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WINTER 2014Action Potentials | Lissencephaly | Neural Implants |
Fixed Neural Ciruits | Fatherhood
SMOOTHBRAIN
What can happen when
neuronalmigration
goes awry?
THE HISTORY OFELECTROPHYSIOLOGYWhat is the Action Potential, and
how do we know?
FEATURING
NEURAL IMPLANTS & IMMUNE RESPONSEKeeping recording devices
inside the brain
FIXED NEURAL CIRCUITS Taking a look at hard-wired neural
circuits
THE NEUROPHYSIOLOGY OF FATHERHOODDoes becoming a dad change the
brain?
www.greymattersjournal.com
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1 GREY MATTERS | vol 1 | issue 2 2GREY MATTERS | vol 1 | issue
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CUTTLEFISH
1 2
TABLE OF CONTENTS
TABLE OF CONTENTS
The human body, during development, is a whirlwind of cellular
pro-
cesses and developmental procedures all marching forward in a
re-
markably organized fashion. But, what happens when some
neurons
ignore the directions?
SMOOTH BRAINA CLOSER LOOK AT LISSENCEPHALY
FIXED NEURALCIRCUITSTaking a look at some of the brains
hard-wired neural circuits.
By Alice Bosma-Moody
NEURAL IMPLANTS ANDIMMUNE RESPONSEKeeping recording devices
inside the brain for neuroprosthetics.
By Chantruyen Ho
Illustrated by Lars Crawford
NEUROPHYSIOLOGY OF FATHERHOODHow does Dads brain change after
child birth?
29
RESEARCH ARTICLES
By Justin Andersen
Illustrated by Justin Andersen
FEATURED ARTICLE
BRAIN BLURBS
22 25
By Alexa Erdogan Illustrated by Benjamin Cordy
17Which part of the brain is most important?
15FEATURED COMIC
By Benjamin Cordy & Jesse Miles Illustrated by Justen
Waterhouse
The History Electrophysiology ...............................
05
The Human Brain Project
.............................................10
GABA Receptors and ADHD ................................08
Processing Perception
..............................................11
Desynchronizers ............................... 09 The
Hypothalamus .............................................13
BRAIN BATTLEWHICH PART OF THE BRAIN WILL REIGN?
What a fascinating
journal. I think Ill take a
looksie.
THE CUTTLEFISHthan expected intelligence. Several recent studies
suggest that it may be among the most intelligent invertebrates.
The television program NOVA has produced a documentary highlighting
some of the
This image was painted by Debbie Gundelach and can be purchased
here: http://bit.ly/1eY31bZ
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3 GREY MATTERS | vol 1 | issue 2 4GREY MATTERS | vol 1 | issue
2
STAFF
3 4
EDITORS NOTE
GREY MATTERS STAFF
Benjamin is a Neurobiology and Compu-tational Neuroscience
student pursuing a career as a physician researcher. He is mildly
obsessed with books, running, and rock climbing.
Editor In Chief
BENJAMIN CORDY
Jesse is a Neurobiology student investi-gating brainstem
development while pur-
-eracy and Jazz.
Senior Editor
JESSE MILES
As a senior majoring in Neurobiology, Stacie pur-sues her
interest in art through indesign. She also enjoys hiking, LOTR, and
drinking tea.
Layout Coordinator
STACIE SHIBANO
studying biochemistry and
James can be found play-ing basketball or doing yoga on the
beach.
Business Development
JAMES LIU
Majoring in Painting and Drawing and Philosophy, Justen is
interested in us-ing art to communicate complex ideas of
neurosci-ence to everyone.
Art Director
JUSTEN WATERHOUSE
Tyler is a Neurobiology student pursuing a medical career
involving the brain. His interests include the social neuroscience
of hu-man gender and sexuality.
Marketing Coordinator
TYLER DEFRIECE
Jacob is a senior whose in-terests include Kendo, phi-losophy,
teaching, and hu-man health. Jacob intends to pursue graduate
studies in neuroscience or biology.
Editing Coordinator
JACOB COLTER
Alexa Edrogan Leah OgierBrooks Gribble Nicole RenoSidney Hauser
Nicole RileyChantruyen Ho Courtney RobertsDarren Hou Miha
Sarani
Justin Andersen Sneha Ingle Khalil SomaniJustin Bethel Ellen
Jane Van Wyk Phanith Touch
Teresa Jiang Jennifer WangAlice Bosma-Moody Baihan Lin Rachel
WhiteheadAnna Bowen Darby Losey Daniel YusupovLars Crawford Maria
Naushab
Autho
rEd
itor
Artis
tLa
yout
SPECIAL THANKSGrey Matters Journal is especial-ly grateful to
those mentors and advisors whose encouragement and support make
this publica-tion a reality.
ADVISORS Dr. Ric Robinson,
Department of Biological Structure
Dr. William MoodyDepartment of Biology
Dr. Martha BosmaDepartment of Biology
Dr. William Catterall, Dr. Stanley Froehner, Dr. Sheri Mizumori,
Dr. Bruce Ransom, Dr. John Scott
EDITORS NOTEThe brain is remarkably fascinating. Everyone, it
seems, is interested in the organ between their ears as they should
be. It is after all, through the brain that we negotiate life and
experience the universe. In many ways, the brain is the most
important organ.
I often feel that Sherlock Holmes perfectly described the
reality of our existence when he explained, I am a brain, Watson.
The rest of me is a mere appendix.
Because we, like Holmes, are indistinguishably tied to our
brains, neuroscience is a deeply personal endeavor. As we uncover
more about the brains structure and function, we inevitably expose
the underlying nature of our own existence.
Moreover, the impacts of neuroscience research are astonishingly
far-reaching. Indeed, there is probably no other subject whose
contributions are so widely applied. Medicine, business, politics,
art, law, philosophy, literature, and more, are shaped in some way
by neuroscience.
It is precisely this personal and ubiquitous nature of
neuroscience that motivates researchers to better understand the
brain and inspires us to write about it.
We are all brains with bodies in tow. And for me, this is
why
This is why we produce Grey Matters.
I hope you enjoy it.
Benjamin CordyEditor-In-Chief
ISSUE NOTESON THE COVERImage by Stephen Sinco
The highly organized neural cir-cuitry typically present in the
human brain can be muddled in a genetic condition known as
lissencephaly. This results in a smooth brain lacking the
charac-teristic grooves and folds. Learn more on page 17.
HAVE YOUR SAYIf you have questions or com-ments regarding this
issue, please write a letter to the [email protected]
ONLINEVisit the Grey Matters Blog for regular neuroscience
updates, stories, and articles.greymattersjournal.com/blog
WRITE FOR GREY MATTERSIf you are interested in writing an
article for publication (print or blog), submit a proposal
online.greymattersjournal.com/
article-proposals
STAFF
Grey Matters
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HISTORY OF ELECTROPHYSIOLOGY
5 6
HISTORY OF ELECTROPHYSIOLOGY
ELECTROPHYSIOLOGYIn the early eighteenth century
the most noteworthy connection be-tween electricity and nervous
func-tion was that very little was known about either. Based on the
ideas of the time, there was little reason to suspect a deep
relationship be-tween the two. Electricity required the possibility
of a spark. The brain
-id movement and pressure1. There was, however, one puzzling
obser-vation.
It had been shown many times that, under experimental
condi-tions, an electric spark could elicit muscular contraction2.
Naturally, this led some to consider whether a relationship existed
between the two, and in doing so, a new scientif-
electrophysiologist. However, when he took up the problem around
1780, he became one of the most important early pioneers. By
devis-ing a clever experiment, in which he exposed the nerves of a
frogs low-er limbs, Galvani was able to show that man-made and
natural (e.g. lighting) electricity led to muscular
contraction2.More important, however, was
his later observation that such con-tractions were possible
without the aid of atmospheric electricity; sim-ply put: in the
absence of a spark. When Galvani jostled the apparatus to which the
frog leg was secured, its muscle twitched. Without an ap-parent
external source of electricity, Galvani surmised the existence of
animal electricity.2
THE DISCOVERYFifty years passed between Gal-
vanis initial experiments and the next substantial
electrophysiolog-ical advancement; the discovery of the action
potential. Following up on the work of Carlo Matteucci, which had
convincingly supported Galvanis ideas, Emil du Bois-Rey-
connection between electricity and nervous function2.
Bois-Reymond, a skilled experi-mentalist with access to
high-quali-ty instruments, was able to demon-strate that, similar
to muscle tissue,
stimulated. Though he could not demonstrate the time-course of
the depolarization (Figure 3) with
correctly hypothesized that rapid reversal in cell polarity
might travel
He claimed, If I do not greatly deceive myself, I have succeeded
in realizing the hundred years dream of physicists and
physiolo-gists, to wit, the identity of the ner-vous principle with
electricity2.
THE SQUID GIANT AXONOf course since Bois-Reymond
many brilliant researchers have fur-ther illuminated our
understanding of the action potential, its ion chan-nels, and
lifespan. Alan Hodgekin and Andrew Huxley, who shared the Nobel
Prize for their work, fa-mously studied the squid giant axon to
expose the detailed ionic mecha-nisms of the action potential.
the squid is equipped with an axon 1,000 times wider than is
typical (up to 1mm vs. 1m). The evolu-
axon is the increased speed, which the squid uses to activate
its jet pro-pulsion system and escape danger. (For a brief
explanation of the phys-ics behind the velocity-diameter re-
research model, however, is the ex-
perimental advantage conferred by the large diameter.
Measuring voltage and current within the axon is a technically
dif-
electrodes into the lumen of the axon. Obviously, this is more
easily accomplished in the giant axon.
Today the contributions of Hodgekin and Huxley remain one of the
major advances in neuro-science. For, as will be discussed below,
the action potential is the currency of information conduc-tance in
the nervous system. Their work set the stage, allowing it to be a
well-understood biophysical phe-nomenon.
THE STRUCTURAL ELEMENTS
Before discussing the action po-tential proper, it is important
to
structural components that permit its existence: the plasma
mem-brane, ion channels, and pumps.
While it might be easy to over-look the plasma membrane, it
plays a critical role by maintaining the necessary
inside-to-outside charge imbalance. As a lipid bilayer, the
membrane is impermeable to charged ions such as sodium (Na+),
potassium (K+), and chloride (Cl-).
THE HISTORY OFELECTROPHYSIOLOGY
The physics behind diameter and velocityPerhaps unsurprisingly,
the spread of voltage with-
telegraph cable. Current (not ions) within axon moves through
the membrane (and is lost) or down the lumen. This voltage decay is
modeled by:
m 0e
m/ri)
Where rm is the membrane resistance and ri is the internal
resistance of the cytoplasm.
As the diameter of the axon increases, internal resistance
decreases (cytoplasmic resistance is re-
and x, or the distance of voltage decay, increaseReference: Dr.
William Moody, Neurobiology
301 course manual, Winter 2014
Enamored by the brain and its hidden secrets, many early
anatomists
dedicated their life to illuminating the mechanisms behind
reason and
consciousness. Today, of course, we understand the nervous
system in
greater detail than Aristotle, Galen, or Descartes, might have
imagined.
And even so, almost rudimentary ideas, such as how electricity
drives
the mushy organ, are sometimes still shocking.
FIGURE 1up to 1 mm in diameter.
Image by Roger Hanlon
Imag
e by
Ju
sten
Wat
erho
use
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HISTORY OF ELECTROPHYSIOLOGY
7 8
GABA RECEPTORS
Without such a barrier, ions would
environment, dissipating any volt-age between the two
Ion channels are trans-mem-brane proteins that act as
conduits
of known human channels3, their structure and function are
broadly the same.
Each channel is capable of an
acts as a gate. Only when it is open
through it. When closed, the mem-brane is again impermeable to
that ion.
The wide variation in ion chan--
ty of stimuli that can open or close gates. Voltage, current,
mechanical force, concentration gradients, and pH are all examples
of stimuli that
a channel. For example, touch is a sensation whose signaling
begins with the application of mechanical force, which opens
channels to ion
In order to reestablish the resting electric potential across
the mem-brane, nerves rely on pumps to ac-
tively transport ions into and out of the cell. Such movement is
typical-ly against the energy gradient and requires metabolic
energy (ATP) to complete. One such example is the well-known
sodium-potassium pump.
THE ACTION POTENTIALThe action potential is a
short-lasting event in which the typ-ically negative (relative
to outside the cell) membrane potential rapid-ly rises, becomes
positive, and falls again. It is the method of informa-tion
conveyance over long distanc-es. Some axons can be more than one
meter long.
There are four properties that guide the initiation and
propagation of action potentials. First, there is a threshold of
initiation. Second, it is an all-or-nothing event. Third, it has
constant amplitude. Fourth, ev-ery action potential is followed by
a brief refractory period4.
The behavior of the action po-tential depends several
properties, including the electrical potential and chemical
concentration of sev-
2, the resting membrane potential is roughly -70mV and due to
the
Na+/K+ pump. Na+ concentrations are lower within the cell, while
K+ is greater.
Each neuron receives excitatory and inhibitory signals. This sum
of such signals results in a membrane potential that is either more
positive (depolarizes) or negative (hyperpo-larizes). This signal
competition is an important type of neural pro-cessing4.
excitatory stimulus to reach the neurons threshold (around
-50mV) voltage-gated Na+ channels open rapidly and the action
potential be-gins.
As Na+of positive charge depolarizes the cell further, causing
additional Na+ channels to open. At the peak volt-age (Figure 3.3)
Na+ channels close and the voltage-gated K+ channels open. This
allows K+, following its electrochemical gradient, to exit the
cell4.
The repolarization phase (Figure
of K+, and, because at the positive membrane potential
voltage-gated Cl- channels open, Cl- ions enter the cell.
This allows the cell to more rap-idly return to its base
membrane
FIGURE 2right, yellow area).
potential as well as introduce a re-fractory period in which the
cell is hyperpolarized (Figure 3.5). This period serves to drive
forward prop-agation as well as limits the fre-quency of action
potentials (another type of neural processing).
After the termination of an action potential, the chemical
equilibrium is reestablished via pumps such as the Na+/K+ - ATPase
(see Figure 2).
action potential leads to exocytosis of neurotransmitter at the
synapse. Depending on the excitatory and in-hibitory properties of
the post-syn-aptic cell, the action potential con-tinues on.
CONCLUSION In order to fully understand neu-
rons, neural circuits, and entire ner-vous systems, it is
essential to have
-anism of their function. This arti-cle provides an
exceptionally brief overview of the historical discovery and
cellular mechanism of the ac-tion potential. More detailed
infor-mation can be found in Eric R. Kan-dels Principles of Neural
Science.
Autism spectrum disorder (ASD) is a developmental disor-der
generally characterized by hindered social interactions.
Hy-persensitivity and motor impair-ments are often symptoms of the
illness.
The potential causes of ASDs remain elusive, though the sci-
link between vaccines and autism.There is, however, mounting
evidence that a neurotransmit-ter, gamma-amino butyric acid
(GABA), may play a role in the disease. GABA is a crucial
inhib-itory neurotransmitter primarily responsible for the
regulation of excitatory signals within the ner-vous system.
Imagine it as a po-liceman, checking the cars and preventing
unwanted excitatory signals from reaching the next dendrite.
Recent Imaging studies have shown decreased levels of GABA in
brain regions associated with
motor control and sound pro-cessing in children with Autism.
Because GABA is inhibitory in na-ture, decreased levels suggests an
increased excitatory response to stimuli1. This model could explain
why children with Autism, unable to regulate incoming signals, are
often hypersensitive to noises and have motor impairments
Furthermore, genetic associa-tion analysis suggest that defects
in genes coding for certain GABA receptors are associated with the
disorder2Rett syndrome, have defects of proteins involved in the
GABAer-gic pathway. In animal models, minute changes in the
GABAer-gic signaling pathway produces Autism-like behaviors3. It is
not unreasonable therefore, to fur-ther investigate such pathways
in humans.
GABA RECEPTORS & AUTISM SPECTRUM DISORDERS
By Benjamin Cordy
References available online at
By Sneha Ingle
References available online at
FIGURE 3
1
2
3
4
Image by Bruce Blaus
Imag
e by
Si
dney
Hau
ser
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9 GREY MATTERS | vol 1 | issue 2 10GREY MATTERS | vol 1 | issue
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DESYNCHRONIZERS
9 10
THE HUMAN BRAIN PROJECT
INTRODUCTIONFrom the blar-
ing televisions to all-in-one smart-phones, it is easy to focus
attention towards screens at all moments of the day. Increas-ing
technological ad-vancement has brought mankind into an era of
unpar-alleled convenience. But, there is at
Developments in technology are transpiring at a rate never
before experienced in the short existence of the human species. As
the days be-
shorter, sleep has been replaced by other activities. Indeed,
accord-ing to Professor David G. Meyers of Michigans Hope College,
young adults sleep less now than they did
DESYNCHRONIZERS AND THE CIRCADIANSLEEP CYCLE
even a century ago6.With the constant
dim glare of hand-held electronic de-
-rescent light bulbs hanging overhead,
it raises an interest-ing question: Do the
technological conve-niences of modern society
A fascinating and delicate pro-cess known as the circadian
rhythm regulates sleep. This is the cycle that causes feelings of
fatigue at night and alertness during the day.
complicated biological clock work together and use environmental
cues to maintain homogeny with the light-dark cycle of the day10.
The most prominent environmental cue is simply the change in light
that oc-
curs as day transitions to night.Throughout the day, the
internal
-riods of drowsiness, the strongest of which occur in the early
morning and mid-afternoon7. In addition to light levels, many other
factors, such as social habits, are important in the regulation of
the circadian rhythm. With a myriad of circadian rhythm
-synchronizers, it is quite easy to knock the sleep-wake cycle
out of line.
LIGHT SLEEPINGThe circadian rhythm maintains
wakefulness during brighter peri-ods of the day through a
cluster of cells called the suprachiasmatic nuclei. This cell
cluster, referred to as the SCN, uses light information from
photoreceptors in the eye to interpret the time of day. Reliance of
the SCN on the day-night cycle is why bright light causes alertness
and darkness results in fatigue7.
Although the internal clock con-tinues to function without light
in-formation (e.g. for someone living
from the typical 24 hour cycle, by an hour or two10.
A protein, suitably called CLOCK, is an important regulator of
the cir-cadian rhythms. CLOCK works in conjunction with a metabolic
pro-tein called SIRTI1, to maintain the circadian balance. However,
if these proteins are disrupted sleep cycles and cellular energy
consumption become disordered. This, of course, indicates that one
potential function
-gy expenditure5.
Given the light-dependent nature of the circadian rhythm, it is
inter-esting to consider the implications
of modern light producing gadgets on the ancient biological
clock. This
technologically capable adolescents, where research has shown a
positive correlation between time spent on
-culties.
A study published in SLEEP, a sleep-dedicated research jour-nal,
showed that adolescents who watched more television report-ed
delayed bedtimes and a great-er overall level of tiredness.
These
-searchers investigated internet and video game use in
adolescents1. Ad-ditionally, a recent review of 36 dif-
of such light-use on adolescent sleep found that prolonged
television and computer use decreased overall sleeptime, prolonged
sleep onset latency, and delayed bedtime.2 The review suggested
that the light pro-duced by electronic devices could fool the SCN
into producing alert-ness in the brain during the day2.
THE RHYTHM OF THE ANIMAL KINGDOM-
cient use of time, it is very proba-ble that humans have evolved
their sleep behaviors in order to increase the likelihood of
survival. For ex-ample: because, humans are poorly equipped to
handle darkness, sleep-ing through the night would allow them to
avoid accidents, such as falling, or nocturnal predators with
excellent low-light vision.
It is not surprising that exam-ples of circadian rhythm are
found
-ilar to humans, have a daily rest-ing period, which lasts
roughly ten hours everyday. And like humans, when their cycle of
sleep is dis-turbed, longer periods of rest are taken to compensate
for lost sleep. Other organisms such as birds,
needs for a sleep-like state.
A NEW PLANE OF THOUGHTThe desynchronization of the cir-
by modern electronic devices, but also by other staples of
modern life jet lag for example. When someone
light and dark, the result is a disrup-tion of the internal 24
hour clock. If moving forward across time zones advances this light
and dark cycle, then it takes about 90 minutes per day to
resynchronize the circadian clock, and when the rhythm shifts
backward as a result of a delay, it takes approximately 60 minutes
per day 5. This constant resynchroniza-tion persists in an attempt
to return our sleep-wake cycle once more to a state of equilibrium.
Jet lag is es-sentially the physical manifestation of these shifts
in our internal sleep clock, causing shifts in our sleep habits,
and by extension, our behav-ior5.
CONCLUSIONIt is easy to take sleep for grant-
-gility of sleep ultimately leads to questioning our social
lives and be-fore-bed habits. Such behaviors can increase the risk
of sleep disorders and health complications.
The biological clock plays a vital role in our day-to-day lives
and one ought to take caution not to disrupt
-gets, jetlag, and other desynchro-nizers on our sleep cycle is
a stark reminder that although technology continues to advance, our
age old physiology remains the same.
The recently launched Human Brain Project (HBP) joins
re-searchers from over 130 institu-tions across Europe to further
the
It is based upon six platforms: neuroinformatics, brain
simu-lation, high-performance com-puting, medical informatics,
neuromorphic computing, and neurorobotics.
As the HBP integrates com-puter processing with the
ev-er-increasing amount of data re-searchers use. Those working on
this project hope for a deeper un-derstanding of the brains
organi-zational patterns as well as new methods for diagnosing
neuro-logical disease and creating neu-roscience-inspired
technologies.
It is anticipated that the HBP will be the launching point for
collaborative neuroscience re-search in Europe.
As stated by Professor Karl-heinz Meier, the co-director of the
HBP, the goal is to collaborate, collaborate, collaborate. This is
especially relevant with the in-tegration of neurobiology and
computing methods, allowing for faster analysis and allowing more
time for drawing conclusions and developing extensions upon
ex-isting work.
No doubt that with the advent of such collaboration by some of
the most well-known researchers
-ence will continue to grow at an ever-increasing rate.
For more information on the Human Brain Project, visit
www.greymattersjournal.com/hbpBy Khalil Somani
and Justin Bethel
References available online at
THE HUMANBRAIN PROJECT
By Darren Hou
Image by Ellen Jane Van Wyk
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PROCESSING PERCEPTION
11 12
PROCESSING PERCEPTION
INTRODUCTION-
deavor is to start with the basics. David Hubel and Torsten
Wiesel were some of the pioneers of sight research who focused on
the mon-umental task of studying the basic processing and
architecture of the visual system.
Humans see the world as a unit-ed and complete picture. However,
the visual system is actually sur-prisingly specialized at a
cellular level1. This was partially revealed by the research of
Hubel and Wiesel in a series of experiments and papers produced
from the 1950s to the 1980s1.
enough that in 1981, they shared the Nobel Prize in Physiology.
To-day, they are considered pioneers of vision research2.
RETINAL-GENICULATE-STRIATE SYSTEMHubel and Wiesel focused
their
research on a series of cells known as the
retina-geniculate-striate
-tion along this pathway, as implied its name, is from the
retina to the lateral geniculate nucleus to the striate cortex,
also known as the primary visual cortex3,4 (Figure 1). Within the
retina, photoreceptors transduce light energy into neural
bipolar cells, then to ganglion cells. These ganglion cells,
then code the intensity and duration of the stimu-lus and project
their axons into the optic nerve4.
The retinal bipolar cells that syn-apse on the photoreceptors
respond to glutamate, and therefore light,
6. The two types of retinal bipolar cells are called on
bipolar cells, which areexcited by
are inhibited by light6. These cells synapse on ganglion cells,
where the inhibition and excitation signals
ganglion cells6. As previously men-tioned, this information
follows a
where processing begins.
RECEPTIVE FIELDS Hubel and Wiesel were interest-
in the striate cortex1.
vision that activate or inhibit a sin-gle neuron in the visual
system4.
Earlier research by Dr. Stephen
inhibitory and excitatory regions in concentric patterns7. In
other
PROCESSING PERCEPTIONReprinted from Corbis.
circular areas, one excitatory region encircled by a larger
inhibitory re-gion.
If light shines on the excitatory region, ganglion cells
depolarize
-ever, light stimulates the inhibitory region, they are less
likely to do so7.
The location and pattern of the
can vary and determines ganglion cell function7. For example, on
cen-ter ganglion cells, shown in Figure 1, best respond to light
falling only
(the excitatory region).These ganglion cells do not re-
causes the excitatory and inhibitory -
cel and results in no further signal7.Based on these
observations,
it was inferred that ganglion cells provide information
regarding con-trast7.
Hubel and Wiesel expanded Kuf-
within the striate cortex with simi-1.
RESEARCH AND DISCOVERIESAlthough Hubel and Wiesels
discoveries were monumental, they had a relatively simple
experimen-tal design. Using an anesthetized
cat with paralyzed eye muscles, the researchers would place
microelec-trodes near individual visual cortex neurons. With such a
set up, they could apply a stimulus (light) to dif-
the corresponding cortical neurons
in the striate cortex.
-ment and shape of light in that re-
of excitation and inhibition8. They found, for example, that
some neu-rons responded optimally to bars
not another8 (e.g. vertical light vs. horizontal light). These
cells be-came known as simple cells1.
Hubel and Wiesel hypothesized
cells were formed in an additive fashion as ganglion cells and
their-
lateral geniculate nucleus1 (Figure
were not easily explained via the addition of retinal ganglion
recep-
-plex cells1.
Hubel and Wiesel further dis-covered that cells with similar
ori-entation preferences existed in or-ganized columns, called
orientation columns, within the striate cortex10. Likewise, they
discovered ocular dominance columns, that prefer-entially respond
to input from one eye, and are responsible for deter-mining depth
perception1,10.
FURTHER RESEARCH AND IMPACT In follow up work, some re-
searchers have argued in favor of
bars of light to study vision because the nervous system
operates in
12. New
FIGURE 1-
-
nucleus (6), then to the striate cortex (7).Continued on page
14
Imag
e by
Rac
hel W
hite
head
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13 GREY MATTERS | vol 1 | issue 2 14GREY MATTERS | vol 1 | issue
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THE HYPOTHALAMUS
13 14
OPTICAL ILLUSION
Until the 1950s, common theo-ries of sleep involved the brain
shut-
to a car engine. Research since then, however, has shown high
levels of activity in the human brain for the duration of the
periods in which it is asleep, especially in the
hypothal-amus1.
The hypothalamus is a region of the brain located just below the
thalamus and above the brainstem that controls hormone release,
tem-perature regulation, nutrient intake, sexual behavior,
emotional respons-es, and physiological cycles
Interestingly, the hypothalamus is inhibited by the same arousal
structures it inhibits during sleep2 (see Figure 1). This creates a
posi-tive feedback loop, which also ex-plains the swift transition
from wakefulness to sleep and vice versa. As such, it would be more
accurate
switch, in which both states indicate that the brain is on but
has alter-nating function.
As a central part of the nervous
and endocrine system, the hypo-thalamus, which broadly receives
and distributes information, is well suited for regulating sleep.
Most im-
hypothalamus contains an ascend-ing pathway to the thalamus
itself and activates thalamic relay neu-rons, allowing the region
to trans-mit information to the cerebral cor-tex and the rest of
the brain.
Within the hypothalamus resides the ventrolateral pre-optic
(VLPO) area, which is a structure crucial for
to sleeping state. An active, func-tioning VLPO is what
maintains the brain in either condition. This is done mainly
through the projection of gamma-aminobutyric acid (GAB-Aergic)
cells3.
During periods of wakefulness, an acetylcholine-generating cell
group referred to as the pedunculo-pontine and laterodorsal
tegmental nucleus (PPT/LDT) relays informa-tion between the
thalamus and cere-bral cortex. It has been shown that this group
has a high activation rate
during wakefulness, which ceases during REM sleep 4. The PPT/LDT
cells are activated by orexin-pro-ducing neurons, and additionally
inhibit the VLPO, which, while un-suppressed, blocks both PPT/LDT
activity as well as orexin produc-tion5. As a result, orexin drives
the maintenance of wakefulness and therefore the continuous
inhibition of VLPO during the day. These neu-rons activations are
maintained by the human brains circadian cycles and photoresponse
mechanisms3.
Because of the mutual inhibition, the activity of either PPT/LDT
or VLPO will suppress activity from the other circuit and therefore
en-sure its own function, making clear the distinct shift in the
human brain into and out of a sleeping state.
The reciprocity of this system en-sures there is no gradual
shift from the sleep state to the wakeful one and vice versa,
another reason why a better model for this transition
-
indicates only the swift transition
FIGURE 1-
THE
HYPOTHALAMUSA SLEEP REGULATION
STRUCTURE
studies are showing that, in some cases, neurons are inhibited
in re-sponse to natural stimuli, but excit-
-li12. Therefore, natural stimuli may better reveal the correct
functional pathways.
Additionally, some researchers
-rons13. It has been shown that stim-uli placed outside of the
observed
-
actually inhibit the neuron13. This
in the visual system are larger than originally thought13.
Continuing research on simple and complex cells, ocular
domi-nance columns, and orientation columns shows that Hubel and
Wi-
time. Their discoveries were mon-umental in describing the
process-ing of the visual system, helping to
clarify its structure, and giving fu-ture researchers a
foundation upon which to build14. There is no doubt that in the
future scientists will continue to use Hubel and Wiesels
groundbreaking work to expand upon the visual system and solve its
remaining mysteries.
By Nicole Riley
References available online at
between awake and asleep, making no suggestion that the brain is
inac-tive in either state.
Because the hypothalamus close-
harm caused to this area can dra-
dependency of the neurotransmit-ters activations on a
functioning VLPO leaves little room for error.
activated by the VLPO, there will not be enough impetus to push
the brain from one state to the other. It is not surprising then,
that research has shown a link between damage to the hypothalamus
and sleep dis-orders. Weakening either side of
malfunction and the creation of an undesirable transition point
in be-tween the two states3.
In any case, it is considered evo-
to have sudden sleep-wake transi-tions. Spending periods in a
half-asleep, half-awake state would de-crease alertness and in many
cases be dangerous as it increases risk from predators.
Indeed, the inability to control this transition is commonly
seen as a symptom of narcolepsy, a neuro-
of sleep would be diminished as well, further demonstrating
little
state5.In properly functioning brains,
the regulation of the VLPO through circadian cycles ultimately
drives
model of sleep explains many of the ways in which sleep is
mediated as well as why disorders arise when the cycle is
damagedthus providing a base and framework for further testing and
analysis.
By Darren Hou
References available online at
OPTICAL ILLUSIONIn addition to being highly enjoyable, op-
tical illusions illustrate an important neu-roscience concept:
what we perceive is not what is.
Take, as an example, the image to the left. It might be hard to
believe, but the two squares (A and B) in this image are
identical-ly colored. Your brain, in reconstructing the scene,
hazards a few guesses - and does so poorly.
Not convinced? Head to www.greymat-tersjournal.com/illusion for
a full explana-tion of this illusion.
PROCESSING PERCEPTION Continued
Imag
e by
Jus
ten
Wat
erho
use
Image by Edward H. Adelson
-
15 GREY MATTERS | vol 1 | issue 2 16GREY MATTERS | vol 1 | issue
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FEATURED COMIC
15 16
FEATURED COMIC
GREY MATTER
messages all over the place the
callosum, the peripheral nervous
get anything done without me. You
-posed of neuronal cell bodies, dendrites, and unmyelinated
energy processing such as cog-
a large amount of oxygen to meet the demands of high-en-ergy
processing.
-
myelinated axons1named because it is insulated by cells with a
high lipid content that causes them to appear white2. Relaying
neu-
1.
WHITE MATTER
be honest, you guys are carrying around a few extra lipid
layers.
Glial cells take on many roles, and nearly as many forms, in the
brain. They are involved
the extra-cellular space, and they have even been shown to form
layers of the myelin sheath .
GLIAL CELLS
in on itself. Aside from its mechanical roles, -
meostasis in the brain. Among other things,
-tracellular materials like secreted proteins1.
CEREBROSPINAL FLUID
importantly, you both have missed the point as
Without me, the brain would collapse on itself. Plus, that skull
would seem a
lot closer and scarier.
-
17 GREY MATTERS | vol 1 | issue 2 18GREY MATTERS | vol 1 | issue
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SMOOTH BRAIN
17 18
SMOOTH BRAIN
SMOOTH BRAIN
BY ALEXA ERDOGAN
INTRODUCTIONImagine a human brain. Visualize
its characteristic grooves and folds. See how they serpentine
across the entirety of its mass, like a thousand rivers through a
forest of grey and white matter. Now imagine if all those rivers
had been dried up from the start. No more grooves. No more folds.
The brains surface is now a blank canvas, a mass of cells waiting
to be painted with rivers. This blank canvas is the work of a
neurological condition called lissencephaly.
WHAT IS LISSENCEPHALY?Lissencephaly, literally smooth
brain from the Greek lisso (smooth) and encephalos (with-in the
head), is a condition aptly named for its characteristic absence of
sulci and gyri. The condition is congenital and has severe even
lissencephaly typically die before the age of ten1.
Mortality is usually a result of the conditions symptoms,
which
or drinking liquid, respiratory dis-eases, and severe epilepsy.
Lissen-
cephaly also hinders intellectual development beyond that of a
3-5 month old child, resulting in men-tal retardation alongside
other de-velopmental challenges1. As of April 2013, this severe
malformation dis-order occurs in 1 of 30,000 births2.
In terms of physiology, the smoothness of the brain can be
at-tributed to complications in early fetal brain development. As
the fe-tus develops, its cells receive signals from their cellular
neighbors to re-locate to certain areas in the body
-entiation. Around 12-16 weeks into
in the brain can result in lissenceph-aly3.
In a healthy brain, neuroblasts migrate from deeper regions of
the
-tions of the cerebral cortex4. This process, termed neuronal
migra-tion, enables neurons to further dif-ferentiate and properly
coordinate wiring of synaptic circuits later in development.
As one can imagine, an immense amount of cell signaling and
com-munication is integral to the success of such a process.
Migrating neuro-
blasts have to travel nearly 1,000
location in the cortex where they begin to form layers5. These
cortical layers form radially from the center towards the surface
of the brain, meaning that each wave of traveling neuroblasts must
maneuver around the layers formed by previous waves of migrated
neurons5. If this process does not run smoothly, neurons can
accumulate near the surface of the cerebral cortex, fail to
migrate, or migrate to the wrong locations. Malfunctions in this
process are of-ten associated with a variety of ge-netic mutations
that lead to incor-rect protein synthesis.
GENETIC MUTATIONSDefective mechanisms can usu-
ally be traced back to cell signaling and genetic mutations. In
general, a genetic mutation is any permanent change to a sequence
of DNA. Two such mutations, which result in lis-sencephaly, can be
due to a perma-nent deletion of a single DNA build-ing block (known
as a nucleotide)
chunk of the chromosome. Each gene is like a word, which
The human body, during development, is a whirlwind of
cellular processes and developmental procedures all
marching forward in a remarkably organized fashion.
But, what happens when some
neurons ignore the directions?
GYRI NEUROBLASTnerve cells.
SULCI
Image by Benjamin Cordy
-
19 GREY MATTERS | vol 1 | issue 2 20GREY MATTERS | vol 1 | issue
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SMOOTH BRAIN
19 20
SMOOTH BRAIN
particular order. These individual letters of the alphabet are
analogous to individual nucleotides. As an ex-ample, the word
neuron carries
by the reader, but if a letter is de-leted, the resulting word,
neron, makes no sense. Similarly, if several letters are deleted,
the reader is left with the term neon, which means
gene is like the instruction manual
that gene can cause confusion (neu-ron vs. neron vs. neon) and
prevent a protein from being constructed correctly.
The structure of each protein is integral to its function, and
as such, construction errors can lead to partial or complete loss
of func-tion (Figure 1). Mutations can be an unfortunate byproduct
of DNA rep-lication; one section might not get copied correctly or
might be skipped over. While cells do have something akin to
spellcheck mechanisms to prevent most replication issues, these
errors still occur.
In the case of disorders that start at birth, many of these
mutations
can occur just after fertilization re-sulting in a new mutation,
or a de
-ery descendent of that cell will then carry that mutated DNA,
which can ultimately lead to medical condi-tions even if there is
no family histo-
Mutations Involved in Lissen-cephaly
Researchers have explored and discovered several genes linked to
neuronal development which,
For the sake of brevity, however, this article will focus only
on two broad categories: classical lissen-cephaly (Type I) and
cobblestone lissencephaly (Type II).
In classical lissencephaly, im-proper neuronal migration causes
neurons to clump together instead of spreading out and forming the
folds and grooves of a healthy brain. As a result of this
accumulation, the cerebral cortex becomes abnormal-ly thick (12 20
mm compared to a typical thickness of around 3-4 mm)6. In some
reported cases of Type I, patients have also presented with cardiac
defects or facial defor-
mations3. In addition to abnormal cortical
development, defective migration can also result in an absence
of cells and consequent lack of develop-ment of the corpus
callosum. This
facilitating the communication be-tween the two hemispheres of
the brain by serving as a physical bridge between them. In some
cases of liss-encephaly, the corpus callosum may be either
partially formed or not formed at all, resulting in a bridge with
limited or no functionality. By hindering this communication,
lissencephaly can result in harmful physical conditions such as
lack of coordination, diminished response to external stimuli, and
seizures3, 7. On the genetic level, classical liss-encephaly has
been associated with mutations on the LIS1, TUBA3/TUBA1A, DCX, ARX,
and RELN genes.
Mutations on the LIS1 gene are associated with abnormal neuronal
migration. The LIS1 gene regulates a protein that is a subunit of
an en-tire protein complex called platelet activating factor acetyl
hydrolase 1B (PAFAH1B). This protein com-
Imag
e by A
lexa E
rdog
an
FIGURE 1
plex regulates the levels of a certain molecule in the brain
called platelet activating factor (PAF), which helps direct the
movement of developing neuronal cells in the brain. When the LIS1
gene is mutated, the ini-tial protein subunit is abnormally small
and rendered nonfunctional. As a result, PAF molecule levels go
unregulated, which can hinder cells
-cations or even from migrating at all8.
The LIS1 gene is also associated with a motor protein called
cyto-plasmic dynein9, which is integral to the developing brain in
terms of migration and nuclear positioning10. Defective dynein
proteins can hin-der proper neuronal migration and have been
associated with numer-ous other neurodegenerative dis-eases in
addition to lissencephaly11.
Overall, these issues with neuro-nal migration can result in
several physical abnormalities of the brain,
such as a lack of grooves and folds on the brains surface.
Research has shown that LIS1 mutations are indeed correlated with
smoothness of the cortex, particularly towards the posterior end of
the brain12. Im-proper neuronal migration would also cause the
formation of larger ventricles, which has been shown using brain
imaging techniques12.
Two other subtypes of classical lissencephaly have been linked
to mutations on TUBA1A/TUBA3 and DCX genes. The TUBA1A/TUBA3 gene
codes for a protein called al-
involved in the formation and orga-
called microtubules13. Microtubules
structure and movement. One can think of these structures as
some-thing akin to the poles comprising the frame of a tent. If
certain poles at the top of the frame are bent out of shape, the
top of the tent will
sag. Similarly, microtubules form a structural frame for the
cell (re-ferred to as a cytoskeleton). De-fective microtubules can
result in a bent frame that hinder the cells function and in an
inability to prop-erly move developing brain cells to their
appropriate locations14,15, 16.
DCX genes, which are located on the X chromosome, regulate a
protein called doublecortin, which binds to microtubules and
stabilizes them. Doublecortin and microtu-bules work as a
relocation team to help move neurons to their proper locations in
the brain. Mutated DCX genes break this team apart by im-pairing
the function of doublecor-tin, thereby leaving microtubules
unstable and disorganized. Without the aid of these two proteins,
many developing neuronal cells are thus rendered immobile17.
Mutations on the ARX gene can also lead to other sub-types of
clas-sical lissencephaly. In order to eluci-date the function of
ARX, research-ers developed a test to examine what happens to the
brains progen-itor cells when the gene is inhibited and when the
gene is overexpressed. When inhibited, progenitor cell-sprematurely
left the cell-division cycle, thus impairing their even-tual
migration. On the other hand, overexpression led to an extension of
the cell-division cycle, causing cells to multiply uncontrollably.
Researchers also tried completely inactivating the ARX gene in
which case, cells could no longer develop into the right structure
and shape, resulting in limited motility18. This evidence suggests
that regulated expression of the ARX gene allows cortical
progenitor cells to divide
VENTRICLES
-
PROGENITOR CELLS-
stem cells.
OVEREXPRESSEDA gene that is overexpressed is more frequently
transcribed and translated. This results in great-er numbers of its
protein than normal.
Imag
e by A
dam
Voo
rhes
FIGURE 2
-
21 GREY MATTERS | vol 1 | issue 2 22GREY MATTERS | vol 1 | issue
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SMOOTH BRAIN
21 22
KEEPING RECORDING DEVICES INSIDE THE BRAIN
guide them towards their cortical destination.
Yet another subtype of lissen-cephaly has been linked to
genet-ic mutations on a gene called the RELN gene. While the common
type of classical lissencephaly is charac-terized by a strict
absence of grooves and folds, RELN mutations actual-ly result in
partial but very shallow grooves and folds (a phenomenon called
pachygyria)19. The RELN gene codes for a protein named reelin.
Early in the development of the brain, reelin signals devel-oping
neurons to migrate radially outwards in order to form the
beginnings of the cortical layers. Later on, reelin promotes the
matu-ration of certain neuronal parts, such as dendrites and
dendritic spines. In a mature brain, the protein also plays a role
in reg-ulating synaptic function20. Natu-rally, RELN mutations that
result in nonfunctional reelin prevent de-veloping neurons from
receiving the proper signaling they need in order to migrate
correctly. In the grand scheme of things, RELN mutations eventually
result in a lack of distinct cortical layer development in the
brain.
-sencephaly (Type II), also known as cobblestone lissencephaly,
is so named for the cobblestone-like ap-pearance of the brain on an
MRI scan. In this version of lissenceph-aly, neuronal development
is almost completely disorganized. Conse-
a high degree of disorganization and a lack of distinguishable
cortical layers. The brain also has a slightly grooved or
cobblestone-like surface, which is the result of cortical neu-rons
migrating outwards more than usual. As in the case of Type I, this
is due to a defective protein21.
Type II lissencephaly is further associated with three types of
neuro-logical disorders: Walker-Warburg syndrome, Fukuyama
syndrome, and Muscle-Eye-Brain (MEB) syn-drome22,23. However, these
three
types of congenital muscular dys-trophy, thus an exploration
into these subtypes would require an in-depth examination of the
biological mechanisms behind muscular dys-
that defective neuronal migration and improper structural
formation,
similar to those discussed in Type I lissencephaly, also play a
part in Type II lissencephaly.
NON GENETIC INFLUENCESIt should be noted that in addi-
tion to genetically linked lissen-cephaly, there is evidence
that sug-gests there may also be a number of environmental factors
involved.
environmental factors being stud-ied is the introduction of
harmful substances or viruses to the fetus during pregnancy.
In 2008, a case study was pub-lished that detailed the
occurrence of lissencephaly in a fetus with a cytomegalovirus
infection (CMV)24.
herpes virus and has been known to attack the brain25 along with
other parts of the body. Further research
-tacks the brains cortical progenitor cells during early
development26. Using mouse models, researchers injected cerebral
ventricles with CMV and later observed that this
resulted in disrupted neuronal mi-
of neurons27. Recently, research has also suggested other
contributing environmental factors that include in utero exposure
to cocaine28, eth-anol, and ionizing radiation29.
CONCLUSIONThere remains much to be stud-
ied in regards to the causes and treatments of lissencephaly. As
with many medical conditions, there are a number of contributing
factors in play, meaning there is no singular,
simple answer. Scientists are currently focusing on two main
angles of attack to better understand the mechanisms behind this
disorder.
First, research is being conducted to further ex-
plore and elucidate the molecular mechanisms behind specialized
and targeted neuronal migration. An en-hanced understanding of how
neu-rons receive their signals to migrate to certain areas of the
brain can help us identify what goes wrong in these mechanisms.
Second, a deeper analysis of the genes and their mutations might
further our understanding of the link between genetic and molecular
mechanisms. By comparing mutat-ed proteins to functional proteins,
we can better pinpoint the genetic mistakes that contribute to
liss-encephaly. Utilizing these two re-search methods can help
construct
-standing of both the human genome and the brain.
The causes and treatments of
lissencephaly... [are] a problem
that is varied and complex.
By Alexa Erdogan
References available online at
KEEPINGRECORDING DEVICES INSIDE THE BRAININ THE MODERN AGE
OFNEUROIMPLANTS INTRODUCTION
neuroprosthetics has exploded, reshaping what was thought
possible. Such devices have allowed people to control the movement
of robotic limbs through a computerized route rather than physical,
muscular means. In 2012, Cathy Hutchinson, a quadriplegic
feed herself with a DEKA prosthetic arm using her mind1.
One of the major challenges of developing this technology for
clinical use is that the number of sig-nals received by these
neuroprosthetic devices dimin-ishes over a period of months2. In a
study published in 2003 by Dr. Miguel Nicolelis of Duke University,
40% of recording electrodes stopped functioning within 18 months4.
Another study by Drs. Patrick J. Rousche and Richard A. Normann
showed that, ini-tially only 7 of 11 electrodes could record and
after 5 months, that number decreased to 4 of 115.
these devices functioning as well as possible for as long as
possible. This means that fewer costly surger-ies are required to
replace the devices. Should tech-nology and current methods
continue to advance, humans may one day no longer need to fear the
loss of motor function associated with various strokes and traumas.
Thus, for Hutchinson and others like her, understanding and
overcoming the decline in
critical step towards a more comfortable future.Image by Lars
Crawford
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23 GREY MATTERS | vol 1 | issue 2 24GREY MATTERS | vol 1 | issue
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KEEPING RECORDING DEVICES INSIDE THE BRAIN
23 24
KEEPING RECORDING DEVICES INSIDE THE BRAIN
EXPLANATIONStudies have suggested this grad-
ual reduction in functionality can be blamed on the brains
immune response to foreign objects2,3. These immune responses come
in two major varieties: an initial acute re-sponse to the
implantation, and a long-term chronic response. When brain tissue
is punctured, the im-planted device will unavoidably strike
capillaries, which are no more than 60 micrometers apart (about the
diameter of a human hair). Part of the initial response is due to
blood cells, activated platelets,
factors leaked from broken vessels. The larger the blood vessel
that is struck, the greater these blood com-ponents contribute to
the immune response.
In addition to the bloods im-mune response, brain cells also
car-ry out their own responses. Microg-lia, the cells involved in
the brains immune response, will try, in an
the device. Because the device is too large for a single cell to
envelop, a sheath of microglial cells forms around the device. Some
studies have shown that microglia may even fuse together to form
multi-nucleat-ed large bodies. These bodies can appear as early as
18 days-post-implant9 and have been found on silicon electrodes10.
When microg-lia are unable to consume foreign objects, they enter a
state known as frustrated phagocytosis**2, in which they
persistently release neu-rotoxic substances.
Killing neurons is one way mi-croglia contribute to the loss of
neu-ronal signals. As part of the immune response, microglia also
send out
-cruit astrocytes and other microglia, which eventually migrate
to the in-jury site and congregate around the device. These cells
might displace
local neurons10 further contribut-ing to the reduction of
signals over time. The proliferation of astrocytes and microglia
around the device constitutes the chronic response2.
One proposed theory for the chronic response involves the
en-capsulation of microglia and as-trocytes around the implanted
device2,11,12,13,14. It is commonly ob-served that astrocytes and
microglia will form a layer of cells surround-ing the implant,
known as a glial scar2. Though, as these cells are ac-tually not
all dead, the area around the implant is not considered true scar
tissue6. Regardless of whether these cells are dead or alive, their
bilayer membranes will act as ca-pacitors, storing electrical
signals. This high concentration of cell membranes around the
implant,
electrical signals that reach the elec-
trodes, which reduces the function-ality of the device. Over
time, these implants receive only a fraction of the original
signals.
The design of implant devices determines its bio-compatibility,
which is the extent of tissue re-sponse to the device. Researchers
have explored the use of plastics, polymers, ceramics, and glass,
to reduce the severity of the initial and chronic responses.
Microwire elec-trode arrays, as used by Dr. Nicole-lis, can be made
of conducting met-als such as platinum, gold, or even stainless
steel2. The next genera-tion of recording devices, however, seems
to be silicon-based electrode arrays2.
In addition to experimenting with materials, researchers have
also tried using various anti-in-
7 and controlled time-release systems8. Currently in
shan
k of r
ecor
ding d
evice
FIGURE 1
astrocytes (red) vessels (yellow) microglia (green) nuclei
(blue)
tab of recording device1 mm
Imag
e by
Tre
tt K
rist
en
GAP JUNCTION transmembrane proteins that connect the cytoplasm
of two cells
testing at the Shain lab at Seattle Childrens Research
Institute, is the introduction of holes to the shank of
6.
HYPOTHESISDr. William Shain has hypoth-
esized that astrocytes play a ma-jor role in the chronic immune
re-sponse. Astrocytes are the most
brain, comprising 30-65% of all glial cells in the central
nervous system15. They support neural function by
one of which is absorbing excess po-tassium ions from the
extracellular space2. During an action potential
neurons release potassium into the extracellular space, where,
without astro-cyte interven-tion, the ions would accumu-late and
inhibit neuronal func-tion (For more information re-garding action
potentials, see page 05).
A s t r o c y t e s form extensive physical net-works with each
other through gap junctions. Ions absorbed by astrocytes
and distribut-ed throughout this network. However, as Dr. Shain
suggests, when foreign
objects, such as neuroprosthetic implant devices, destroy these
intercellular con-nections, they interrupt the ions
concentrations build up inside the astrocytes, and osmosis
causes the cells to swell. Under stress, astro-cytes will enter a
reactive mode in which they exhibit increased mi-gration,
proliferation, and matrix production16. They will also increase
production of molecules that signal for other microglia and other
astro-cytes. This results in further congre-gation of cells around
the device in the chronic response.
Building on the hypothesis that
a chronic response is aggravated by the disruption of the
astrocyte network, Dr. Shain is testing devic-es that may allow the
rebuilding of such networks. The project seeks
-ing astrocytes to re-form connec-tions through, and not just
around, the device. This is done by building electrodes with 20
micrometer-wide holes throughout the device shank. In the rat
cortex, an astrocytes pro-cesses are as long as 30 microme-ters,
and the hole is 15 micrometers thick. Two astrocytes, then, can
theoretically form a 60 microme-ter-long connection
body-to-body.
THE FUTUREWhat researchers want to know
is how proteins, cells, and cell pat-terns change in response to
im-plantation. Tissue samples, which may range from 100 to 300
microns thick, are captured in 3D images using spinning-disk
confocal mi-croscopy. Using a program called FARSIGHT, the cell
count and cell locations can then be recorded from these 3D images,
resulting in us-able, quantitative data. Through the analyses of
these data, researchers can better understand the brains responses
to implantation.
This ongoing research into neu-roprosthetic devices will further
aid scientists in the quest to explain the physiology of the
chronic response. These discoveries will ultimate-
forms of paralysis, by allowing im-planted devices to function
longer and continue to improve the pa-tients day-to-day lives.
-tory.
PHAGOCYTOSISsolid, usually another cell.
FIGURE 2 -
assembled by NeuroNexus Tech-nologies.
astrocytes (red) vessels (yellow) microglia (green) nuclei
(blue)
By Chantruyen Ho
References available online at
Imag
e by
Tre
tt K
rist
en
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25 GREY MATTERS | vol 1 | issue 2 26GREY MATTERS | vol 1 | issue
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FIXED NEURAL CIRCUITS
25 26
FIXED NEURAL CIRCUITS
FIXED NEURALCIRCUITS
INTRODUCTIONEarly work in developmental
neuroscience led researchers to conclude that axonal growth in
the developing and regenerating brain
not simply random or determined by neuronal proximity. Roger
Sper-ry demonstrated this in 1963 when he cut the optic trunk of a
Xenopus frog and rotated the eye 180 de-grees1.
The purpose of this experiment was to understand whether an
in-trinsic mechanism (as opposed to an external mechanism) is
respon-sible for axonal growth.
If an external stimulus, for ex-ample, light, were involved in
the regrowth of the circuit, the frogs
in the correct direction. In time, the frog would see normally
despite an inverted retina. But if an internal mechanism were
responsible for ax-onal regeneration, the newly formed connections
would not depend on the orientation of the retina and the
vision (Figure 1).Sperry hypothesized the ex-
istence of an exclusive lock and key mechanism, where every
axon
marker compatible with specif-ic receptors of a target cell.
Under such a hypothesis, optic nerve wir-ing would not change,
leading to post-experimental circuitry identi-cal to the
pre-experimental connec-tions.
Indeed, Sperry found that after severing and reconnecting the
op-tic nerve, axonal regeneration led to pre-experimental
connections,
-sion for the frog. He concluded from these results that a
molecular or electrical mechanism was at work guiding axons to
target regions and target cells before a synapse is ever
formed
BACKGROUND AND CURRENT RESEARCH
This work in the early 1960s paved the way for current
under-standing of the complex mecha-nisms of developmental
circuitry. Axonal regeneration of the optic nerve is only one
example of target-ed growth and development in the brain. Sperrys
work showed that neuronal regeneration follows pre-viously made
connections, but did not explain how those connections
-ment.
Over a century ago, Santiago Ramn Y Cajal proposed that
de-veloping axons were directed along a particular trajectory. His
idea was based on observations of the shape of the growing tip, or
growth cone (Figure 2).
Today, we know that when axons grow, the position of its tip the
growth cone changes, and is in
fact responsible for the direction of growth and movement2. The
growth cone contains a dynamic network
that mediate the orientation of the -
tion through a polymerization and depolymerization mechanism in
response to extracellular stimuli via second messengers (molecules
or ions, such as calcium ions, that are released within the neuron
in response to extracellular ligand-re-ceptor binding.).
Further evidence supporting the role of growth cones in
axonal
-
set of axons to migrate, and follower neurons, the later sets.
In contrast
growth cones of pioneer axons, follower axonal growth cones are
much simpler and less extensive. Their shape seems to be pointed in
a particular direction. This suggests that pioneering axons behave
as
FIGURE 1
(A) (B) (C)
Imag
e by
Sta
cie
Shib
ano
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27 GREY MATTERS | vol 1 | issue 2 28GREY MATTERS | vol 1 | issue
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FIXED NEURAL CIRCUITS
27 28
FIXED NEURAL CIRCUITS
trailblazers, laying the path for cells to follow, while
follower axons are guided along via cell-to-cell signals.
Follower axons have relatively
indicating that growth is largely undetermined by external
stimu-li2. Furthermore, recent research shows that protein movement
with-in growth cones occurs at a higher rate among following axons
than pioneering axons, indicating that axons grow and synapse at a
faster rate in the presence of a guidance axon3 (Figure 3).
When growth cones are actively searching for a target, or
trailblaz-ing, growth-signaling molecules
growth: repulsion or attraction2. Depending on the second
messen-ger pathways that exist in the re-ceptor cell, molecular
signals can be
require cell-to-cell contact.Netrin, for example, is an im-
portant signaling molecule in spinal
substance that can act as a repel-lent or attractant. In the
presence of Netrin a growth cone expressing only DCC receptor will
turn towards the source of Netrin. If, however, a growth cone
co-expresses Unc5 re-ceptor, it will grow in an adjusted direction,
usually away from the Ne-trin4. In the developing spinal cord,
midline secrete Netrin, and growing axons respond in a variety
of ways.
-stances, such as Ephrin, require that that growth cones come in
nearly direct contact with another neuron
-ment of the visual system, for exam-ple, retinal axons
containing Ephrin receptors bind to membrane-bound Eph ligands in
the tectum, usually triggering a repellent response5.
If axonal regeneration and growth primarily follow a pattern
determined during development, there must be intricate
cell-to-cell signaling that takes place as a pre-cursor to
synaptogenesis. Sperry hypothesized that a unique sig-nal-receptor
pair exists for every axon-dendrite synapse pair. How-ever, this is
not plausible due to the sheer number of unique molecules
that would have to exist for every synapse in a mammalian brain
to be uniquely recognized.
Evidence suggests instead that the developing brain is
regionalized before neuronal development. Thus,
-gions follow a similar set of patterns and cues throughout
their growth6.
FIGURE 2An axonal growth cone showing pr -
(red).
http://bit.ly/19Ux3Og
FIGURE 3-
here to the template presented by pioneer axons (purple).
DCC - DELETED IN COLORECTAL CANCER -
ulates axon growth via second messenger path-ways towards the
ventral midline.
UNC5repulsive response to Netrin. The cell responds to Netrin by
growing down its gradient.
FIGURE 4-
iment. Commissural neurons exist along the length of the
spi-
midline, leave the midline, and then turn rostrally according to
a repulsion gradient (purple) that decreases caudal to rostral
along the spinal cord.
Rostral
Caudal
Research in the mid-1990s showed
gene expression leads to predicted
from that region7. But even in cas-es of identical gene
expression, not all regionally similar axons follow the exact same
patterns of growth and migration; there is some spatial variation.
For vexample, axons can
without originating from the ex-act same area. This suggests
that a seemingly homogeneous population of neurons acquire a
spatial aware-ness and behave accordingly. The most recent research
suggests that a gradient mechanism is responsible for the majority
of axonal growth and recognition mechanisms.
RETINAL ORGANIZATION AND COMMISSURAL NEURON GROWTH IN THE
DEVELOPING SPINAL CORD
Two well-studied areas of devel-opment best illustrate the
gradient mechanism: visual and spinal de-velopment. Before Sperry,
scientists had established that axonal projec-tions from the retina
to the tectum (or superior colliculus in mammals)
axons project to the ventral tectum and ventral retinal axons
project to the dorsal tectum. Similarly, ante-rior retinal axons
and the posterior tectum are connected, as are poste-rior retinal
axons and the anterior tectum.
A group examined the nature of ligand-receptor interactions
among tectal and retinal axons and found it to be repulsive. It was
observed that posterior retinal axons contain
high levels of Eph receptor, while anterior retinal axons
contain little to no Eph receptor. Furthermore, the absolute amount
of Eph recep-tor expressed was found to decrease posterior to
anterior in the retina.
The expression of Ephrin ligand, which binds to Eph receptors,
was found to be highest in the posterior tectum, and almost
non-existent in the anterior tectum. These obser-vations, coupled
with the repulsion hypothesis, led researchers to con-clude that
ligand-expressing ante-rior cells repel posterior retinal ax-ons.
To explain why anterior retinal axons which display no prefer-ence
for tectal placement group at the posterior tectum, researchers
hypothesized that competition from posterior retinal axons forced
ante-rior retinal axons to the posterior8.
Another example of a gradient mechanism that orders a large,
ho-mogeneous population of neurons comes from studies of
commissu-ral neurons in the developing spi-nal cord. These neurons
function in sensory integration from the spinal cord to the brain
and are located in bundles on one side of the develop-ing spinal
cord.
Commissural axons migrate
extend toward the ventral midline, traverse through that midline
to the contralateral side, then imme-diately turn 90 degrees and
extend rostrally. It was found that two sep-arate signaling
molecules were re-
the midline and then, away from the it. The rostral extension,
how-ever, puzzled scientistsall com-missural axons behaved in this
way, but these bundles were distributed throughout the length of
the spinal cord. If one signaling molecule were responsible for
this, as a common response would suggest, there is no way to
determine in which way, rostral or c, the commissural axons
would turn.Once again, a gradient mech-
anism is in fact responsible. Wnt protein decreases in
concentration along the midline caudal to rostral, and repels
commissural axons. Axo-nal growth thus occurs in the direc-tion of
decreasing Wnt concentra-tion. This allows every commissural
bundle, irrespective of rostro-cau-dal position to migrate
rostrally9 (Figure 4).
CONCLUSIONThe result is general. Axonal
-tion is dependent upon two import-ant factors: spatial
organization, due to the expression of a unique population of genes
in each region, and signal gradients. Such gradient mechanisms in
signaling are emerg-ing in current research as a com-mon theme of
axonal growth, and development in general. The orig-inal lock and
key mechanism hy-pothesized by Roger Sperry nearly
by new observations in the mecha-nisms of recognition, growth,
and targeting.
The developing brain is remark-ably consistent among
individuals
Axonal recognition and targeted synaptogenesis in the early
stages of development are essential to the
-ral circuits that are consistent be-tween individuals.
Variations based on experience then builds on those
connections.
TECTUMThe tectum is a region of the midbrain involved
-
nerve.
By Alice Bosma-Moody
References available online at
Imag
e by
Al
ice
Bosm
a-M
oody
Image by Alice Bosma-Moody
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29 GREY MATTERS | vol 1 | issue 2 30GREY MATTERS | vol 1 | issue
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THE NEUROPHYSIOLOGY OF FATHERHOOD
29 30
THE NEUROPHYSIOLOGY OF FATHERHOOD
the neurophysiology of
By Justin Andersen
Image by Justin Andersen
FATHERHOODthe end of the gestational journey for the infant and
her mother, for
dad, it seems, the journey of fatherhood has just begun. But is
this
really true? This question has recently stirred up considerable
attention,
encouraging researchers to further investigate the
neurophysiology
of fatherhood. Today, scientists are rapidly uncovering the
neural
mechanisms that initiate, develop, and sustain fathering
behaviors in
preparation for, and during, childrearing.
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31 GREY MATTERS | vol 1 | issue 2 32GREY MATTERS | vol 1 | issue
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THE NEUROPHYSIOLOGY OF FATHERHOOD
31 32
THE NEUROPHYSIOLOGY OF FATHERHOOD
INTRODUCTIONIn recent decades, the investiga-
tion to understand the neural and hormonal correlates of
motherhood has yielded important insights into the
neurophysiological changes that mark maternal development. In
ad-dition to initiating and supporting gestation, parturition, and
lacta-tion, these changes are responsible for a host of
accompanying behav-
maternal parenting behavior after birth1,2.
For as much as scientists cur-rently understand about maternal
preparation, until recently, very few studies have examined the
changes if any that occur as males un-dergo preparations for
fatherhood3. Perhaps the general disinterest in such a research
project was due to the rarity of active fatherhood. Hu-man beings
are a part of a small mi-nority one that includes only 5% of all
mammalian species which
-pation in childrearing4,5,6. Even still, it has long been
recognized that hu-man fathers play an important role in the
development and well-being of their children7,8,9,10,11,12.
Recently, however, research has revealed that the transition to
fa-
developmental changes that en-hance fathering behaviors13. This
ar-
ticle examines such research, which has lead to new
understandings of the initiation of paternal behaviors across
mammalian species and the neuroplasticity that sustains these
behaviors long into fatherhood.
NEUROENDOCRINOLOGY OFPATERNAL CARE
phases associated with gestation, parturition, and lactation
require an adaptable maternal physiology that supports the
requirements of these phases without harming the mother1. Various
signaling mech-anisms, many of which are the re-sult of conception,
drive maternal changes through childbirth. After childbirth,
however, many of these signals are the consequence of be-havioral
interactions between the
-tation)3,14.
Because the maternal brain plays an important role in directing
the neuroendocrine system and sub-sequent maternal behaviors15,
re-searchers have begun to investigate whether there is homology in
the initiation and maintenance of pa-rental behavior that extends
to fa-thers in biparental species.
Some of the mechanisms behind -
enced by hormones such as oxyto-cin, prolactin, and vasopressin.
Re-
intensely on three neuropeptides, which have important functions
in motherhood physiology, and have been implicated in triggering
and maintaining maternal and paternal behavior16,17.
PROLACTINProlactin (PRL) is a single-chain
(198 amino acids) neuropeptide molecule that is synthesized
pri-marily in the anterior pituitary gland. Though, its presence in
sev-eral areas of the brain (e.g. hypo-thalamus, amygdala, and
caudate) provides indications that it is also synthesized within
the brain18.
PRL is most commonly known as a chemical messenger that
stim-ulates the mammary glands to initi-ate milk production.
Furthermore, PRL induces the lobuloalveolar growth of the mammary
gland to create the necessary alveoli cells for milk
secretion19.
During gestation, however, PRL receptors are upregulated in
brain regions associated with social be-havior, which likely
facilitates ma-ternal care responses20,21,22. Because of its
nervous system activity, PRL has been the target of research into
the neuroendocrinological mecha-nisms of paternal behavior.
Male cotton-top tamarins exhibit paternal behaviors associated
with
before and after the birth of their 23
experienced fathers display such behaviors, there is a greater
deploy-ment of PRL in experienced fathers. And, as expected, both
experienced
levels of PRL than non-fathers24. Similarly, in the biparental
Califor-nia mouse, plasma PRL levels have been shown to be higher
in fathers than expectant fathers and both have levels higher than
those of vir-gin males25.
Such examples, as well as oth-ers26,27,28,29, demonstrate that
pa-ternal males exhibit a hormonal
-spring. In humans, however, the in-teraction is more
complicated.
It has been shown that in human fathers there are interesting
and unclear associations between PRL levels and paternal
responsiveness to child cues. For example, after
PRL levels in fathers decreased30,31. However, the same fathers
experi-enced increased PRL levels when holding their second newborn
for
31.Additional behavioral studies
have shown that fathers with high-er PRL levels are more alert
to their infants cues and exhibit more pos-itive parental behaviors
(higher sympathetic response) than fathers with lower PRL levels.
Further-more, experienced fathers show an even greater increase in
PRL con-
-thers when listening to infant cues32. However, as the infant
grows older
becomes less clear33. During fa-ther-child interactions, PRL
levels have shown short-term increases
six months of fatherhood38; how-ever, short-term declines have
also
been observed during father-child -
texts35,36.
OXYTOCIN & VASOPRESSINOxytocin (OT) and vasopressin
(AVP) are two neuropeptides that have also been implicated in
the ini-tiation and expression of parental behaviors across
biparental mam-malian species37. OT is known for its function
during the milk letdown
uterine contractions during child-birth38. AVP is implicated in
pair bonding, parental aggression, and protective
behaviors39,40,41.
AVP has been shown to be in-
paternal behaviors in the medial preoptic area of the brain42,
as well as in the bed nucleus of the stria terminalis. For their
role in regu-lating maternal behaviors, these areas have been
termed the ma-ternal brain region43. Special neu-rons called
magnocellular neurose-cretetory cells, located in both the
supraoptic and the paraventricular nuclei of the hypothalamus,
syn-thesize and transport OT and AVP into the bloodstream. Because
they can each bind to the others magno-cellular receptors, these
neuropep-tides support many crossover func-tions44. Much like PRL,
OT and AVP also function on the brain in crucial ways that have
been associated with the propagation of parental bond-ing and the
attachment behaviors
Increasingly, researchers are un-covering that OT and AVP play
sig-
behaviors beyond those tied to par-turition such as trust, tribe
mentali-ty, sexual arousal, and bonding.
In animal models, it has been -
ternal care are correlated with the density of OT receptors in
brain areas associated with maternal be-
haviors45. Recently OT has been associated with paternal-bond
development, initiation of paternal behaviors46 -tion
behaviors47,48,49. For example in the California mouse, OT plasma
levels measured across expectant fathers, current fathers, and
virgin males have revealed that expect-ant fathers had the highest
levels of OT50evidence51 of the role of OT in pater-nal
behaviors52, has shifted research
AVP53,54,55. In male prairie voles (biparen-
tal species), positive paternal be-haviors, such as pup
retrieval and grooming, have been correlated with an increased
density of AVP
nucleus of the stria terminalis. Furthermore, after 10 minutes
of pup-exposure, males exhibit in-creased expression and activity
of OT and AVP related neurons in the paraventricular nucleus56.
When AVP is directly admin-istered (intranasally), paternal
behaviors are enhanced. And, as expected, AVP antagonists, which
block the binding of AVP, decrease paternal behaviors48. Many of
these
fathers as well57,58,33,46.Recently researchers found that
during a 15-minute play session with their toddler, fathers
displayed more positive parental behaviors
-IMPORTANT TERMINOLOGYbirth.
Neuroendocrine hormones of the endocrine glands
processes.
a hormone in the endocrine system
Neurogenesis generated
Perhaps less obvious,
however no less
important, are those
[changes] that usher in
fatherhood.
Such examples...
demonstrate that
paternal males
exhibit a hormonal
response to the birth
of their
-
33 GREY MATTERS | vol 1 | issue 2 34GREY MATTERS | vol 1 | issue
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THE NEUROPHYSIOLOGY OF FATHERHOOD
33
ing, a measure of the ability of par-ents to support learning
and child autonomy) and less hostility fol-lowing intranasal
administration of OT59,60.
Studies conducted in which both OT and AVP have been analyzed
during father-infant involvement suggest that OT is important for
so-
-ject-directed stimulation61. Howev-er, more recently,
researchers have experimentally shown that serum AVP in fathers is
directly correlat-ed with social cognitive stimulatory circuits. In
this particular experi-
behavior (social cognitive stimu-lation) were associated with
AVP serum levels and researchers were able to experimentally
distinguish these associations from the ancil-
60.
NEUROPLASTICITY OF PATERNAL CARELike many other critical
devel-
opmental milestones that occur throughout the human lifespan,
parenting is marked by changes in hormonal and neural processes.
With the information now known about the neuroendocrine chang-es
that underly fatherhood, many researchers have begun examining the
potential of paternal brain plas-ticity62,63,64,65,66.
More broadly, neuroplasticity is the ability of neurons to form
new neural networks. Not only can such networks change behaviors,
but
they can also become changed in response to new stimuli.
As previously mentioned, PRL is known to mediate paternal
behav-iors in certain mammalian species. This is likely related to
PRLs ability to increase cell proliferation in cer-tain areas of
the brain and protect against cell death in others. The
subventricular zone and the dentate gyrus, areas of the brain
important for infant recognition, have been
for PRL67. In mice given a PRL-neu-tralizing antibody, there is
a drastic reduction in neurogenesis and a corresponding inability
to recog-
67. In another study, both biological
fathers and virgin male mice who were placed into a paternal
role showed increased cognitive abili-ties and an enhancement in
spatial memory capacities, as demonstrat-ed by their ability to
learn how to successfully navigate a maze. But, while both groups
exhibited neuro-nal changes, the biological fathers showed
exaggerated gains in both hormonal levels and cognition68.These
abilities translate to better
--
or ability to handle stress, and the capacity to work through
complex problems68.
CONCLUSION
The research highlighted in this article has shown that changes
in
paternal behavior may be linked to neurophysiological changes
associ-
OT, and AVP appear to exert a rath-
behavior. It should be noted, how-ever, that most studies rely
on cor-relational evidence because causal relationships have not
yet been de-termined.
Previous research has revealed the degree to which a dynamic and
malleable mammalian neurophysi-ology is able to change and adapt to
new circumstances. This is clearly evident by the physiological
chang-es that accompany gestation and nurturing behaviors in
mothers. Perhaps less obvious, however no less important, are those
that ush-er in fatherhood. As shown here, males undergo a cascade
of neuro-physiological changes that prepare them for the rigors of
childrearing.
endeavor to understand the biologi-cal and evolutionary roles of
father-hood and provide profound insight into the reciprocal impact
of pater-nal care to both father and child.
By Justin Andersen
References available online at
TABLE 1HORMONE SYNTHESIS ROLES
Primarily in the anterior pituitary gland
Maternal Paternal
nuclei of the hypothalamusMaternal -chrony. Paternal
nuclei of the hypothalamus
Maternal: Associated with high-level maternal social behaviors
such as pair-bonding, tribe-mentality, pro-Paternal
All Things Neuroscience
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