Trends%20in%20Biomedical%20Science

1
Trends in Biomedical Science

• Making Memory

2

• The following slides are mostly derived from
• The Brain from Top to Bottom, an Interactive
  Website about the Human Brain and Behavior
  http//thebrain.mcgill.ca/flash/index_a.html

3

• Every time you learn something, neural circuits
  are altered in your brain.

4

• When you learn something, it is these synapses
  whose efficiency increases.
• Nerve impulses can more easily travel along a
  particular circuit.

5

• For example,
• You hear a new word.
• You make new connections among neurons in your
  brain.
• Neurons in your visual cortex will recognize the
  spelling.
• Neurons in your auditory cortex will hear the
  pronunciation.
• Neurons in the associative regions of the cortex
  will relate the word to your existing knowledge.

6

• Neurons in the visual cortex are making stronger
  connections.

7

• PLASTICITY IN NEURAL NETWORKS

8

• Learning depends on the plasticity of the
  circuits in the brain - the ability of the
  neurons to make lasting changes in the efficiency
  of their synaptic transmission.

9

• We can say the brain stores information in
  networks of modified synapses (the arrangement
  makes the information) and to retrieve this
  information by activating these networks.

10

• If two neurons are active at the same time, the
  synapses between them are made stronger.

11
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16

• LONG-TERM POTENTIATION (LTP) was discovered in
  the hippocampus and has been found in many
  regions of the cortex.
• LTP can cause the long-term strengthening of the
  synapses between two neurons that are activated
  simultaneously.

17

• LTP can cause the long-term strengthening of the
  synapses between two neurons that are activated
  simultaneously.

18

• Here is a synapse between two neurons.

19

• http//thebrain.mcgill.ca/flash/i/i_07/i_07_m/i_07
  _m_tra/i_07_m_tra.html

20

• After single stimulus.

21

• Glutamate is a major excitatory neurotransmitter
  that is associated with learning and memory.

22

• Glutamate is also thought to be associated with
  Alzheimers disease, whose first symptoms include
  memory malfunctions.

23

• Glutamate, the neurotransmitter released into
  these synapses, binds to several different
  receptors on the post-synaptic neuron. Two of
  these, the receptors for AMPA and NMDA, are
  especially important for LTP.

24

• The AMPA receptor is paired with an ion channel
  so that when glutamate binds to this receptor,
  this channel lets sodium ions enter the
  post-synaptic neuron.

25

• The sodium causes the post-synaptic dendrite to
  become locally depolarized, and if this
  depolarization reaches the threshold to trigger
  an action potential, the nerve impulse is
  transmitted to the next neuron.

26

• The NMDA receptor is also paired with an ion
  channel, but this lets calcium ions into the
  post-synaptic cell.

27

• When this cell is at resting potential, the
  calcium channel is blocked by magnesium ions
  (Mg2), so that even if glutamate binds to the
  receptor, calcium cannot enter the neuron.

28

• For these magnesium ions to leave the channel,
  the dendrites membrane potential must be
  depolarized.

29

• During the high-frequency stimulation that causes
  LTP the sustained activation of its AMPA
  receptors makes the post-synaptic neuron
  depolarized. The magnesium then leaves the NMDA
  receptors and allows large numbers of calcium
  ions to enter the cell.

30
(No Transcript)
31

• This increased concentration of calcium in the
  dendrite starts several biochemical reactions
  that make this synapse more efficient for an
  extended period.

32

• These calcium ions are extremely important
  intracellular messengers that activate many
  enzymes by altering their shape.
• There is a cascade of biochemical reactions which
  can have many different effects.

33
http//thebrain.mcgill.ca/flash/a/a_07/a_07_m/a_07
_m_tra/a_07_m_tra.html
34

• LTP involves at least two phases establishment
  (or induction), which lasts about an hour, and
  maintenance (or expression), which may last for
  several days.

35

• The first phase can be experimentally induced by
  a single, high-frequency stimulation. It involves
  the activity of various enzymes (kinases) that
  continue after the calcium is eliminated, but no
  protein synthesis.

36

• For the maintenance phase a series of
  high-frequency stimuli must be applied.
• This phase needs the synthesis of new proteins -
  for example, the ones that form the receptors and
  the ones that contribute to the growth of new
  synapses (that also occurs during the maintenance
  phase).

37

• LONG-TERM DEPRESSION

38

• Long-term depression (LTD) may return potentiated
  synapses in the hippocampus to a normal level so
  that they will be available to store new
  information.

39

• But in other parts of the brain, LTD may be
  actively responsible for the storage of new
  information, eg in the cerebellum.

40

• LTD develops when a presynaptic neuron is active
  at low frequencies (1 to 5 Hz) without the
  postsynaptic neurons being subjected to strong
  depolarization, as it is with LTP.

41

• This raises the concentration of calcium in the
  postsynaptic neuron, but much less than in LTP.

42

• So, instead of proteins such as kinases being
  activated, enzymes called phosphatases are
  activated. These enzymes remove certain phosphate
  groups from the AMPA receptors in other words,
  they dephosphorylate them.

43

• An AMPA receptor subunit has two sites that can
  be phosphorylated (by CaM kinase II, and PKA).
• These sites on the receptor seem to be the target
  for phosphatases.

44

• In the hippocampus, the dephosphorylation of the
  AMPA receptor reduces the amplitude of the
  postsynaptic potential to the normal level where
  it was before LTP.

45

• It is also believed that the number of AMPA
  receptors decreases during LTD. These receptors
  would be removed from the postsynaptic membrane.

46

• Long term depression (LTD)

47

• The following questions can be done as a gap fill
  exercise on https//dl.dropboxusercontent.com/u/56
  510853/MakingMemory2-part1.htm

48

• Every time you learn something, _________
  circuits are altered in your brain.

49

• Every time you learn something, neural circuits
  are altered in your brain.

50

• When you learn something, it is these synapses
  whose ____________ ___________.
• Nerve impulses can more easily travel along a
  particular circuit.

51

• When you learn something, it is these synapses
  whose efficiency increases.
• Nerve impulses can more easily travel along a
  particular circuit.

52

• For example,
• You hear a new word.
• You make new ___________ among neurons in your
  brain.
• Neurons in your ________ cortex will recognize
  the spelling.
• Neurons in your ________ cortex will hear the
  pronunciation.
• Neurons in the __________ regions of the cortex
  will relate the word to your existing knowledge.

53

• For example,
• You hear a new word.
• You make new connections among neurons in your
  brain.
• Neurons in your visual cortex will recognize the
  spelling.
• Neurons in your auditory cortex will hear the
  pronunciation.
• Neurons in the associative regions of the cortex
  will relate the word to your existing knowledge.

54

• Neurons in the visual cortex are making stronger
  connections.

55

• PLASTICITY IN NEURAL NETWORKS

56

• Learning depends on the _________ of the circuits
  in the brain - the ability of the neurons to make
  ________ _________ in the efficiency of their
  synaptic transmission.

57

• Learning depends on the plasticity of the
  circuits in the brain - the ability of the
  neurons to make lasting changes in the efficiency
  of their synaptic transmission.

58

• We can say the brain ________ ___________ in
  _________ of __________ ____________ (the
  arrangement makes the information) and to
  ________ this information by _________ these
  networks.

59

• We can say the brain stores information in
  networks of modified synapses (the arrangement
  makes the information) and to retrieve this
  information by activating these networks.

60

• If two _________ are _______ at the ____ _____,
  the synapses between them are made stronger.

61

• If two neurons are active at the same time, the
  synapses between them are made stronger.

62
(No Transcript)
63

• LONG-TERM POTENTIATION (LTP) was discovered in
  the _____________ and has been found in many
  regions of the cortex.
• LTP can cause the long-term ____________ of the
  ___________ between two neurons that are
  _____________ simultaneously.

64

• LONG-TERM POTENTIATION (LTP) was discovered in
  the hippocampus and has been found in many
  regions of the cortex.
• LTP can cause the long-term strengthening of the
  synapses between two neurons that are activated
  simultaneously.

65

• LTP can cause the long-term strengthening of the
  synapses between two neurons that are activated
  simultaneously.

66

• LTP can cause the long-term strengthening of the
  synapses between two neurons that are activated
  simultaneously.

67

• Here is a synapse between two neurons.

68

• After single stimulus.

69

• Glutamate is a major excitatory ___________ that
  is associated with _________ and _________.

70

• Glutamate is a major excitatory neurotransmitter
  that is associated with learning and memory.

71

• Glutamate is also thought to be associated with
  ___________rs disease, whose first symptoms
  include __________ malfunctions.

72

• Glutamate is also thought to be associated with
  Alzheimers disease, whose first symptoms include
  memory malfunctions.

73

• Glutamate, the neurotransmitter released into
  these synapses, binds to several different
  ________ on the post-synaptic _______. Two of
  these, the receptors for AMPA and NMDA, are
  especially important for ___.

74

• Glutamate, the neurotransmitter released into
  these synapses, binds to several different
  receptors on the post-synaptic neuron. Two of
  these, the receptors for AMPA and NMDA, are
  especially important for LTP.

75

• The AMPA receptor is paired with an ion channel
  so that when _______ binds to this receptor, this
  channel lets ______ ions enter the post-synaptic
  neuron.

76

• The AMPA receptor is paired with an ion channel
  so that when glutamate binds to this receptor,
  this channel lets sodium ions enter the
  post-synaptic neuron.

77

• The sodium causes the post-synaptic dendrite to
  become locally __________, and if this
  depolarization reaches the __________ to trigger
  an _____ ________, the nerve impulse is
  transmitted to the next neuron.

78

• The sodium causes the post-synaptic dendrite to
  become locally depolarized, and if this
  depolarization reaches the threshold to trigger
  an action potential, the nerve impulse is
  transmitted to the next neuron.

79

• The NMDA receptor is also paired with an ion
  channel, but this lets calcium ions into the
  post-synaptic cell.

80

• The NMDA _______ is also paired with an ion
  channel, but this lets _______ ions into the
  post-synaptic cell.

81

• When this cell is at _______ ________, the
  calcium channel is ________ by __________ ions
  (Mg2), so that even if glutamate binds to the
  receptor, calcium cannot enter the neuron.

82

• When this cell is at resting potential, the
  calcium channel is blocked by magnesium ions
  (Mg2), so that even if glutamate binds to the
  receptor, calcium cannot enter the neuron.

83

• For these magnesium ions to leave the channel,
  the dendrites membrane potential must be
  ___________.

84

• For these magnesium ions to leave the channel,
  the dendrites membrane potential must be
  depolarized.

85

• During the high-__________ stimulation that
  causes LTP the sustained __________ of its
  ______ receptors makes the post-synaptic neuron
  __________. The ___________ then leaves the
  ______ receptors and allows large numbers of
  ________ ions to enter the cell.

86

• During the high-frequency stimulation that causes
  LTP the sustained activation of its AMPA
  receptors makes the post-synaptic neuron
  depolarized. The magnesium then leaves the NMDA
  receptors and allows large numbers of calcium
  ions to enter the cell.

87
(No Transcript)
88

• This increased concentration of calcium in the
  dendrite starts several ____________ reactions
  that make this synapse more _________ for an
  ___________ period.

89

• This increased concentration of calcium in the
  dendrite starts several biochemical reactions
  that make this synapse more efficient for an
  extended period.

90

• These ________ ions are extremely important
  intracellular ___________ that _________ many
  _________ by altering their shape.
• There is a ________ of biochemical reactions
  which can have many different effects.

91

• These calcium ions are extremely important
  intracellular messengers that activate many
  enzymes by altering their shape.
• There is a cascade of biochemical reactions which
  can have many different effects.

92
http//thebrain.mcgill.ca/flash/a/a_07/a_07_m/a_07
_m_tra/a_07_m_tra.html
93

• LTP involves at least two phases ___________ (or
  induction), which lasts about an hour, and
  ______________ (or expression), which may last
  for several days.

94

• LTP involves at least two phases establishment
  (or induction), which lasts about an hour, and
  maintenance (or expression), which may last for
  several days.

95

• The first phase can be experimentally induced by
  a single, high-__________ stimulation. It
  involves the _________ of various ________
  (kinases) that continue after the calcium is
  eliminated, but no ________ synthesis.

96

• The first phase can be experimentally induced by
  a single, high-frequency stimulation. It involves
  the activity of various enzymes (kinases) that
  continue after the calcium is eliminated, but no
  protein synthesis.

97

• For the _____________ phase a __________ of
  high-frequency stimuli must be applied.
• This phase needs the _________ of new proteins -
  for example, the ones that form the ________ and
  the ones that contribute to the growth of new
  _________ (that also occurs during the
  maintenance phase).

98

• For the maintenance phase a series of
  high-frequency stimuli must be applied.
• This phase needs the synthesis of new proteins -
  for example, the ones that form the receptors and
  the ones that contribute to the growth of new
  synapses (that also occurs during the maintenance
  phase).

99

• LONG-TERM DEPRESSION
• The following questions can be done as a gap fill
  exercise on https//dl.dropboxusercontent.com/u/56
  510853/MakingMemory2-part2.htm

100

• Long-term ____________ (LTD) may return
  potentiated __________ in the __________ to a
  normal level so that they will be available to
  store new information.

101

• Long-term depression (LTD) may return potentiated
  synapses in the hippocampus to a normal level so
  that they will be available to store new
  information.

102

• But in other parts of the brain, LTD may be
  actively responsible for the storage of new
  information, eg in the _____________.

103

• But in other parts of the brain, LTD may be
  actively responsible for the storage of new
  information, eg in the cerebellum.

104

• LTD develops when a presynaptic neuron is active
  at low ___________ (1 to 5 Hz) without the
  ___________ neurons being subjected to strong
  _____________, as it is with LTP.

105

• LTD develops when a presynaptic neuron is active
  at low frequencies (1 to 5 Hz) without the
  postsynaptic neurons being subjected to strong
  depolarization, as it is with LTP.

106

• This _______ the concentration of calcium in the
  postsynaptic neuron, but much ________ than in
  LTP.

107

• This raises the concentration of calcium in the
  postsynaptic neuron, but much less than in LTP.

108

• So, instead of proteins such as kinases being
  activated, enzymes called phosphatases are
  _________. These enzymes remove certain _________
  groups from the _________ receptors in other
  words, they __________ them.

109

• So, instead of proteins such as kinases being
  activated, enzymes called phosphatases are
  activated. These enzymes remove certain phosphate
  groups from the AMPA receptors in other words,
  they dephosphorylate them.

110

• An AMPA _________ ______ has two sites that can
  be _______________ (by CaM kinase II, and PKA).
• These sites on the receptor seem to be the target
  for ______________.

111

• An AMPA receptor subunit has two sites that can
  be phosphorylated (by CaM kinase II, and PKA).
• These sites on the receptor seem to be the target
  for phosphatases.

112

• In the hippocampus, the __________________ of the
  AMPA receptor _______ the amplitude of the
  postsynaptic ________ to the normal level where
  it was before LTP.

113

• In the hippocampus, the dephosphorylation of the
  AMPA receptor reduces the amplitude of the
  postsynaptic potential to the normal level where
  it was before LTP.

114

• It is also believed that the __________ of AMPA
  receptors _________ during LTD. These receptors
  would be removed from the postsynaptic membrane.

115

• It is also believed that the number of AMPA
  receptors decreases during LTD. These receptors
  would be removed from the postsynaptic membrane.

116

• Long term depression (LTD)

117

• Describe what happens to your neural circuits
  when you learn a new word.
• What happens to the efficiency of the circuits?

118

• What does learning depend on?
• How does the brain store information?
• Draw a diagram showing when synapses between
  neurons would be made stronger.

119
(No Transcript)
120

• What is LONG-TERM POTENTIATION (LTP)?

121

• Use this diagram as a basis to explain LTP

122

• What is glutamate?

123

• What are two of the important receptors that
  glutamate binds to and seem to be important for
  LTP?

124

• What does the AMPA receptor do?
• Then what happens?

125

• What does the NMDA receptor do?
• Then what happens?

126
(No Transcript)
127

• What happens with an increased concentration of
  calcium in the dendrite?

128
http//thebrain.mcgill.ca/flash/a/a_07/a_07_m/a_07
_m_tra/a_07_m_tra.html
129

• Describe the phases of LTP.

130

• Why might we have long-term depression (LTD)?
• How does LTD develop?

131

• What are the enzymes activated to begin LTD?

132

• What does the dephosphorylation of the AMPA
  receptor do?

133

• What happens to the number of AMPA receptors
  during LTD?

134

• Describe what this picture is showing.