Neurons and Glial Cells

The Neuron Doctrine

• Neurons are the basic structural and functional unit of the nervous system, conforming to Cell Theory.
• A cell is the individual functional unit of all living organisms.
• The nervous system comprises the Central Nervous System (CNS) and the Peripheral Nervous System (PNS).

Brain Cells

• The brain has two cell types: glia and neuronal cells.
• Glia outnumber neuronal cells in a 10:1 ratio.
• Glia insulate, support, and nourish neurons.
• Neurons process information, sense environmental changes, communicate changes to other neurons, and command the body's responses to environmental stimuli.

Glia (Neuroglia)

• Glia are smaller than neurons and 5 to 50 times more numerous.
• There are two types of glia in the PNS: Schwann cells (myelin forming) and satellite cells.
• The CNS has four types of glia: astrocytes, oligodendrocytes (myelin forming), microglia, and ependymal cells.

Neuron Gross Anatomy

• Neurons differ structurally from other cells in the body.
• Unique structures enable neurons to perform their function.
• Key neuronal structures include the axon, cell body/soma, dendrites, and synaptic terminals.

A Typical Neuron

• The human brain contains about 100 billion neurons with over 100 types.
• Neurons have 5,000-100,000 synapses each.
• There exist 1,500 trillion synapses in the human brain.

Neuron Classification

• Neurons are classified based on structural and functional characteristics.
• Structural classification considers the number of processes extending from the soma (axons and dendrites).
  • Unipolar neurons have a single neurite.
  • Bipolar neurons have two neurites, with one as the axon.
  • Multipolar neurons possess three or more neurites.
• Functional classification is based on the role neurons play.
  • Sensory neurons carry messages toward the brain.
  • Motor neurons carry messages from the brain to muscles and glands.
  • Interneurons connect neuronal cells.
• Neurons release neurotransmitters that can have excitatory or inhibitory effects.

Structural Classification of Neurons

• Multipolar neurons have several dendrites and one axon and are the most common cell type in the brain and spinal cord.
• Bipolar neurons have one main dendrite and one axon and can be found in the retina, inner ear, and olfactory areas.

Functional Classification of Neurons

• Afferent neurons transmit information into the CNS from receptors via peripheral endings and a short central axon.
• Efferent neurons transmit information out of the CNS to effector cells, possessing multiple dendrites, with most of their axon in the PNS.
• Interneurons function as integrators and signal changers, integrating groups of afferent and efferent neurons into reflex circuits.

Functional Classification of Neurons

• Interneurons lie entirely within the CNS and comprise about 90% of all neurons.

Terms to Know

• Voltage (V) measures potential energy between two points from charge separation.
• Potential difference is the voltage difference between two points.
• Membrane potential is the voltage difference between the inside and outside of a cell.
• Resting membrane potential is the steady transmembrane potential of a cell not producing an electrical signal, about -70mV in neurons.

Resting Membrane Potential

• All cells have a potential difference across their plasma membranes at rest, where the cell inside is negatively charged relative to the outside.
• Resting membrane potential exists because of a tiny excess of negative ions inside and positive ions outside the cell.
• 80% of RMP is caused by selective permeability of the cell membrane to K+ ions, which diffuse out according to the concentration gradient.
• 20% of RMP is caused by the Na+/K+ pump.

Resting Membrane Potential - Definition & Causes

• Resting membrane potential: potential difference recorded across the cell membrane at rest
• 80% is caused by selective permeability of the cell membrane to K+
  • K+ diffuses out of the cell & Na+ diffuses into the cell according to concentration gradient
  • K+ permeability is 50-75 times more than Na+
• 20% is caused by the Na+ K+ pump
  • Is an active process that needs energy taken from ATP
  • Is very important to maintain the concentration gradient across the cell membrane

Establishing and Maintaining Ion Gradients

• The Na+/K+ pump transports K+ into neurons and Na+ out of neurons to establish and maintain ion gradients.

Equilibrium Potential

• The membrane potential to oppose concentration of an ion is the equilibrium potential. Eion = Ena, ECl, EK.
• Potassium EP, or EK, is the potential where chemical and electrical gradients are equal, resulting in no net K movement.
• The Nernst or Goldman equation calculates equilibrium potential.
• Na¹ EP is +60mV, and K¹ EP is -90mV.

Nernst Equation

• The Nernst Equation calculates the membrane potential of an ion at equilibrium.
• The Nernst Equation represents the electrical potential required to maintain a concentration gradient of a permeable solute.
• Z is valence of the ion.

Goldman's Equation

• Goldman's Equation calculates overall membrane potential when multiple ions are involved.
• It incorporates permeability of each ion.
• The permeability of K+ > Na+ > Cl, which means K+ drives Resting Membrane Potential.

Electrical Signals in Neurons

• All living cells have a resting membrane potential (RMP) due to ion pumps and leak channels, measurable in millivolts.
• Some cells possess gated ion channels, enabling electrical signal production for information transmission.
• This excitability defines excitable membranes.

Electrical Signals in Neurons

• Neurons and muscle cells, along with some endocrine, immune, and reproductive cells, produce electrical signals.
• Electrical signals manifest as graded potentials (GP) and action potentials (AP).
• GPs are for short-range signaling, while APs are long-range, especially in neuronal and muscle cell membranes.

Terms to Know

• Depolarize, repolarize, and hyperpolarize are used to describe membrane potential changes, which act as electrical signals.
• Resting membrane potential (RMP) is "polarized," indicating the cell's inside and outside have different net charges.
• The membrane is depolarized when its potential becomes less negative.

Terms to Know - Overshoot, Repolarizing, Hyperpolarized

• Overshoot: a reversal of the membrane potential polarity--inside of a cell becomes positive relative to the outside
• Repolarizing: when a membrane potential that has been depolarized is returning toward the resting value
• Hyperpolarized: the membrane is hyperpolarized when the potential is more negative than the resting level.

Communication Along and Between Neurons

• Communication occurs through graded potentials and action potentials.
• Synaptic potentials are graded.

Graded Potential

• GPs in neurons involve depolarizations or hyperpolarizations in dendrites and cell bodies, or near axon terminals.
• Changes in membrane potential are called "graded" because their size/amplitude is proportional to the strength of the triggering event.
• A larger stimulus will cause a strong graded potential, and a small stimulus will result in a weak graded potential.

Graded Potential

• GP: a change of variable amplitude and duration that is conducted decrementally
  • Usually die out in 1-2mm of the origin
  • Has no threshold and refractory period
• GPs are given a variety of names relating to the location of the potential or the function they perform
  • Receptor potential, synaptic potential and pacemaker potential

Graded Potentials, Summary

• Graded potentials are short-lived and local changes in membrane potential: either depolarizations or hyperpolarizations
• Cause currents that decreases in magnitude with distance
• Magnitude varies directly with stimulus strength – the stronger the stimulus the more the voltage changes and the farther the current spreads
• Sufficiently strong graded potentials initiate Action Potentials

Action Potential

• Action potential (AP): regenerating depolarization of membrane potential that propagates along an excitable tissue to communicate over long distances.
• Threshold of most membranes is about 15mV less negative than the RMP.
  • If RMP of a neuron is -70mV→threshold potential may be -55mV.

Action Potential Con't

• Steady resting potential is near EK, where Ek > ENa due to K¹ channels.
• A local membrane can be brought to its threshold voltage by a depolarizing stimulus.
• When voltage-gated Na¹ channels open, a current rapidly depolarizes the membrane causing more Na¹ channels to open.
• Membrane depolarization is halted by the inactivation of Na¹ channels and the delayed opening of voltage-gated K¹ channels.

Action Potential Con't

• Outward current through open voltage-activated potassium channels repolarizes the membrane back to a more negative potential.
• Persistent current through slowly closing voltage-gated sodium channels hyperpolarizes the membrane toward Εκ
  • Sodium channels return from inactivated state to closed state (without opening)
• Closure of voltage-gated potassium channels returns the membrane potential to its resting value

Voltage-Gated Channels

• Change shape due to changes in membrane potential
  • Closed at resting potential
• Positive feedback
  • Influx of Na+ →local depolarization →more Na+ channels open →more depolarization
• Na+ channels open first (depolarization)
• K+ channels open more slowly (repolarization)
• Na+ channels close
• K+ channels close slowly causing a relative refractory period

Propagation of Action Potentials

• AP travels along axon without decrement in size.
• This occurs because the voltage change during AP is up to 5x as large as needed to exceed threshold.
• Extra depolarization causes the membrane is to depolarize ahead of AP and produce the next AP.

Propagation of Action Potentials

• Na channel gets activated.
• AP Propagation
• Na channel gets inactivated.

Characteristics of AP

• Action potentials
  • Need to reach threshold
  • Are all-or-none events
  • Have constant amplitude
  • Do not summate
  • Initiated by depolarization
  • Involve changes in permeability
  • Rely on voltage-gated ion channels

Applications of Action Potentials

• Local anesthetics are drugs that temporarily block action potentials in axons
  • They are called Local because they are injected directly into the tissue where anesthesia (the absence of sensation) is desired

Action Potential Con't

• Local anesthetics like procaine/lidocaine prevent AP generation by blocking voltage-gated Na¹ channels, preventing opening in response to depolarization.
• Without APs, graded signals in sensory neurons cannot reach the brain or cause the sensation of pain.

Action Potential Con't

• Some animals produce toxins (poisons) that block nerve conduction in same way that local anesthetics do.
• Some organs of the pufferfish produce the extremely potent toxin tetrodotoxin, which bind to voltage-gated sodium channels and prevents the sodium component of the AP

Absolute Refractory Periods

• During an action potential, a second stimulus, no matter how strong, is not able to produce a second action potential.
• The absolute refractory period represents the time required for Na channel gates to reset to their resting positions.
  • This ensures that a second action potential will not occur before the first has finished.
• APs cannot overlap and cannot travel backward because of their refractory periods.

Relative Refractory Period

• A relative refractory period follows the absolute refractory period
  • A stronger than normal depolarizing graded potential is needed to bring the cell up to threshold, and the AP will be smaller than normal.

Uses of Refractory Periods

• Refractory periods limit the number of AP an excitable membrane can produce in a given period of time.
• Most neurons respond at frequencies of up to 100 APs per second, and some may produce much higher frequencies for brief periods
  • RPs contribute to the separation of these APs so that individual electrical signals pass down the axon
• The RPs also are the key in determining the direction of AP propagation.

Functions of Action Potentials

• Information delivery to CNS: carriage of all sensory input to CNS
• Information encoding: the frequency of APs encodes information
• Rapid transmission over distance (nerve cell APs)-
  • Note: speed of transmission depends on fiber size and whether it is myelinated
    • Information of lesser importance is carried by slowly conducting unmyelinated fibers
• Not so nervous tissue APs are the initiators of a range of cellular responses - Muscle contraction - Secretion (example: adrenalin from chromaffin cells of medulla)

Conduction Speed

• Velocity of AP propagation depends on fiber diameter and myelination.
• The larger the fiber is in diameter, the faster the AP propagates.
• Larger fibers offer less internal resistance to local current, allowing more ions to flow, and bringing adjacent regions of the membrane to threshold more quickly.

Large Diameter Neurons in Vertebrates

• Disadvantage of large diameter axons:
  • Take up a lot of space which limits number of neurons that can be packed into nervous system
  • Have large volumes of cytoplasm making them ..........to produce and maintain
• Solution: Look at electrical insulation of axons

Insulate Axon with Myelin

• PNS: insulate axon with myelin

Propagation of Action Potentials

• Myelin is an electrical insulator, not allowing ions to move across.
• This results in depolarization further down the axon.

Saltatory Conduction

• This method relies on myelin insulation.
• At the Node, depolarization causes Na⁺ to enter the axon through open channels, resulting in an action potential.
• The depolarization encounters the next node.
• The apparent leapfrogging of APs from node to node along the axon

Four Classes of Sensory Axons Differ in Size and Speed

• Αα (Alpha-alpha) fibers have diameter of Axon 13–20µm, speed of transmission 80-120m/sec with receptor types: Feedback from muscle fibers.
• AB (Alpha-beta) fibers- 6-12µm- 35-75m/sec- Mechanoreceptors of skin: Meissner's corpuscles, Merkel's disks, Pacinian corpuscles, Ruffini's endings.
• Αδ (Alpha-delta) 1-5µm, 5-30m/sec, Pain, temperature receptors of skin, Free nerve endings.
• C fibers- 0.2-1.5µm, 0.5-2m/sec, Pain, temperature and itch receptors of skin, Free nerve endings

Effect of Myelin on Conduction Velocity

• Equal conduction velocities can be achieved with myelin.
  • 6 mm diameter w/ myelin equals 500 mm diameter w/o myelin

Uses of Myelin

• Conduction velocity is increased
• Size requirement is diminished
• Electrical insulation
• Reduced cell-energy requirement

PROTECTION AND NOURISHMENT OF THE BRAIN

• Due to the very delicate fragile, irreplaceable nature of CNS tissue it must be well-protected. There are four major protection features:

1. Enclosure by hard, bony structures.
2. Three protective and nourishing membranes called the meninges.
3. The brain floats in "cerebrospinal fluid (CSF).
4. Selective blood-brain barrier.

Protection and Nourishment

• Meninges are the three wrap, protect, nourish membranes of the central nervous system. From outermost to innermost, they are the dura mater, the arachnoid mater, and the pia mater and consist of two tissue layers.
• The dura mater- tough, inelastic covering with two layers.
• The arachnoid mater- delicate, richly vascularized layer with a "cobwebby" appearance.
• Pia mater- The innermost meningeal layer, the most fragile.

Cerebro-Spinal Fluid (CSF)

• CSF is formed primarily by the choroid plexuses found in regions of the ventricles.
• Choroid plexuses consist of vascularized masses of pia mater tissue that dip into pockets formed by ependymal cells.
• The composition of CSF differs from that of blood.
  • CSF surrounds and cushions the brain and spinal cord.
  • The CSF helps prevent the brain from bumping against the interior of the hard skull when the head is subjected to sudden movements. CSF plays an important role in the exchange of materials between the neural cells and the interstitial fluid surrounding the brain.

Cerebro-Spinal Fluid (CSF): Fluid Regulation

• The brain interstitial fluid directly bathes the neural cells
  • It's composition is critical
• The composition of the brain interstitial fluid is more heavily influenced by CSF than the blood. This makes materials exchanged between the CSF and brain interstitial fluid, far more free than materials exchanged between the blood and brain interstitial fluid.
• CSF must be carefully regulated in its composition:
  • Lower K and slightly higher in Na+ than typical fluids
  • Almost no proteins normally present but they are present in the blood
  • Proteins can't exit the brain capillaries to leave the blood during formation of CSF
• CSF flows through interconnected ventricles of the brain and through the spinal cord's narrow central canal.

Cerebro-Spinal Fluid (CSF): Flow & Pressure

• CSF also escapes through small openings from the fourth ventricle at in the brain.
• CSF reaches upper regions of hte brain before it flows down spinal cord
• Flow is facilitated by ciliary beating- 10 mm Hg is CSF pressure
• 125–150ml CSF is replaced more than 3x a day.
• Disruption of flow causes hydrocephalus from CSF accumulation.

Blood Brain Barrier

• The brain is shielded from harmful blood changes by blood-brain barrier (BBB.)
• The body's materials are exchanged between body's blood and interstitial fluid only across the smallest blood vessels: capillaries .
• Unlike other capillaries elsewhere, BBB's exchanges are carefully regulated:
  • Even if K+ level in the blood is doubled, little change occurs in fluid' K+.
  • It helps prevent neuronal function harm.

Key Features of the Blood Brain Barrier

• The BBB has both anatomic and physiologic features.
• Capillary walls throughout the rest of the body are formed by a single layer of cells. The all blood plasma components are freely exchanged between the blood and interstitial fluid through pores between the cells.
• In brain capillaries, the cells are joined by tight junctions,
• This creates the only possible exchanges are the capillary cells themselves: -The BBB protects the delicate brain minimizing potentially harmful from blood
  • Prevents brain's hormone and neurotransmitters from entering

The Blood Brain Barrier: Substances and Delivery

• Lipid-soluble substances (O2, CO2, alcohol, and steroid hormones) penetrate these cells.
• Small water molecules also diffuse (aquaporins).
• Substances (glucose, amino acids, and ions), are transported by membrane-bound carriers.

Blood Brain Barrier

• Strictly limiting exchange is is how BBB protects brain:
  • Chemical fluctuations
  • Minimizes blood born subs reaching central neural tissue
  • Prevents hormones that could act as neurotransmitters from reaching brain.
• Neg side: BBB limits drugs use for brain and spinal chord since many drugs can't penetrate.

Blood Brain Barrier: Brain Specifics and Details

• Certain brain areas aren't subject to BBB: notably a portion of hypothalamus because it needs to "sample" blood to maintain homeostasis.
• This sampling means hypothalamic capillaries aren't sealed by tights.
• Unlike other tissues, brain is more dependent than any other on a constant blood supply
• Andunlike other tissues Brain can't made ATP wO oxygen.
• The scientists recently discovered an O2-binding protein, neuroglobin, in the brain (the O2-carrying protein in red blood cells)

Brain Energy

• The brain normally uses only glucose but doesn't store it.
  • Therefore, the brain depends on a continuous, adequate blood supply of O2 and glucose.
  • Brain is 2% body weight: receives 15% body weight

Blood Supply & Brain Damage

• Brain damage results if the it is deprived of O2 for 4-5 minutes or of glucose for 10-15 min.
• The most common cause of not enough blood supply to the brain is a stroke.

Explore the structure and function of neurons and glial cells. Understand neuron types, action potentials, and the neuron doctrine. Learn about resting membrane potential and interneuron function.