A New Mechanism for Neurovascular Coupling in FMRI

Originally published on the PLOS Neuroscience Community

Although fMRI is the most commonly used tool for detecting human brain activity, the blood oxygen level dependent (BOLD) signal does not directly reflect neuronal activity, but instead, measures changes in blood flow and oxygen metabolism. This “neurovascular coupling” – the translation of neural to vascular signals – lies at the core of fMRI’s utility as a proxy for neural activity, yet there’s still uncertainty over exactly how neural processes drive vascular signals. The neural-to-vascular link is largely obscured by the complex cascade of events involved in neural activity, including glucose metabolism, oxygen consumption, neurotransmitter release and recycling, and changing membrane potentials. Past research has pointed to astrocytes as key players in the neurovascular coupling game, as these cells envelop both neurons and blood vessels. A key signaling molecule, both within astrocytes and between astrocytes and other cells, is ATP, best known for its role as the “cellular energy currency.” In their recent paper published in the Journal of Neuroscience, Jack Wells, Isabel Christie and colleagues explored the physiological mechanisms by which astrocytes might serve as the neurovascular interface of fMRI. Their study tested whether astrocytic purines – including ATP and its products ADP and AMP – are critical for the BOLD response.

ATP is key to eliciting the BOLD response

The authors speculated that, if astrocytic ATP mediates the vascular response to neural activity, blocking ATP should impair the BOLD signal. In normal rats, electrically stimulating one forepaw induces a BOLD response and ATP release in the somatosensory cortex of the opposite side of the brain. Therefore, to test if ATP is required for the BOLD response, they first disrupted ATP on only one side of the somatosensory cortex, and then stimulated both forepaws. They expressed TMPAP, which breaks down purines, into one side of the forepaw region of the rats’ somatosensory cortices, and a control into the other side. Oddly enough, although these vectors weren’t cell-specific, they were mainly expressed in astrocytes – but not neurons – a convenient pattern for testing the selective role of astrocytes in neurovascular coupling.

As expected, the BOLD response to forepaw stimulation was typical in control somatosensory cortex. But the signal was reduced in cortex expressing TMPAP (see Figure, A left and B top). This suggested that purine signaling is indeed important for a normal BOLD response. But what if the altered signal resulted from some other effect of the TMPAP expression, besides the intended purine reductions? For instance, breaking down ATP and its products could lead to build-up of the inhibitory neurotransmitter adenosine, which could interfere with normal neural activity. The authors repeated the experiment, this time using an adenosine antagonist to block any effects of adenosine accumulation. The results were the same. The BOLD response was reduced with TMPAP and did not normalize by blocking adenosine (see Figure, A right and B bottom), confirming that the effect wasn’t simply an artifact of adenosine build-up.

Group activation maps (A) and response curves (B) show that the BOLD response to forepaw stimulation is reduced after blocking purine signaling (TMPAP), compared to control (EGFP). The effect remains even after accounting for adenosine build-up with the adenosine antagonist DPCPX. From Wells et al., 2015.

Group activation maps (A) and response curves (B) show that the BOLD response to forepaw stimulation is reduced after blocking purine signaling (TMPAP), compared to control (EGFP). The effect remains even after accounting for adenosine build-up with the adenosine antagonist DPCPX. From Wells et al., 2015.

Does ATP support neural and vascular signaling or just their coupling?

If astrocytic purine signaling is truly involved in the translation of neural activity to a cerebrovascular response, interfering with purines should diminish the BOLD effect (as they showed), but neural activity and the background vascular state should remain unchanged. Indeed, multiunit recordings showed that TMPAP did not affect the neural response to forepaw stimulation, and arterial spin labeling indicated no change in resting blood flow or vascular reactivity.

Astrocytic ATP: One piece of the puzzle

Results from each of these experiments provided a critical piece of the neurovascular puzzle, illustrating the role of astrocytic purines in the series of events translating neural activity to the BOLD response. Together, they suggest that ATP signaling in astrocytes is critical for a normal vascular response to neural activity, but importantly, is not needed for either neural or vascular function alone. In other words, astrocytic ATP selectively underlies the coupling of neural and vascular activity.

It’s important to note that, although these findings show that ATP is important for neurovascular coupling, it’s unlikely this is the only mechanism supporting the BOLD response. While this study doesn’t directly trace the intricate events by which ATP mediates neurovascular coupling, the authors offer several plausible pathways. ATP is known to trigger calcium responses in astrocytes, which – through a series of downstream processes – could cause vascular effects like blood vessel dilation that are key to the BOLD response. However, ATP does not just support communication between astrocytes, but is also involved in neuron-to-astrocyte and astrocyte-to-blood vessel signaling. Any of these interactions could feasibly explain why ATP is required for the vascular response to neural activity. Of course, we can’t rule out the influence of ATP in neurons, which also may modulate vascular function independent of astrocytes. Although TMPAP was primarily expressed in astrocytes, this wasn’t exclusive; it’s possible that ATP levels were also reduced in neurons and may have affected the BOLD response in distinct ways.

Many questions remain regarding the physiological origins of the BOLD response to neural activity. However, these findings from Wells, Christie and colleagues help to solidify the role of astrocytes, and to introduce ATP as a key player, in the neurovascular coupling game.

References

Wells JA, Christie IN et al. (2015). A Critical Role for Purinergic Signalling in the Mechanisms Underlying Generation of BOLD fMRI Responses. J Neurosci 35(13):5284-92. doi: 10.1523/JNEUROSCI.3787-14.2015

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