Blood: Neurons calling, I must go
Blood ebbs and flows throughout the body, carrying various hormones and nutrients and catering to the needs of the entire body. Cerebral circulation or the way blood flows in the brain is crucial for its normal functioning. The blood vessels innervating the various pockets of the brain deliver oxygen and glucose. When this circulation is impaired, it can lead to conditions such as stroke, cerebral haemorrhage, and certain age related disorders such as Alzheimer’s disease. An important question here, is exactly which cell type is responsible for controlling the blood flow into areas of energy requirement in the brain? Is it solely the nerve cells, which signal the blood vessel flow, or is the control the other way round?
A role reversal?
Any process that tinkers with blood flow, be it diseases such as diabetes or common drugs like statins and anti-inflammatories, can have cascading effects in the brain. Doctors often prescribe statins for people with high cholesterol to lower their total cholesterol and reduce their risk of a heart attack or stroke. However, use of statins for a prolonged period, reportedly caused memory loss and confusion in some patients, following which FDA had issued a warning regarding its adverse effects on cognition. Different research groups have shown controversial findings and claimed to not only improve learning and memory, but also provide protection against the onset of Alzheimer’s disease. The underlying fact is that blood seems to make decisions for the brain and opens a completely unexplored facet of neurovascular signaling.
So how does the blood exert control over the brain? Questions such as how do neurons come up with a request and which cell types secrete molecules for the neuron-to-blood messaging, still leaves researchers puzzled. Neuroscientists have come up with various suspects such as astrocytes in the central nervous system, pericytes that dot the capillaries and the endothelial cells.
Astrocytes are star shaped cells in the brain and spinal cord, which provide nutrients, maintain extracellular ion balance and aid in repair and scarring process following an injury.The astrocyte is at a strategic position, with one arm at the blood vessel, and the other at the neuronal membrane and was viewed as a neurovascular bridge. Increased activity of neurones triggers Ca2+ signals in astrocytes and this could be the integrating signal for the neurovascular unit. This astrocyte activity leads to the release of vasoactive agents that regulate the local blood flow. However, this theory is too simple, and especially when considering effects of blood on brain, does not make perfect sense. Recent studies have begun to directly challenge the involvement of astrocytes in neurovascular coupling. Hence, cell types, which originate from blood vessels, may hold the key to this puzzle.
Neuroscientist Atwell and his colleagues, University College London, focused on pericytes, the contractile cells outside of capillaries. Their results were based on the concept that most neurons are closer to capillaries than to arterioles, thus making pericytes the target for neuron signaling. The team in 2014 demonstrated that pericytes are the first vascular elements to dilate during neuronal activity. They further observed rapid pericyte death in a neuropathological condition, ischemia. This led to their conclusion that pericytes may regulate cerebral blood flow.
Whether blood flow is controlled solely by capillary pericytes, or also by arteriole smooth muscles still remained controversial. Neuroscientists Robert Hill and Jaime Grutzendler of Yale University and colleagues published a paper in 2015, in Neuron claiming that pericytes do not have contractile ability, as they lack actin. They identified that distinction between arterioles and capillaries based on diameter is the cause of such a contradictory conclusion in the previous study by Atwell and his team. Hill concluded that SMA (smooth muscle actin) and cell morphology are the only reliable means of distinction and that it is the smooth muscles in the arterioles, which actually control blood flow in the brain.
Next, the endothelial cells. As the innermost layer of all the blood vessels in the body, endothelial cells are perfectly poised to detect chemical signals from their surroundings and carry ultrafast messages along vessels, Hillman says. To establish the critical role of endothelial cells in neurovascular coupling, the team in Columbia led by Hillman selectively disrupted endothelial vasculature in rat brains. They found that blood no longer responded to sensory stimulus. This means that even drugs that do not cross the blood–brain barrier, but act on the endothelium, could influence neurovascular coupling. The team has also proposed the most plausible mechanisms that could be involved and the molecules responsible for triggering the signals. This area remains to be further explored to answer how endothelium cooperates with astrocytes and other cells types to bridge the neurovascular junction.
Taking baby steps to head rush
A baby’s brain is being shaped up as they grow, and in terms of neuron-blood signaling, quite literally! Functional magnetic resonance imaging (fMRI) is a neuroimaging procedure, which measures brain activity by detecting changes associated with blood flow. Increased metabolic demand in an area causes increased blood flow and thus a positive signal. However, in young babies, it was observed that in response to an external stimulus, blood does not rush to the area, thus resulting in a negative signal. Research in young rats showed similar results, confounding the researchers as to how the hunger cries of neurons go unanswered. The team found that as the rats age, blood rushes into the regions of metabolic demands. So why does the transition from negative to positive signal take time? Are there actually starving areas in an infant’s brain, and would that not damage the developing brain?
In a series of whisker plucking experiments in mice, another group demonstrated that enhancing the neural activity leads to an increase in vascular density and branching. Thus in young brains, vascular architecture is built over time, responding to metabolic stimulus. Thus, the neurovascular signaling is not innate and the intricate pathway by which neurons call to blood is more of an acquired skill. The hunger patches in the neonatal brain, is thus the driving force to build the vascular microarchitecture.
From the body of research done so far, there is definitely a link between blood modulation and neuron signaling in the brain. This has the potential to open up a much wider area of therapeutics, by targeting blood to modulate the brain in the case of diseases such as hypertension, stroke, dementia and epilepsy.
The original article can be accessed here .