Summary: Researchers have discovered a novel mechanism called electrocalcium (E-Ca) coupling, which integrates electrical and calcium signaling in the brain’s capillaries. This process ensures proper blood flow to active neurons, which is critical for brain health and cognitive function.
Using advanced imaging, they showed how electrical waves increase calcium activity, improving blood flow through the brain’s capillary network. The discovery could pave the way for targeted treatments for neurological disorders such as Alzheimer’s by restoring disrupted blood flow.
Important facts:
- Electrocalcium coupling: Integrates electrical and calcium signals to regulate blood flow in the brain’s capillaries.
- Improvement in blood flow: Electrical signals increase calcium activity by 76%, improving the coordination of the capillary network.
- Treatment potential: Provides information on treating neurological disorders such as Alzheimer’s by restoring blood flow.
Source: University of Vermont
A team of UVM scientists led by Mark Nelson, PhD, of the University of Vermont’s Larner College of Medicine, has discovered a new mechanism that is changing our understanding of how blood flow is regulated in the brain.
The research, published in the peer-reviewed journal The Proceedings of the National Academy of Sciences (PNAS), introduces electrocalcium (E-Ca) coupling, a process that integrates electrical and calcium signaling in brain capillaries to ensure proper blood flow to active neurons.
In the human body, blood reaches the brain through superficial arteries, through arterioles (very small blood vessels that branch off from arteries) and through capillaries hundreds of kilometers long, which significantly increase the perfusion area.
The brain, an organ with high metabolic demands and inadequate energy reserves, maintains a constant blood flow despite fluctuations in blood pressure (autoregulation). However, this relies on a demand-supply process in which neuronal activity triggers local increases in blood flow to selectively deliver oxygen and nutrients to active areas.
Nelson explains that use-dependent increases in local blood flow, known as functional hyperemia, are critical for maintaining normal brain function. This process occurs through a set of mechanisms collectively referred to as neurovascular coupling (NVC), which ensures that active regions of the brain receive an adequate supply of oxygen and nutrients during periods of heightened neural activity. Importantly, these localized blood flow changes are not only vital for supporting brain function but also form the physiological foundation for functional magnetic resonance imaging (fMRI), a widely used technique to visualize brain activity in real time. Without properly functioning NVC, the brain’s ability to match blood flow with metabolic demand would be compromised, leading to potential cognitive and physiological impairments.
In addition, research has shown that impairments in cerebral blood flow (CBF)—including deficits in functional hyperemia—often emerge as some of the earliest signs of neurological conditions such as small vessel disease (SVD) and Alzheimer’s disease. These changes in blood flow can occur well before the onset of noticeable clinical symptoms, making them a potentially valuable biomarker for early detection and intervention. The disruption of normal neurovascular coupling in these conditions suggests a breakdown in the brain’s finely tuned communication between neurons and blood vessels, which may contribute to the progression of cognitive decline. Understanding and preserving these mechanisms could therefore play a crucial role in preventing or slowing the onset of neurodegenerative diseases.
Blood flow in the brain depends on mechanisms such as electrical signaling, which travels through capillary networks to upstream arteries to transport blood, and calcium signaling, which regulates local blood flow. For many years, these mechanisms were thought to operate independently.
However, Nelson’s research shows that these systems are intimately connected through E-Ca coupling, whereby electrical signals increase the influx of calcium into cells, amplifying local signals and extending their influence to neighboring cells.
The study shows that electrical hyperpolarization in hair cells is rapidly propagated through activation of capillary endothelial Kir2.1 channels. These are specialized proteins in the cell membrane that detect changes in potassium levels and amplify the electrical signal as it travels from one cell to the next.
This creates a wave-like electrical signal that travels through the capillary network. Simultaneously, calcium signals, initiated by IP3 receptors (proteins on the membranes of intracellular storage sites), release stored calcium in response to specific chemical cues.
This local calcium release improves blood flow by activating vascular responses. Ca-E coupling links these two processes, and electrical waves generated by Kir2.1 channels increase calcium activity, creating a coordinated system that adjusts blood flow locally and over long distances.
Using advanced imaging and computer modeling, the researchers were able to observe this mechanism in action. They found that electrical signals in the hair cells increased calcium activity by 76 percent, significantly increasing their ability to influence blood flow.
When the team stimulated these cells to mimic brain activity, calcium signals increased by 35 percent, showing how these signals travel through the capillary network.
Interestingly, they discovered that the signals are distributed evenly across the capillary bed. This ensures balanced blood flow to all areas, without biasing in one direction or the other.
“Recently, the UVM team also showed that the reduction in cerebral blood flow in small vessel disease and Alzheimer’s disease can be corrected by a cofactor essential for electrical signaling,” Nelson noted.
Current research suggests that calcium signaling can also be restored. The “Holy Grail,” then, is whether early restoration of cerebral blood flow after stroke can slow cognitive decline.
This discovery indicates the essential role of capillaries in regulating blood flow in the brain.
By identifying how electrical and calcium signals work through electro-calcium coupling, the research sheds light on the brain’s ability to efficiently deliver blood to areas that need oxygen and nutrients most.
This is especially important because disruption of blood flow is a symptom of many neurological disorders, such as stroke, dementia, and Alzheimer’s disease.
Understanding the mechanism of E-CA coupling offers a new framework for investigating treatments for these conditions. It could potentially lead to treatments that restore or improve blood flow and protect brain health.
This breakthrough also provides a better understanding of how the brain maintains its energy balance, which is crucial for maintaining cognitive and physical functions.
About this neuroscience research news
Author: Angela Ferrante
Source: University of Vermont
Contact: Angela Ferrante – University of Vermont
Image: The image is credited to StackZone Neuro
Original Research: The findings will appear in PNAS
Funding: The research discussed in this publication was supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) under grants K99-AG-075175 (AM), R01-NS-110656 (MTN), RF1-NS-128963-01 (R91-NS-MT), R91-NS-128963 (R91MT-01).
Additional funding was received from the National Institute of General Medical Sciences (NIGMS) through grant P20-GM-135007 (MTN and Mary Cushman), from the National Heart, Lung, and Blood Institute (NHLBI) through grant R35-HL-140027 (MTN), and from the American Heart Development Association through a Careerdo861 After a Careerdo89 and 89 AM Fellowship (20POST35210155 to AM).
Support was also received from the Totman Medical Research Trust (MTN), the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement 666881, SVDs@target, MTN) and the Leducq Foundation’s Transatlantic Network of Excellence (International Network of Excellence on Cerebral Palsy, MTN).
