NPB 101 MT2 (Neurons+AP) L15-20

Acetylcholine is in which pathways?

Both the sympathetic and parasympathetic pathways

Autonomic Nervous System

• Controls the function of our organs and glands; can be divided into the sympathetic and parasympathetic divisions

• Complex network of cells that control the body’s internal state — plays a critical role in maintaining homeostasis

• Regulates and supports many different internal processes, often outside of a person’s conscious awareness (Involuntary control)

Ganglion

A cluster of neuronal cell bodies outside of the CNS

Sympathetic pathway

Parasympathetic pathway

Dorsal Root Ganglia

Clusters of neuron cell bodies that transmit signals from CNA to organs

Diffusion

The process of movement of molecules under a concentration gradient

Net diffusion

Difference between two opposing movements

Rate of diffusion through a membrane depends on the following factors:

• Magnitude

• Permeability

• Surface area

• Molecular weight

• Distance

How does the magnitude of the concentration gradient relate to the rate of diffusion through a membrane?

↑ α ↑ rate of diffusion

How does the permeability of the membrane relate to the rate of diffusion through a membrane?

↑ α ↑ rate of diffusion

How does the surface area of the membrane relate to the rate of diffusion through a membrane?

↑ α ↑ rate of diffusion

How does the molecular weight of the substance relate to the rate of diffusion through a membrane?

↑ α ↓ rate of diffusion

How does the distance (membrane thickness) over which diffusion takes place relate to the rate of diffusion through a membrane?

↑ α ↓ rate of diffusion

Electrochemical gradient

• Diffusion down a concentration (chemical) gradient

• Movement along an electrical gradient

Movement along an electrical gradient

Electrostatic force (voltage) caused by the separation of electrical charge

Movement along an electrochemical gradient

The combined force of concentration (chemical) and electrical gradients

Neurons

• Nerve cells specialized for electrical signaling over long distances (thanks to the long axon)

• Soma has a nucleus

• Electrically excitable and highly polarized

Membrane potential (mV)

A separation of opposite charges across the plasma membrane

Charge Separation Across a Membrane

• Most fluid is electrically neutral

• Separated charges form a layer along the plasma membrane

• Immediately inside the plasma membrane are negative charge

How does the cell create charge separation?

1. Establishes and maintains concentration gradients for key ions (Na+, K+).

2. Ions diffuse through the membrane down their concentration gradients.

3. Diffusion through the membrane results in charge separation, creating a membrane potential (electrical gradient).

4. Net diffusion continues until the force exerted by the electrical gradient exactly balances the force exerted by the concentration gradient.

5. This potential that would exist at this equilibrium is “equilibrium potential.”

Equilibrium potential for K+

1. Because K+ is more ICF, K+ tends to move out of the cell.

2. The outside of the cell becomes more positive because K+ moves out.

3. The membrane is impermeable to the large intracellular protein anion. Therefore, the inside of the cell becomes more negative. 

4. The resulting electrical gradient tends to move K+ into the cell.

5. No further net movement of K+ occurs when electrical gradient counterbalances concentration gradient. 

6. The equilibrium potential of K+ at -90mV.

Equilibrium potential for Na+

1. The concentration gradient for Na+ tend to move into the cell.

1. The inside of the cell becomes more positive because Na+ moves in.

1. The outside becomes more negative as Na+ moves in, negatively charged ions, mostly Cl- is outside.

2. Therefore, Na+ move out of the cell. 

3. No further net movement of Na+ occurs when the electrical gradient exactly counterbalances the concentration gradient. 

4. The equilibrium potential for Na+ at +60mV. 

Nernst Equation

Describes the equilibrium potential for a particular ion (i)

E_i = RT/zF ln [i]_o/[i]_i 

Where R is the gas constant, T is the temperature in degrees Kelvin, z is the valence of the ionic species, and F is the Faraday constant.

Is sodium more abundant extracellularly or intracellularly?

Extracellularly

Is potassium more abundant extracellularly or intracellularly?

Intracellularly

Why is the resting membrane potential closer to the K+ potential than the Na+ potential?

The membrane is 20-30x more permeable to K+ than Na+, so there is a large net diffusion of K+ and a small net diffusion of Na+ (which neutralizes some of the potential created K+)

How do K+ and Na+ penetrate the cell membrane?

Leak channels — permit ions to flow down concentration gradients passively (without ATP use)

Why is Na+ higher outside of the cell and K+ higher inside?

Na/K ATPase — establishes and maintains concentration gradients. Specifically pumps 3 Na+ out of the cell for every 2 K+ pumped into the cell

Resting Membrane Potential

• Has a balance of passive leak channels and active Na/K ATPase

• Neither K+ nor Na+ is at their equilibrium potentials

• Concentration gradients and permeabilities for Na+ and K+ remain constant

What would happen to a cell’s membrane potential if the cell was deprived of ATP?

Na/K+ ATP would not be functional → no membrane potential

Homeostatically Regulated Factors

• Nutrients

• O₂ and CO₂

• Waste products

• pH

• Water, Salt, and other electrolytes

• Volume and pressure

• Temperature

Direct intercellular communication

• Gap junctions

• Transient direct linkup of cells’ surface market

Endocrine signaling

Acts via hormones and neurohormones secreted into the blood to control processes that rely on duration rather than speed

Main regulatory systems of the body

• Nervous system

• Endocrine system

Nervous System

Anatomic Arrangement: A “wired” system: a structural arrangement exists between neurons and their target cells, with structural continuity in the system

Type of chemical messenger: neurotransmitters released into the synaptic cleft

Distance of action of the chemical messenger: short distance (diffuses across the synaptic cleft)

Specificity of action on the target cell: dependent on the close anatomic relationship between neurons and their target cells

Speed of response: rapid (milliseconds)

Duration of action: brief (milliseconds)

Major functions: coordinates rapid, precise responses

Endocrine System

Anatomic Arrangement: A “wireless” system: glands are widely dispersed and not structurally related to one another or to their target cells

Type of chemical messenger: hormones released into the blood

Distance of action of the chemical messenger: long distance (carried by the blood)

Specificity of action on the target cell: dependent on the specificity of target cell binding and responsiveness to a particular hormone

Speed of response: slow (minutes to hours)

Duration of action: long (minutes to days or longer)

Major functions: controls activities that require long duration rather than speed

Organization of the nervous system

• CNS (brain and spinal cord)

• PNS (nerve fibers; has afferent and efferent divisions)

• Enteric Nervous System — ENS (nerve network of the digestive tract)

Organization of the Efferent Division of the PNS

• Somatic nervous system: fibers of the motor neurons that supply the skeletal muscles

• Autonomic nervous system: fibers that innervate smooth muscle, cardiac muscle, and glands

• Both receive information from efferent division (PNS)

Somatic Nervous System

• Fibers of the motor neurons that supply the skeletal muscles

• Receive information from PNS efferent division

Autonomic Nervous System

• Fibers that innervate smooth muscle, cardiac muscle, and glands

• Receive information from PNS efferent division

• Consists of a two-neuron chain

• Subdivided into the Sympathetic and Parasympathetic nervous systems

Parasympathetic Nervous System

• Division of the autonomic nervous system that maintains resting functions of the internal organs.

• “Maintaining homeostasis”

Sympathetic Nervous System

• Division of the autonomic nervous system that prepares the body for strenuous physical activity.

• “Fight or flight response”

Is eating food a part of the autonomic sympathetic division or parasympathetic division?

Sympathetic

Is digesting food a part of the autonomic sympathetic division or parasympathetic division?

Parasympathetic

Integration of the stress response by the hypothalamus

HPA Axis

Hypothalamus-pituitary-adrenal cortex

Stressors activate which system?

Sympathetic

Depolarization

Change in membrane polarization to more positive values than resting membrane potential

Hyperpolarization

Change in membrane polarization to more negative values than resting membrane potential

Repolarization

Change in membrane polarization back to the original polarity

Action Potential

• Brief all-or-nothing reversal in membrane potential (spike), lasting on the order of 1 millisecond, that is brought about by rapid changes in membrane permeability to Na⁺ and K⁺ ions.

• Once initiated in the axon hillock, action potentials are conducted the length of an axon; do not decay with distance

• Refractory period ensures one-way propagation of action potentials and limits their frequency (cannot be initiated in a region that has just undergone an AP)

• Myelination increases the speed of conduction of AP saltatory conduction

Rising phase of Action Potential

Voltage-gated Na⁺ channel - opens quickly (< 0.5 ms) in response to depolarization, allowing Na⁺ to flow down its electrochemical gradient into the cell

Falling phase of Action Potential

Voltage-gated K⁺ channel - opens slowly in response to depolarization allowing K⁺ ions to flow out of the cell down their electrochemical gradient

What are the mechanisms that control these Na+ and K+ specific movements?

Voltage-gated Na+ and K+ channels

Climax of Action Potential

↓ P_Na+ ↑P_K+

Events Underlying the Rising Phase of the Action Potential

Events Underlying the Falling Phase of the Action Potential

Dendrites

Input zone of neuron; receives incoming signal

Soma

Cell body of neuron

Axon hillock

Trigger zone of neuron, initiates action potentials

Axon

Long tail of neuron

Axon terminals

Output zone of neuron, releases neurotransmitters

Neuron nucleus

Action potential propagation

1. Occurs when locally generated depolarizing current spreads to adjacent regions of membrane causing it to depolarize

2. The original active area returns to resting potential, and the new activate area induces an action potential in the next adjacent inactive area. The cycle repeats itself down the length of the axon.

Contiguous conduction

Propagation of action potentials in unmyelinated fibers by spread of locally generated depolarizing current to adjacent regions of membrane, causing it to depolarize

Absolute refractory period

• A brief period during a spike

• Repolarization: Voltage Gated Na+ channel inactivation gate closes

• A second spike cannot be generated

Relative refractory period

• A brief period following a spike

• Below resting membrane potential: Voltage Gated Na+ channel inactivation gate opens

• Capable of opening in response to depolarization

• Hyperpolarization: a higher intensity stimulus is needed

Contiguous conduction (of action potentials through a nerve fiber)

Unmyelinated fibers: touching, next to in sequence

Saltatory conduction (of action potentials through a nerve fiber)

Propagation of action potentials in myelinated axons by jumping from node to node, skipping over the myelinated sections of the axon

Faster conduction propagation!

How does the refractory period ensure the one-way communication of action potentials?

Action potential cannot be initiated in a region that has just undergone an action potential

Myelin

A multilayered sheath of plasma membrane, derived from specialized glial cells, that wraps around axonal fibers and acts as an insulator to the flow of current

Nodes of Ranvier

Gaps in myelin insulation containing high densities of voltage-gated Na⁺ and K⁺ channels

Schwann cells

Myelin-forming glial cells in the peripheral nervous system

Oligodendrocytes

Myelin-forming glial cells in the central nervous system

Multiple Sclerosis (MS)

• 1 out of 1000 patients in the US

• MS begins between ages 20 and 40

• An autoimmune disease (the body’s defense system attacks the myelin sheath.)

• Slow transmission of impulse in the affected neurons

Graded potentials

• Local changes in membrane potential 

• Occur in varying grades or degrees of magnitude or strength (size correlates with stimulus)

• Spread by passive current flow

  • Current: any flow of electrical charges 

  • Resistance: hindrance to electrical charge movement

• Die out over short distances

Synapse

Junction between two neurons, or between a neuron and a muscle or gland that enables one cell to electrically and/or biochemically influence another cell

Electrical synapse

Neurons connected directly by gap junctions

Chemical synapse

• Most synapses in the human nervous system

• Chemical messenger transmits information one way across a space separating the two neurons

Gap junctions

• Made up of multiple proteins called connexins (a large family of trans-membrane proteins that allow intercellular communication and the transfer of ions and small signaling molecules between cells)

• The small diameter of the “tunnel” permits water-soluble particles (such as ions) to pass between cells but blocks the passage of larger molecules.

Convergence

The synaptic input of many neurons into one neuron

Divergence

The synaptic output of one neuron onto many neurons

Synaptic transmission

• Primary means of rapid inter-neuronal communication in the brain

• Presynaptic axon initiates the signal

• Neurotransmitter carries the signal across a synapse; binds to postsynaptic receptors

• Postsynaptic (target) cell receives the signal

  • targets can be a muscle, gland, or another neuron

Postsynaptic targets

Muscles, glands, other neurons

Sequence of events of a Chemical Synapse

1. AP propagation in presynaptic neuron

2. Ca+ entry into synaptic knob (terminal button?)

3. Release of neurotransmitter by exocytosis

4. Binding of neurotransmitter to postsynaptic receptor

5. Opening of specific ion channels in subsynaptic membrane

Presynaptic release (chemical synapse)

• Voltage-gated Ca⁺⁺ channels

• Synaptic vesicles

Postsynaptic response (chemical synapse)

• Postsynaptic receptors

• Postsynaptic potential (PSP)

Excitatory postsynaptic potential (EPSP)

• Most common excitatory neurotransmitters are glutamate (Glu) and acetylcholine (ACh)

• Depolarizing potential that brings mV towards threshold for generation of an action potential

Inhibitory postsynaptic potential (IPSP)

• Most common inhibitory neurotransmitters are gamma-amino butyric acid (GABA) and glycine (Gly)

• Hyperpolarizing potential that brings mV away from threshold for generation of an action potential

(Neuro)Transmitter removal

• Degradation — enzymatic breakdown (ie: AChE)

• Transport — active transport back into the presynaptic cell “reuptake”

• Diffusion — the transmitter simply diffuses away from the synaptic terminal

Degradation Transmitter removal

Enzymatic breakdown (ex: AChE)

Transport Transmitter removal

Active transport back into the presynaptic cell “reuptake”

Diffusion Transmitter removal

The transmitter simply diffuses away from the synaptic terminal

Temporal summation

The additive effect of PSPs (Post-Synaptic Potential) occurring close together in time

Spatial summation

The additive effect of PSPs (Post-Synaptic Potential) occurring together on nearby parts of the same cell

Cancellation summation

EPSP and IPSP cancel each other out