When a person senses danger, the body and the brain go on high alert. New research maps how the brain responds during moments of perceived harm and reveals how specific molecules help to prevent a potentially dangerous situation from triggering an epileptic seizure. A researcher says that this new knowledge could lead to improved antiseizure treatments or more effective insomnia medicines.
Imagine strolling through a park when a lion suddenly appears on the path ahead. In that instant, your brain automatically activates the fight-or-flight response, preparing you to either stand your ground or make a swift escape – the latter being the usual course of action.
The fight-or-flight response is one way people cope with perceived danger. It speeds up the heart rate, suppresses the immune system and increases blood glucose and blood pressure, priming for action.
For years, researchers have examined the physiological effects of perceiving potential harm, but the assumption has been that the fight-or-flight response has different effects on the brain.
Recent research challenges this by showing how the brain undergoes its own major metabolic upheaval to prepare for fighting or fleeing.
The findings uncover molecular biological defence mechanisms that could potentially be harnessed to develop new medicines for conditions such as epilepsy or insomnia.
“The same mechanisms that drive the fight-or-flight response also wake us up each morning. More deeply understanding how the brain regulates this process could thus lead to more effective insomnia medicines. However, this requires more advanced techniques for studying this phenomenon in living animals,” explains a researcher behind the study, Maiken Nedergaard, Professor, Center for Translational Neuromedicine, University of Copenhagen, Denmark and Center for Translational Neuromedicine, University of Rochester, NY, USA.
The research has been published in Cell Metabolism.
How the body reacts in panic situations
When the fight-or-flight response is activated, norepinephrine levels surge dramatically. Norepinephrine helps to release glucose from the liver’s glycogen stores and frees fatty acids from brown fat tissue.
The muscles can then use these energy sources, ensuring that sudden confrontation with a lion immediately primes muscles for action, regardless of whether fleeing or fighting is chosen. At such moments, energy is never a limiting factor.
“The physiological effects of norepinephrine are well understood, and research has long established that the brain also releases norepinephrine, influencing its access to glucose. However, since the brain does not metabolise fatty acids, why they are released has remained an open question,” says Maiken Nedergaard.
Researchers have now answered this crucial question.
Free fatty acids affect the cell membranes
The researchers assessed the effects of exposing both cultured cells and living animals to elevated concentrations of free fatty acids. They also analysed the effect of inhibiting lipase – the enzyme that converts fat into fatty acids.
“Free fatty acids also function as signalling molecules. This affects cell membranes, which undergo structural changes under their influence. These changes affect membrane channels, transport molecules and pumps, rapidly altering cells’ signalling capabilities,” explains Maiken Nedergaard.
Free fatty acids influence brain cell pumping
For the first time, this research showed that norepinephrine – and the resulting increase in free fatty acid concentration in the brain – affects brain functioning through both astrocytes and neurons.
Like liver cells, astrocytes contain glycogen, and one effect of norepinephrine is that this glycogen is released as glucose into the brain, providing additional energy.
Free fatty acids are also released, and they influence the sodium–potassium pump in cell membranes, reducing astrocytes’ ability to absorb potassium effectively and making them swell.
A high concentration of free fatty acids in neurons leads to hyperpolarisation, reducing their ability to participate in electrical signalling within the brain.
“Although it was already known that free fatty acids affect the sodium–potassium pump, their broader implications for brain functioning had not been considered until now,” notes Maiken Nedergaard.
Mice deficient in free fatty acids developed epilepsy
In other experiments, researchers reduced the concentration of free fatty acids in the brains of mice by inhibiting lipase. As a result, neurons were no longer hyperpolarised and could be more easily activated.
This might seem beneficial, but Maiken Nedergaard explains why this can be problematic when people become afraid.
“During moments of intense fear, neurons may becoming overactivated, which could lead to an epileptic seizure. This is why having a mechanism that limits neuronal activity during the fight-or-flight response is crucial – and free fatty acids serve precisely this function,” she says.
The researchers found that giving mice a lipase inhibitor, preventing them from producing free fatty acids in the brain, caused epileptic seizures in all of them.
Improving medicines
Maiken Nedergaard explains that the study offers new insight into how the brain responds to fear. Norepinephrine is released in the brain, triggering the release of glucose from astrocytes’ glycogen stores and increasing the concentration of free fatty acids from the brain’s fat reserves.
The brain needs glucose to make rapid and accurate decisions, and free fatty acids help to regulate this process – preventing excessive neuronal activity that could lead to an epileptic seizure.
According to Maiken Nedergaard, this insight could be harnessed to develop improved medicines.
“One potential approach would be to create medicines that enhance lipase activity, thereby increasing free fatty acid concentrations in the brain and reducing the risk of neuronal overactivation – especially important for people with epilepsy. The same mechanism might also be useful for developing improved insomnia medicines, since both free fatty acids and norepinephrine contribute to wakefulness,” concludes Maiken Nedergaard.
