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No Title Reza Shadmehr


									JHU BME 580.422 Biological Systems II

           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
         • Trigger area (soma)
         • Conductive component (axon)                                 Inhibitory
         • Output component (synapse)                                               Cell body
                                                     synapse                        Nucleus


                                                                         myelin      Node of Ranvier


                                                                                                Presynaptic terminal

                                                                                                Synaptic cleft

                                                                                                Postsynaptic dendrite

Kandel et al. (2000) Principles of Neural Science
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.








                    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.
                                             Node of
As the cell body re-grows the axon, it       Ranvier
uses the path that is marked by the
glia cells.                                         injury

In this way, the glia cells act as a road       Myelin
map for the injured neuron to find its          sheath
previous destination.
         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

           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


            0 volts
                                            Intra-cellular recording
                                                   in the axon

  Recording electrode
                   Low-pass filtered signal
                                              Electrode signal (uV)
pulses   Filtered signal (V)
                                                                      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
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
Cell injury causes excessive release of glutamate.

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 has been implicated in sleep, mood, depression, and anxiety.
Depending on the receptor, Serotonin can either excite or inhibit the post-
synaptic 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
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
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                                                              Hippocampal
                           Schaffer                                                                   Slice


                 Mossy Fibers

       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)


                                                   (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                                                     After 100Hz stimulation
                       1                                                            of CA3 for 1 minute
        1 mV
               10 ms


                                          EPSP slope (% baseline)
                         CA1 neuron
                                                                    200                                                2
 CA3 neuron                                                                           1

                                                                              -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


                                                                                                           Frostig RD et al. (1990) Proc Natl. Acad. Sci. 87:6082.




       5 sec                                                                                     2.3s
       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         2.8s
       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.
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

                              Stimulus Onset
                                Asynchrony      4                              500ms
                              (15-17 seconds)
100ms                                           3

500ms                                                                      100ms

         0       1500ms                                        0   1   2   3   4 5     6   7   8   9 10 11
                                                                   Time (sec)
            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.
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.

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