Rosenegger David G, Tran Cam Ha T, Wamsteeker Cusulin Jackie I, Gordon Grant R
Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
J Neurosci. 2015 Sep 30;35(39):13463-74. doi: 10.1523/JNEUROSCI.1780-15.2015.
According to the current model of neurovascular coupling, blood flow is controlled regionally through phasic changes in the activity of neurons and astrocytes that signal to alter arteriole diameter. Absent in this model, however, is how brain blood flow is tonically regulated independent of regional changes in activity. This is important because a large fraction of brain blood flow is required to maintain basal metabolic needs. Using two-photon fluorescence imaging combined with patch-clamp in acute rat brain slices of sensory-motor cortex, we demonstrate that reducing resting Ca(2+) in astrocytes with intracellular BAPTA causes vasoconstriction in adjacent arterioles. BAPTA-induced vasoconstriction was eliminated by a general COX blocker and the effect is mimicked by a COX-1, but not COX-2, antagonist, suggesting that astrocytes provide tonic, steady-state vasodilation by releasing prostaglandin messengers. Tonic vasodilation was insensitive to TTX, as well as a variety of synaptic and extrasynaptic receptor antagonists, indicating that the phenomenon operates largely independent of neural activity. Using in vivo two-photon fluorescence imaging of the barrel cortex in fully awake mice, we reveal that acute COX-1 inhibition reduces resting arteriole diameter but fails to affect vasodilation in response to vibrissae stimulation. Our findings demonstrate that astrocytes provide tonic regulation of arterioles using resting intracellular Ca(2+) in a manner that is independent of phasic, neuronal-evoked vasodilation. Significance statement: The brain requires both phasic and tonic regulation of its blood supply to service energy needs over various temporal windows. While many mechanisms have been described for phasic blood flow regulation, how the brain accomplishes tonic control is largely unknown. Here we describe a way in which astrocytes contribute to the management of basal brain blood flow by providing steady-state vasodilation to arterioles via resting astrocyte Ca(2+) and the continuous release of prostaglandin messengers. This phenomenon may be important for understanding the declines in basal brain blood flow that occur in aging and dementia, as well as for the interpretation of fMRI data.
根据当前的神经血管耦合模型，血流量通过神经元和星形胶质细胞活动的相位变化进行局部控制，这些细胞发出信号以改变小动脉直径。然而，该模型中缺少的是脑血流量如何在不依赖于活动区域变化的情况下进行紧张性调节。这一点很重要，因为维持基础代谢需求需要很大一部分脑血流量。我们使用双光子荧光成像结合急性大鼠感觉运动皮层脑片的膜片钳技术，证明用细胞内BAPTA降低星形胶质细胞的静息Ca(2+)会导致相邻小动脉收缩。BAPTA诱导的血管收缩被一种通用的COX阻滞剂消除，并且这种效应可被COX-1拮抗剂模拟，但不能被COX-2拮抗剂模拟，这表明星形胶质细胞通过释放前列腺素信使提供紧张性、稳态血管舒张。紧张性血管舒张对TTX以及多种突触和突触外受体拮抗剂不敏感，表明该现象在很大程度上独立于神经活动。我们使用完全清醒小鼠桶状皮层的体内双光子荧光成像，发现急性COX-1抑制会减小静息小动脉直径，但不影响对触须刺激的血管舒张反应。我们的研究结果表明，星形胶质细胞利用静息细胞内Ca(2+)以独立于相位性、神经元诱发血管舒张的方式对小动脉进行紧张性调节。意义声明：大脑需要对其血液供应进行相位性和紧张性调节，以满足不同时间窗口的能量需求。虽然已经描述了许多用于相位性血流调节的机制，但大脑如何实现紧张性控制在很大程度上尚不清楚。在这里我们描述了一种方式，即星形胶质细胞通过静息星形胶质细胞Ca(2+)和持续释放前列腺素信使为小动脉提供稳态血管舒张，从而有助于基础脑血流量的管理。这种现象对于理解衰老和痴呆中发生的基础脑血流量下降以及功能磁共振成像数据的解释可能很重要。
