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Unlike most cells in the human body, neurons-the functional cells of our nervous system-cannot typically replace themselves with healthy copies after being damaged. 

Rather, after an injury from something like a stroke, concussion or neurodegenerative disease, neurons and their axons, fiber-like projections that relay electrical signals, are far more likely to degrade than regenerate. 

But new research from the University of Michigan opens new ways to think about neurodegeneration that could help protect patients against that degradation and neurological decline in the future. The study, published in the journal Molecular Metabolism, could even bring us a step closer to understanding the rare cases when brains do heal and open new pathways to developing treatments, the researchers said. 

Their findings, made using a well-established fruit fly model, suggest that how resilient neurons are to degradation is connected to the fundamental process of how these cells process sugar. The work was supported by the National Institutes of Health, the U.S. National Science Foundation, the Rita Allen Foundation and the Klingenstein Fellowship in the Neurosciences.

“Metabolism is often changed in brain injury and diseases like Alzheimer’s, but we do not know whether this is a cause or consequence of the disease,” said senior author Monica Dus, U-M associate professor of molecular, cellular, and developmental biology.

“Here we found that dialing down sugar metabolism breaks down neural integrity, but if the neurons are already injured, the same manipulation can preemptively activate a protective program. Instead of breaking down, axons hold on longer.” 

Postdoctoral research fellow TJ Waller, the lead scientist in the study, found that two particular proteins appear to be involved in extending the health of axons. One is called dual leucine zipper kinase, or DLK, which senses neuronal damage, and is activated by a disrupted metabolism. The other protein is known as SARM1-short for Sterile Alpha and TIR Motif-containing 1-which has been implicated in axon degeneration and is coupled with the DLK response.

“What surprised us is that the neuroprotective response changes depending on the cell’s internal conditions,” Dus said. “Metabolic signals shape whether neurons hold the line or begin to break down.”

Generally, in cases where neurons and axons don’t degrade, DLK becomes more active and the movement of SARM1 is suppressed. But there are wrinkles. In fact, prolonged DLK activation over time leads to progressive neurodegeneration, the study showed, effectively reversing earlier neuroprotective effects. 

DLK, in particular, has emerged as a target for treating and studying neurodegenerative disease. But researchers will need to confront technical challenges to control DLK’s dual harmful and beneficial functionality, Waller said.

“If we want to delay the progression of a disease, we want to inhibit its negative aspect,” Waller said. “We want to make sure that we’re not at all inhibiting the more positive aspect that might actually be helping to slow the disease down naturally.” 

Mediating a molecule like DLK’s double functionality presents a compelling puzzle researchers have yet to solve. Uncovering the mechanisms underlying how modulators like DLK switch between these protective and harmful states could hold massive implications for the treatment of neurodegenerative disease and brain injury, directly impacting clinical populations. 

Dus and Waller said that understanding this mechanism “provides a new perspective on injury and disease, one that goes beyond simply blocking damage to focusing on what the system is already doing to reinforce it.” 

Ōtākou Whakaihu Waka-led research has found stress-controlling brain cells switch on and off in a steady rhythm about once every hour – even when nothing stressful is happening.

Senior author Associate Professor Karl Iremonger, of Otago’s Department of Physiology and Centre for Neuroendocrinology, says these rhythms shape activity patterns and alertness.

“These bursts of brain cell activity seem to act like a natural ‘wake-up’ signal, and often lead to a rise in stress hormones, or cortisol.

“This world first research opens the door to exploring how these patterns affect health, mood, and sleep,” he says.

For the study, published in high-profile journal PNAS, the researchers used an optical technique called photometry to track brain cell activity of mice and rats.

“This involved shining light into the animals’ brains, allowing us to monitor brain cell activity over the day and night as the animals moved around freely. We could then look at how the activity of brain pathways is coordinated with sleep/wake patterns and stress hormone levels.”

A group of brain cells called corticotropin-releasing hormone (CRH) neurons were found to be particularly important for the daily rhythms of stress hormone release.

“These neurons turn on and off in a regular pattern about once every hour. Interestingly, we found that these changes were coordinated with patterns of sleep and waking which suggests that the pattern of release is coordinated with wakefulness or alertness.

“We also found when the CRH neurons were artificially activated, this changed the animals’ behaviour – animals that were previously quietly resting became hyper-active.”

Associate Professor Iremonger says the research findings may lead to a better understanding of how disrupted stress rhythms can result in changes in mood and disrupted sleep.

Drugs that decrease CRH stress neuron activity may also be beneficial at treating conditions associated with hyper-active stress responses.

“Our new research is helping us to understand how the brain controls these normal rhythms of stress hormone release. Knowing how these brain signals work will help us understand the links between stress hormone levels, alertness and mental health.”

More than a decade ago, researchers found that an acute complication of type 1 diabetes, diabetic ketoacidosis (DKA), can be resolved with the hormone leptin, even in the absence of insulin. 

An analysis published today in The Journal of Clinical Investigation explains how leptin affects the brain and how it might be used in future therapeutics. 

DKA happens when the body is unable to make insulin and begins to break down fat for fuel. This can lead to a life-threatening buildup of sugar (glucose) and ketoacids in the blood. Doctors have typically administered insulin to address the complication, authors noted. 

But evidence now shows that, when insulin is insufficient, the brain plays a key role in driving DKA, according to the new analysis, based in literature and research that includes studies conducted at UW Medicine since 2011. 

When the pancreas can’t make insulin, “the brain gets the message that the body is out of fuel, even if it’s not. This information is being communicated in part by a low blood level of the hormone leptin,” said senior author Dr. Michael Schwartz, professor of medicine, Division of Metabolism, Endocrinology and Nutrition at the University of Washington School of Medicine. 

Leptin helps the brain regulate appetite and body weight. Leptin is produced by your body’s fat cells. The hormone is carried by the bloodstream into your brain, particularly an area called the hypothalamus. This is the part of your brain that controls when and how much you eat. Insufficient leptin leads the brain to activate circuits that mobilize energy sources, including glucose and ketones. 

Schwartz and his team discovered this connection in 2011 when they first administered leptin into the brain of rats and mice with type 1 diabetes. At first, nothing happened. But four days later, they were astonished when the animals’ blood glucose and ketone levels became completely normal, despite ongoing severe insulin deficiency.

“I think the most amazing thing is that the blood sugars just didn’t come down, but that the levels stayed down,” he said. “If you tried to get them to rise, they came back down. If you tried to lower them, they came back up.” 

These responses suggested that the brain can maintain normal blood sugar levels even in the absence of insulin, Schwartz said. 

At the time, the diabetes research community didn’t know what to make of the discovery. 

“We now have a much better understanding of a finding that was largely ignored by the scientific community when it was first reported in 2011,” Schwartz said. 

Schwartz said he will seek FDA approval to begin human trials to test whether leptin is capable of normalizing blood sugar levels in people with type 1 diabetes. 

Positive results would open the door to pharmaceutical therapies for type 1 diabetes that target the brain.

“This is one of the most exciting discoveries of my career,” said co-author Dr. Irl Hirsch, a UW Medicine’s diabetes treatment and teaching chair and a professor of metabolism, endocrinology and nutrition at the University of Washington School of Medicine. 

Hirsch said controlling blood glucose with leptin could unlock new avenues of treatment for patients.

“Don’t get me wrong, discovering insulin 104 years ago is one of the greatest discoveries of the last century,” said Hirsch, who has had type 1 diabetes since childhood. “But this, this is the next step. This might be a better way.” 

Schwartz noted that insulin management is a substantial burden for patients and their families. 

“I think if you could treat type 1 diabetes without daily insulin injections and blood sugar monitoring, patients would say that is the greatest thing ever,” he added.

If the brain can be convinced that fuel stores are not depleted, or if specific brain neurons that trigger the production of glucose and ketones are turned off, the body stops the reaction that leads to severe hyperglycemia and DKA. 

“This new framework challenges that conventional wisdom about insulin deficiency as the sole cause of diabetic ketoacidosis that has been widely accepted for decades,” said Schwartz. “It shows that the brain plays a powerful role in the genesis of uncontrolled diabetes – and may hold the key to new treatments.” 

Funding for this research was supported by National Institutes of Health (grants DK083042, DK101997, DP2DK128802, DK089056, DK124238 and S10OD036208); the NIH-NIDDK funded Nutrition Obesity Research Center (NORC P30DK035816), Diabetes Research Center (DRC P30DK017047) and the Diabetes, Obesity and Metabolism Training Grant (T32 DK007247) at the University of Washington; and the Department of Defense Peer-Reviewed Medical Research Program (W81XWH-20-1-0250).