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Homeostatic balancing of excitation and inhibition in vivo

Periodic Reporting for period 3 - HomeoBalanceExcInh (Homeostatic balancing of excitation and inhibition in vivo)

Reporting period: 2018-10-01 to 2020-03-31

When a neuron fires, it excites or inhibits other neurons it connects with. Neural networks are precisely tuned to a narrow range between too much excitation (seizure) and too much inhibition (silence). Somehow the brain stabilises itself on this knife-edge, compensating for perturbations that disrupt the balance between excitation and inhibition. This process is called homeostatic compensation ('homeo'=similar, 'stasis'=staying still) and is thought to be impaired in disorders such as epilepsy, autism and schizophrenia. How does homeostatic compensation occur?

We will address this question using an ideally-suited circuit in the fruit fly, in which 'Kenyon cells', the neurons that store odour-associated memories, receive both excitation and inhibition. Altering the E/I balance dramatically changes the magnitude of Kenyon cells' odour responses, but with time the circuit compensates for the disruption.

Using state-of-the-art gene targeting techniques, we will measure Kenyon cells' neural activity while altering their excitatory or inhibitory inputs to address questions like: What perturbations can this circuit compensate for? Is this affected by age or sleep? We will find genes whose regulation is affected by altered E/I balance and genes that are functionally required for homeostatic compensation, and uncover how these genes carry out the physiological and morphological changes underlying homeostatic compensation.
We have discovered that the Kenyon cell circuit can compensate for too much inhibition (too much activity in a neuron that inhibits Kenyon cells) but not too little inhibition (blocking signalling from the neuron that inhibits Kenyon cells). We are now investigating the physiological mechanisms underlying this adaptation.
We are developing a novel model system for studying homeostatic compensation. Expected potential impact includes:
- impact on other researchers in neuroscience, including clinicians
- novel understanding of homeostatic plasticity
- communication of results to general audiences through public engagement events, press releases, etc.
- training in advanced skills to staff and students