by analysing the transcriptional differences between these neuronal subsets.
We anticipate that this will yield differentially expressed targets (e.g. receptors and peptides) that can enable selective modulation of
subsets of noradrenergic neurons and will provide information about how each module performs its role and how this is affected in disease. This project will take advantage of our ability to transduce subsets of LC neurons projecting to different parts of the brain in
rats using custom designed retrograde viral vectors (already built). This enables the expression of GFP-tagged ribosomes allowing pull down of the actively translated mRNA for RNAseq expression profiling. We will undertake a systematic comparison of the expression profiles of the LC neurons projecting to frontal cortex, hippocampus, amygdala and spinal cord. Differentially expressed genes will be validated by in situ hybridisation, immunocytochemistry and pharmacological characterisation in combination with lectrophysiology/calcium imaging both in vitro and in vivo. The student will learn a broad range of skills from our multidisciplinary academic, clinical and industrial team including in vivo recovery surgery, the use of viral vectors, genetic profiling & bioinformatic analysis along with electrophysiological and pharmacological techniques. Successful application of these methods to a question of broad interest to the neuroscience
community will form a strong foundation for an academic career.

Deadline for applications: 5pm on Friday 23rd November 2018.