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. 2012 Dec;32(12):2135-45.
doi: 10.1038/jcbfm.2012.115. Epub 2012 Aug 8.

The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand

Lane K Bekar  1 , Helen S Wei, Maiken Nedergaard
Affiliations

The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand

Lane K Bekar et al. J Cereb Blood Flow Metab. 2012 Dec.

Abstract

Given the brain's uniquely high cell density and tissue oxygen levels bordering on hypoxia, the ability to rapidly and precisely match blood flow to constantly changing patterns in neural activity is an essential feature of cerebrovascular regulation. Locus coeruleus-norepinephrine (LC-NE) projections innervate the cerebral vasculature and can mediate vasoconstriction. However, function of the LC-mediated constriction in blood-flow regulation has never been addressed. Here, using intrinsic optical imaging coupled with an anesthesia regimen that only minimally interferes with LC activity, we show that NE enhances spatial and temporal aspects of functional hyperemia in the mouse somatosensory cortex. Increasing NE levels in the cortex using an α(2)-adrenergic receptor antagonist paradoxically reduces the extent of functional hyperemia while enhancing the surround blood-flow reduction. However, the NE-mediated vasoconstriction optimizes spatial and temporal focusing of the hyperemic response resulting in a sixfold decrease in the disparity between blood volume and oxygen demand. In addition, NE-mediated vasoconstriction accelerated redistribution to subsequently active regions, enhancing temporal synchronization of blood delivery. These observations show an important role for NE in optimizing neurovascular coupling. As LC neuron loss is prominent in Alzheimer and Parkinson diseases, the diminished ability to couple blood volume to oxygen demand may contribute to their pathogenesis.

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Figures

Figure 1
Figure 1
Enhanced cortical norepinephrine (NE) is associated with decreased vessel diameter. (A, B) Multiphoton images of fluorescein isothiocyanate (FITC)-dextran loaded pial vessels and penetrating arterioles before (pre), 25 and 40 minutes after administration of the α2-adrenergic receptor antagonist atipamezole (ati). Note that surface arteries show constriction (red arrows), whereas veins (blue arrows) do not. Scale bar in (A) is 100 μm and in (B) 20 μm. (C, D) Histograms showing % change in vessel diameter at 25, 40, and 55 minutes after atipamezole administration show that the response remains significant for >1 hour. *P<0.05, **P<0.01, paired t-test.
Figure 2
Figure 2
Characterization of norepinephrine (NE)-mediated effects on temporal dynamics of the blood distribution response to hindlimb stimulation. (A) Schematic of animal preparation with thin skull cranial window and limb stimulation. (B) Intrinsic imaging of total hemoglobin (570 nm) in response to hindlimb stimulation showing response in a cortical NE-depleted (top), nontreated (middle), and NE release-enhanced mouse (bottom) for comparison. The seven image sequences illustrate 1 second bins before and after stimulation normalized to the 1 second bin before stimulation. A, anterior; ati, atipamezole; con, control; FL, forelimb; HL, hindlimb; L, lateral; M, medial; P, posterior; stim, stimulation. Scale bar is 1 mm. (C) Average intensity over 15 seconds in hindlimb and forelimb regions for the different treatment groups (control, n=24; DSP-4, n=15; atipamezole, n=9). (D) Histogram comparing full widths at half maximal hindlimb hyperemic responses shown in (C) (Holm-Sidak test, *P<0.05, **P<0.01). (E) Comparison of maximal changes in light reflectance after hindlimb stimulation (Holm-Sidak test, *P<0.05, **P<0.01).
Figure 3
Figure 3
The locus coeruleus decreases blood distribution to optimize neurovascular coupling. (A) Optical imaging for spatial assessment of the blood distribution response to hindlimb stimulation. Corresponding 20% peak threshold masks are attached. (B) Combined temporal and spatial aspects of drug effects determined by summing pixel intensities of the three 1-second 20% threshold masks 1 to 4 seconds after stimulation (control, n=24; DSP-4, n=15; atipamezole, n=9; Dunn's test, *P<0.05). (C) 20% threshold mask of reduced (left, 610 nm), and total (570 nm) minus reduced (right) hemoglobin response. Hbr, reduced hemoglobin; Hbt, total hemoglobin. (D) Quantifying Hbt 20% threshold mask pixels outside the corresponding Hbr threshold mask gives a measure of metabolism-flow disparity. Hbr volumes show no difference (top) whereas Hbt-Hbr volumes are significantly different (bottom) (DSP-4, n=7; control, n=8; t-test, P=0.003). Scale bars in (A) and (C) are 1 mm. FL, forelimb; HL, hindlimb.
Figure 4
Figure 4
The locus coeruleus-mediated decrease in vessel diameter enables rapid redistribution of red blood cells. (A) Intrinsic imaging of total hemoglobin in response to hindlimb stimulation (HLS) followed by forelimb stimulation (FLS) showing responses in a cortical norepinephrine (NE)-depleted (top), nontreated (middle), and NE release-enhanced mouse (bottom) for comparison. Scale bar is 500 μm. (B) Average intensity over 15 seconds in hindlimb and forelimb regions. Note the HLS-evoked decrease in blood volume in the forelimb region immediately before being overridden by an FLS-mediated blood distribution increase in the control and atipamezole groups. (DSP-4, n=5; control, n=9; atipamezole, n=5). (C) The blood distribution increase in the HL region is prolonged in NE-depleted animals (Holm-Sidak test, P=0.01). Reflectance sum is the temporal sum of the % change in reflectance after hindlimb stimulation as shown by the pink shaded area in (B).
Figure 5
Figure 5
The locus coeruleus affects rate of blood redistribution. (A) Forelimb region responses (570 nm) to hindlimb (HLS), forelimb (FLS), and combined hindlimb-forelimb stimulation (hlFLS). (B) The slope of the FLS-mediated blood distribution increase is greater after HLS (with associated norepinephrine (NE)-mediated constriction) compared with FLS alone (paired t-test, P=0.03). (C) Schematic summarizing the proposed impact of NE on the sensory hyperemic response. On the left are the average blood distribution responses to HLS from Figure 2C representing low NE (DSP-4), mid NE (con) and high NE (ati). They show the NE-mediated effects on the temporal aspects of the hyperemia. On the right are the corresponding pictorials of single blood vessels representing the vascular tree spanning the somatosensory cortex, before and after HLS. Under low NE conditions (lowest baseline vascular tone), HLS leads to release of local vasodilators with an increase in blood flow and limited corresponding constriction or redirection of blood flow in the surrounding cortex. Under high NE conditions, HLS releases vasodilators with subsequent global NE release to constrict the vasculature and spatially and temporally synchronize the hyperemic response with the active HL region.
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