ASCI 438: Systemic Physio

Which tissues are “excitable”? 

• Neural and Muscle tissues

Signal transduction

refers to the process by which incoming signals are conveyed into the target cell where they are transformed into the dictated cellular response 

Neurons send signals to what other cells?

• Other neurons

• Muscles

• Glands

Resting Membrane Potential

• The membrane potential in a cell at rest is negative, not neutral 

• -70mV

Why is the neuron interior negatively charged relative to the exterior? 

3 influences 

• Na+ K+ pumps on the cell membrane pump 3 Na+ out of the cell for every 2 K+ into the cell 

• Large negatively charged protein molecules exist inside the cell 

• K+ leak channels are more active than Na+ leak channels 

Na+ K+ ATPase

• Moves 3 Na+ out of the cell and 2 K+ into the cell with each cycle

• Over time this yields more positive charges outside the cell relative to inside the cell

• Requires Energy

Leak Channels

• Also play a role in maintenance of resting potential

• Concurrently with the ions being moved by the pumps, Na+ and K+ are also passively leaking across the membrane through their specific leak channels

• These leak channels are always open

The membranes pumps purpose is:

• to set up a gradient that the Na+ and K+ can Flow down

  • Once the gradient is in place, ions will flow down their gradient across the membrane once a channel opens

  • In addition to the leak channels, the ions will also flow through transiently opened gated channels

Threshold Potential 

-55 mV

4 Types of Gated Channels 

• Voltage Gated 

• Chemically Gated

• Mechanically Gated 

• Thermally Gated

A flow of positive ions into the ICF —— the cell

depolarizes (makes less negative)

A flow of positive ions into the ECF —— the cell after depolarization

Depolarizes

From resting state, a flow of positive ions out of the cell into the ECF—- the cell

hyper polarizes

Graded Potentials vs. Action Potentials 

Graded Potential: Short distance decremental signal 

• different sizes

• propagate in both directions 

Action Potential: long distance non decremental signal 

• same sizes (all or none principle) 

• travel in only one direction in the axon 

Graded potentials

• Short distance signals

• Decremental 

• Spreads in both directions away from the site of initiation 

• The stronger the triggering event, the more ion channels will be opened and the larger the resulting graded potential (but they then still dwindle down) 

Neuron Anatomy

• Cell Body

  • Has dendrites (“receiving zone”) 

    • The cell membrane covering the cell body and dendrites is where graded potentials arise

  • Axon 

    • Axon Hillock ('“trigger zone”) 

      • The axon hillock is where action potentials arise 

    • Axon 

    • Terminals 

Action Potentials

• An action potential happens when the excitable cell membrane is depolarized to threshold potential (-55mV) by a graded potential 

• At threshold potential, voltage gated Na+ and K+ channels open  

  • The opening of these channels elicits a momentary increase in the permeability of the neuronal membrane to these ions  

  • The ions flow through their channels, causing a transient reversal of membrane potential from –70 to +30 mV 

    • This is an action potential 

• If enough Na+ enters locally from a graded potential to take the neuron from –70 to –55 in the area of the hillock, the neurons threshold voltage is reached  

  • At threshold voltage, the voltage gated Na+ channels open, allowing an immediate influx of Na+ 

  • As the Na+ enters, the membrane potential becomes increasingly more positive. This is the upstroke of the action potential  

• After a millisecond, the voltage gated Na+ channels close and the voltage gated K+ channels, which began opening slowly at threshold become fully open. K+ flows out of the neuron  

  • As K+ leaves, the exit of positive charge causes the downstroke of the action potential 

  • The k+ channels close slowly, so that K+ continues to flow out and the membrane potential briefly becomes hyperpolarized  

• The Na+/K+ pumps which are always active, help return the ions to their respective spaces across the membrane and reestablish resting potential  

• The action potential causes a brief reversal of membrane potential in that it starts at –70mV, goes up to around +30mV and then returns to –70mV 

  • This is the nerve impulse that travels along at hundreds of meters per second  

 

Action Potentials 

• Long distance signals  

• Fast moving, large changes in membrane potential  

• All or none phenomenon: once threshold reached, a uniform AP will be triggered irrespective of magitude of stimulus 

• Each AP generated by a neuron is uniform and of maximum magnitude each time  

• An AP does not diminish in strength or die out after a short distance: they are conducted down entire length of membrane to the nerve terminals  

Voltage Gates Na+ Channel Configurations 

• Closed but capable of opening  

  • Internal Activation gate is closed  

  • Inactivation gate open  

• Open (activated)  

  • Activation gate open  

  • Inactivation gate open 

• Closed and not capable of opening (inactivated)  

  • Inactivation gate closed  

  • Activation gate open  

Voltage Gated K+ Channel Configuration

The voltage gated K+ channels exist in two configurations  

• Open  

• Closed 

 

Refractory Period

• the time after a neuron fires an action potential when it cannot fire another. This prevents the neuron from firing too rapidly 

• The refractory period limits the number of action potentials and ensures AP’s only travel unidirectionally 

Absolute Refractory Period

• during this time a second stimulus will not elicit a new AP  

Relative Refractory Period

• the interval in which a second AP can be produced but only if the stimulus is considered greater than normal  

Action Potential Sequence with Activation Gates ?

• At resting potential (-70mV) the Na+ voltage gated channel, the inactivation gate is open, activation gate closed (closed but capable of opening)  

  • Voltage Gated potassium channel at –70 is closed  

• At threshold (-55 mV) both Na+ gates are open, sodium comes flooding in due to concentration gradient created by Sodium Potassium ATPase pump  

• At +30 mV, Na+ gates activation gate is open but inactivation gate is closed (closed)  

  • K+ channel opens  

  • Potassium will flood out (going down its concentration gradient) (Repolarize, get more negative)  

• Na+ channel resets to closed but capable of opening  at negative 70 again  

Where are voltage gated Na+ and K+ channels concentrated

At the Nodes of Ranvier (Schwaan Cell)

Cells that create myelination in peripheral nervous system

Schwaan Cells

cells that create myelination in central nervous system

oligodendrocytes

Synapse

• What happens when a traveling electrical signal (action potential) reaches the nerve terminal at the end of the axon? 

  • It innervates another neuron, a muscle cell or a gland  

• The tiny spatial gap between nerve ending and target is called a synapse 

Events at the Synapse

1. Arriving Action potential triggers voltage gated Ca2+ channels in presynaptic knob to open  

2. Ca2+ ions rapidly flow into the cell from ECF 

3. Synaptic vesicles containing neurotransmitters fuse with the plasma membrane 

4. Neurotransmitters diffuse across synaptic junction and bind with receptor on postsynaptic membrane  

5. This chemical binding activates chemically gated ion channels  

 

 

Neuronal Configuration and Events at the Synapse

• Voltage gated calcium channels, calcium comes in 

  • Calcium is the cation that facilitates things contracting or moving (actin filaments contract in response to calcium)  

• Synaptic vesicles (preformed neurotransmitter vesicles) packaged and stores by Golgi  

• Neurotransmitter vesicles made of same phospholipid bilayer, contract down and fuse, NT is released, goes down and binds to proteins in postsynaptic membrane (receptors are CHEMICALLY gated Na+ channels)  

  • On dendrite they are chemically gated Na+ channels  

  • On axon/ hillock they are voltage gated Na+ channels  

• In this picture: presynaptic membrane belongs to axon terminal, postsynaptic membrane dendrite  

What type of Na+ channels are on the dendrite?

CHEMICALLY gated Na+ channels

What type of Na+ channels are on the axon/hillock

VOLTAGE gated Na+ channels

Excitatory Post-synaptic Potential (EPSP)

• If binding of NT (such as ACh) opens Na+ and K+ channels the result is a small depolarization called an excitatory post-synaptic potential (EPSP)  

• EPSP’s bring the cell closer to threshold  

• A type of graded potential 

Inhibitory Post-Synaptic Potential (IPSP)

• If binding of NT (such as GABA) opens either K+ or Cl- channels the result is a small hyperpolarization called an inhibitory post-synaptic potential (IPSP)  

• IPSP’s polarize the cell further making it less likely to reach threshold  

• A type of graded potential 

Synaptic Summation

the sum of all the EPSP’s and IPSP’s will determine whether the postsynaptic neuron reaches threshold 

Temporal Summation

EPSP’s or IPSP’s from a single, repetitively firing presynaptic input occur so rapidly that they add together 

Spatial Summation

Adding of EPSP’s or IPSP’s simultaneously from different presynaptic inputs  

Grand Post Synaptic Potential 

• The summation of all inputs is called the grand post synaptic potential (GPSP)  

• If excitatory inputs dominate, the cell is brought closer to threshold  

• If inhibitory inputs dominate, the cell is taken farther from threshold  

• If excitatory and inhibitory activity is balanced, the membrane potential remains close to resting  

Summary of events at Posysynaptic membrane

• If positive Ion gates open (allowing more Na+ and Ca2+ to enter than K+ to exit) the membrane becomes depolarized, which results in an excitatory post synaptic potential (EPSP)  

• If the EPSP’s summate such that treshold potential is reached at the hillock, an action potential is generated and will travel down the axon.  

• If K+ or Chloride Ion (Cl-) gates open (allowing K+ to exit or Cl- to enter) the membrane becomes more polarized which results in an inhibitory postsynaptic potential (IPSP)  

• If IPSP’s dominate, the hillock region moves away from threshold and the neuron is less likely to generate an action potential  

Convergence and Divergence 

• By converging input, a single cell is influenced by thousands of presynaptic cells  

• By divergence, branching axon terminals of one neuron affect thousands of postsynaptic cells  

• At the dendrite, EPSPs and IPSPs can sum in time (temporal summation) and space (spatial summation)  

• The result is synaptic silence or the grand post synaptic potential, representing the integration of signals from many neurons  

Actions of chemical messengers (3 types of receptors)

• Opening receptor-channels

• Activating receptor-enzymes

• Activating an intracellular second messenger via G-protein coupled receptors 

GCPR (G-Protein Couples Receptors) 

• Have 7 membrane domains (7 points of structure that passes through membrane) 

• These receptors are the mechanism by which water-soluble hormones work  

• Cannot diffuse across the membrane and enter cell so use an elaborate signaling mechanism to transduce the message into the cell even if the signal molecule cannot enter  

• Note that the G protein is composed of 3 different subunits and that the alpha subunit can dissociate from the beta and gamma subunits once activated by replacing GDP with GTP  

• These receptors are all about generaing intracellular second messengers  

  • cAMP 

  • IP3 and DAG: increase Ca2+ 

• Which seconf messenger is generated depends on the type of subunits contained in the G protein connected to the receptor 

GCPR’s subunits and monomers 

1. The G protein exists as 3 monomers: Alpha Beta and Gamma  

2. The alpha subunit exists in multiple forms : α_S, α_i, α_q/11, and α_12/13 

3. We will concern ourselves with α_S  and α_q/11  

4. _{If a GPCR’s alpha subunit is an} α_{S it will lead to adenylyl activation and cAMP production}  

5. _{If the alpha subunit is an} α_{q/11 it will lead to phospholipase C (PLC) activation and IP3 and DAG production}  

 

4. _{If a GPCR’s alpha subunit is an} α_{S it will lead to————}

_{adenylyl activation and cAMP production} 

_{If the alpha subunit is an} α_{q/11 it will lead to——-}

_{phospholipase C (PLC) activation and IP3 and DAG production}  

 

GCPR: “Alpha S Subunit”

• The effector for a G protein containing an Alpha S subunit is the membrane protein adenylyl cyclase  

• Activation of AC--> cAMP 

• CAMP activates PKA  

• PKA activates other proteins in the cytoplasm that will culminate in whatever cellular response was indicated by the binding of the signal molecule at the cell surface  

GCPR: Alpha Q Subunit

The effector for a G protein containing an Alpha Q subunit is the membrane protein phospholipase C  

2. PLC cleaves the membrane phospholipid phosohatidylinositol biphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG)  

3. IP3 goes to its receptors on the ER, where it binds and liberates Ca2+ into the cytosol  

4. DAG remains associated with the cell membrane and activates protein kinase C (PKC)  

5. PKC phosphorylates other cytosolic proteins, activating them and leading to a cellular response  

 

Hyperpolarize a cell

• open more potassium channels, or open a chloride or other ion channel  

An action potential is from opening what channels

from opening voltage gated Sodium and Potassium Channels 

If you open a channel for potassium ———-

it will rush from the inside of the cell to the outside (get more negative)  

if you open a channel for sodium ——-

sodium will move from outside cell to inside cell

Where are voltage gated calcium channels found 

synaptic knob/axon terminal 

Sodium potassium ATPase pumps how many ions in and out

3 Na+ (Sodium) ions out and 2 K+ (Potassium) in

Central Nervous System

• Consists of the brain and Spinal Cord

Peripheral Nervous System

• Afferent and Efferent divisions 

  • Afferent 

  • Efferent 

    • Somatic 

    • Autonomic 

      • Parasympathetic 

      • Sympathetic 

Enteric Nervous System

the nerve network of the digestive tract

Afferent Divisions

• Division of PNS 

• Two afferent divisions carry information into the CNS:  

  1. Somatic carries sensory information from skin, skeletal muscles  

  2. Visceral carries sensory information from smooth muscle, glands and organs  

Efferent Division

• Division of PNS 

• Two efferent divisions carry information out of the CNS:  

  • Somatic nervous system supplies skeletal muscles  

  • Autonomic nervous system innervates smooth muscle, cardiac muscle and glands  

    • Two divisions of the autonomic nervous system  

      • Sympathetic and parasympathetic systems  

 

Divisions of Autonomic Nervous System

Sympathetic and Parasympathetic

Afferent Neurons

• sensory neurons that supply input to the CNS from the internal environment or from the periphery, info about the external environment 

• SENSORY  

• Sensory= Ascending = Afferent

Efferent Neurons

• carry instructions from CNS to organs, muscles and glands (periphery)  

• MOTOR  

• Motor= Descending = Efferent

Interneurons

• responsible for integrating afferent information and formulating an efferent response.  

• These are the most numerous types of neurons  

Afferent neurons axon terminals terminate where?

On the dendrites of the Interneuron

The nerve terminals of the interneuron terminate where?

on the dendrites of the efferent neuron

The nerve terminals of the efferent neurons terminate where?

On the effector organ (muscle, gland or another neuron)

Protection of the CNS

• Enclosed by the skull or vertebral column: hard, bony structures  

• Meninges cover CNS, three layers:  

  • Dura mater  

  • Arachnoid mater  

  • Pia mater

• Blood-brain barrier limits access of blood-borne materials into brain tissue  

• Cerebrospinal fluid (CSF) is the fluid that fills the ventricles and also surrounds and gives hydraulic cushioning to the CNS  

Cerebrospinal Fluid (CSF) 

• is the fluid that fills the ventricles and also surrounds and gives hydraulic cushioning to the CNS  

• Surrounds and cushions brain and spinal cord  

• Serves as a shock-absorber to prevent brain from hitting skull  

• Exchange of materials between neural cells and interstitial fluid surrounding brain  

• Constant production and flow out of CNS and into venous system  

Brain Ventricles

• Two Lateral Ventricles

• Third and Fourth

• (4 total)

• Produce CSF 

Meninges layers

• Dura Mater (outermost)

• Arachnoid

• Pia Mater (innermost)

Coup-Contrecoup Injury

• Example of one way in which the CSF helps protect the fragile brain tissue  

• Coup-contrecoup refers to the 2 impact type of closed brain injury that results from traumatic impact  

  • First there is the initial impact and direct crushing injury  

  • A second later comes the secondary impact of the brain against the other side of the skull (when the force knocks the soft brain against the back of the skull)  

• Closed brain injury without direct trauma: acute acceleration and deceleration  

  • Coup-contrecoup injury can also happen even without direct contact to the head  

    • Whiplash --> there is no direct impact on the head, but the brain still strikes the inner surface of the cranium 

      • In addition, the abrupt acceleration and deceleration causes stretching of the neurons as the brain moves forward and backward inside the cranium: called shear injury  

      • Shear injury damages and destroys neurons and is a significant component of the morbidity associated with closed brain injuries  

Skull Interior

• The bony skull protects the brain most of the time but can be the source of injury as well  

• The interior contours of the cranium are not homogenous and smooth  

• The CSF lies between the brain and cranium, and helps cushion the tender neural tissue from the hard surfaces of the surrounding cranium  

Brain Anatomy Overview

• The major parts of the brain from the most complex to most primitive level:  

• Cerebral cortex  

• Basal nuclei  

• Thalamus  

• Hypothalamus  

• Cerebellum 

• Brain Stem  

Cerebral Cortex Lobes

• Frontal Lobe

• Parietal Lobe

• Temporal Lobe 

• Occipital Lobe 

Lobes of the Cerebrum

• Hemispheres are divided into four major lobes (each has left and right)

• Occipital 

• Temporal 

• Parietal 

• Frontal 

Occipital Lobe

• Houses the visual cortex

• Interpretation of visual stimuli and inout 

Temporal Lobe

• houses the auditory cortex

• Auditory processing 

• Interpretation of language and other things we hear 

Parietal Lobe

• responsible for reception and perception of somatosensory input (touch,pain, temperature) 

• Processing of sensory tactile information 

• The anterior most gyrus in the parietal lobe is the somatosensory cortex

Frontal lobe

• responsible for voluntary motor movement 

• Responsible for cognition, reasoning, higher language composition: poetry, music 

• The posterior most part of the frontal lobe is the motor cortex where voluntary movement is initiated 

Gyri / Gyrus

Elevated ridges on the brain

Sulci/ Sulcus

depressions or grooves on the brain

Somatosensory Cortex

• Located in the front portion of each parietal lobe just behind the central sulcus (the rostral most gyrus just caudal to the central sulcus)  

• Site for initial processing and perception of both somesthetic and proprioceptive input  

  • Somesthetic Sensations are from the surface of the body (touch, pressure, heat, cold and pain  

  • Proprioception is the awareness of body position 

• The somatosensory cortex receives ascending (Afferent) sensory input from the opposite side of the body  

• Specific regions of the somatosensory cortex receive input from specific areas of the body  

  • The distribution map of sensation in this area is called a sensory homunculus  

  • The size of each body part in the homunculus is proportional to the level of sensory perception associated with each body part  

    • Fingers, lips and the tongue are highly innervated and highly sensitive, command more surface area on the sensory homunculus 

Proprioception

is the awareness of body position

Primary Motor Cortex

• Located in posterior portion of frontal lobes, just in front of central sulcus  

• Controls voluntary movement by skeletal muscles  

• Motor cortex on each side of the brain primarily controls muscles on the opposite side of body  

Basal Nuclei

• Consists of several masses of gray matter located deep within white matter 

• Primary Functions:  

  • Inhibiting muscle tone throughout the body  

  • Selecting, maintaining purposeful motor activity  

  • Suppressing unwanted patterns of movement  

  • Coordinates slow, sustained contractions  

• Lesions of injuries involving the Basal Nuclei result in unwanted motor activity or body rigidity.  

• Basal Nuclei Lesions  

  • Putamen  

    • Lesions here cause chorea—involuntary flicking motions of hands, face, shoulders  

  • Globus pallidus 

    • Lesions here cause athetosis- writhing motions of the hands, arms, neck, face 

  • Substantia nigra 

    • Lesions here cause rigidity and tremor—Parkinsons Disease  

Spinal Chord White Matter tracts

• White matter is organized into nerve tracts—bundles of nerve fibers with a similar function  

  • Each tracts begin or ends within a particular area of the brain  

  • Ascending tracks transmit afferent (sensory) input 

  • Descending tracts relay efferent (motor) input  

• White matter is myelinated  

Brain and Spinal Chord White and Grey Matter 

• In brain grey matter outside/ in periphery white matter more internal 

• In spinal cord white matter is outside/more superficial and grey matter more internal  

Gray Matter

• The gray matter is divided into three horns 

  • Dorsal horn  

    • Contains cell bodies of interneurons on which afferent neurons terminate 

  • Ventral horn  

    • Contains cell bodies or efferent motor neurons supplying skeletal muscles (somatic efferent)  

  • Lateral horn 

    • Contains cell bodies of autonomic efferent nerve fibers (sympathetic or parasympathetic)  

• Grey matter is non-myelinated (cell bodies)  

Dorsal Horn (grey matter)

• Contains cell bodies of interneurons on which afferent neurons terminate

Ventral horn (grey matter)

• Contains cell bodies or efferent motor neurons supplying skeletal muscles (somatic efferent)  

Lateral Horn

• Contains cell bodies of autonomic efferent nerve fibers (sympathetic or parasympathetic)

Anatomic Orientation to Spinal Nerves

• Afferents enter dorsally (dorsal root carries incoming afferents)  

  • Dorsal Root Ganglion  

• Efferent enter ventrally (ventral root carries efferent)  

  • No Ventral Root  

Spinal Nerves 

• Any given spinal nerve contains both afferent and efferent neurons  

• Just like the cranial nerves, spinal nerves can carry both sensory and motor neurons  

• Both Cranial nerves and spinal nerves are peripheral nerves!  

• The nerves exit the spinal cord in the intervertebral spaces

Nerve vs Neuron

A nerve is a bundle of neurons  

Coverings of a Neuron

• Epineurium

• Perineurium

• Endoneurium 

Dermatomes

• Each spinal nerve innervates a slice of the body corresponding to where it comes off = dermatome  

  • Each slice of the body is innervated by a single spinal nerve = its dermatome  

    • “ a sensory unit of the skin that is innervated by a single spinal nerve”  

  • Useful diagnostically: if a patient can't feel a pinpoint at a given body site, you can map what nerve is injured and where the injury is 

Afferent neurons carry action potentials from —- to blank ——

Carry action potentials from the periphery to the CNS (brain and spinal cord)

What is in the dorsal horn of the grey matter?

Cell bodies of the interneurons and afferent neurons are synapsing on them  

What is in the ventral horn of grey matter

Cell bodies of efferent motor neurons going to skeletal muscle  

What is in the lateral horn of grey matter

Cell bodies of autonomic efferent neurons (parasympathetic and sympathetic) going to smooth muscles and glands  

Thalamus

• Serves as “relay station” and synaptic integrating center for sensory input  

• Helps direct attention to stimuli of interest  

• Reinforces voluntary motor actions initiated by motor cortex  

• Capable of crude awareness of sensations but cannot distinguish their location or intensity: relaying the stimuli coming up the spinal cord to the appropriate higher centers is how the specificity of experience occurs