Final Activity Report Summary - NEUROVASC (Investigating the coupling between synaptic activity and cerebral blood flow in the olfactory glomerulus in vivo using two-photon laser scanning microscopy) Changes in activity of neurons have to be matched by local increases in blood flow to ensure the delivery of nutrients to the activated brain region. This phenomenon, named functional hyperemia, is being used extensively by most modern functional neuroimaging techniques to map brain activity, and has been implicated in a variety of common neurological diseases, such as stroke and Alzheimer's disease. Despite the importance of functional hyperemia for clinical neurology and neuroscience, the underlying mechanisms and cellular pathways have remained largely unknown.The goal of this project was to elucidate these pathways in the intact brain of living mice. To this end, we employed multiphoton microscopy to image neurotransmitter release, cellular activity and blood flow in the olfactory system of genetically altered mice (Petzold et al., Neuron 2008). We found that functional changes in blood flow are triggered by the release of the excitatory neurotransmitter glutamate. Moreover, we found that neurons elicit their activities on blood flow by activating non-neuronal brain cells called astrocytes, which physically link neurons and blood vessels. Finally, we identified two separate astrocytic pathways that regulate functional hyperemia - activation of astrocytic glutamate receptors and subsequent calcium-induced synthesis of secondary signalling molecules called prostaglandins, and direct uptake of glutamate into astrocytes. These findings may have implications for the treatment of perturbed functional hyperemia in the aforementioned diseases.In a second project, we investigated how neuronal activity, as measured by monitoring glutamate release in the olfactory bulb by multiphoton microscopy; can be modulated by the brain transmitter serotonin (Petzold et al., Nature Neurscience 2009). We found that serotonin, by specifically acting on local neurons through serotonergic receptors, strongly modulates sensory-evoked glutamate release. These findings may have implications for the understanding of diseases as diverse as pain and schizophrenia, in which serotonin is centrally involved.