Objective Balanced excitation and inhibition is a fundamental principle of neural circuit function, 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. Yet despite recent progress in elucidating molecular mechanisms underlying homeostatic plasticity in reduced preparations, little is known about such mechanisms in the intact brain.I propose to address this gap using a simple and genetically tractable neural circuit that I recently characterized. In Drosophila, Kenyon cells (KCs), the neurons underlying olfactory associative memory, receive excitation from projection neurons (PNs) as well as feedback inhibition from a single identified neuron (‘APL’). The balance between these two forces maintains sparse odour coding in KCs, which enhances the odour-specificity of associative memory by reducing overlap between odour representations. Preliminary evidence indicates that KCs adapt to prolonged disruption of E/I balance, providing a ground-breaking opportunity to use the powerful genetic tools of Drosophila to uncover the molecular mechanisms underlying homeostatic balancing of excitation and inhibition in vivo in a defined circuit that mediates a sophisticated behaviour.Specific aims:1. Characterize homeostatic plasticity in the PN-KC-APL circuit.2. Identify genes up- and down-regulated in response to perturbations of E/I balance.3. Determine role of candidate genes and cellular mechanisms in homeostatic plasticity. Establishing the PN-KC-APL circuit as a novel model system for homeostatic plasticity will reveal for the first time the molecular mechanisms underlying homeostatic balancing of excitation and inhibition in the intact brain. Fields of science natural sciencesbiological sciencesneurobiologymedical and health sciencesbasic medicineneurologyepilepsyagricultural sciencesagriculture, forestry, and fisheriesagriculturehorticulturefruit growingmedical and health sciencesclinical medicinepsychiatryschizophrenianatural sciencescomputer and information sciencesartificial intelligencecomputational intelligence Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-StG-2014 - ERC Starting Grant Call for proposal ERC-2014-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Host institution THE UNIVERSITY OF SHEFFIELD Net EU contribution € 1 500 000,00 Address FIRTH COURT WESTERN BANK S10 2TN Sheffield United Kingdom See on map Region Yorkshire and the Humber South Yorkshire Sheffield Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 500 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE UNIVERSITY OF SHEFFIELD United Kingdom Net EU contribution € 1 500 000,00 Address FIRTH COURT WESTERN BANK S10 2TN Sheffield See on map Region Yorkshire and the Humber South Yorkshire Sheffield Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 500 000,00
