Final Report Summary - NEUROGAIN (Nonlinear synaptic integration in morphologically simple and complex neurons)
The main aim of the NEUROGAIN Project was to understanding how individual neurons in the brain represent and transform information. To tackle this fundamental question, we studied morphologically simple and complex cells in vitro, in vivo and in silico. We used 3D acousto-optic lens (AOL) two photon microscopy, a method we have developed, to image neuronal and network activity. This was combined with electrophysiological, photolysis, anatomical and mathematical modelling approaches to study chemical and electrical synaptic properties, synaptic integration in excitatory and inhibitory neurons and explore how individual neurons process information. At the synaptic level, our experimental results and modelling show that during sustained rate coded signaling the maximal vesicle supply rate to synapses is limited by the crowded cytoplasmic environment in the synaptic terminal. Our experimental studies of synapses also suggest a new model for transmitter release that explains how synapses maintain temporally precise signaling during trains of activity. By studying how neurons with different numbers of synaptic input transmit and transform signals, we discovered that simple neurons, such as cerebellar granule cells, that have few synaptic inputs are near optimal for conserving information and performing pattern separation. These findings provide a computational explanation for why cerebellar granule cells (> 50% of all neurons in the brain), have approximately 4 dendrites and why this simple morphology has been evolutionarily conserved. Our studies of inhibitory interneurons and the electrical synapses formed between them has provided new insight into their function. This work suggests that excitatory synaptic input into one dendrite can be shared across the dendrites of neighboring cells, potentially increasing the gain of an interneuron network, making it more sensitive to input. This work suggests that within electrically coupled networks of inhibitory interneurons there is a complex interplay between chemical and electrical synaptic signaling. Our studies of layer 5 pyramidal cells have shown that the dendritic tuft exhibits highly nonlinear dendritic behavior. Moreover, modeling of these cells has reveled a novel dendritic mechanism that could confer a network activity dependence to the integration of synaptic input. This implies that neurons embedded within active regions of the cortex can integrate a wider range of inputs over a longer time window than those in quiescent regions. Thus, the main outcome of the NEUROGAIN project has been to generate new knowledge about how information is processed at the cellular level. By helping to bridge the gap in our understanding between synaptic mechanisms and neuronal processing these discoveries provide a framework understanding how information is represented and processed in the brain.