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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
1 GREY MATTERS | vol 1 | issue 2 2GREY MATTERS | vol 1 | issue 2
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
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
5 GREY MATTERS | vol 1 | issue 2 6GREY MATTERS | vol 1 | issue 2
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
7 GREY MATTERS | vol 1 | issue 2 8GREY MATTERS | vol 1 | issue 2
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
9 GREY MATTERS | vol 1 | issue 2 10GREY MATTERS | vol 1 | issue 2
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
11 GREY MATTERS | vol 1 | issue 2 12GREY MATTERS | vol 1 | issue 2
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
13 GREY MATTERS | vol 1 | issue 2 14GREY MATTERS | vol 1 | issue 2
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
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ten
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use
Image by Edward H. Adelson
15 GREY MATTERS | vol 1 | issue 2 16GREY MATTERS | vol 1 | issue 2
FEATURED COMIC
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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 2
SMOOTH BRAIN
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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 2
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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
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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
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dam
Voo
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FIGURE 2
21 GREY MATTERS | vol 1 | issue 2 22GREY MATTERS | vol 1 | issue 2
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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
23 GREY MATTERS | vol 1 | issue 2 24GREY MATTERS | vol 1 | issue 2
KEEPING RECORDING DEVICES INSIDE THE BRAIN
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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
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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
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Tre
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25 GREY MATTERS | vol 1 | issue 2 26GREY MATTERS | vol 1 | issue 2
FIXED NEURAL CIRCUITS
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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)
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FIXED NEURAL CIRCUITS
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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
29 GREY MATTERS | vol 1 | issue 2 30GREY MATTERS | vol 1 | issue 2
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.
31 GREY MATTERS | vol 1 | issue 2 32GREY MATTERS | vol 1 | issue 2
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 2
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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