Week 2: Neuronal Signaling Part 1

The nervous system

- 2 major divisions, CNS and PNS - The functional unit of the nervous system is the individual cell called the neuron

Excitability

- Ability to generate action potentials - Possessed by neurons, muscle cells, and some other cell types

Directionality of action potentials in most neurons

- Action potentials in most neurons are initiated at one end of the cell and propagate towards the other end - They can only proceed forward down the axon, since the space behind is in its refractory period

Benefits of myelination

- Adds speed - Reduces metabolic cost - Saves room in the nervous system because the axons can be thinner

Action potential summary

- All or none: once membrane is depolarized, amplitude is independent of size of initiating event - Cannot be summed - Has a threshold that is usually about 15 millivolts depolarized relative to resting potential - Has a refractory period - Is conducted with out decrement, depolarization is amplified to a constant value at each point along the membrane - Duration is constant for a given cell type under constant conditions - Is only a depolarization - Initiated by a graded potential - Mechanism depends on voltage-gated ion channels

Graded potential summary

- Amplitude varies with the size of the initiating event - Can be summed - Has no threshold - Has no refractory period - Amplitude decreases with distance - Duration varies with initiating conditions - Can be depolarization or hyperpolarization - Initiated by environmental stimulus (receptor), by neurotransmitter (synapse), or spontaneously - Mechanism depends on ligand-gated ion channels or other chemical or physical changes

Plasticity

- Brain can modify structure/function in response to stimuli/injury - Degree of neural plasticity decreases with age - Basic shapes/locations of major circuits cannot change

Graded potentials

- Changes in membrane potential that are confined to a relatively small region of the plasma membrane - Are called graded potentials because magnitude of the potential change can vary - Graded potential only happens in a small region where there is a change in permeability

Beginning of nervous system development/growth cone

- Development of nervous system in embryo begins with stem cells that can develop into neurons or glia - After the last cell division each neuronal daughter cell differentiates, migrates to its final destination, and sends out processes that will become axons and dendrites - Specialized enlargement called the growth cone forms tip of each extending axon and finds correct route/final target for the process

Absolute refractory period

- During action potential: second stimulus, no matter how strong, will not produce second action potential - That region of the membrane is then said to be in its absolute refractory period - This occurs during the period when the voltage-gated Na+ channels are either already open or have proceeded to the inactivated state during the first action potential

Relative refractory period

- Following the absolute refractory period, there is an interval during which a second action potential can be produced, but only if the stimulus strength is considerably greater than usual - This is the relative refractory period, which can last as long as 15 milliseconds and coincides roughly with the period after hyperpolarization

Influences on force

- Force increases with quantity of charges - Force increases with decreased distance between charges

Interneurons

- Function as integrators and signal changers - Integrate groups of afferent and efferent neurons into reflex circuits - Entirely within the CNS - 99% of all neurons

Names of graded potentials

- Graded potentials are given various names related to the location of the potential or the function they perform - E.g. receptor potential, synaptic potential, pacemaker potential

Astrocytes

- Help regulate composition of ECF by removing potassium ions and neurotransmitters around synapses - Stimulate formation of tight junctions - Sustain neurons metabolically

Action potentials and ion channels

- In order to cause and propagate an action potential, a cell must utilize several types of ion channels - Graded potentials produced from a ligand-gated ion channels and mechanically gated ion channels often serve as the initiating stimulus for an action potential - Voltage-gated ion channels give a membrane the ability to undergo active potentials

Schwann cells

- In the PNS - Form individual myelin sheaths surrounding 1-1.5 mm-long segments at regular intervals along some axons

Refractory periods...

- Limit the number of action potentials an excitable membrane can produce in a given period of time - Contribute to the separation of these action potentials so that individual electrical signals pass down the axon - Are key in determining direction of action potential propagation

Ependymal cells

- Line fluid-filled cavities within the brain and spinal cord - Regulate production and flow of cerebrospinal fluid

Voltage-gated ion channels: K+

- Open and close slowly

Voltage-gated ion channels: Na+

- Open and inactivate rapidly - Opening causes depolarization - Can be open but inactivated

Efficiency of myelination

- Propagation via saltatory conduction is faster than propagation in nonmyelinated fibers of the same axon diameter. - Moreover, because ions cross the membrane primarily at the nodes of Ranvier, the membrane pumps need to restore fewer ions. - Myelinated axons are therefore metabolically more efficient than unmyelinated ones.

New attempts to repair nervous system damage

- Researchers are trying a variety of ways to provide an environment that will support axonal regeneration in the CNS. - They are creating tubes to support regrowth of the severed axons, redirecting the axons to regions of the spinal cord that lack growth-inhibiting factors, preventing apoptosis of the oligodendrocytes so myelin can be maintained, and supplying neurotrophic factors that support recovery of the damaged tissue. - Medical researchers are also attempting to restore function to damaged or diseased brains by implanting undifferentiated stem cells that will develop into new neurons and replace missing neurotransmitter or neurotrophic factors.

Axon regrowth

- Severed axons can repair themselves/restore significant function if damage is outside CNS and doesn't affect neuron's cell body - Axon separated from cell body degenerates - Attached part gives rise to growth cone, which can grow to effector organ and restore function - Regrows 1mm per day

Microglia

- Specialized, macrophage-like cells - Perform immune functions in the CNS - May also contribute to synapse remodeling and plasticity

Myelin sheath

- Speeds up conduction of electrical signal along axon - Conserves energy - Oligodendricytes in CNS

Spinal injuries

- Spinal injuries usually crush rather than cut tissue - Primary problem is apoptosis of nearby oligodendrocytes, leading to loss of myelin sheath, so axons cannot transmit info as effectively

Electrical potential/potential difference

- The difference in charge between 2 points - A little bit like a concentration gradient

Velocity with which an action potential propagates along a membrane depends on...

- The velocity with which an action potential propagates along a membrane depends upon fiber diameter and whether or not the fiber is myelinated - Size principle: The larger the fiber diameter, the faster the action potential propagates; because a large fiber offers less resistance to local current, more ions will flow in a given time.

Why doesn't ion concentration change?

- There are an infinite number of ions in the intracellular/extracellular space compared to the number at the membrane - The Na+/K= ATPase pumps maintain the concentration gradient

Efferent neurons

- Transmit info out of the CNS to effector cells, particularly muscles, glands, neurons, etc - Cell body with multiple dendrites and a small segment of the axon are in the CNS, most of the axon is in the PNS

Afferent neurons

- Transmit info to the CNS from the receptors at the peripheral endings - Signal process from the cell body splits into a long peripheral process (axon) that is in the PNS and a short central process (axon) that enters the CNS

Goldman-Hodgkin-Katz (GHK) equation

- We can calculate resting potential of a membrane by analyzing the contributions of individual ions with the Goldman-Hodgkin-Katz (GHK) equation - GHK equation is essentially an expanded version of the Nernst equation that takes into account individual ion permeabilities

Action potentials

- large alterations in the membrane potential - Membrane potential may change by up to 100 mV - Generally very rapid (1-4 milliseconds) and may repeat at frequencies of several hundred per second

Resting membrane potential

-70mV for most cells

Action potential steps

1. Steady resting membrane potential, membrane permeability is near normal levels for Na+ and K+ 2. Local membrane is brought to threshold by a depolarizing stimulus 3. Current through opening voltage-gated Na+ channels rapidly depolarize the membrane, causing more Na+ channels to open 4. Inactivation of Na+ channels and delayed opening of voltage-gated K+ channels halt membrane depolarization 5. Outward current through open voltage-gated K+ channels repolarizes the membrane back to negative potential 6. Persistent current through slowly closing voltage gated K+ channels hyperpolarizes membrane towards Ek, Na+ channels return from inactivated state to closed state (without opening) 7. Closure of voltage-gated K+channels returns the membrane potential to its resting potential

Saltatory conduction

Action potentials appear to jump from one node to the next as they propagate along a myelinated fiber

Nodes of Ranvier

Action potentials occur only at the nodes of Ranvier, where the myelin coating is interrupted and the concentration of voltage-gated Na+ channels is high.

Where are afferent neurons, efferent neurons, and interneurons located in the nervous system? Are there places where all three are found?

Afferent neurons have projections located near associated organs, as well as cell bodies that are located outside of the CNS in the dorsal root ganglia. They also have central processes that project into the CNS. The cell bodies of efferent neurons exist within the CNS, and their axons project outwards to either muscles, glands, or other neurons. Interneurons only exist within the CNS. All three types of neurons are contained within parts of the CNS and within the intrinsic nervous system.

Generation of a membrane potential due to diffusion of K+ through K+ channels

As potassium moves across the membrane due to the concentration gradient, the electrical potential difference increases until reaching an equilibrium potential

Equilibrium potential

Balance between electrical potential and concentration gradient

Central nervous system (CNS)

Brain and spinal cord

Dynein

Carries recycled membrane vesicles along microtubule of axon towards the cell body

Kinesin

Carries secretory vesicles along microtubule of the axon away from the cell body

Changes in membrane potential are due to...

Changes in membrane potential are due to movement of ions

Peripheral nervous system

Consists of the nerves that connect the brain or spinal cord with muscles, glands, sense organs, and other tissues

Creation/removal of synaptic contacts

Creation/removal of synaptic contacts begun during fetal development throughout life as normal part of growth, learning, and aging

Damage to the developing nervous system

During early stages of neural development, (from early pregnancy to infancy) alcohol, drugs, radiation, malnutrition, and viruses can cause permanent damage to the developing nervous system.

The Nernst Equation

Eion = equilibrium for an ion, in mV 61 = constant that takes into account the universal gas constant, the temperature (37C) and the farraday electrical constant Z = represents the valence of the ion [ion] = concentration of the ion inside or outside of the cell Eion = (61/Z) x log([ion out]/[ion in])

Na+

Extracellular concentration (millimoles/liter) = 145 Intracellular concentration = 15

Cl-

Extracellular concentration = 100 Intracellular concentration = 7

K+

Extracellular concentration = 5 Intracellular concentration = 150

Oligodendrocytes

Form myelin sheath for CNS axons

Subthreshold stimulus

Generate a small potential, but aren't quite high enough to generate an action potential

Resistance

Hinderance to movement

Describe the direction of information flow through a neuron in response to input from another neuron. What is the relationship between the presynaptic neuron and the postsynaptic neuron?

In most neurons, the information being transferred flows from into the dendrites and the cell body, and out through the axon and the axon terminals. Neurotransmitters are released from the presynaptic neuron into the synaptic cleft, and then bind to receptors located in the postsynaptic neuron in order to lead to an effect or to further transmission through another neuron.

Directionality of action potentials in skeletal muscle cells

In skeletal muscle cells, the action potentials are initiated near the middle of the cells and propagate towards the two ends.

Myelin

Insulator that makes it more difficult for charge to flow between intracellular and extracellular fluid compartments

Membrane potential and concentration gradients

Membrane potential changes as a result of changes in permeability, and NOT due to changes in ion concentration, because ion concentration doesn't change

Explain the conditions that give rise to the resting membrane potential. What effect does membrane permeability have on this potential? What role do Na+/K+-ATPase membrane pumps play in the membrane potential? Is this role direct or indirect?

Membrane potentials are generated when ions diffuse across a membrane according to concentration gradients and the permeability of the membrane to the specific ions. Membrane permeability has a considerable impact on the resting potential of a membrane, for example, K+ being much more permeable across the cell membrane causes the equilibrium potential of K+ to be much closer to the resting membrane potential for most cells compared to the less permeable K+. Na+/K+ ATPase membrane pumps play an indirect role maintaining membrane potential. They do so by pumping K+ into the cell and Na+ out of the cell, influencing the potential difference in charge across the membrane.

Neurons' response to action potentials

Most neurons respond to action potentials at frequencies of up to 100 action potentials per second, and some may produce higher frequencies for brief periods

Current

Movement of electrical charge

Calculating equilibrium potential examples

Na+: E of Na = (61/+1) x log([145]/[15]) = +60mV K+: E of K = (61/+1) x log([5]/[150]) = -90mV Notice that the equilibrium potential for K+ is closer to the membrane potential for most cells. This is because cells are considerably more permeable to K+ than Na+.

Once growth cone reaches target...

Once growth cone reaches its target, synapses form.

Contrast the two uses of the word receptor.

One use of the word "receptor" refers to proteins either located within the cell or on the cell's plasma membrane, which function to initiate the cell's response to a chemical messenger. The other use of the word refers to the most peripheral portion of an afferent neuron, where receptors react to changes in the environment and subsequently generate electrical signals.

Overshoot

Potential is moving above 0 in a positive direction

Hyperpolarization

Refers to the potential moving away from RMP in a more negative direction

Depolarization

Refers to the potential moving from resting membrane potential (RMP) to less negative (closer to zero) values

Repolarization

Refers to the potential returning to RMP

Route axon follows depends on...

Route axon follows depends largely on attracting, supporting, deflecting, or inhibiting influences from cell adhesion molecules and soluble neurotrophic factors (growth factors for neural tissue) in ECF surrounding growth cone or distant target

Severed axons within the CNS

Severed axons within the CNS may grow small new extensions, but no significant regeneration of the axon occurs across the damaged site, and there are no well-documented reports of significant return of function

Which two factors involving ion diffusion determine the magnitude of the resting membrane potential?

The magnitude of the resting membrane potential is determined by the relative concentrations of ions on the other side of the membrane, and by the relative permeability of the membrane to those ions.

Resting membrane potential in neurons

The magnitude of the resulting membrane potential in neurons is generally in the range of -40 to -90 mV

Explain why the resting membrane potential is not equal to the potassium membrane equilibrium potential.

The reason why the resting membrane potential is not totally equal to the membrane equilibrium potential for potassium, is because the membrane also has some permeability to Na+ and Cl-. Therefore, Na+ and Cl- will pass between sides of the membrane, and thus influence the magnitude of charge on either side.

Variance of extra/intra Cl- concentrations

There is more variance in extracellular and intracellular Cl- concentrations across different cells, it tends to have a smaller effect on membrane potential

Explain threshold and the relative and absolute refractory periods in terms of the ionic basis of the action potential.

Threshold level of depolarization occurs when influx of Na+ barely exceeds outflux of K+, and therefore the net flux of charge into the cell is positive. K+ is driven further out of the cell as the membrane further depolarizes, while the membrane also becomes more permeable to Na+ so the positive-feedback cycle can continue. Absolute refractory periods correspond roughly to when voltage-gated Na+ channels are already open or inactivated (first part of action potential repolarizing phase). Relative refractory periods correspond to periods when the membrane is more permeable to K+ and some of the Na+ channels have closed.

GHK equation and variables

Vm = 61 x log((Pk[K out] + PNa[Na out] + PCl[Cl in])/(Pk[K in] + PNa[Na in] + PCl[Cl out])) = about -70mV Vm = Voltage of the membrane Pk = permeability of K+, 1.0 PNa = permeability of Na+, 0.04 PCl = permeability of Cl-, 0.45

Ohm's law

Voltage = current(I) x resistance, or I = V/R

When ions can move across a membrane...

When ions can move across a membrane, they will bring the membrane potential to their equilibrium potential