Farma 1.1. Introduction

Neural signaling & neuromodulation

Human nervous system consists of:

1) Brain
 ->gyri & sulci to limit brain

 ->cerebral cortex with pyramidal cells covers tissue (=most typical layer of cells in brain)

2) Spinal cord

3) Peripheral nerves (interaction between NS & rest of body)

 ->psychopharmacology =effect of chemicals on brain

4 lobes of brain

1) Frontal lobe:
 -> word production, problem solving, planning, behavioral control, emotion… (humans have largest proportionally frontal cortex, ‘most typically human’)

2) Parietal lobe: sensory awareness, pain

3) Temporal lobe: memory, emotion (deeper in brain), word understanding…

4) Occipital lobe: vision

 ->cerebral cortex: outer layer, pyramidal cells

 ->connections: needed to function properly (connectivity between sections as important as size!)

Cortex

=buitenste laag met grijze stof (cellichamen) + diepere kernen (vb. thalamus, striatum)

<->witte stof binnenin

Corpus callosum

=over 10k fibers which connect hemispheres (both sides work together + are coordinated)

 ->hemispheres function together!

3 types cells in NS

1) Pyramidal
2) Purkinje cells (important role cerebellum)

3) Glial cells
 =supporting cells (10x more than neurons)
 ->support brain structurally & functionally

 ->astrocytes, microglia, schwann & oligodendrocytes

Astrocytes

=important role in blood-brain barrier

1. Feeding neurons (supplies neurons) + holds neurons in place (structure)

2. Star shape

3. Digest parts of dead neurons

4. Each astrocyte has its own territory (no overlap), they may interact with several neurons and very many synapses

5. ‘End feet’ (connection: signals from astrocytes expand or narrow blood vessels, controlling flow of oxygen & nutrients)

6. Release gliotransmitters (eg glutamate) to send signals to neighbouring neurons

Microglia

=defense & recovery

 ->!recovery after stroke is only partially possible! (only neurogenesis in a few areas)

 

1. Special immune cells found only in the brain

2. Detect damages or unhealthy neurons

3. Eat foreign invaders (bacteria/viruses)

 ->then display the chewed-up parts on their cells surface to signal for help

Oligodendrocytes

~myelination of axons (CNS)

1. Wrap tightly around axons to form myelin sheath

 =>speed up electrical signaling (AP 30x slower without oligo)

2. Can cover up to 40 axons

Schwann-cells

~myelination of axons (PNS)

1. Mostly in cerebellum (also in grey nuclei in brainstem and diencephalon)

2. Different morphology depending on location

Multipolar neuron

=1 axon + multiple dendrites (come out of cell body at diff locations)

 ->can be motorneuron, pyramidal or purkinje cell

Axon

~used to guide nerve impulses away from cell body

1. Isolated by myelin sheath
 ->nodes of Ranvier (openings sheath: AP occur here)

2. have microtubule (helps move vesicles through axon)

Synapses

=connection between 2 cells: release of NTs here
 ->stimulus transmission between 2 cells occurs via synapse (which can have diff. places: axo-axonal synapse, axo-dendritic synapse, or axo-somatic synapse)

Presynaptic nerve terminal & postsynaptic membrane
 ->synapses often situated at dendrites of postsynaptic cells
 ->Cherles Sherrington introduced synapse cleft (“gap is important”)

Resting potential

=state of cell with stable membrane potential

-70mV (difference of electrical charge inside cell more neg, outside more pos)

 ->charge difference=important! (rapid changes in potential provide means for neurons to conduct information)

Charge difference

~unequal distribution of charged ions in & out cell
 =>in ALL CELLS OF BODY! (Excitable cells use it to form electrical signals)

 ->A- ions and K+ ions: higher concentration in cytoplasm of axon (cause inside of cell to be negative)

->Cl- ions and N+ ions: higher concentration out cytoplasm of axon (cause outside of cell to be positive)

If cell loses resting potential: death

1. All ion channels will open
2. Calcium can enter cell =>cell death

Action potential

=rapid change in membrane potential that is propagated down the length of the axon (state of cell in which membrane potential rapidly rises & falls (explosive depolarization))

 

->membrane must be changed from resting (-70 mV) to threshold for firing (-50 mV)

->at -50mV: voltage-gated Na+ channels open =>generates rapid change in membrane potential

Process of AP

1. Resting

2. Depolarization: Na+ gate opens and goes from outside to inside of cell 

3. Repolarization: K+ gate opens and goes from inside to outside of cell 

4. Hyperpolarization: Sodium-potassium ion pump restores initial distribution

5. Resting

Local potentials

=small local changes in ion distribution that disturb membrane & can open ion channels momentarily

1. They’re graded (larger stimulus=greater magnitude of hyper/depolarization!)

2. When st. ends: ion channels close, potential back to RP

3. Potentials decay rapidly as they passively travel along the cell membrane

Integration

=summation of potentials

~several small hyper/depolarizations can add up to larger changes in membrane potentials
 ->small changes sum up to big changes & cause action

Significance of local potentials to pharmacology

~when drugs/NTs bind to particular receptors in NS

 ->they may momentarily open specific ion channels

 =>causing excitatory/inhibitory effect

 

1. Excitatory post synaptic potentials (EPSP)
2. Inhibitory postsynaptic potentials (IPSP)

 ->integrations of E/IPSPs occurs at axon hillock & is responsible for generation of AP

Net sum of E/IPSPs that cell receives is important

1. If it leads to depolarization of cell: opening of voltage-gated sodium (Na) channels

2. If it leads to repolarization of cell: opening of voltage-gated potassium (K) channels

Local vs action potentials

Local potentials
1) Graded
2) Decremental (decay rapidly as they travel along membrane so local?)
3) Spatial & temporal summation
4) Produced by opening of ligand-gated channels
5) Hyper- or depolarization

 

Action potentials
1) All-or-none
2) Nondecremental
3) Intensity of stimulus coded by rate of firing
4) Produced by opening of voltage-gated channels

5) Depolarization

Pharmacologic example

~drugs & toxins affect axon conduction: saxitoxin

=blocks voltage-gated Na+ channels by physically binding to the channel’s outer pore (preventing sodium ions from entering cell)

 ->caused by shellfish from red tide

 ->numbness, paralysis & respiratory failure

Eg of drugs: some drugs block potentials from being generated (operation: block pain signals, can be operated awake)

Propagation of AP in unmyelinated axons

=slow process!

1. Starts at an axon hillock

2. Influx of Na+ ions & efflux of K+ ions

3. Na+ is attracted to neg side and K+ to pos side of cell membrane

4. Voltage spread: each part of cell membrane depolarizes and repolarizes

5. AP propagates along axon

Propagation of AP unmyelinated dutch

Geleiding van actiepotentiaal=gevolg van ladingsverschuivingen
 ->verschuiven van ladingen
 ->elk naburig deeltje van axonale membraan wekt opnieuw AP op als drempelwaarde bereikt is, geeft dit weer door
 (<->sneller bij myeline: enkel doorgeven naar knopen Ranvier)

Propagation of AP in myelinated axons

=fast process: saltatory transmission 100x faster
1. Starts at an axon hillock

2. Adjacent parts of membrane can’t generate AP due to myelin sheath

3. Distances between nods of Ranvier =exactly right distance so that voltage spread is sufficient to generate a next AP   
 ->AP generation only possible at unmyelinated spots

Example of problem with myelination

=multiple sclerosis (MS): immune system (glial cells) attacks myelin sheets in brain & spinal cord

 =>disrupts nerve transmission (inflammatory damage)