NEUROVASC · Investigating the coupling between synaptic activity and cerebral blood flow in the olfactory glomerulus in vivo using two-photon laser scanning microscopy
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-08-01 → 2009-07-31
- EU contribution
- €249,752
- Participants
- 2
- Scheme
- OIF
Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Neuronal activation induces a spatially and temporally confined increase in cerebral blood flow. This neuro-vascular coupling forms the physiological basis of functional magnetic resonance imaging. Neuro-vascular coupling has been implicated as a major patho physiological factor in stroke, brain trauma, migraine, Alzheimer's disease, and aging. However, the cellular and sub-cellular mechanisms that govern neuro-vascular coupling are largely unknown. It has been hypothesised that astrocytes may convert neuronal activity into changes in vessel diameter. Indeed, glutamate released by stimulated neurons increases astrocytic calcium levels in brain slices.However, the astrocytic calcium surge may induce both vasodilation and vasoconstriction, depending on the triggering techniques and pharmacological pre-treatment. Investigating these open issues in vivo has been hampered by the low spatial resolution of most blood flow measurement techniques. Recently, two-photon laser scanning microscopy (2PLSM) has been shown to accurately and non-invasively measure capillary blood flow in vivo with high resolution. The aim of this project is to use 2PLSM to image synaptic activity in vivo in olfactory glomeruli of transgenic mice expressing pH-sensitive fluorescent proteins that are genetically targeted to the synapse, and to simultaneously measure astrocytic calcium levels and capillary blood flow using fluorescent markers.Specifically, the goal is to:1) determine the temporal and spatial pattern by which synaptic activity leads to vascular changes,2) identify the changes in vascular diameter triggered by physiological astrocytic calcium elevations and the molecular pathways that underlie them, and3) investigate how and to what extend neuro-vascular coupling becomes perturbed in aged mice and in an animal model of cerebral ischaemia.The project may help to understand the physiological basis of neuro-imaging techniques and the role of neuro-vascular coupling in neurological diseases.
Original text from CORDIS.
Participants
- CHARITé - UNIVERSITäTSMEDIZIN BERLIN · BERLINCoordinatorGermany
- PRESIDENT AND FELLOWS OF HARVARD COLLEGEDEPARTMENT OF MOLECULAR AND CELLULAR BIOLOGY · CAMBRIDGE, MACity levelUnited States
Links
Data: CORDIS, © European Union