Module 3 - Alcohol, Cell Suicide, and the Adolescent

Module 3 Alcohol, Cell Suicide, and
the Adolescent Brain
MODULE 3 - STUDENT HANDOUT
What Happened Last Night?
Justin and a few of his friends started drinking alcohol their second year in high
school. Although they didn't drink alcohol very often, when they did drink it, they
drank excessively, to the point of intoxication. Actually, Justin was surprised at
how much they could drink before getting really "tipsy," compared to adults he
had seen drink alcohol. Sometimes he had "blackouts;" he had trouble
remembering the next day what had happened the night before, but that didn't
seem to affect his decision to continue drinking alcohol. He continued drinking
alcohol only on some weekends into his junior year—he knew that this was a key
year in high school because he needed to have decent grades for his college
applications the following year.
But something strange was happening. Even if he wasn't drinking any alcohol,
he was starting to have trouble remembering some of the things that he would
learn in class earlier in the day, and when it came time to taking his exams, he
had trouble remembering some of the things he thought he knew when he was
studying. He never had these kinds of problems before. He got a little worried,
and confided in his friend Katy, who remarked, "Gee, it sounds similar to my
grandmother who has Alzheimer's disease". Justin responded, "Don't be
ridiculous, only older people get that disease."
So Justin continued to drink alcohol to the point of intoxication through the end
of high school. During his college years (he did not get into the colleges on his
wish-list, but he did get into one local college), Justin drank more often and
increased the amount that he drank. He still had some memory problems, but he
figured that's just the way his brain worked.
However, one night after having only 2 beers, he decided to drive back to his
dorm and had a car accident. Luckily, no one was killed, but he had some head
trauma and was taken to the hospital to get an MRI scan. The doctor who did
the scan was surprised to see that a certain part of Justin's brain called the
hippocampus was smaller than normal. He showed Justin the part of his brain
that was abnormal. The doctor did not think this was caused by the accident.
Upon questioning him, Justin admitted that he drank alcohol every weekend, but
he felt that it didn't affect his normal life in any negative way. The doctor told
him that his smaller hippocampus was associated with his alcohol drinking and it
puts him at increased risk of Alzheimer's disease (Katy wasn't so far off!). Justin
got quite concerned and agreed to consider working with a counselor to decrease
his usage of alcohol.
In the story Justin is surprised that he reacts to alcohol differently than the way in which an adult reacts
to alcohol.
1. What are the major differences in the ways in which an adolescent and adult respond to alcohol?
2. Could these differences be related to the extent of brain maturation? Why or why not?
When Justin drank alcohol he stated that sometimes he had "blackouts" or inability to remember some
events that happened when he was drinking. Studies in humans show that when alcohol is in the body
(and the brain) it actually prevents memories from being formed so they can't be recalled later.
3. How does alcohol cause memory lapses or blackouts? Which brain region and neurotransmitter
systems are involved? Where in the cell does alcohol act to cause memory problems?
Repeated exposure of the brain to alcohol especially levels that are present during intoxication causes
damage to specific parts of the brain. In the adolescent brain the hippocampus is especially vulnerable.
Damage to the hippocampus caused by alcohol may be due in part to an inhibition of neurogenesis the
"birth" of new neurons from neural stem cells. Alcohol can inhibit neurogenesis by preventing cell growth
and division or by promoting death of the neural stem cells by a process of apoptosis—a form of cell
suicide.
4. What is a stem cell? How does it give rise to a neuron?
5. Which step(s) in the cell cycle are most likely affected by alcohol? How does this affect cell
growth and division?
6. Explain how a cell dies by apoptosis. Why is the process described as cell suicide?
As described in the story MRI brain scans show a smaller hippocampus in people who started drinking
alcohol as adolescents.
7. Describe how an MRI scan is obtained (be general). What kind of atom is the MRI scanner
targeting to get an image? Why this atom?
8. Do you think that the alcohol caused a smaller hippocampus, or that people with a smaller
hippocampus are more likely to abuse alcohol? Why?
9. Suppose you had lab rats trained to drink alcohol (they do!). What kind of experiment could you
devise using the rats to determine whether the smaller hippocampus is produced by the alcohol or
whether the smaller hippocampus causes them to drink alcohol? (Hint—MRI scanners have been
developed for rats!)
Studies show that damage to the hippocampus (e.g. loss of hippocampal neurons) from alcohol use is
similar to that found in some neurodegenerative diseases like Alzheimer's disease.
10. What happens to brain function when the hippocampus is damaged?
11. How might alcohol abuse increase the risk for Alzheimer's disease?
MODULE 3 - CONTENT
A - Alcohol affects adolescents and adults differently
B - Brain maturation is complete at about 24 years of age
C - Alcohol, memory, and the hippocampus
D - Alcohol, neurogenesis, and stem cells
E - Alcohol inhibits cell growth
F - Alcohol causes cell death...by murder and suicide
G - Visualizing hippocampal damage from alcohol
3A - Alcohol affects adolescents and adults differently
Adolescents and adults differ in their physical and cognitive responses to alcohol. Typically, adolescents
are less sensitive to the intoxicating effects of alcohol. For example, the same blood alcohol concentrations
cause less sedation in adolescents than in adults.
Learn more about the intoxicating effects of alcohol and the brain areas that are affected.
In contrast adolescents are more sensitive to the memory disruption and neurotoxic effects produced by
alcohol compared to adults. Detectable after only one or two drinks the severity of memory loss is
proportional to the amount of alcohol ingested. In fact heavy drinking episodes can actually result in a
blackout whereby a person is later unable to recall events that occurred during the time of drinking.
Interestingly, animal studies have helped us to understand these differences. For example when compared
to adult rats, adolescent rats demonstrate less alcohol-induced impairments in balance and coordination
(signs of intoxication) and more alcohol-induced impairments in learning and memory.
This combination of different sensitivities is rather unfortunate for the adolescent. Adolescents may drink
more alcohol compared to adults and consequently achieve much higher (and more dangerous) blood
alcohol concentrations (BACs) before becoming incapacitated. The higher alcohol levels that are achieved
in a maturing brain increases the adolescent's risk for neurotoxicity and memory problems.
In addition to the effects of alcohol on the adolescent brain drinking alcohol at an early age has other
risks. There is extensive research to show that the earlier a person drinks alcohol in his/her life the more
likely (s)he will have an alcohol use disorder as an adult. More specifically an adolescent who starts to
drink alcohol before the age of 15 is 4 times more likely to develop addiction to alcohol as an adult
compared to a person who starts to drink alcohol at the age of 21.
Learn more about BACs and the effects of alcohol.
Adolescents are less sensitive to the intoxicating effects of alcohol, but more sensitive to the memory
disruption and neurotoxic effects of alcohol.
3B - Brain maturation is complete at about 24 years of age
The major reason that adolescents have different sensitivities to alcohol compared to adults is that their
brains are still maturing. Although it was once thought that the brain is fully mature around birth this
hypothesis has been disproven; now there is clear evidence that the brain does not mature fully until
about age 24. One of the areas of the brain that matures late is the prefrontal cortex the area important
in impulse control risk-taking behavior and judgment.
During development in the womb as many as 250,000 new neurons (the major cells in the brain) are
created each day. These neurons use spatial and chemical cues to find their synaptic targets. By the time
we are born our brains contain billions of neurons with trillions of connections. However the infant brain
contains far more neurons than are present in the adult brain.
During the subsequent months and through adolescence careful pruning of neuronal connections
eliminates all but the most "useful" connections between neurons. The result is a "thinning-out" process
that selects for those neuronal connections strengthened through repeated experience. In this sense "cells
that fire together wire together" while those that do not make meaningful contacts do not survive. In
other words "use it or lose it"! These early pruning processes not only establish the neuronal networks to
support learning throughout life but also allow the brain to be "sculpted" based on a person's unique
experiences.
Thus one might imagine how the presence of alcohol can interfere with this time-critical process of neuron
pruning that forms the adult brain.
Figure 3.1 The brain undergoes maturation over the first 24 years of life; the sculpting and pruning of
neurons and synapses is indicated by the decrease in gray matter (in red) in the cerebral cortex.
(Courtesy of Gogtay et al. with permission). For an animated version click here.
The adolescent brain is not yet fully developed. As a result, alcohol can interfere with critical cellular
events that help to form the adult brain.
3C - Alcohol, memory, and the hippocampus
Learning and memory are crucial events during adolescence, when the brain is maturing both physically
and functionally. Thus, it is not surprising that cognitive processes are exquisitely sensitive to the effects
of chemicals such as alcohol. Among the most serious problems is the disruption of memory, or the ability
to recall information that was previously learned. When a person drinks alcohol, (s)he can have a
"blackout." A blackout can involve a small memory disruption, like forgetting someone’s name, or it can
be more serious—the person might not be able to remember key details of an event that happened while
drinking. An inability to remember the entire event is common when a person drinks 5 or more drinks in a
single sitting ("binge").
Learn more about the formation of memory.
In order to affect cognitive functions such as learning and memory alcohol must first enter the brain. Due
to its small size alcohol in the blood can passively diffuse (through the blood brain barrier) into the brain.
The ability of alcohol to cause short term memory problems and blackouts is due to its effects on an area
of the brain called the hippocampus. The hippocampus is a structure that is vital to learning and the
formation of memory.
Learn more about the passive diffusion of alcohol through the blood brain barrier.
Review the basics of neuron structure.
Thus without a properly functioning hippocampus learning and memory become problematic. In fact there
is a famous story about a patient H.M. whose hippocampus was actually removed surgically in an effort to
relieve him of uncontrollable seizures. Read all about H.M.'s incredible story.
Figure 3.2 Originally named for its resemblance to a seahorse (genus Hippocampus) the hippocampus is
a small curved structure located within the temporal lobes of the brain (one in each hemisphere)
When alcohol reaches the hippocampus it decreases the electrical activity of neurons by binding to
specialized proteins (or receptors) that are embedded in the neuronal membrane. The decreased firing of
impulses in the hippocampus disrupts the formation of the short term memory and accounts for the
subsequent blackouts experienced the next day.
Review the basics of neurotransmission
Learn more about the ability of alcohol to decrease neuron firing
Over time with repeated use of alcohol especially by people who binge drink alcohol can cause actual
damage to the hippocampus leading to more sustained cognitive and memory problems. Interestingly the
hippocampus is a unique structure in which new neurons are constantly "being born" and this
neurogenesis plays a very important role in learning and memory. One of the ways in which alcohol can
damage the hippocampus is by disrupting neurogenesis.
3D - Alcohol, neurogenesis, and stem cells
It has been known for some time that when a fetus is exposed to alcohol (i.e., a pregnant woman drinks
alcohol) alcohol disrupts neurogenesis in the fetal brain leading to neuron degeneration and neurological
dysfunction after birth. However recent research has shown that alcohol (as well as disease injury and
drug abuse) can significantly disrupt neurogenesis or the birth of new neurons in the brain—specifically in
the adult hippocampus. Actually it was only recently that scientists even discovered that new neuron
growth occurs after birth and well into adulthood.
Using new technological tools scientists have found dividing cells (stem cells) in the adult hippocampus
that give rise to neurons. Stem cells have unique qualities—they can divide indefinitely renew themselves
and mature into a variety of daughter cells—in this case, neurons. These stem cells give rise to new
neurons that incorporate into the hippocampal circuitry, thereby facilitating the ability to form new
memories.
Figure 3.3 Neural stem cells give "birth" to new neurons which then migrate to specific areas in the
hippocampus where they participate in the formation of memory.
The inhibition of hippocampal neurogenesis by alcohol may contribute to the memory problems that occur
with alcoholism. In experiments with rats, it has been shown that a single dose of alcohol, equivalent to a
drinking binge in humans, can sufficiently damage the hippocampus to cause severe, lasting disruptions in
learning and memory. Though the exact mechanism is under investigation, scientists hypothesize that
alcohol halts the growth of neural stem cells and/or actually causes their death.
Learn more about neurogenesis.
The ability of alcohol to affect memory may be due, in part, to its ability to inhibit the formation of new
neurons or neurogenesis in the hippocampus.
3E - Alcohol inhibits cell growth
Cell growth is an elegantly coordinated series of steps; any of these steps are subject to interference by
drugs and chemicals. Specifically, alcohol disrupts neural stem cell growth and division. Alcohol causes
cells to progress more slowly through the cell cycle. The cycle consists of 4 major stages, during which
cells grow and produce new proteins (G1), synthesize DNA (S), produce new organelles (G2) and divide
by mitosis (M). The most susceptible stage of the cell cycle is the G1 phase where alcohol inhibits the
transcription and translation of genes that regulate the remaining steps of the cell cycle. The result is that
cells won't proceed into S phase to duplicate their chromosomes in preparation for cell division. With a
reduction in cell proliferation, the loss of neurons within the hippocampus can lead to significant learning
and memory problems. The loss of neurons may explain the smaller hippocampus observed in the brains
of adolescents with alcohol use disorder (read on!).
Learn more about cell growth and division.
Learn more about gene transcription and translation.
Figure 3.4 Alcohol affects stem cells during G1 when DNA transcription and translation to new proteins
takes place. Alcohol disrupts the duplication of DNA in S phase, leading to reduced mitosis. Move your
cursor over each phase to see what occurs.
The pattern by which adolescents drink alcohol may have a large effect on the drug's ability to damage
the adolescent brain. Adolescents often binge drink or consume at least 5 drinks over a several hour
period. This mode of drinking can achieve blood alcohol concentrations (BACs) that will block the growth
of neural stem cells. Even one month after a single binge episode neurogenesis remains diminished.
Figure 3.5 A single dose of alcohol in rats (equivalent to a dose that is highly intoxicating in a human)
decreases the proliferation of neural stem cells in the hippocampus by 40% 5 hours later (left panel).
After 4 weeks the actual number of new hippocampal neurons is decreased by more than 50% (right
panel). Adapted from Crews & Nixon; http://pubs.niaaa.nih.gov/publications/arh27-2/197-204.htm
A single binge of alcohol can inhibit neural stem cell proliferation in the hippocampus, leading to a reduced
number of new neurons in the hippocampus, an area important in learning and memory.
3F - Alcohol causes cell death...by murder and suicide
It has been known for many years that alcohol can kill both mature neurons as well as the stem cells that
give rise to new neurons. Only recently have scientists been able to demonstrate how neurons die by
actually visualizing the effects of cell death in a human brain. Let's take a closer look at what happens.
First not all cell death is the same. Alcohol is toxic in high doses and can kill cells quickly. It is metabolized
by alcohol dehydrogenase (ADH) to form acetaldehyde a very reactive molecule that can cause damage to
many types of cells.
Review how alcohol is metabolized by ADH
The metabolism of alcohol also generates reactive forms of oxygen (oxygen radicals) that are toxic to cells
by damaging proteins DNA and lipids. Thus in high doses alcohol can cause an acute cell death or
necrosis. Necrosis occurs when a cell is damaged traumatically (for example when the cell membrane is
destroyed). The necrotic cell swells up and ruptures spilling its contents into the extracellular space. This
creates an inflammatory mess resulting in the death of neighboring cells. Necrosis can be thought of as a
"quick and dirty" form of cell death.
On the other hand alcohol can cause a more tidy kind of cell death called apoptosis. This form of cell
death is actually genetically programmed by the cell itself—the cell dies by suicide. Cells not only contain
instructions to grow and divide but also to ultimately die in the event that they are injured or just a bit too
old! When alcohol injures cellular organelles (for example by generating oxygen radicals), this triggers
DNA transcription and translation to produce a series enzymes that direct the cell death process; the
cellular cytoskeleton is dismantled the chromatin condenses in the nucleus the cells shrink and small
"blebs" of cell membrane containing cytoplasm bud off. The dying cell and blebs are consumed by
macrophages a type of white blood cell that moves in to remove the debris. Unlike necrosis, cell death
by apoptosis usually doesn't affect neighboring healthy cells.
Figure 3.6 Cells can die in a tidy manner by apoptosis; macrophages (white blood cells) clean up the
mess. Taken from: http://ghr.nlm.nih.gov/handbook/illustrations/apoptosismacrophage
Learn more about apoptosis.
Alcohol can kill cells by necrosis, or by apoptosis, a form of cell suicide that is genetically programmed by
nuclear DNA.
3G - Visualizing hippocampal damage from alcohol
Not only does alcohol disrupt short-term memory (i.e., recall of recent events) but repeated use of alcohol
can cause cognitive learning and memory problems even if one is not actually drinking. This observation
suggests that repeated alcohol use or binging can cause damage specifically to the hippocampus in
adolescents.
While most research on alcohol-induced cell death has been performed in animals newer technologies
have enabled us to detect damage in the human brain. The brain can be visualized with imaging
technologies such as magnetic resonance imaging or MRI. MRI detects the energy given off by spinning
protons in hydrogen atoms (most of these are in water and fat) in the tissues throughout the body. Using
MRI scans scientists have shown that people who began drinking alcohol as adolescents have significantly
smaller hippocampi than their non-drinking peers.
Learn more how an MRI scan works.
When studying the MRI scans, scientists noted that there is an association between the (smaller ) size of
the hippocampus and the number of years of alcohol abuse, suggesting that the earlier that a teen begins
abusing alcohol, the greater the risk of harm to the hippocampus. Most strikingly, the damage that alcohol
causes in the developing brain can last through adulthood. These data provide compelling evidence that
the adolescent hippocampus is highly sensitive to the neurotoxic effects of alcohol and that the damage
can be long-lasting. Scientists are now assessing whether the damage is irreversible.
Similarly, MRI has also been used to show that the early stages of Alzheimer's disease are marked by
physical changes in the hippocampus. Researchers have found that the reduction in hippocampal size is
associated with an increased risk for the development of Alzheimer's disease. Thus, those who start
drinking alcohol as adolescents may have an increased risk for developing Alzheimer's disease when they
get older.
Repeated binge drinking by adolescents damages the hippocampus, possibly increasing the risk of
cognitive problems or even Alzheimer's disease in later life.
Figure 3.7 MRI scans show a smaller hippocampus (in the red circles) in a person with adolescent
alcohol-use disorder (right) compared to a healthy person of the same age (left). (Adapted from M.D. De
Bellis with permission).
Module 3 - Student Quiz
1) Why are there are so many dendrites associated with each neuron cell body?
A. The branch-like structure keeps the neurons from crowding together.
B. The branch-like structure increases the surface area for synapses and communication between
neurons.
C. The more dendrites there are, the more surface area for myelin to cover.
D. The more dendrites there are, the greater the chance of receiving information from neighboring
neurons.
2) Why do neurons use both electrical and chemical signals to communicate with each other?
A. Electrical signals can't jump across the synaptic space.
B. Neurons need fast and slow ways to pass information between them.
C. Neurons need chemical signals to stop the electrical signals.
D. Electrical signals can degrade over the distance of an axon.
3) Alcohol causes blackouts or inability to recall certain events that occurred earlier when one was drinking
alcohol. What could explain the production of the blackout?
A. Alcohol damages cells in the hippocampus.
B. Alcohol increases electrical impulses in the hippocampus.
C. Alcohol decreases electrical impulses in the hippocampus.
D. Alcohol shrinks the hippocampus.
4) Alcohol can damage the hippocampus, an area of the brain involved in learning and memory. It actually
causes the hippocampus to shrink. What could explain this?
A. Alcohol accelerates the stem cell cycle.
B. Alcohol causes stem cell proliferation.
C. Alcohol dehydrates the hippocampus .
D. Alcohol decreases neurogenesis.
5) Magnetic resonance imaging (MRI) is a technique that measures energy released when protons, the
nucleus of H atoms, spin in an electromagnetic field. Why does the MRI focus in on protons?
A. Protons are abundant in the body; they are found in water and fat, which is most of us!
B. Protons spin at the right frequency to be detected by the MRI scanner.
C. Protons do not get destroyed by the magnetic field produced by the MRI scanner.
D. Protons are charged particles that are easily detected by the magnet in the MRI scanner.