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Roles of Peptidergic Interneurons in Neurovascular and Neurometabolic Coupling| old_uid | 7922 |
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| title | Roles of Peptidergic Interneurons in Neurovascular and Neurometabolic Coupling |
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| start_date | 2010/01/11 |
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| schedule | 16h |
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| online | no |
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| summary | Tight coupling between neuronal activity, local cerebral blood flow and metabolism is essential for normal brain function and is at the basis of contemporary brain imaging techniques widely used to infer neuronal activity in health and disease. This complex phenomenon involves numerous vasoactive messengers released by different cell types, including neurons and astrocytes. A growing number of evidence shows that functional hyperemia, the increase in blood flow in response to neuronal activity, is accompanied by a spatially and temporally restricted reduction in blood perfusion and neuronal activity, a phenomenon known as functional deactivation whose cellular and molecular mechanisms as well as physiological significance remain largely unknown.
Some GABAergic inhibitory cortical interneurons express vasodilatory and/or vasoconstricting substances and might be therefore involved in functional hyperemia and/or functional deactivation. However, due to their large electrophysiological, molecular and morphological diversity their precise identity remains poorly defined making it difficult to study their specific functions in cortical physiology. By combining whole-cell recordings, single-cell RT-PCR and biocytin labeling together with polythetic clustering algorithms we defined distinct population of putative vasomotor interneurons intimately associated with blood vessels. We showed that the evoked firing of single identified interneurons was sufficient to elicit vascular movements of nearby blood vessels. These vasomotor interneurons were dilating if they expressed VIP or nNOS and constricting if they expressed somatostatin or NPY.
During evoked neuronal activity functional hyperemia is followed by a transient increase in lactate released by astrocytes while glucose levels remain fairly constant. To evaluate the physiological significance of these metabolic dynamics we studied the molecular and functional expression of ATP sensitive K+ (K-ATP) channels. These channels couple energetic states with membrane excitability. They are closed when ATP level is high and opened when ATP level is low, and might provide feedback mechanisms to energy supply. We report that in addition to glutamatergic neurons, the large majority of cortical GABAergic interneurons express functional K-ATP channels composed of Kir6.2 and SUR1 subunits. This corresponds to the molecular composition of K-ATP channels found in pancreatic beta cells that couple extracellular glucose level with insulin secretion. Using perforated patch recordings, to preserve intracellular metabolism, we found that glucose levels had little or no effect on evoked neuronal activity in striking contrast with lactate which dramatically enhanced it, an effect that was blocked by a lactate transporter inhibitor. This lactate effect occluded the action of tolbutamide, a K-ATP channel blocker, and was reversed by diazoxide, a K-ATP channel opener, indicating that lactate uptake by neurons and neuronal K-ATP channels act sequentially to enhance neuronal activity.
These observations strongly suggest that the in vivo increase in lactate levels would further enhance evoked neuronal activity through increased ATP production and closure of K-ATP channels, in full support with the hemo-neuronal hypothesis. Functional deactivation might be recruited as a negative feedback mechanism to compensate this metabolic effect on neuronal activity. We propose that superficial NPY-expressing interneurons through their vascular effects on diving arterioles and their inhibitory action on neuronal activity are good cellular candidates to operate this functional deactivation. |
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| responsibles | Levenes, Mongillo |
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