Andrew Qian

IR1/3/10GT
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I. Introduction

Traumatic Brain Injury affects approximately 2.8 million people in the United States each

year, and around 50,000 of those people will die from TBI related causes. Those who survive are

at risk of suffering from life long disabilities, such as impaired thinking or memory, loss of

motor control, and even loss in emotion functioning. These chronic issues not only affect the

individuals with TBI, but can have lasting effects on families and communities as well. Today, as

a cumulative result of past traumatic brain injuries, an estimated 5.3 million men, women, and

children are living with a permanent TBI-related disability in the United States. ​(“How Many

People Are Affected”)​.Clearly, traumatic brain injuries pose a serious problem to the well-being

of the people of the United States. Currently, however, there remains no efficient method to treat

traumatic brain injuries. This paper discusses the potential of astrocytes as a area of study, and

how astrocytes may be the key in allowing researchers to develop an effective treatment method

for Traumatic Brain Injury. Overall, the evidence points to the possibility that ​Stimulating

astrocytes will allow for increased cell communications among brain cells, acceleration of the

process of neurogenesis and neuroplasticity, and increase in the efficiency of recovery of the

brain after traumatic brain injury.​ Astrocytes have the potential to treat the effects of TBI, and

could play a key role in curing this issue that ails millions of Americans.

Background Section:

A. TBI is caused by an external injury to the head where the brain is damaged after collision
with the sides of the brain.
a. Despite the detrimental effects of TBI, it is relatively easy to receive as they can
come from everyday things, such as falls, and traffic accidents.
i. “The leading causes of TBI are falls, motor vehicle crashes and
traffic-related incidents, collisions with an object, and assaults.”
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(“What Causes TBI?”) - ​Simply here to show that TBI can result from
everyday things, despite the long lasting effects that it may have.
Important because it shows the urgency in needing to find an effective
treatment method.
b. TBI has disastrous effects due to the way the brain is structured - The neurons in
the brain are responsible for certain areas of the body. After injury, these neurons
are impaired and are no longer able to function properly, resulting in the
previously noted disabilities.
i. “A limited number of neurons responsible for specific tasks perform
the brain’s many functions. A specific region in the brain controls the
muscles moving the hand, for example, while another group of
neurons controls the muscles involved in talking... This very specific
localization of functions within the brain is the reason injuries to
different brain regions lead to varied symptoms.” (Pekna, 2) ​-
Important to include because it explains how TBI works; it explains why
TBI can cut off certain parts of the body depending on which part of the
brain is injured. This is important to include in the background section as
it lets readers know why certain things happen.
ii. “Brain injury affects neuronal circuitry by causing the death of
neurons and glial cells and destroying connections between them. This
includes the cellular extensions (dendrites and axons) through which
neurons receive and emit signals by means of molecules called
neurotransmitters.” (Pekna, 12) - ​This, like the one above it, is
important to include because it continues the explanation of what happens
into the molecular levels. It details how all the connections between the
brain cells and the rest of the body are cut off, which supports the previous
evidence in showing that it would result in the lost of certain bodily
functions.
c. In the brain, after injury, it will begin to perform neurogenesis, which allows the
brain to recover some of the functions that were lost after injury
i. “Brain injury leads to increased neural plasticity in the spared
regions. This allows the neurons in these regions to take over the
sensory or motor functions that had been performed by the damaged
areas. This remapping of function (indeed similar to drawing a new
map) is critical in the recovery of function.” (Pekna 3) ​ - Important
because it gives information on how the brain heals.
B. Astrocytes are a type of glial cell in the brain that is responsible for a lot of neuronal
processes
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a. Astrocytes are a type of glial cell. It is one of the main macroglia, and is the focus
of this research paper.
i. Astrocytes generally play a very supportive role in the human brain, and
they it has been discovered that they also play a main role in
communication between cells in the brain.
1. “Astrocytes have hundreds of 'endfeet' spreading out from
their body. They look like mini octopi, and they link these
endfeet with blood vessels, other astrocytes and neuronal
synapses. Calcium is released from internal stores in astrocytes
as they are stimulated, then calcium travels through their
endfeet to other astrocytes. The term 'calcium waves' describes
the calcium release and exchange between astrocytes and
between astrocytes and neurons. Scientists at Yale, most
notably Ann H. Cornell-Bell and Steven Finkbeiner, have
shown that calcium waves can spread from the point of
stimulation of one astrocyte to all other astrocytes in an area
hundreds of times the size of the original astrocyte.
Furthermore, calcium waves can also cause neurons to fire.”
(“​The Root of Thought”) - ​ This is important to put because it not
only gives information onto what glial cells do in the brain, but it
also gives information that directly applies to many of the key
ideas that will be presented later in the paper. It mentions
communication, which is one of the main supporting factors of my
thesis that proves how astrocytes are able to regulate many of those
neuronal processes, which is important for the controls.
ii. Astrocytes have many different jobs in the brain besides communication.
Astrocytes also control the flow of blood in the brain as well.
1. “Astrocytes make extensive contacts with blood vessels and
have multiple bidirectional interactions with blood vessels,
including regulation of local CNS blood flow. Recent findings
show that astrocytes produce and release various molecular
mediators, such prostaglandins (PGE), nitric oxide (NO), and
arachidonic acid (AA), that can increase or decrease CNS
blood vessel diameter and blood flow in a coordinated manner.
Moreover, astrocytes may be primary mediators of changes in
local CNS blood flow in response to changes in neuronal
activity” (Sonfroniew, Vinters 4) - ​This is important because it
gives more information on what astrocytes do in the brain, and
shows just how important these cells are to brain function.
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iii. Finally, astrocytes have shown to be important for brain development in

both gray and white matter of the brain.
1. “Molecular boundaries formed by astrocytes take part in
guiding the migration of developing axons and certain
neuroblasts. In addition, substantive evidence is accumulating
that astrocytes are essential for the formation and function of
developing synapses by releasing molecular signals such as
thrombospondin.” (Sonfroniew, Vinters 6) - ​This evidence, like
the one above it, is very important because it gives information on
what astrocytes do in the brain. This, however ,is slightly more
important to focus on because it notes that astrocytes play a role in
development in the brain, which is highly important because aiding
in developments means that astrocytes could potentially help
develop new neurons in the brain as well, allowing the brain to
recover from TBI.

Control 1: ​Neurogenesis
A. By stimulating astrocytes in the brain, it will cause them to release gliotransmitters,
which will allow them to communicate with the neurons to enhance neurogenesis.
a. TBI can promote Neuronal Stem Cell (NCS) proliferation
i. “The results showed that mild TBI did not affect neurogenesis at any
of the three stages. Moderate TBI promoted NSC proliferation
without increasing neurogenesis. Severe TBI increased neurogenesis
at all three stages.” (Wang 2016) ​ - Important because it shows that
something in the response to TBI causes more NSC proliferation. This
means that when TBI occurs, the change in the environment of the brain
triggers a chemical response, which includes the precipitation of
neurogenesis.
B. Through cell signaling, astrocytes are able to induce, and regulate, NSC differentiation
a. Astrocytes, through ephrin B signaling, regulates neurogenesis in the brain. This
is highly important because it shows that astrocytes control the process of
neurogenesis, so they could probably enhance it, or cause it to happen.
i. “We show that ephrin-B2 presented from rodent hippocampal
astrocytes regulates neurogenesis ​in vivo​. Furthermore, clonal analysis
in NSC fate-mapping studies reveals a novel role for ephrin-B2 in
instructing neuronal differentiation.” (Randolph 2012) ​- Important
because it supports the idea that astrocytes are responsible for controlling
neurogenesis, so it is plausible that by some sort of stimulation, we can
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manually cause the astrocytes to induce neurogenesis. Being able to

control neurogenesis is important because it means that scientists could
induce it whenever it was necessary, and the brain could develop new
neurons to replace the ones that were lost, effectively treating TBI.
b. A detailed explanation shows that the different types of ephrin signaling instructs,
or causes, certain types of proliferation to happen
i. “Recent studies have also indicated that ephrin/Eph signaling plays an
earlier role in regulating stem cell behavior. For example,
ephrin-A/EphA signaling promotes embryonic telencephalic NSC
differentiation, and ephrin-B3/EphB3 signaling may exert an
anti-proliferative effect on NSCs in the developing SVZ. Within the
adult CNS, infusion of ephrin-B2 or EphB2 ectodomains into the
lateral ventricles induced SVZ NSC proliferation...” (Ashton et al. 2) -
This piece of evidence is important because it shows that ephrin signaling
plays a very important role in regulating stem cell behavior. This is
important, because if we can prove that astrocytes control much of Eph
signaling in the brain, then the connection can be made that astrocytes
play a very large role in causing and regulating neurogenesis. Being able
to control neurogenesis is important because it means that scientists could
induce it whenever it was necessary, and the brain could develop new
neurons to replace the ones that were lost, effectively treating TBI.
C. Another Way that astrocytes may play a role in neurogenesis is through the
Jagged1-mediated Notch Pathway
a. “The Notch receptor family is involved in a large number of cell fate
decisions during development and their activation can promote an
undifferentiated, precursor cell state. Notch1 and its cognate ligand Jagged1
are expressed in the neurogenic niches in the adult mammalian brain”
(Wilhelmsson et al. 3) - ​This piece of evidence is important because, like the
evidence about ephrin signaling, indicates that astrocytes may regulate the process
of neurogenesis. This provides another possible way that astrocytes may regulate
neurogenesis, which allows one to infer that the process of neurogenesis requires
activation from many different factors. Being able to control neurogenesis is
important because it means that scientists could induce it whenever it was
necessary, and the brain could develop new neurons to replace the ones that were
lost, effectively treating TBI.

Main Idea 3​: Neuroplasticity

A. Stimulation of astrocytes will contribute to improved neuroplasticity in the brain.
Increase neuroplasticity allows the brain to adapt to injury, and relocate the functions of
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certain bodily functions so people do not experience the horrible effects of TBI such as
paralysis.
a. Using calcium signaling, the astrocytes can actually stimulate surrounding
neurons, and therefore regulate many neuronal processes.
i. “For example, a plethora of studies have shown that Ca​2+​ signals
stimulate gliotransmission and the consequent modulation of neurons
and synapses. A significant endogenous source of the Ca​2+​ signal of the
astrocyte is from the IP​3​-sensitive Ca​2+​ store. Thus, when an IP​3​R​2
knockout mouse was used and it was found to have no impact on
synaptic transmission and plasticity , the field was rocked.” (Haydon,
Nedergaard 2) ​- This piece of evidence is important because it shows two
things. First off, it shows that calcium signals will stimulate
gliotransmission, which in turn will cause the regulation of neurons and
synapses. Thus, it can be shown that through calcium signaling, astrocytes
have the potential to improve the neuroplasticity in the brain

Conclusion:​ Evidently, Traumatic Brain Injury is a major issue in the United States. It is

important for researchers to develop a treatment method as early as possible as it will allow

people to recover from chronic injuries. Currently,, astrocytes contain an immense potential to be

a valuable area of research. Their location in the brain, and its control over various neuronal

pathways and receptors allow it be a valuable factor of many different neuronal processes. The

structure of the astrocyte is very unique, with many different endfeet ​(“​The Root of Thought”)​,

so it is able to be in contact with many different cell in the brain. This allows them ​not only to

play a supporting role in regulating things like providing vitamins and blood flow, but they can

also send chemical signals throughout the cell promoting development of the brain en vivo

(Sonfroniew, Vinters 17)​. With further research, it is not unreasonable to suppose that

astrocytes could be the key in discovering an efficient method to induce neurogenesis and

neuroplasticity in the brain, creating an efficient method for treating traumatic brain injury.
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Appendix:
Vocabulary:
● G Protein Receptor: A type of receptor that is attached to G proteins;
Controls many functions of the body such as hearing, sight, etc.
● Ephrin Receptors: A kind of receptor that generally modulates neuronal
processes in the brain
● Neurotransmitter: chemical messengers that enable neurotransmission.
● Neuroplasticity: the ability to adapt to and learn from experiences
● NSC: Neuronal Stem Cell, a type of cell in the brain that can differentiate
into another kind of cell.
● En vivo: In the body
● Notch1: a human gene encoding a single-pass transmembrane receptor.
● Neurogenesis: the growth and development of nervous tissue.
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