It’s not just in your head: Stress may lead to altered blood flow in the brain

UNIVERSITY PARK, Pa. — While the exact causes of neurodegenerative brain diseases like Alzheimer's and dementia are still largely unknown, researchers have been able to identify a key characteristic in affected brains: reduced blood flow. Building upon this foundational understanding, a team at Penn State recently found that a rare neuron that is extremely vulnerable to anxiety-induced stress appears to be responsible for regulating blood flow and coordinating neural activity in mice. 

The researchers found that eliminating type-one nNOS neurons — which make up less than 1% of the brain’s 80 billion neurons and die off when exposed to too much stress — resulted in a drop in both blood flow and electrical activity in mice brains, demonstrating the impact this neuron type has on the proper brain functions of animals, including humans. They published their research today (Nov. 11) in eLife. 

Patrick Drew, professor of engineering science and mechanics at Penn State and principal investigator on the project, explained that although more than 20 different varieties of neurons make up any section of the brain, type-one nNOS neurons in the somatosensory cortex — the region that processes touch, temperature and other sensory input from the body — play a critical role in stimulating the "spontaneous oscillation” of arteries and veins in the brain. 

“In your brain, arteries, veins and capillaries help move fluid around by constantly dilating and constricting every few seconds, which we call spontaneous oscillation,” Drew said. “Previous work from our lab has shown that nNOS neurons are important for regulating blood flow in the brain. After targeting and eliminating a subset of these neurons, we observed a significant reduction in the amplitude of these oscillations.” 

According to Drew, who also holds affiliations with the biomedical engineering, neurosurgery and biology departments at Penn State, when mice are exposed to mentally stressful experiences, these delicate neurons can easily die. While other researchers have previously connected aging with reduced brain performance and increased risk to neurodegenerative diseases, Drew said there is much less research on stress and the negative impacts it can have on blood flow. 

“We are broadly interested in how blood flow is regulated in the brain, as it supplies nutrients and oxygen to neurons,” Drew said. “Reduced blood flow is one of many contributing factors to reduced brain function and neurodegenerative diseases. While we know aging plays a major role in this, losing these rare neurons to chronic stress could be an unexplored environmental cause for poor brain health.” 

To understand what happens without type-one nNOS neurons in the brain, the team injected mice with a mix of saporin — a toxic protein capable of killing neurons — and a chemical chain of amino acids known as a peptide, which can identify and latch onto specific genetic markers emitted by type-one nNOS neurons. These markers differentiate type-one nNOS neurons in the brain, allowing the researchers to systematically deliver saporin and eliminate them without harming other neurons. The team at Penn State is the first to use this method to target these specific neurons, according to Drew. While a mouse brain isn’t a perfect model for the human brain, much of the physiology — including neuronal type and composition — match, Drew said, so this type of work can reveal information that likely maps to humans.  

After injecting the mice, the researchers recorded changes in brain activity and physical behaviors like eye dilation and whisker movement. The team observed cerebral blood vessel oscillations at micrometer-level resolution — roughly 100 times smaller than the width of a human hair, according to Drew. The researchers also used electrodes and advanced imaging to track electrical currents in the brain. 

The mice showed not just reduced blood flow, but weaker neural activity across the brain, indicating that these type-one nNOS neurons seem to be important in helping neurons communicate with one another, Drew explained. Additionally, the team identified these reductions in blood flow and neural activity were higher during sleep than in the awake state, indicating these neurons could play a role in supporting the brain during sleep. 

According to Drew, optimizing this procedure will provide an efficient and non-genetic way for researchers to study type-one nNOS neurons and the impacts of losing them in further detail. Although it is too early to draw a direct connection between reduced density of these neurons with increased risk of Alzheimer’s and dementia, Drew said the future of this research will focus on investigating how the loss of these neurons interacts with genetic risk factors for the diseases. 

Other Penn State-affiliated authors on the project include Nicole Crowley, associate professor of biology; Kevin Turner, who obtained his doctorate in bioengineering and biomedical engineering at Penn State; Dakota Brockway, who obtained his doctorate in neuroscience from Penn State; Kyle Gheres, who obtained his doctorate in molecular cellular and integrative biosciences from Penn State; Md Shakhawat Hossain, a biomedical engineering doctoral student; Keith Griffith, a doctoral student in the College of Medicine; and Denver Greenawalt, a molecular, cellular and integrated biosciences doctoral student. Additionally, Qingguang Zhang, assistant professor of biomolecular science, neuroscience and physiology at Michigan State University, contributed to this research.  

This work was supported by the U.S. National Institute of Health and the American Heart Association’s predoctoral fellowship.