Brainwide blood volume reflects opposing neural populations | Nature

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Subjects

- Neural circuits

- Neuro–vascular interactions

Abstract

The supply of blood to brain tissue is thought to depend on the overall neural activity in that tissue1,2,3,4,5,6,7,8,9, and this dependence is thought to differ across brain regions3,4,10,11,12,13 and across brain states3,14,15,16,17. However, studies supporting these views have measured neural activity as a bulk quantity and related it to blood supply following disparate events in different regions. Here we measure fluctuations in neuronal activity and blood volume across the mouse brain, and find that their relationship is consistent across brain states and brain regions but differs in two opposing brainwide neural populations. Functional ultrasound imaging (fUSI) revealed that whisking, a marker of arousal, is associated with brainwide fluctuations in blood volume. Simultaneous fUSI and Neuropixels recordings showed that neurons that increase activity with whisking have distinct haemodynamic response functions compared with those that decrease activity. Their summed contributions predicted blood volume across states. Brainwide Neuropixels recordings revealed that these opposing populations coexist in the entire brain. Their differing contributions to blood volume largely explain the apparent differences in blood volume fluctuations across regions. The mouse brain thus contains two neural populations with opposite relations to brain state and distinct relationships to blood supply, which together account for brainwide fluctuations in blood volume.

Main

The blood supply to the brain is tightly correlated with neuronal activity1,2,3, and this neurovascular coupling is usually described by a haemodynamic response function (HRF) that acts as a filter on the neural activity4,5,6,7,8,9,18,19. It is not clear, however, whether neurovascular coupling is consistent across brain regions3,10 and across brain states3,14. Whereas some studies argued that the HRFs are similar across regions8,15 and always positive20, others have reported that in some sites or brain regions3,4,10, HRFs are weaker or even negative11,12,13. Moreover, some studies suggested that the HRF is stronger in non-rapid eye movement (NREM) sleep16 or during rest15; however, others found it to be weaker during rest17. Potentially, blood supply might be influenced by arousal21, attention22 or anticipation18,23 independently of neuronal firing1.

These and other studies of neurovascular coupling, however, summarized neural activity with bulk measures, which cannot distinguish the potentially different correlates of different neurons. Neurovascular coupling may differ across cell types3,24,25—for example, in neurons versus glia26 or in excitatory versus inhibitory27,28,29 neurons, and might be mediated by neuromodulators30,31 that are released by a minority of neurons. Indeed, some neurons appear to correlate positively, and others appear to correlate negatively, with local blood signals32. Neurons with different activities and different coupling to blood supply would not be distinguishable in bulk measurements of neural activity.

Moreover, studies of neurovascular coupling in different regions—olfactory bulb33, visual cortex18,23, somatosensory cortex34, frontal cortex35 or wider regions of the cortex14—have measured activity with respect to disparate sensory stimuli or behavioural events. These results, therefore, are difficult to compare and assemble into a unified view of neurovascular coupling across the brain.

To overcome these limitations, we measured brainwide blood volume and brainwide neural activity in relation to brainwide neural events. Functional ultrasound imaging (fUSI)36 revealed that arousal is associated with stereotyped, brainwide changes in blood volume. Simultaneous Neuropixels recordings8 revealed that neurons that increase activity with arousal37,38,39 have distinct HRFs compared with those that decrease activity with arousal37,38,39. Their summed contributions predicted blood volume across brain states. Brainwide recordings40 with Neuropixels probes41 revealed that these opposing populations coexist in every brain region. Their combined activity predicts brainwide fluctuations in blood volume. These results indicate that neurovascular coupling reflects two opposing brainwide neural populations and is consistent across brain regions and brain states.

Arousal events modulate brainwide blood volume

We used fUSI to measure changes in blood volume across multiple brain regions. In each session we imaged a coronal plane (Fig. 1a) and we varied the plane across sessions so as to cover the posterior half of the cerebrum, the interbrain, most of the midbrain and part of the pons (Supplementary Table 1). We assigned each voxel to a brain region42 (Methods), and computed the median activity within each region. Mice were head-fixed but were free to run on a wheel and spontaneously went through varying states of arousal.

Fig. 1: Arousal events modula