PhD Research Project: Cellular mechanisms underlying homeostatic balancing of neuronal excitation a
Neuronal excitation and inhibition are very carefully balanced in the brain, and perturbed excitation/inhibition (E/I) balance has been linked to diseases such as epilepsy, autism and schizophrenia. Maintaining E/I balance within normal bounds depends in part on homeostatic plasticity, in which neurons compensate for deviations in activity levels by adjusting their responsiveness to excitation and inhibition. Although we are starting to understand the molecular mechanisms underlying homeostatic plasticity in reduced preparations, we still know very little about such mechanisms in the intact brain.
We have recently developed a new model system for addressing this question. In the fruit fly Drosophila, Kenyon cells (KCs), the neurons underlying olfactory associative memory, receive excitation from projection neurons as well as feedback inhibition from a single identified neuron. The balance between these two forces maintains sparse odour coding in Kenyon cells, which enhances the odour-specificity of associative memory by reducing overlap between odour representations. Preliminary evidence indicates that Kenyon cells adapt to prolonged disruption of E/I balance, providing a unique opportunity to use the powerful genetic tools of Drosophila to uncover the molecular mechanisms underlying homeostatic plasticity in the intact brain, in a defined circuit that mediates a sophisticated behaviour.
This project will test candidate cellular mechanisms underlying homeostatic compensation. For example, to compensate for insufficient inhibition onto Kenyon cells, excitatory synapses onto Kenyon cells might become weaker or smaller, or Kenyon cells might decrease their input resistance to become intrinsically less excitable. In testing whether these or other mechanisms underlie homeostatic plasticity in vivo, the student will develop skills in a wide range of techniques from fly genetics and confocal microscopy to patch-clamp electrophysiology, two-photon imaging of neural activity, and computational modelling.
Applications from self-funded students or students with secured funding are also welcome.
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD Studentship, you must complete the University's application form using the following link: http://www.sheffield.ac.uk/bms/prospective_pg/how_to_apply
*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.
About the model system:
Lin, A.C., Bygrave, A.M., de Calignon, A., Lee, T., Miesenböck, G. (2014). Sparse, decorrelated odor coding in the mushroom body enhances learned odor discrimination. Nature Neuroscience, 17, 559-68.
Review about homeostatic plasticity:
Davis, G. W. (2013). Homeostatic signaling and the stabilization of neural function. Neuron 80, 718–728.
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