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JHU BME 580.422 Biological Systems II
Neurons
Reza Shadmehr
Retinal ganglion cell (neuron) and the surrounding blood vessels
David Becker, Univ. College London
This is a ferret retinal ganglion cell injected with Lucifer Yellow and Neurobiotin. The image also includes blood vessels with hemoglobin. The shadow
from the neuron has made some of the hemoglobin appear dark. The image was captured by confocal microscopy.
Neurons have four functional regions:
• Input component (dendrite)
Apical
dendrites
• Trigger area (soma)
• Conductive component (axon)
Inhibitory
synapse
• Output component (synapse)
Cell body
Excitatory
synapse
Nucleus
Presynaptic
cell
axon
myelin
basal
dendrites
Axon
hillock
Node of Ranvier
axon
Presynaptic terminal
Postsynaptic
cell
Synaptic cleft
Kandel et al. (2000) Principles of Neural Science
Postsynaptic dendrite
Glia: support cells for neurons
• Produce myelin to insulate the nerve cell axon.
• Take up chemical transmitters released by neurons at the synapse.
• Form a lining around blood vessels: blood-brain barrier.
neuron
axon
mylein
Oligodendrocyte
synapse
dendrite
neuron
neuron
astrocyte
blood vessel
R. D. Fields, Sci Am April 2004
Injury in a peripheral nerve
When a peripheral nerve is cut, the
portion of the axon that was separated
from the cell body dies.
Cell body
The glia cells that produce the myelin
sheath around the dying axon shrink,
but stay mostly in place.
As the cell body re-grows the axon, it
uses the path that is marked by the
glia cells.
In this way, the glia cells act as a road
map for the injured neuron to find its
previous destination.
Node of
Ranvier
injury
Myelin
Myelin
sheath
sheath
Neurons
Neurons in different parts of the CNS are very similar in their properties. Yet
the brain has specialized function at each place.
The specialized function comes from the way that neurons are connected with
sensory receptors, with muscles, and with each other.
Kandel et al. (2000) Principles of Neural Science
The conductive component (axon) propagates an action potential
• An action potential is a spike that lasts about 0.5 ms.
• Signal travels down the axon no faster than ~100 m/sec.
• Action potentials do not vary in size or shape. All that can vary is the
frequency.
Voltage (mv)
An action potential recorded
by putting an electrode inside
the giant axon of a squid
Timing marker
2 ms
Kandel et al. (2000) Principles of Neural Science
Recording the electrical activity of neurons
100 mV
0 volts
Intra-cellular recording
in the soma
Extra-cellular
recording
0 volts
Intra-cellular recording
in the axon
Recording electrode
Filtered signal (V)
Low-pass filtered signal
Timing
pulses
Electrode signal (uV)
Extra-cellular recordings
Extra-cellular recordings: spike sorting
Recordings from the human thalamus
(Haiyin Chen, Fred Lenz, and Reza Shadmehr)
Kandel et al. (2000) Principles of Neural Science
Neurotransmitters
A neuron can produce only one kind of neurotransmitter at its synapse. The
post-synaptic neuron will have receptors for this neurotransmitter that will either
cause an increase or decrease in membrane potential.
Acetylcholine (ACh)
Released by neurons that control muscles (motor neurons), neurons that control
the heart beat, and some neurons in the brain.
Antibodies that block the receptor for ACh in the muscle cell cause myasthenia
gravis, a disease characterized by fatigue and muscle weakness.
In Alzheimer’s disease, ACh releasing neurons die in the brain.
Glutamate and GABA
These are two different amino acids that serve as neurotransmitters in the brain.
Glutamate excites the post-synaptic cell. In contrast, GABA inhibits the firing of
the post-synaptic neuron.
In HD, GABA producing neurons in the basal ganglia die, causing uncontrollable
movements.
Cell injury causes excessive release of glutamate.
Neurotransmitters
Dopamine
Patients with Parkinson’s disease exhibit a deficiency of this neurotransmitter in
their brain. Depending on the receptor, Dopamine can either excite or inhibit the
post-synaptic cell. May signal reward prediction errors.
Serotonin
Serotonin has been implicated in sleep, mood, depression, and anxiety.
Depending on the receptor, Serotonin can either excite or inhibit the postsynaptic cell. Prozac is a common drug that alters the action of Serotonin (it
inhibits the re-uptake of Serotonin, resulting in increased concentration of this
neurotransmitter in the synaptic junction).
Second messengers
Second messengers are chemicals within the post-synaptic cell that are trigged
by the action of the neurotransmitter. (Neurotransmitter is the first messenger.)
Second messengers affect the biochemical communication within post-synaptic
cell.
Whereas a neurotransmitter has an effect that lasts only a few milliseconds, the
second messenger’s effect may last as long as many minutes.
When a neurotransmitter binds to its receptors on the surface of the neuron’s
synapse, the activated receptor binds G proteins on the inside of the
membrane. The activated G protein causes an enzyme to convert ATP to
cAMP. The second messenger cAMP exerts a variety of influences on the cell,
ranging from changes in the function of ion channels in the membrane to
changes in the expression of genes in the nucleus.
Modifiability of connections results in learning and adaptation
With repeated activation of pre- and post-synaptic neuron, their connection
via the synapse gets stronger. This is called Long-term Potentiation (LTP)
for an excitatory synapse and Long-term depression (LTD) for an inhibitory
synapse.
Over the long-term, a neuron can grow and make more synapses or shrink
and prune its synapses.
Setup for inducing Long-term Potentiation (LTP)
Rat hippocampus slice
Intracellular stimulating Electrode
Intracellular recording Electrode
CA1
Schaffer
Collaterals
Hippocampal
Slice
CA1
CA3
Perforant
Path
Mossy Fibers
DG
Modified from Blitzer et al., Biol Psychiat. 57:113 (2005)
Stimulating Electrode
Recording Electrode
An action potential in the CA3 axon results in the release of glutamate at the
synapse. Glutamate crosses the synaptic junction and opens sodium and
calcium channels, resulting in an EPSP in the CA1 synapse.
Stimulating Electrode
(CA3 neuron)
glutamate
(Excitatory Post-Synaptic Potential)
(High Frequency Stimulation)
Recording Electrode
(CA1 neuron)
Following a brief period of high frequency stimulation of the CA3 axon, the
EPSP in the CA1 synapse in response to the CA3 action potential is increased
Excitatory post-synaptic potential (EPSP) recorded in CA1 synapse in response to a single
action potential in the CA3 axon
Control
1
After 100Hz stimulation
of CA3 for 1 minute
2
1 mV
CA1 neuron
CA3 neuron
EPSP slope (% baseline)
10 ms
250
2
200
High
frequency
stimulation
150
1
100
0
-20
0
20
40
60
80
TIME (min relative to high frequency stimulation)
What are the mechanisms of LTP?
The induction of LTP in the CA3-CA1 synapse involves mostly changes in how
the CA1 synapse responds to the glutamate released from the CA3 synapse.
The CA1 synapse becomes highly sensitive to a small amount of glutamate.
How long after the high frequency stimulation does LTP last?
In the brain slice preparation, LTP can last many hours. In the behaving rat,
LTP in the hippocampus can last for more than a year.
Invention of functional imaging of the brain.
When neurons are active, they consume more energy. The vascular system
responds to the change in their activity by increasing the blood in the vessels
that are near these neurons.
By imaging the blood flow, one can make a rough estimate of where in the
brain neurons are more active than before.
Optical imaging: image the visible light that reflects off the surface of the
brain. The brighter the light, the more oxygenated blood it carries.
PET: Positron Emission Tomography. A radioactive substance is injected into
the blood stream. Detectors estimate amount of blood flow at a given location
in the brain by the amount of radiation detected from there.
FMRI: functional magnetic resonance imaging. Strong magnetic fields are
used to detect amount of oxy-hemoglobin in a particular region of the brain.
Intrinsic optical signal response to neural activity
Increased activity of neurons results in a small decrease in the oxy-hemoglobin.
This decrease is visible in the light that reflects off the surface of the cortex (the
image becomes darker) and can be optically measured using a camera.
4.9 mm
800ms
1.3s
1.8s
0.1%
5 sec
Composite image of the blood vessel pattern overlying somatosensory cortex of a
rat with the optical signal superimposed. The image shows the blood vessel pattern
as imaged through the dura when the camera was focused on the surface of the
brain. Signals are average of 24 trials, where the trial begins with stimulation of one
whisker of the rat and continues in the 5 sec period. Each signal is an average of
24 trials. X-axis is time and Y-axis is fractional change in signal. By convention, the
signals are shown as up-going although cortical activation actually causes a
decrease in light reflectance.
2.3s
2.8s
Frostig RD et al. (1990) Proc Natl. Acad. Sci. 87:6082.
300ms
FMRI response to neural activity
Increased activity of neurons results in a small decrease in the oxy-hemoglobin.
This decrease often cannot be detected by fMRI.
About 3 seconds after the increased activity in the neuron, the capillary dilates
and dramatically increases the amount of oxy-hemoglobin. This produces a very
large increase in the fMRI signal.
Percent signal change in the visual cortex
6
1500ms
5
Stimulus Onset
Asynchrony
(15-17 seconds)
4
500ms
3
100ms
2
500ms
100ms
1
0
1500ms
0
1500ms
0
1
2
3
4 5
Time (sec)
6
7
8
9 10 11
How old are the cells in a person’s brain? Carbon dating of DNA
The levels of 14C in the atmosphere have been
stable over long time periods, with the exception
of a large addition of 14C in 1955–1963 as a result
of above ground nuclear bomb tests.
14C levels from modern samples are by convention
given in relation to a universal standard and corrected
for radioactive decay, giving the Δ14C value. 14C
half-life is 5730 years.
After the test ban treaty in 1963,
there has been no above-ground
nuclear detonation leading to
significant 14C production.
14C levels spanning the last decades
were measured in cellulose taken from
annual growth rings of local pine trees.
The levels have dropped after 1963,
not primarily because of radioactive
decay, but due to diffusion and
equilibration with the oceans and
the biosphere (that is, taken up in
water and in plants and animal).
Spalding, Bhardwaj, Buchholz, Druid, and Frisen (2005) Cell 122:133-143.
Cerebellar gray matter is on average about 2 years younger than the person.
Cortical gray matter is on average about 5 years younger.
14C in the atmosphere reacts with oxygen and forms CO2, which enters the biotope through
photosynthesis. Our consumption of plants, and of animals that live off plants, results in 14C levels
in the human body paralleling those in the atmosphere.
Most molecules in a cell are in constant flux, with the unique exception of genomic DNA, which is
not exchanged after a cell has gone through its last division. The level of 14C integrated into
genomic DNA should thus reflect the level in the atmosphere at any given time point. The
determination of 14C levels in genomic DNA was used to retrospectively establish the birth date of
cells in the human body.
Birth of person
Amount of
14C in DNA
(occipital lobe)
Average age of the tissue
Spalding, Bhardwaj, Buchholz, Druid, and Frisen (2005) Cell 122:133-143.
Summary
Axons propagate action potentials, resulting in the release of
neurotransmitter at the synapse.
Second messengers are chemicals within the post-synaptic cell that are
trigged by the action of the neurotransmitter.
Modifiability of synaptic strength results in learning and adaptation.
The vascular system responds to the change in the neuron’s activity by
increasing the blood in the vessels that are near these neurons.
The neurons that we have in adulthood are mostly the neurons that we had
in very early childhood. However, there is some turnover, as the average
age of cells in the cortex is 5 years younger than the person.