• Researchers found that aura altered brain fluid in mice, which flowed directly into part of the peripheral nervous system that detects migraine pain.
• This previously unknown pathway of communication could potentially be targeted to develop new treatments for migraines with aura.

·         About a third of people who suffer from migraines experience a phenomenon called aura before the pain sets in. Aura includes visual disturbances and other neurological symptoms. These usually appear within the hour before migraine pain begins.

·         Scientists know that a widespread disruption of electrical activity in the brain called cortical spreading depression (CSD) causes aura. But how this disruption might trigger the pain of a migraine has been poorly understood. The sensory neurons that drive migraine pain sit outside the brain. It had previously been thought that the blood-brain barrier lies between the areas of the brain where CSD happens and the neurons that trigger migraine. This could prevent signaling molecules caused by CSD from reaching these neurons.

·         A research team led by Dr. Martin Kaag Rasmussen, formerly at NIH and now at the University of Copenhagen, and Dr. Maiken Nedergaard of the University of Rochester has been studying ways that fluids flow through and from the brain. In their new study, funded in part by NIH, they tracked the flow of cerebrospinal fluid from the brain to the peripheral nervous system in mice after CSD. Their results were published on July 5, 2024, in science.

·         Using advanced imaging techniques, the researchers observed markers injected into the cerebrospinal fluid flow from the brain rapidly and directly into a peripheral nerve structure called the trigeminal ganglion. Molecules injected into the cerebrospinal fluid were able to activate receptors on cells in the trigeminal ganglion, indicating a direct route of chemical communication.

·         Further imaging work found that the membrane that prevents external molecules from entering the trigeminal ganglion was lacking from one end of the ganglion. This created a path for cerebrospinal fluid to flow directly from the brain into the ganglion.

·         The team next traced the path of molecules injected directly into the visual cortex. This part of the brain is the most common site of aura. They found that a compound injected into the visual cortex of mice made its way into the trigeminal ganglion in about half an hour. This time delay corresponds to the typical interval between aura and headache onset.

·         To better understand the actual substances released by the brain after aura, the researchers induced CSD in mice and then measured changes in proteins found in their cerebrospinal fluid. After CSD, levels of more than 150 proteins changed in cerebrospinal fluid. Twelve of these bound directly to receptors in the ganglion. These included proteins known to be involved in migraine headache, like calcitonin gene-related peptide, or CGRP. It also included other proteins whose potential role in headache need further study.

·         “These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies,” Nedergaard says.

·         The changes in proteins observed in the cerebrospinal fluid after aura were short lived. It’s therefore likely that other processes play a role in the long duration of migraine headache. More work is needed to uncover these processes and understand how they might be targeted therapeutically.

References: Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model. Kaag Rasmussen M, Møllgård K, Bork PAR, Weikop P, Esmail T, Drici L, Wewer Albrechtsen NJ, Carlsen JF, Huynh NPT, Ghitani N, Mann M, Goldman SA, Mori Y, Chesler AT, Nedergaard M. Science. 2024 Jul 5;385(6704):80-86. doi: 10.1126/science.adl0544. Epub 2024 Jul 4. PMID: 38963846.

2.Understanding how exercise affects the body

At a Glance

• A study of endurance training in rats found molecular changes throughout the body that could help explain the beneficial effects of exercise on health.
• Large differences were seen between male and female rats, highlighting the need to include both women and men in exercise studies.

·         Exercise is one of the most beneficial activities that people can engage in. Regular exercise reduces the risk of heart disease, diabetes, cancer, and other health problems. It can even help people with many mental health conditions feel better.

·         But exactly how exercise exerts its positive effects hasn’t been well understood. And different people’s bodies can respond very differently to certain types of exercise, such as aerobic exercise or strength training.

·         Understanding how exercise impacts different organs at the molecular level could help health care providers better personalize exercise recommendations. It might also lead to drug therapies that could stimulate some of the beneficial effects of a workout for people who are physically unable to exercise.

·         To this end, researchers in the large, NIH-funded Molecular Transducers of Physical Activity Consortium (MoTrPAC) have been studying how endurance exercise and strength training affect both people and animals. The team is examining gene activity, protein alterations, immune cell function, metabolite levels, and numerous other measures of cell and tissue function. The first results, from rat studies of endurance exercise, were published on May 2, 2024, in Nature and several related journals.

·         Both male and female rats underwent progressive exercise training on a treadmill over an 8-week period. By the end of training, male rats had increased their aerobic capacity by 18%, and females by 16%. Tissue samples were collected from 18 different organs, plus the blood, during the training period and two days after the final bout of exercise. This let the researchers study the longer-term adaptations of the body to exercise.

·         Changes in gene activity, immune cell function, metabolism, and other cellular processes were seen in all the tissues studied, including those not previously known to be affected by exercise. The types of changes differed from tissue to tissue.

·         Many of the observed changes hinted at how exercise might protect certain organs against disease. For example, in the small intestines, exercise decreased the activity of certain genes associated with inflammatory bowel disease and reduced signs of inflammation in the gut. In the liver, exercise boosted molecular changes associated with improved tissue health and regeneration.

·         Some of the effects differed substantially between male and female rats. For example, in male rats, the eight weeks of endurance training reduced the amount of a type of body fat called subcutaneous white adipose tissue (scWAT). The same amount of exercise didn’t reduce the amount of scWAT in female rats. Instead, endurance exercise caused scWAT in female rats to alter its energy usage in ways that are beneficial to health. These and other results highlight the importance of including both women and men in exercise studies.

·         The researchers also compared gene activity changes in the rat studies with those from human samples taken from previous studies and found substantial overlap. They identified thousands of genes tied to human disease that were affected by endurance exercise. These analyses show how the MoTrPAC results from rats can be used to help guide future research in people.

·         “This is the first whole-organism map looking at the effects of training in multiple different organs,” says Dr. Steve Carr, a MoTrPAC investigator from the Broad Institute. “The resource produced will be enormously valuable, and has already produced many potentially novel biological insights for further exploration.”

References: Temporal dynamics of the multi-omic response to endurance exercise training. MoTrPAC Study Group; Lead Analysts; MoTrPAC Study Group. Nature. 2024 May;629(8010):174-183. doi: 10.1038/s41586-023-06877-w. Epub 2024 May 1. PMID: 38693412.