1. Cell communication III: the nerve system

2. Nature 510: 38; 2014.

4. Resting membrane potential is maintained by Na-K ATPase and ATP hydrolysis

8. Two characteristics of action potential of neuron
All or none;
Unidirectional!

10. The refractory period after opening of voltage gated ion channel makes unidirectional propagation of action potential

11. Conduction of the Action Potential All-or-None Law
the principle that once an action potential is triggered in an axon, it is propagated, without decrement, to the end of the fiber
Rate Law
the principle that variations in the intensity of a stimulus or other information being transmitted in an axon are represented by variations in the rate at which that axon fires

14. Schwann cell is responsible for myelination of peripheral neuron
Why different cell type for myelination in CNS and PNS?

16. Transmission of this message, hopping from node to node, is called saltatory conduction, from the Latin saltare, “to dance.”
Saltatory Conduction
Conduction of action potentials by myelinated axons: the action potential appears to jump from one node of Ranvier to the next.

26. Most of neurotransmitter receptor are ligand gated ion channel

27.  EPSP: excitatory postsynaptic potential 

30. How to terminate the postsynaptic signaling?
The neurotransmitter is degraded by the enzyme in postsynaptic terminal.
Acetylcholinesterase inhibitors in Alzheimer’s disease
The neurotransmitter is dissociated from the receptor and reuptake by presynaptic transporter.
Prozac is the blocker of presynaptic serotonin transporter

31. The cortex has ~109 neurons.
Each Neuron has up to 104 synapses

32. Spine

34. Central Hypothesis of learning – Synaptic plasticity
Changes in synaptic structure and biochemistry
Long-term potentiation (LTP)
Change in the strength of synaptic connections
Results from repeated activation

37. Aplysia 20,000 neurons in the CNS
The gill-withdrawal reflex, can be modified by
five different forms of learning:
habituation,
dishabituation,
sensitization,
classical conditioning,
operant conditioning.

39. Why?

48. Sensitization Pathway
Release more serotonin at presynaptic terminal

49. Persistent activation of protein kinase A
Long-term sensitization of the gill-withdrawal reflex of Aplysia leads to two major changes in the sensory neurons of the reflex (learning and memory)
Persistent activation of protein kinase A
Structural changes in the form of the growth of new synaptic connections.

50. Long-term memory in Aplysia modulates the total number of varicosities of single identified sensory neurons
PNAS 85, pp , 1988

51. Long-term sensitization of the gill-withdrawal refex in Aplysia involves posttranslational modifications and alterations in protein synthesis.
Short-term and long-term sensitization of the gill-withdrawal refex in Aplysia involves posttranslational modifications and alterations in protein synthesis. (Left) The gill-withdrawal circuit. A tactile stimulus to the siphon causes a sensory neuron to release glutamate to excite a motor neuron. (Center) A shock to the tail causes serotonin release from interneurons. This activates a stimulatory G protein (G), which activates adenylyl cyclase (AC), leading to production of cAMP and PKA-dependent phosphorylation of different substrates, including K+ and Ca2+ channels, which enhances glutamate release from the sensory neuron terminals. (Right) Repeated shocks to the tail elicit a persistent increase in cAMP, leading to altered gene transcription and protein synthesis. This leads to growth of new synapses.

52. Two major memory systems in the brain:
declarative (explicit) and
procedural (implicit)

54. Donald Hebb, “Organization of Behavior”, 1949
Hebb’s Postulate
“When an axon of cell A is near enough to excite a cell B and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.”
Donald Hebb, “Organization of Behavior”, 1949

55. Classical Conditioning Hebb’s rule
Ear A
Nose B
Tongue
The fundamental question that draws most of my scientific attention is how experience shapes the brain.
During this talks I will speak about two central concepts in Neuroscience receptive field plasticity and synaptic plasticity.
Synaptic plasticity is the change in synaptic efficacy that occurs due to pre and postsynaptic activity.
One of the first people to suggest that synaptic plasticity serves as the basis for learning is the Canadian Psychologist Donald Hebb who said
Is his famous book in 1949 the following sentence …
In this slide I will try to illustrate with a simple example how synaptic plasticity is connected to behavior.
Today there is strong evidence for the existence of synaptic plasticity and it is considered the major candidate for
The basis of learning memory and some aspects of development. Therefore it is very important to know
What are the rules that govern synaptic plasticity. The central theme in my work and throughout this talk is to
Find out what these rules are. I think it is imperative that such work would involve a combination of theoretical and
Experimental work.
D. O. Hebb (1949)

59. Synaptic Plasticity
Synaptic efficacy (strength) is changing with time.
Many of these changes are activity-dependent, i.e. the magnitude and direction of change depend on the activity of pre- and post-synaptic neuron.
Some of the mechanisms involved:
- Changes in the amount of neurotransmitter released.
- Biophysical changes in ion channels.
- Morphological alterations of spines or dendritic branches.
- Modulatory action of other transmitters.
- Changes in gene transcription.
- Synaptic loss or sprouting.

60. LTP: long term potentiation
Typical LTP experiment: record from cell in hippocampus area CA1 (receives Schaffer collaterals from area CA3). In addition, stimulate two sets of input fibers.

61. LTP Typical LTP experiment: record EPSP’s in CA1 cells (magnitude)
Step 1: weakly stimulate input 1 to establish baseline
Step 2: give strong stimulus (tetanus) in same fibers (arrow)
Step 3: continue weak stimulation to record increased responses
Step 4: throughout, check for responses in control fibers (input 2)

62. LTP LTP is input specific. LTP is long-lasting (hours, days, weeks).
LTP results when synaptic stimulation coincides with postsynaptic depolarization (achieved by cooperativity of many coactive synapses during tetanus).
The timing of the postsynaptic response relative to the synaptic inputs is critical.
LTP has Hebbian characteristics (“what fires together wires together”, or, in this case, connects together more strongly).
LTP may produce synaptic “sprouting”.

63. NMDA receptors and LTP
LTP relies on calcium influx at NMDA glutamate receptors
Calcium channels controlled by the NMDA receptor are blocked by a magnesium ion
Magnesium ion is ejected by:
1. simultaneous glutamate binding AND
2. depolarization of the post-synaptic cell (by activity at AMPA receptors on the membrane)
3. Calcium enter the cell and is critical to establishing LTP

64. Strengthening synapses
Dendritic spike – an action potential results in a backwash of depolarization up the cell body and dendrites
Dendritic spike + glutamate binding at NMDA receptor = calcium channels open to allow calcium influx

65. Strengthening synapses
Three synaptic modifications will support LTP
Addition of receptors
Addition of synapses
Increased glutamate release from the presynaptic membrane

66. Synaptic modifications supporting LTP – Increased receptors
Individual synapses are strengthened by an increase in AMPA receptors on the post-synaptic membrane
Increases the cell’s response to glutamate release
Hypothesized mechanism:
Calcium activates the CaMK enzyme
Activated CaMK binds to an intracellular portion of the NMDA receptor
Linking proteins bind to the CaMK
AMPA receptors bind to the linking proteins and are embedded into the cell membrane

67. Synaptic modifications supporting LTP – Synaptogenesis
LTP results in the multiplication of synapses
Most synapses are located on dendritic spines
LTP results in division and multiplication of these spines
Mechanism:
Postsynaptic density expands until it splits into multiple densities
Following perforation, the presynaptic active zone splits into corresponding regions
Perforated synapse further divides, until the spine branches
Branched spine ultimately becomes two spines, each containing a synaptic region

68. Synaptic modifications supporting LTP – Synaptogenesis
Results in the terminal button of one presynaptic neuron synapsing with multiple spines on the postsynaptic neuron
Increases communication potential between the two cells
Threefold increase in synapses has been found experimentally

69. Synaptic modifications supporting LTP – Presynaptic changes
LTP is associated with an increase in glutamate release by the presynaptic neuron
Influenced by retrograde messengers
Nitric oxide – major retrograde signal from NMDA receptors to the presynaptic membrane
NO is synthesized in the postsynaptic membrane in response to calcium influx
Unstable and short-lived, can only diffuse across the synapse before breaking down
Acts as a limited, direct messenger

70. Long-term depression
Opposite of LTP, long-term depression is a long-lasting weakening of synapses that are not associated with strong inputs/production of action potentials
Seen when two inputs are stimulated at significantly different times, or when a synapse is activated while a cell is weakly depolarized or hyperpolarized
Results in the removal of AMPA receptors from the synapse
Weakening of synaptic strength may be necessary when new learning eliminates the need for previously established synaptic modifications
Ex. Remembering a new locker combination

72. Synaptic connections between neurons are not immutable but can be modified by learning and that those anatomical modifications serve as elementary components of memory storage. Memory storage depends on neural architecture but not on specialized memory neurons.

75. Different place cells could be active in different places and the combination of activity in many place cells created an internal neural map representing a particular environment

76. The grid pattern had not been seen in any brain cells before
The grid pattern had not been seen in any brain cells before! The grid cells were part of a path integration system and provided a solution to measuring movement distances and added a metric to the spatial maps in hippocampus.

78. Hippocampus contains an inner map that can store information (learning and memory) about the environment!

79. London taxi drivers had significantly larger hippocampal volume than control subjects!
Acquiring "the Knowledge" of London's layout drives structural brain changes.
Current. Biology, 21, ; 2011

80. How memories of spatial routes achieved during active navigation are consolidated?
Groups of place cells that are activated in a particular sequence during the behaviour display the same sequence of activation in episodes during the subsequent sleep.