Tug of War During Traumatic Brain Injury

Human behavior depends on the cooperation of about 100 billion brain cells, called neurons. The generation of new neurons occurs through a process called neurogenesis. Previously, scientists thought that neurogenesis stopped before birth. However, scientists have recently found that neurogenesis can still occur after birth and continues throughout life. Injuries to the brain can lead to the death of neurons, which is called neurodegeneration. Hence, one-time severe damage or repeated smaller injuries to brain neurons can lead to serious diseases called neurodegenerative disorders. Neurogenesis is important to replace damaged neurons, especially after brain injury. Scientists try to find ways to decrease the adverse effects of brain injury. One way is to help the brain to make more neurons following injury, by enhancing neurogenesis. This can help to treat brain injuries and neurodegenerative diseases.


Figure Figure
Sites of neurogenesis in the brain. This figure shows an adult human brain where neurogenesis, or the formation of new neurons, occurs in two regions. These two regions are the hippocampus and the sub-ventricular zone (shown in blue). In the hippocampus, neurogenesis specifically occurs in an area called the dentate gyrus. One way to detect newly formed neurons is to use BrdU staining. BrdU becomes part of the DNA of a new cell and can then be seen under the microscope using specific detector molecules. The picture in the upper left shows the neurons from the hippocampus of a mouse. The mature, old neurons show a green color, while the new neurons show an additional red color because they contain BrdU in their DNA.

NEURAL STEM CELLS: THE BENCH PLAYERS
The brain is the most complex organ in the body. Our brains allow us to think, observe, analyze, move, feel, and do many other tasks. Like other organs, the brain is made up of several types of cells. Neurons NEURONS Are fundamental cells of the brain that transmit information to other cells.
are the main cells of the brain. They are considered the main players in producing the wonderful range of human behavior. A neuron connects with other neurons to transmit messages. This message transmission allows us to do all the things we do. The brain also consists of other types of cells with di erent jobs, such as supporting and nourishing the neurons, helping the neurons to transmit their signals, or defending the brain against foreign organisms [ ].
Not long ago, scientists believed that no new neurons could join the "team" of brain cells once it was formed before birth-it was thought that new neurons were not made after a person was born. Later, scientists discovered that two areas in the brain could make new neurons. These two brain areas contain special cells called neural stem cells (NSCs), which can generate new neurons through a process

NEURAL STEM CELL
Are cells that can renew themselves and can form new neurons. called neurogenesis. The two areas of the brain that contain NSCs and NEUROGENESIS A process by which new neurons are produced.
can perform neurogenesis throughout life are: ( ) the sub-ventricular zone, which is the area of the brain where most of the neurogenesis happens; and ( ) a region in the hippocampus, which is the part of the brain responsible for memory (Figure ). Interestingly, it has also been found that NSCs can act as "bench players" that join the brain-cell team in case of injury, meaning that neurogenesis increases following damage to the brain [ ].

HOW DO WE SPOT THE NEWBIES?
There are several ways to spot the neurons that have recently joined the team. BrdU staining is one method used to detect the new neurons, which are usually produced by NSCs. BrdU is a chemical that can be added to brain cells in the lab and then it becomes incorporated into the DNA of new neurons. BrdU becomes a part of and marks the DNA of new cells only, and the mature older cells do not get marked by BrdU. The staining by BrdU molecules in new cells can be detected under a microscope (Figure ).
Another strategy to find newly formed neurons is to look for their mascot. Let us pretend that each type of cell in the brain has a specific mascot. If we can spot the mascot, then we will know the team and the team is the type of brain cell! But, what is the mascot of a neuron? Newly formed neurons will have specific molecules that are made only by them (their mascot). What scientists do is to look for the presence of these specific molecules. To find these specific molecules, scientists then use specific detector molecules that stick only to the mascot of new neurons and not to other mascots. The detector molecules can be seen under a special microscope.
Yet another method is to determine the age of the new neurons. This is possible because new neurons are much younger than the neurons that you were born with. Scientists do this by looking at the carbon content of neurons. Carbon is an element found in nature and is a building block of everything in life, including cells. The properties of carbon change over time, and we can know how old something is by looking at the type of carbon it has. Think of it this way: every year, the newcomers get a new bracelet as a welcome gift, which di ers from bracelets distributed in the previous years. So, we can tell which year a member joined the team by looking at their bracelets. The bracelets are the type of carbon they have [ ].

BRAIN INJURY AND NEURODEGENERATION
Most of us have bumped our heads once or twice in our lifetimes. We may have felt some sort of pain, but woken up the next day as if nothing happened. This is known as a head injury. Head injuries usually do not lead to long-term consequences. But, if the hit to the brain was repeated or if the initial bump was very severe, head injury can lead to a traumatic brain injury (TBI). The worse the TBI, the more serious TBI An injury to the brain that disrupts normal brain functioning. the outcome will be for the injured person and the more changes will occur in that person's brain.
There are two stages to TBI, called primary injury and secondary injury ( Figure ). The primary injury involves changes in the brain that occur immediately after hitting our heads. There will be damage to cells,  Figure Events that occur following TBI. Traumatic brain injury consists of two phases: the primary injury and the secondary injury. The primary injury takes place within seconds to minutes following the onset of TBI. Primary injury involves direct damage to neurons caused by the blow to the head. The secondary injury takes place later, within minutes to weeks following the injury. The secondary injury involves the release of inflammatory molecules by microglia and other immune cells. In severe cases, microglia and other immune cells release a lot of inflammatory molecules during the secondary injury, which can lead to neuron death.
bleeding near the area of injury, and pain. Hours or even days after the primary injury, the secondary injury takes place. The secondary injury involves more changes in the brain, including excitotoxicity (when neurons are damaged or even killed because of being highly active) and inflammation. of the immune cells of the brain that are called microglia. Activated

MICROGLIA
A type of immune cell that is found in the brain. microglia release inflammatory molecules, which recruit other types of immune cells to the location of the brain injury, thus increasing the inflammation even more. This increase in inflammation is a normal response to injury and is vital to the maintenance of health. However, an uncontrolled increase of inflammation is harmful to cells.
In addition, during the secondary injury, brain cells become stressed and start to accumulate toxin molecules that can eventually lead to the death of neurons, or what we call neurodegeneration.

NEUROGENESIS AND NEURODEGENERATION: TUG OF WAR
Injury to the brain, as mentioned above, causes inflammation. Inflammation in the brain is caused by the activation of microglia and other immune cells called macrophages. These cells secrete  Figure Balance between neurogenesis and neurodegeneration following TBI. The balance between neurogenesis and neurodegeneration is determined by the environment caused by the injury. In mild TBI, there is a balance between inflammatory molecules that favor neurogenesis and other inflammatory molecules that favor neurodegeneration. The inflammatory molecules that favor neurodegeneration act as toxin molecules that kill neurons. As a result, in the cases of severe or repeated TBI, the balance is disrupted and tips more toward neurodegeneration, since the production of toxin molecules is highly increased. chemicals, such as the inflammatory molecules, that can promote either neurogenesis or neurodegeneration (Figure ). But, how?
If the brain injury is very mild, controlled inflammation in the brain will occur. This controlled inflammation has a positive e ect on neurogenesis, since it aims to replace the lost neurons. However, if the injury to the brain is very severe or if the brain injury is repeated, as often seen in certain sports activities, then this can lead to severe inflammation. Severe inflammation cannot be controlled. Some inflammatory molecules released during severe inflammation have a negative e ect on neurogenesis and form a harsh environment for growth of new neurons. In the presence of these inflammatory molecules, even if newborn neurons form then they cannot survive. So, in the case of severe or repeated head injuries, there will be more neurodegeneration than neurogenesis.
This situation is like weighing two things on a pan balance. If there diseases characterized by the progressive loss of neurons or neural function. They lead to problems with movement, or mental functioning. Most of these diseases are not curable.

MACROPHAGE
A type of immune cell involved in the process of inflammation.
are equal weights on both sides, the balance is at equilibrium. This is what happens in the case of controlled inflammation: the amount of neurogenesis that occurs is somewhat equal to the amount of neurodegeneration that took place as a result of the injury. However, if one side of the balance is heavier than the other, this will cause the balance to tilt. In the case of severe brain injury, there is uncontrolled inflammation. This causes the amount of neurodegeneration to be greater than the amount of neurogenesis (Figure ). In this situation, the balance tilts toward neurodegeneration and the secondary injury can lead to serious neurodegenerative diseases [ ].

THE EFFECTS OF NEURODEGENERATION
Neurons work together to perform all brain functions. If neurons start to die, the functions of the brain are a ected. People who su er a mild or a moderate TBI may lose a few neurons. They may experience problems with their thinking or memory, or with their ability to pay attention.
kids.frontiersin.org September | Volume | Article | Severe TBI occurs when the brain receives a severe injury, for example, during car crashes or hard falls. People who perform contact sports, such as football players, hockey players, soccer players, and boxers are examples of people who may be exposed to severe TBI or repeated TBI.
During severe TBI, many neurons die and this causes neurodegeneration to outweigh neurogenesis. Severe TBI or repeated hits on the head may put people at risk of developing neurodegenerative diseases because a great number of neurons die.
Neurodegenerative diseases can show up tens of years following TBI. Neurodegenerative diseases include Alzheimer's disease, which causes memory loss, and Parkinson's disease, in which people start to shake because they lose control of their muscles. Amyotrophic lateral sclerosis (ALS), a disease in which people lose control of their muscles, and chronic traumatic encephalopathy are other types of neurodegenerative diseases. Encephalopathy refers to diseases that a ect the function or structure of the brain and in chronic traumatic encephalopathy the patients show problems in their behavior, mood, and thinking, leading to confusion and forgetfulness.

CONCLUSION
TBIs should always be taken seriously. The damage that occurs following TBI is not always visible immediately. If you experience a TBI, it can a ect you in the long run. There are many factors that influence the outcome of TBI. If the injury is very severe, neurogenesis is not as e ective, and this can shift the balance toward neurodegeneration. So, you should always protect your head when doing dangerous activities or when playing sports. Protecting your brain is a must [ , ]!

CONFLICT OF INTEREST:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
COPYRIGHT © Hasan, Tabet, Abdelhady, Halabi, Habashy, Kobeissy and Shaito. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

EUNBI, AGE:
My name is Eunbi and I am from San Francisco. I am currently in eighth grade. Reading science articles and discovering further wonders about the world and mechanisms of human diseases are very fascinating for me. I believe that even small discoveries could influence the future of this world.

AUTHORS
HIBA HASAN I am currently a volunteer in the Biochemistry and Molecular Genetics department at the American University of Beirut. The lab focuses on understanding the pathological basis of brain injuries and tests cell-and drug-based therapies for traumatic brain injuries. I have a Master's in Biology with a specialization in Immunology, where I tested the anti-inflammatory and antioxidant activities of di erent natural agents on autoimmune diseases. I hope to pursue a Ph.D. focusing on the immunopathological basis of autoimmune disorders and hope to find a cure for such diseases.