Homeostatic balancing of excitation and inhibition in vivo

Projektinformationen

HomeoBalanceExcInh

ID Finanzhilfevereinbarung: 639489

DOI

10.3030/639489

Projekt abgeschlossen

EK-Unterschriftsdatum 7 August 2015

Startdatum 1 Oktober 2015

Enddatum 30 September 2021

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 500 000,00

EU-Beitrag

€ 1 500 000,00

Koordiniert durch

THE UNIVERSITY OF SHEFFIELD
United Kingdom

Periodic Reporting for period 4 - HomeoBalanceExcInh (Homeostatic balancing of excitation and inhibition in vivo)

Berichtszeitraum: 2020-04-01 bis 2021-09-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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 have addressed 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 measured Kenyon cells' neural activity while altering their excitatory or inhibitory inputs, and discovered that this 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 further discovered that this compensation occurs through a combination of decreased activity in the inhibitory neuron, plus increased excitation onto Kenyon cells.

Through computational modelling, we also discovered that homeostatic plasticity can make the mushroom body more efficient at its main behavioural function, i.e. allowing flies to learn to discriminate between different odours. We further found that predictions of compensatory variability made by our models were confirmed in the fly hemibrain connectome.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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 further discovered that this compensation occurs through a combination of decreased activity in the inhibitory neuron, plus increased excitation onto Kenyon cells.

We also made further discoveries through side projects that emerged out of our main project:
- We showed that feedback inhibition in the Kenyon cell circuit operates locally, i.e. within a limited spatial scale, which has implications for how strongly Kenyon cells can inhibit each other
- We showed that homeostatic plasticity can make the mushroom body more efficient at its main behavioural function, i.e. allowing flies to learn to discriminate between different odours
- We applied insights from the mushroom body to machine learning /artificial intelligence
- We showed that a particular neurotransmitter receptor is required in Kenyon cells for olfactory memory, and that this receptor is unexpectedly inhibitory rather than excitatory

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We have developed a novel model system for studying homeostatic compensation. 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

Map of Kenyon cells responding to an odour (responsive cells shown by false colouring)