1. Computational Neuroscience
How Real Neurons Work.
Computational Neuroscience

2. The Neuron : Overview
Cell body gives rise to dendrites, and an axon.
Dendrites receive incoming signals from other nerve cells.
The axon is the main conducting unit carrying signals to other neurons from 0.1mm to 3m.
This is done by action potentials, rapid, transient, all-or-none signals, amplitude 100mV, duration 1ms.
AP’s initiated at the axon hillock, and regenerated throughout the axon at the nodes of renvier.
Action potentials are thought to be the basic units of communication within the brain.
At the end of the axon are terminal boutons which are the pre-synaptic terminals which connect to the dendrites of other neurons or to muscles.
Neurons differ in shape.
Thanks to Ramon y Cajal for the Neuron doctrine. (v. reticular theory).
Principles of Dynamic Polarization : Signals flow only in one direction.
Principle of Connectional Specificity : Neurons don’t make random connections.
These doctrines are now being called into question.

3. Overview (2)

4. Inside a Neuron. Most differentiated cells in the body.
Neurons develop from epithelial cells.
Proteins are synthesised in the cell body.
They are modified in the ER and Golgi complex and exported along the axon.

5. Classification of Neurons.
Unipolar : Invertebrates.
Bipolar : Retina, Olfactory epith.,
Multipolar : e.g. motor neuron, pyramidal cell, perkinje cell.
The Cytoskeleton determines shape of neuron, (disrupted in Alzheimer’s disease).
Dynamic microtubules and microfilaments.
Spinal motor cell recieves 10,000 contacts. Purkinjie cells receive 150,000 contacts.

6. The Resting Cell Membrane
Ionic concentration gradient established by Na/K ATPase Pump (100 ions/s).
K channels allow K to diffuse freely at a certain rate.
K leaves the cell, so making the outside positive and the inside negative.
This is self-limiting, as the positive external charge opposes the further efflux of K+
I.E 2 forces : Channel Driving Force, Electrical Driving Force, when balanced we have the Equilibrium Potential of K+ .
All cells, including neurons maintain a difference in electrical potential on either side of the plasma membrane.
This is the resting membrane potential. Rm = -65mV (may vary from -40 to -80 in different nerve cells). Muscle is -90 !
Net charge outside the membrane is arbitrarily defined as 0.
This results from the unequal distribution of electrically charged ions, Na and K ad the selective permeability of the membrane to just one of these ions K.
The Na-K pump pumps Na out of and K into to the cell.
When the cell is at rest K channels are open and K leaks out.
As K+ leaks out they leave behaind a cloud of negative charge on the inner surface of the membrane.

7. Ion Channels PROPERTIES.
Ion Channels are crucial for rapid membrane potential changes.
Ion Channels are proteins that span the cell membrane.
Q. How can a water-filled channel conduct at high rates and yet be selective to ions surrounded by their waters of hydration? A.
PROPERTIES.
Conduct Ions.
Recognize and select specific ions.
Open and close in response to specific electrical, mechanical or chemical signals.
Rapid rate of flow 108 /s
Opening and Closing of a channel involves conformational changes.
Ion channels allow the ionic permeability of the neuron to alter rapidly allowing an action potential to be produced.

8. The Action Potential
An Action Potential is due to channels opening and closing in a voltage dependent manner. Na channels open above a threshold voltage.
An action potential lasts about 1 ms, after which the membrane potential returns to resting.
Action potentials are ACTIVELY PROPOGATED along the axon, and so can travel LONG DISTANCES.
Receptor potentials, Synapse potentials are not actively propogated and typically decay after a few millimeters.
A reduction of membrane potential is called DEPOLORISATION i.e. from -65mV to -55mV. This enhances the membranes ability to produce an AP and so it is excitatory. Hyperpolorisation is the opposite.
Consider a cell stimulated by a receptor. A receptor potential is produced. This is a LOCAL SIGNAL. The depolorisation of the cell membrane opens Na+ channels that are voltage-sensitive allowing Na+ to flow in down its concentration gradient.
Na+ channels are concentrated at the initial segment of the axon, an uninsulated portion of the axon just beyond the neuron’s input region.
This region thus has the lowest threshold for generating an action potential.
Therefore it is known as the trigger zone.
Here the activity of all receptor(or synaptic) potentials is summed.
Action Potentials are ALL-OR-NONE.
HIGHLY-STEREOTYPED.

9. The Sodium Channel

10. The Ceylon Puffer Fish
Tetrodotoxin injected by Hodgkin and Huxley to block Voltage-gated Na Channels.

11. Cocaine
From coca leaves was the first anaesthetic, and also blocks Na+ channels with lower affinity and specificity than tetradotoxin.

12. The K Channel
An outward K+ current increases the repolarization rate of the action potential
Using Brownian dynamics simulations, we follow the trajectories of interacting ions in the potassium channel. With a fast supercomputer, we simulate the motion of 26 potassium ions and 26 chloride ions interacting through the intermolecular potential. Here we apply a potential difference across the channel such that inside is positive with respect to outside. The motion of each ion during each discrete time step is determined by, first, the net electrical force acting on it; secondly, the frictional force and, finally, random force originating from incessant collisions of the ion with its surrounding water molecules.
Variations in the properties of voltage-gated ion channels increase the signaling capabilities of neurons.
Gating of voltage gated ion channels can be influenced by cytoplasmic factors, e.g. with Ca2+ channels.
An energy profile can be calculated based on molecular structure.

13. The Axon Hillock

14. Propagation of Action Potential
Is forwards, because of the inactivated Na channels.
AP travels at 80m/s
PASSIVE ELECTRICAL PROPERTIES OF NEURONS :
Membrane Resistance determines the magnitude of passive changes in membrane potential. Related to [ion channel].
Membrane Capacitance prolongs the time course of electrical signals. Related to surface area of cell.
Membrane and Axoplasmic resistance affect the efficiency of signal conduction.

15. Salutatory Conduction
Myelin is a fatty insulating sheath.
AP is regenerated at the nodes of Renvier.

16. Chemical Synaptic Transmission
When AP reaches a neurons terminal
It stimulates neurotransmitter release.
Output signal is graded, amount of NT released is determined by the number and frequency of the action potentials.
After release, NT diffuses across the cleft to receptors on the post-synaptic neuron. Binding then results in the post-synaptic cell generating a synaptic potential.
Chemical synaptic transmission has several advantages over electrical. i.e. allows inhib and excit transfer, long term changes in efficacy are easier, i.e. modifiable transfer function possible!!! Also amplification is possible.
The sign of this synaptic potential
depends on the type of receptors.

17. Pre-Synaptic Mechanisms
Action Potential reaches Synapse.
Synaptic terminal is depolarized.
Voltage sensitive calcium channels open.
Calcium enters synaptic terminal.
Release of chemical neurotransmitter

18. Neurotransmitters Are Kept in Vesicles.

19. Mechanism of Vesicle Docking.

20. Neurotransmitters.

21. Amanita muscaria
A Muscurinic Agonist. Stimulates one of the receptors that AcetylCholine binds to.
The Black widow spider (Latrodectus) is so toxic because of massive release of acetylcholine from neurones.
Nicotine is a Nicotinic receptor agonist.
Atropia Belladonna is used to achieve mydriasis, it has atropine which is an antagonist of muscarinic receptors
Sweating, salivation, abdominal cramps, bradycardia

22. Post-Synaptic Mechanisms
Neurotransmitter binds to receptors.
Change in ionic permeability of post-synaptic cell.
Change in membrane potential of post-synaptic cell.
The same neurotransmitter can have different effects depending on the post-synaptic receptors present, i.e. inhibitory or excitatory.

23. Many Types of NT Receptor Exist.
1. Ionotropic
2. Metabotropic

24. Dendritic Spines.
The video clip shows miniature synaptic calcium transients visualized with the fluorescent calcium probe (fluo-3) in a spiny cultured rat cortical neuron dendrite. The image shows activity over a 10 sec period.

25. THE END