A Brief History of Neuroscience
There is evidence, however, that at least some Egyptians knew about the importance of the brain. The Edwin
Smith Papyrus, dating back to 1700 BC, is the earliest known medical text in history. The papyrus discusses
the brain, the meninges, the spinal cord and cerebrospinal fluid. It contains details of 48 medical cases,
including seven that deal directly with the brain, which indicate that the Egyptian author knew the brain
controls movement. However, the serious cases of brain injury are described in the papyrus as untreatable.
We have come a long way since ancient Egypt. We now know the parts of the brain responsible for many of
its functions; we can operate successfully on the brain and use medication to effectively treat many
neurological disorders.
Getting to this point hasn’t been easy. Have you ever heard of trepanation? It’s the once popular belief that
cutting a hole in your skull would relieve pressure on your brain and lead to enlightenment. Or how about
phrenology, popular in the 1800s? Phrenologists thought that you could learn everything you needed to know
about someone’s character by measuring the shape of his or her skull.
The rapid pace of developments in neuroscience facilitated by modern imaging techniques is astounding. Yet
many of the most important questions regarding the brain have yet to be answered. Why do we sleep and
dream? How does the chemical and electrical activity in the brain result in consciousness? These and other
questions will fuel neuroscience in the 21st century.
A Brief History of Neuroscience
These missteps aside, neuroscience has advanced like most sciences: one small step after another —
until the 20th century, when it flies into a sprint.
170 B.C. the Roman physician Galen, whose day job was fixing up gladiators, insists that a person’s
temperament and bodily functions are controlled by the brain. His theories are dominant for the next
1200 years.
1000 A.D. The great Islamic surgeon Abu al-Qasim al-Zahrawi describes several treatments for
neurological disorders in his 35-volume encyclopedia of medical practices, the Kitab al-Tasrif.
1543 The first true medical textbook to deal with neuroscience, “On the Workings of the Human Body,”
is published by Andreas Vesalius.
1649 The French philosopher René Descartes comes up with the influential idea that while the brain
may control the body, the mind is something intangible, distinct from the brain, where the soul and
thought resides. This concept is still with us, much to the chagrin of many neuroscientists.
1664 Thomas Willis publishes “Anatomy of the Brain,” which describes reflexes, epilepsy, apoplexy
and paralysis. He uses the term neurology for the first time.
1791 Italian physiologist Luigi Galvani proposes that nerves operate through electricity.
1837 J. E. Purkinje is the first man to describe a neuron.
1862 Paul Broca pinpoints the part of the brain necessary for speech, henceforth known as Broca’s area.
1878 William McEwen performs the first successful modern neurosurgery.
1911 Aptly named British neuroscientist Henry Head publishes “Studies in Neurology.”
1929 Hans Berger invents the EEG (electroencephalography), a device that measures electrical activity
in the brain.
1932 Lord Edgar Douglas Adrian and Sir Charles S. Sherrington win the Nobel Prize for describing how
neurons transmit messages.
1938 Isidor Rabi discovers nuclear magnetic resonance, facilitating the development of magnetic
resonance imaging (MRI). Rabi’s discovery would go on to win the Nobel Prize in 1944.
1950 Karl Spencer Lashley determines that memory relies on several sites in the brain working together.
1970 The Society for Neuroscience is established.
1973 Candace Pert discovers opiate receptors in the brain.
1974 A mouse is the subject of the first nuclear magnetic resonance (NMR) scan.
1974 The first Positron Emission Tomography (PET) scanner is invented, providing visual information
about brain activity.
1987 Prozac is introduced.
1990 George H. W. Bush declares the last decade of the 20th century as the Decade of the Brain.
1992 Functional magnetic resonance imaging (fMRI) is first used to map activity in the human brain.
Neuroscience booms.
The Central Nervous System
The Central Nervous System has Seven
Main Parts.
1) The spinal cord, the most caudal part
of the central nervous system, receives
and processes sensory information from
the skin, joints, and muscle of the limbs
and trunk and controls movement of the
limbs and the trunk. It is subdivided into
cervical, thoracic, lumbar, and sacral
regions.
2) Medulla oblongata
3) Pons
4) Midbrain
5) Cerebellum
6) Diencephalon
7) Cerebrum
The Central Nervous System
The Central Nervous System has Seven Main Parts.
2) The medulla oblongata, directly rostral to the spinal cord, includes several centers responsible for vital
autonomic functions, such as digestion, breathing, and the control of heart rate.
3) The pons, rostral to the medulla, conveys information about movement from the cerebral hemispheres to
the cerebellum.
4) The midbrain, rostral to the pons, controls many sensory and motor functions, including eye movement
and the coordination of visual and auditory reflexes.
5) The cerebellum lies behind the pons is connected to the brain stem by several major fiber tracts called
peduncles. The cerebellum modulates the force and range of movement and is involved in the learning of
motor skills.
6) The diencephalon lies rostral to the midbrain and contains two structures. The thalamus processes most
of the information reaching the cerebral cortex from the rest of the central nervous system. The
hypothalamus regulates autonomic, endocrine, and visceral functions.
7) The cerebrum comprises two cerebral hemispheres, each consisting of a heavily wrinkled outer layer (the
cerebral cortex) and three deep-lying structures (the basal ganglia, the hippocampus, and the amygdaloid
nuclei). The cerebral cortex is divided into four distinct lobes: frontal, parietal, occipital, and temporal.
The brain is also commonly divided into three broader regions: the hindbrain (medulla oblongata, pons, and
cerebellum), midbrain, and forebrain (diencephalon and cerebrum).
The brain has distinct functional regions
The frontal lobe is largely concerned with short-term memory and planning future actions and with control of
movement; the parietal lobe with somatic sensation, with forming a body image and relating it to
extrapersonal space; the occipital lobe with vision; and the temporal lobe with hearing and – through its
deep structures, the hippocampus and amygdaloid nuclei – with learning, memory, and emotion.
Brain Diagram
Areas involved in language
Wernicke’s area processes auditory
input for language and is important for
understanding speech. It lies near the
primary auditory input with information
from other senses.
Broca’s area controls the production of
intelligible speech. It lies near the region
of the motor area that controls the mouth
and tongue movements that form words.
Wernicke’s area communicate with
Broca’s area by a bidirectional pathway,
part of which is made up of the arcuate
fasciculus.
Pierre Paul Broca, a French neurologist, was the first to identify specific areas (Broca’s area) of the brain
concerned with language. In 1864, he announced “Nous parlons avec l’hemisphere gauche! (We speak with
the left hemisphere!)”. In 1876, Karl Wernicke, published a paper, “The Symptom-Complex of Aphasia: A
Psychological Study on an Anatomical Basis”.
Whereas Broca’s patients could understand language but not speak, Wernicke’s patient could form words but
could not understand language.
Brodmann’s division of the human cerebral cortex into 52 discrete
functional areas
Brodmann identified these areas on the
basis of distinctive nerve cell structures
and characteristic arrangement of cell
layers. For instance, area 4 is the motor
cortex, responsible for voluntary
movement. Areas 1, 2, and 3 constitute
the primary somatosensory cortex,
which receives sensory information
primarily from the skin and joints. Area
17 is the primary visual cortex, which
receives sensory signals from the eyes
and relays them to other areas for
further processing. Areas 41 and 42
constitute the primary auditory cortex.
Inspired in part by Wernicke’s advances and led by the anatomist Korbinian Brodmann, a new school of
cortical localization arose in Germany at the beginning of the 20th century, one that distinguished functional
areas of the cortex based on the shapes of cells and variations in their layered arrangement.
Using this cytoarchitectonic method, Brodmann distinguished 52 anatomically and functionally distinct areas
in the human cerebral cortex.
MRI (magnetic resonance imaging) images of an adult patient with
a brain tumor
PET (positron emission tomography) images of an adult brain
Functional MRI (magnetic resonance imaging) images of the
brains of bilingual subjects during generation of narratives in two
languages
“Early” bilinguals had learned two language together prior to the age of 7 years, whereas “late” bilinguals
acquired a second language after age 11 years.
• Red: native language
• Yellow: native and second language
• Orange: overlap between the two areas
Model organisms in Neuroscience
Estimated genome sizes of humans and
several model species.
-The number of genes in an organism’s
genome does not correlate with cellular or
organismal complexity; the simple
nematode C. elegans, for example, has
almost the same number of genes as a
human.
-Much genetic activity is dependent on
transcription factors that regulate when
and to what degree a given gene is
expressed.
The genome and the brain
(A) In this Venn diagram of the human genome, the blue
and purple regions represent genes that are expressed
selectively in the nervous system along with those that
are expressed in the nervous system as well as in all
other tissues.
(B) The locations and levels of expression of a single gene
in the human brain. Dots indicate brain regions where
mRNA for this particular gene are found.
(C) Single gene mutation (ASPM, Abnormal Spindle-like
Microcephaly-associated) shows the reduced size of the
brain (left) compared with control (right).
Neuron
Growth cone
Nerve cells are the signaling units of the nervous system
A typical neurons has four morphologically defined regions: (1) the cell body, (2) dendrites, (3) axon, and (4)
presynaptic terminals.
-
Cell body: the metabolic center of the cell, containing the nucleus (genes), the endoplasmic reticulum
-
The cell body usually gives rise to two kinds of processes: several short dendrites and one long, tubular
axon. Dendrites branch out in tree-like fashion and are the main apparatus for receiving incoming signals
from other nerve cells. The axon typically extends some distance from the cell body and carries signals
to other neurons. An axon can convey electrical signals over distances ranging from 0.1 mm to 2 m.
Action Potential
This historic tracing is the first published intracellular recording of an action potential.
It was recorded in 1939 by Hodgkin and Huxley from a squid giant axon, using glass capillary electrodes filled
with sea water. The timing pulses are separated by 2 ms. The vertical scale indicates the potential of the
internal electrode in millivolts, the sea water outside of the internal electrode in millivolts, the sea water
outside being taken as zero potential. (The action potential: from experiment to theory. Nature
Neuroscience, 2000). Action Potentials are the signals by which the brain receives, analyzes, and conveys
information. Here we see a key principle of brain function: the information conveyed by an action potential is
determined not by the form of the signal but by the pathway the signal travels in the brain. The brain
analyzes and interprets patterns of incoming electrical signals and their pathways, and in turn creates our
sensations of sight, touch, smell, and sound.
Neuron Doctrine
-
Camillo Golgi: Golgi developed a method of staining neurons with silver salts that revealed their entire
cell structure under the microscope. He suggested “reticular theory”, in which each nerve cell was
connected to tis neighbors by protoplasmic links, forming a continuous directly interconnected nerve cell
network.
-
Santiago Ramon y Cajal: Using Golgi’s technique, Ramon y Cajal discovered that nervous tissue is not
a syncytium, a continuous web of elements, but a network of discrete cells. Nerve cells are discrete
entities, and that they communicate with one another by means of specialized contacts that are not sites
of continuity between cells. He developed some of the key concepts and much of the early evidence for
the neuron doctrine-the principle that individual neurons are the elementary building blocks and
signaling elements of the nervous system.
-
Charles Scott Sherrington: apparent transfer of electrical signal via reflex pathways, called these
specialized contacts synapses.
-
*Near its end the axon divides into fine branches that contact other neurons at specialized zones of
communication known as synapses. The nerve cell transmitting a signal is called the presynaptic cell;
the cell receiving the signal is the postsynaptic cell.
Neuron Doctrine
These drawings are tracings of actual nerve cells
stained by impregnation with silver salts (the socalled Golgi technique, used in the classic studies
of Golgi and Cajal).
Some cells, such as the retinal bipolar cell, have very short axons,
while others, such as the retinal amacrine cell, have no axon at all.
Synaptic plasticity
Morphological synaptic plasticity
Microtubule
Membrane trafficking in the neuron
1.
Proteins are lipids of secretory organelles are synthesized in
the endoplasmic reticulum and transported to the Golgi
complex, where large dense-core vesicles (peptide-containing
secretory granules) and synaptic vesicle precursors are
assembled.
2.
Large dense-core vesicles and transport vesicles that carry
synaptic vesicle proteins travel down the axon via axonal
transport.
3.
At the nerve terminals the synaptic vesicles are assembled
and loaded with nonpeptide neurotransmitters. Synaptic
vesicles and large dense-core vesicles release their contents
by exocytosis.
4.
Following exocytosis, large dense-core vesicle membranes
are returned to the cell body for reuse or degradation. Synaptic
vesicle membrane undergo many cycles of local exocytosis
and endocytosis in the presynaptic terminal.
Protein synthesis in the endoplasmic reticulum
Mitochondrial trafficking in neurons- Fast axonal transport carries
membranous organelles
Synapses
1. Electrical synapses
-
Electrical synapses permit direct, passive flow of electrical current from one neuron to
another.
-
Current flow at electrical synapses arises at an intercellular specialization called a gap
junction. Gap junction contain a unique type of channel, termed a connexon, which
provides the path for electrical current to flow from one neuron to another.
2. Chemical synapses
-
The space between the pre and postsynaptic neurons is substantially greater at chemical
synapses than at electrical synapses and is called the synaptic cleft.
-
Synaptic vesicles: small, membrane-bounded organelles
-
These spherical organelles are filled with one or more neurotransmitters, chemical signals
that are secreted from the presynaptic neuron and detected by specialized receptors on
the postsynaptic cell.
Structure of electrical synapses
Signaling transmission at chemical synapses
- The presynaptic terminal, with its abundance of synaptic vesicles, as well as the
postsynaptic cell separated by a synaptic cleft.
- Filamentous elements in both pre- and postsynaptic processes, as well as structures in the
synaptic cleft
- In the presynaptic terminal, dense projections are associated with the active zone, the
place where synaptic vesicles discharge their neurotransmitters in the synaptic cleft
- The change in membrane potential caused by the arrival of the action potential leads to the
opening of voltage-gated calcium channels in the presynaptic membrane.
- Elevation of the presynaptic Ca2+ concentration, in turn, allows synaptic vesicles to fuse
with the plasma membrane of the presynaptic neuron.
- Exocytosis: most importantly neurotransmitters, to be released into the synaptic cleft
- Following exocytosis, transmitters diffuse across the synaptic cleft and bind to specific
receptors on the membrane of the postsynaptic neuron.
Synapse
Synapse
Axon -> dendrites
Structure of chemical synapses
저분자 신경전달물질과
펩타이드 신경전달물질의 대사
Differential release of neuropeptide and small-molecule cotransmitters
Molecular mechanisms of exocytosis during neurotransmitter release
신경전달물질 분비 중 exocytosis의 분자적 기전
SNARE 복합체의 구조. 소포 SNARE인 synaptobrevin (blue)은 세포막 SNARE인 syntaxin (red), SNAP-25
(green)와 나선형 복합체를 형성. 소포의 Ca2+ 결합 단백질인 synaptotagmin의 구조도
Neurotransmitters
다양한 신경전달물질

세로토닌 – 의지력, 활동 의욕, 기분을 향상시킨다

노르에피네프린 – 사고와 집중력, 스트레스 대처 능력을 증강한다

도파민 – 쾌감을 증가시키고, 나쁜 습관을 고치는데 꼭 필요하다

옥시토신 – 신뢰감, 사랑, 연대감을 증진하고 불안을 떨어뜨린다

가바 – 긴장을 풀어주고 불안을 감소시킨다

멜라토닌 – 수면의 질을 높인다

엔도르핀 – 고통을 완화하고 고양된 감정을 안겨준다

엔도카나비노이드 – 식욕을 증진하고 평온함과 안녕감을 증가시킨다
Examples of small-molecule and peptide neurotransmitters
Small-molecule transmitters can
be subdivided into acetylcholine,
amino acids, purines, and biogenic
amines.
C: black
H: gray
N: blue
O: red
ACh was the first substance identified as
a neurotransmitter.
ACh is synthesized in nerve terminals
from the precursors acetyl coenzyme A
(acetyl CoA) and choline.
Acetylchoinesterase (AChE), this
enzyme is concentrated in the synaptic
cleft, ensuring a rapid presynaptic
terminal.
Five well-established biogenic amine
neurotransmitters
(1-3) The three catecholamines : dopamine,
norepinephrine, and epinephrine
(4) Histamine
(5) serotonin
Dopamine
• Dopamine is present in several brain regions, although the
major dopamine-containing area of the brain is the corpus
striatum, which receives major input from the substantia nigra
and plays an essential role in the coordination of body
movements.
• In Parkinson’s disease, for instance, the dopaminergic
neurons of the substantia nigra degenerate, leading to a
characteristic motor dysfunction.
• Dopamine is also believed to be involved in motivation,
reward, and reinforcement.
• catecholamine 신경전달물질의 생합성 경로. Amino acid
tyrosine은 catecholamine의 세 종류 모두의 전구체이다. 이
반응경로의 첫 단계는 rate-limiting 효소인 tyrosine
hydroxylase에 의한 촉매이다.
많은 펩타이드가 호르몬으로 알려져 있고 신경전달물질로 작용한다. 일부 peptide
transmitters는 감정상태를 조절하는 것으로 밝혀졌다. Substance P와 opioid peptides와
같은 펩타이드는 통증지각에 관계 있다. Melanocyte-stimulating hormone,
adrenocorticotropin, β-endorpin과 같은 여러 peptides은 스트레스에 대한 복합적인 반응을
조절한다.
이례적인 신경전달물질들
Endocannabinoids는 cannabinoid
수용체와 상호작용하는 내성
신호와 관계 있는 family.
마리화나 식물 Cannabis sativa.
고대인들도 이 식물이 relaxation, euphoria 등 많은 정신 약리학적인
작용을 하는 물질을 생산해 내는 능력이 있다는 것을 알고 있었다.
Ion channels
Rapid Signaling in the Nervous System depends on
Ion channels
Ion channels have three important properties:
(1) They recognize and select specific ions
(2) They open and close in response to specific
electrical, mechanical, or chemical signals
(3) They conduct ions across the membrane
Ion channels
Ion channels are proteins that span the
cell membrane
Ions attract water because water molecules
are dipolar. The oxygen atom in a water
molecule tends to attract electrons and so
bears a small net negative charge, whereas
the hydrogen atoms tend to lose electrons
and therefore carry a small net positive
charge. Ions attract water; in fact they
become surrounded by electrostatically
bound waters of hydration.
Ion channels – Conformational change
Three physical models for the opening and closing
of ion channels.
A. A localized conformational change occurs in one
region of the channel
B. A generalized structural change occurs along the
length of the channel
C. A blocking particle swing into and out of the channel
mouth.
Recording current in single ion channels: the Patch Clamp
Ion channels (Current–voltage relations)
In many ion channels the relation between current through the open channel and membrane voltage is
linear. Such channels are said to be “ohmic” because they follow Ohm’s law, i = Vm/R or Vm x γ, where γ
is conductance.
In other channels the relation between current and membrane potential is nonlinear. This kind of channel
is said to “rectify”, in the sense that it conducts current more readily in one direction than the other. The
right plot shows an outwardly rectifying channel where positive current is larger than the negative current
for a given absolute value of voltage.
The X-ray crystal structure of a bacterial K+ channel
A pair of ions hops in between a pair of binding sites
in the selectivity filter. In the initial state, the “outer
configuration”, a pair of ions is bound to sites 1 and
3. As an ion enters the inner mouth of the channel,
the ion in the inner chamber jumps to occupy the
innermost binding site of the selectivity filter (site 4).
This causes the pair of ions in the outer
configuration to hop outward, expelling an ion form
the channel.
A Chemical Messenger must meet Four criteria to be considered
a Neurotransmitter
1. It is synthesized in the presynaptic neuron
2. It is present in the presynaptic terminal and is released in amounts sufficient to exert a
defined action on the postsynaptic neuron or effector organ.
3. When administered exogenously in reasonable concentrations it mimics the action of
the endogenous transmitter (for example, it activates the same ion channels or secondmessenger pathway in the postsynaptic cell).
4. A specific mechanism usually exists for removing the substance from the synaptic cleft.
(1) Presynaptic neuron에서 물질이 합성되어야 한다
(2) 물질은 presynaptic terminal에 존재하면서 depolarization에 반응하여 충분한 양이 분비되어야 하고,
postsynaptic neuron 또는 effector organ에서 작동해야 한다.
(3) 외부적으로 넣어주었을 경우, 내재적인 신호전달 물질의 활성을 mimic해야 한다.
(4) Synaptic cleft에서는 물질의 제거가 이루어지는 특정 기전이 존재해야 한다.
Myasthenia gravis (MG) – acetylcholine (ACh) receptor에 대한
자가면역반응
Myasthenia gravis (MG)
Turnover of ACh receptors increases in myasthenia