Quiz 2 Flashcards
Nonessential
Synthesized in the body; Alanine Asparagine Aspartate Glutamate Serine
Conditional Essential
Synthesis can be limited under special pathophysiological conditions (prematurity of infants or those with severe catabolic distress) Arginine Cysteine Glutamine Glycine Proline Tyrosine
Essential
Indispensible aa; can't be synthesized de non so must be supplied by diet Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine
ketogenic
AA that are converted to acetyl CoA or acetoacetate so precursors of FA and ketone bodies
Glucogenic
AA converted to precursors for glucose synthesis like alpha ketogluterate, succinyl coA, fumerate, pyruvate, oxaloacetate
Both ketogenic and glucogenic
Isoleucine, Phenylalanine, Tyrosine, Tryptophan, Threonine
Stereoisomerism in alpha- AA
L and D configurations ; most in nature are L
AA are all chiral except glycine (enantiomers)
Nonpolar, aliphatic R groups
Glycine, Alanine, Proline, Valine, Leucine, Isoleucine, Methionine
Aromatic R groups
Relatively nonpolar; absorb UV (Tryptophan absorbs most followed by tyrosine the Ph)
Tryptophan, Phenylalanine, Tyrosine
Polar, uncharged R groups
Serine, Threonine, Cysteine, Asparagine, Glutamine
Positively Charged R groups
Lysine, Arginine, Histidine
Negatively charged R groups
Aspartate, Glutamate
Reversible formation of a disulfide bond by the oxidation of 2 cysteine
Hair straightening (safer; most representative aa in hair)
Uncommon amino acids/ modifications of aa
Hydroxyproline and hydroxylysine found in collagen
Addition of phosphate, methyl, adenosine (reversible)
AA not found in proteins
Ornithine (urea cycle, bad breath) and citrulline (byproduct of production of nitric oxide- vasodilator)
Non-ionic or zwitterion forms of AA
Zwitterion- neutral molecules with a positive and negative electrical charge though multiple positive and negative charges can be present
a characteristic pH, called the isoelectric point (pI), the negatively and positively charged molecular species are present in equal concentration; characteristic pH at which the net electric charge is zero
Effects of chemical environments on pka
pka -COOH 1.8-2.4 [4.8?]
pka -NH3 8.8-9.7 [10.6]
isoelectric pt: 5.5-6.2
Titration of amino acids
pI=1/2 (pka1+pka2) of the pkas closest to each other? (+1, -1)
Proteins are polymers built from aa joined by peptide bonds
usually peptides- have ~50 or fewere AA vs proteins (1 or more polypeptide)
Formation of peptide bond by condensation
Removal of water (OH from carboxy and H from amine)
AA residues; not rotatable around peptide bond but can rotate around alpha carbon
As increase residues, increase of MW
Conjugated proteins
Lipoproteins, Glycoproteins, phosphoproteins, hemoproteins, Flavoproteins, metalloproteins
Levels of structure in proteins
Primary (aa string), secondary (alpha helix or beta pleated sheets; H bonds), tertiary (folding; polypeptide chain) quaternary (assembled subunits)
A change of a single aa can alter the function of protein
Ex. sickle cell anemia Glu–> Val
Collagen Synthesis
Need vitamin C (not enough OH without it- can’t attain full strength)
Hydroxyproline and hydroxylysine found in collagen
Diseases related to collagen
Scurvy, Osteogenesis imperfecta, Ehlers- Danlos Syndrome, Spondylopiphyseal Dyplasia
Elastin
highly elastic protein in CT; allows many tissues in body to resume their shape after stretching or contracting
Production of most plasma proteins occurs in the LIVER
Human serum albumin, osmolyte and carrier protein
α-fetoprotein, the fetal counterpart of serum albumin
Soluble plasma fibronectin, forming a blood clot that stops bleeding
C-reactive protein, opsonin on microbes
Acute phase protein
factors in hemostasis and fibrinolysis, carrier proteins, hormones, prohormones and apolipoproteins
The planar peptide group
Carbony O has partial neg. and amide N partial Pos. setting up small eltric dipole. All peptide bonds in proteins occur in trans configuration
alpha helix and beta pleated sheets
Alpha helix has cross linked disulfide bonds that make it tough, protective [alpha keratin of hair, feathers, nails]
Beta sheets can be parallel or antiparallel (H bonds are straight); soft/flexible [silk fibroin]
collagen triple helix (high tensile strength, without stretch); collagen of tendons, bone matrix
Pathways that contribute to proteolysis
process by which cells control the abundance and folding of the proteome, and consists of a highly interconnected network that integrates the regulation of gene expression, signaling pathways, molecular chaperones and protein degradation systems
Histones
Each chromosome consists of a single molecule of DNA complexed with an equal mass of proteins. Collectively the DNA associated with these proteins is called chromatin. Most of these proteins are histone; Have Arg and Lys bind phosphate groups (neg) form nucleosomes
Proteins denature and renature
Native state; catalysis active–> (addition of urea and mercaptoethanol) unfolded state, inactive (DISULFIDE cross links reduced to yeild Cys)–> Native, catalytically active state; disulfide cross links correctly reformed
Due to temp, pH
Quaternary structure
polypeptide chain (collagen) vs 2 beta and 2 alpha chains in Hemoglobin associated with Iron and Heme
Nervous System
Have 100 billion nerve cells (neurons) in human brain with each connected to ~10,000 others= 100 trillion nerve connections
CNS
Brain and spinal cord
PNS
Somatic (voluntary)
Autonomic (Involuntary)- Sympathetic (fight/flight, epinephrine) vs Parasympathetic (rest/digest, acetylcholine)
Neuron Morphology
Cell body (perikaryon, soma; has nucleus; metabolic and synthesis center), axon (myelinated, emerges from axon hillock [final site where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon]), dendrites
Dendrites
Typically short, small processes emerging and branching off the cell body; USUALLY COVERED WITH MANY SYNAPSES [PRINCIPAL SIGNAL RECEPTION AND PROCESSING SITE]; large number and extensive arborization of dendrites allows a single neuron to receive and integrate signals from many other nerve cells;
“changes in dendritic spines are of key importance in the constant changes of the neural plasticity that occurs during embryonic brain development and underlies adaptation, learning, and memory postnatally”
Axon
Conduct AP from cell body to synaptic terminal (allow rapid communication), most neurons have only one axon, typically longer than its dendrites, axonal processes vary in length and diameter (motor neuron axons innervate the foot muscles have lengths of nearly a meter)
Terminals (Boutons)- activated by transmitter and will shut down release and synthesis of Neurotransmitters
Astrocyte
most abundant CNS glial cell; star shaped, uptake of transmitters and potassium, produce growth factors and neuroactive factors, Help form the blood brain barrier, regulates interstitial fluid composition, provides structural support and organization to the CNS, assists with neuronal development, replicates to occupy space of dying neurons
Ependymal Cell
CNS glial cell; Epithelial like cells that form a single layer lining the fluid filled lines ventricles of brain and spinal cord, lining the ventircles of the cerebrum, columnar ependymal cells extend cilia and microvilli from the apical surfaces into the ventricles, assists in the production and circulation of cerebrospinal fluid
Microglial
CNS glial cell; not interconnected unlike the others, normally rare but common at sites of injury/ neurodegeneration, motile cells, constantly used in immune surveillance of CNS tissues, when activated by products of cell damage or by invading microorganisms, the cells retract their processes, begin phagocytosing the damage or dnager related material and behave as APCs, phagocytic cell that move through CNS, protects the CNS by engulfing infectious agents and other potential harmful substances
Oligodendrocyte
CNS glial cell; extend many processes, each of which becomes sheet like and wraps repeatedly around CNS axons, many are needed to cover entire length of axon, during wrapping, most cytoplasm gradually moves out of the growth extension leaving mutliple compacted layers of cell membrane called myelin; myelinates and insulates CNS axons, allows faster AP propagation along axon in CNS (myelin sheath electrically insulates axon and facilitates rapid transmission of nerve impulses)
Schwann Cell (Neurolemmocyte)
PNS glial cell; surround and insulate PNS axons and myelinate those having large diameters, allows faster AP propagation along axon in PNS
Schwann cells become aligned along axon and extend a wide cytoplasmic process to encircle it–> the spiral wrapping becomes compacted layers of cell membrane (myelin) as cytoplasm leaves the growing process
Gray vs White matter
Within brain and spinal cord, regions with tracts of myelinated axons compromise white matter while regions rich in neuronal perikarya (cell body of neuron with nucleus) and astrocytes compromise gray matter
Cell membrane
phospholipid bilayer; amphipathic
palmitate (16, saturated) and oleate (18,cis unsaturated)
unusual cell membrane
Archael bacteria (proks with no nucleus) have lipids with ether bonds instead of esters (bacteria/eukarya); opposite stereochemistry, branched chains
Biological membranes need to be fluid to allow proteins to move around and to respond to external deformations and damage. Likewise, they need to be impermeable to protons and other charged ions, to allow formation of EC gradient that powers life [lipids in our cells have these properties but only in a narrow range of temp]
Archael lipids form membranes with these properties over a wide range of temp. from freezing cold to boiling hot
selectively permeable membrane
size and charge affect the rate of diffusion: hydrophobic molecules (CO2, O2, N2)> small, uncharged polar molecules (H20, indole, glycerol)>large uncharged polar molecules (glucose, sucrose; can’t passively diffuse)> ions (lowest permeability, cant passively diffuse)
Different Membrane Proteins
Integral membrane proteins (embedded within; can’t be easily removed from bilayer without using harsh detergents that destroy it, float freely in bilayer; usually transmembrane- amphipathic)
associated membrane proteins (not directly attached; change in pH, chelating agent, urea, carbonate)
(GPI) anchor membrane proteins (phospholipase C cuts and get protein glycan)
peripheral (amphitropic) membrane proteins (easily separated from bilayer without harming it, less mobile within; biological regulation removes)
Each type of membrane has characteristic (dif composition/ concentration) lipids and proteins; and organelles also have them
Fluid Mosaic Model
Two-dimensional liquid in which phospholipid and protein molecules diffuse easily. The original model has been updated to account for membrane domains that restrict the lateral diffusion of membrane components (have special lipids and protein composition- lipid rafts; important for cell-cell signaling, apoptosis, cell division, membrane budding, and cell fusion)
Asymmetric Distribution of phospholipids in plasma membranes
lipids are associated differently from inside/outside; some cells on outside have more sphingomyelin receptors; signal transduction on inside
Distribution of Lipids in a typical cell
Golgi has different composition than trans goli network than transport vesicle (this one matches plasma membrane)
Transbilayer deposition of glycophorin (membrane spanning protein that carries sugar molecules ) in a RBC
N terminus outside and C terminus inside (most common?)
Integral proteins
Type 1 (carboxy in, amino out) Type 2 (amino in, carboxy out) Type 3 Type 5- transmembrane receptor/like a channel protein Type 7- single transmembrane
Lipid linked membrane proteins
different FA that attach them ex. GPI anchor on C terminus
Membrane Dynamics
2 extremes of lipid bilayer: liquid ordered state and liquid disorder state (heat produces thermal motion of side chains)
saturated need more energy to melt (increase melting point= S–>L) as well as longer length [dictate how membrane behave- fluidity]
In order to survive in low temp, need more oleic acid (18:1) than palmitric acid (16:0) to keep membrane fluid
Transbilayer movements require catalysis
Uncatalyzed transbilayer (flip flop diffusion)- very slow
Uncatalyzed lateral diffusion (very fast)
Catalyzed transbilayer translocation (ATP)- Flippase (p type ATPase, moves Pe and Ps from outer to cytosolic leaflet), Floppase(ABC transporter, moves phospholipid from cytosolic to outer leaflet)
Scramblase (moves lipids in either direction, toward equilibrium)
Movement of Proteins across membrane
plasma membrane is supported by cytoskeleton- assembly/disassembly during fusion
React cell with fluorescent probe to label lipids–> intense laser beam bleaches small area –>with time unbleached phospholipid diffuses into bleached area which shows lipids move in membrane
Membrane Microdomains
Lipid rafts are specialized membrane microdomains that compartmentalize cellular processes by serving as organizing centers for the assembly of signaling molecules, influencing membrane fluidity, and membrane protein trafficking, and regulating NT and receptor trafficking
Caveolins are a family of integral membrane proteins that are principal components of caveolar membranes and involved in receptor independent endocytosis. Act as a scaffolding (support) protein within caveolar membrane by compartmentalizing and concentrating signaling molecules; various classes of signaling molecules, including G- protein subunits, receptor and nonreceptor tyrosine kinases, endothelial nitric oxide synthase and small GTPases, bind Cav-1 through its ‘Caveolin scaffolding domain’
Solute Transport Across the Membrane
Simple Diffusion-nonpolar compounds only, down concentration gradient (passive)
Facilitated Diffusion- down EC gradient (passive)
Primary active transport- against EC gradient diven by ATP ex. Na/K ATPase
Secondary active transport- against EC, driven by ions moving down its gradient
Ion channel- down EC gradient, may be gated by ligand or ion (passive)
Ionphore- mediated ion transport down EC gradient
Simple diffusion without transporter requires more free energy than diffusion with transporter
CO2 in respiring tissues
CO2 produced by catabolism enters RBC–> Bicarbonate dissolves in blood plasma through chloride (goes in)- bicarbonate exchange (goes out)
CO2+ H20–> HCO3- H+ Cl- (carbonic anhydrase)
CO2 in respiring lungs
Bicarbonate enters RBC from blood plasma through
chloride (goes out)- bicarbonate exchange (goes in)–> CO2 leaves RBC and is exhaled
HCO3- H+ Cl- –>CO2+ H20 (carbonic anhydrase)
Types of transporters
Uniport
Cotransporters (Symport [same direction] or antiport [opposite direction])
ex. On apical membrane (facing intestinal lumen) have microvilli with 2 Na/1 Glucose symporter (drivent by high extracellular Na
On basal surface (facing blood) have 3Na (out)/ 2K (in) ATPase antiport AND have Glucose uniporter GLUT 2 (facilitates downhill efflux)
Membrane Fusion Events
Budding of vesicles from Golgi, exocytosis, endocytosis, fusion of endosome and lysosome, viral infection, fusion of sperm and egg, fusion of small vacuoles (plants), separation of 2 plasma membranes at cell division
Nervous System Overview
CNS (brain and spinal cord)
PNS (Cranial nerves and spinal nerves)–> somatic (voluntary; conscious) OR ANS (involuntary, subconscious)–> Sympathetic/ Parasympathetic
Neuron cell bodies receive input from dendrites, they send info via axons to other neurons or to target organs, axons degenerate due to damage and injury but can regenerate in the periphery, cell bodies last to die in injury and disease and rarely replaced in CNS
Spinal Cord Function
Relays info to and from brain, has local circuits (reflexes) and preserves segmental body plan (trunk/abdomen)
Spinal Cord Location
rostral extent- emerges from foramen magnum (hole in base of skull through which spinal cord passes)
caudal extent- ends between L1 and L2 vertebrae
In the developing fetus, L5 spinal cord and L5 nerve root location different because vertebral elements grow faster and further than spinal cord and nerve is dragged down with it (intervertebral foramen) - L5 spinal cord level is ABOVE L5 vertebrae, specifically around T12 /L1 level; cauda equina is around L5 vertebrae/nerve root
Vertebrae
Segmental organization of the vertebral column, vertebrae protect the spinal cord and support the body, spinal nerves emerge directly below their corresponding vertebrae, with one exception (don’t worry about coccygeal vertebrae)
C1-7 (transverse foramen), T1-12 (costal facets, spinous process protrudes down), L1-5 (huge body), S1-5 (all fused)
Spinal Cord Organization
segmental organization
7 cervical vertebrae, 8 cervical spinal levels, 8 spinal nerves; first spinal nerve emerges above C1 vertebrae, C8 nerve emerges below C7
12 thoracic vertebrae, spinal levels, and thoracic spinal nerves (nerve always emerges below vertebrae) [spinal cord located between T1 and T11 vertebrae)
5 lumbar vertebrae, spinal levels, spinal nerves (nerve always emerges below vertebrae) [spinal cord located between T11 and L1 vertebrae) Different growth IS NOW APPARENT
5 fused Sacral vertebrae, spinal levels, Spinal nerves (nerve always emerges below vertebrae) [spinal cord is located between L1 and L2 vertebrae]
Meninges- 3 CT layers
Dura mater (outermost layer, under bone, dense/tough)
Archanoid mater(middle layer, has blood vessels going through, thin; has subarchanoid space which holds CSF)
Pia mater- dentate ligaments (help spinals to sides)
Gray matter
Has cell bodies
Dorsal horn (sensory neurons- somatic and visceral; secondary sensory neurons)
Lateral horn (motor neurons- visceral)
Ventral horn (motor neurons- somatic)
- Thoracic grey matter smaller (not as many neurons in this region because not alot of motor action in trunk; cervical and lumbosacral enlargement)
- The colors are reversed on schematic (many stains coat myelin, so white matter is often darker in stained sections)
- There is a lot more white matter in the cervical regions (more axons close to CNS ; as get closer to brain, more traffic)
White matter
myelinated axons; ascending neuronal axons (pain, temp, touch) and descending neuronal axons (pathways for muscle)
Pathway for sensory info from each segmental level to brain, motor information from brain to segmental levels
Spinal Nerves
Roots- dorsal (has ganglia) and ventral
Trunk- very short
Rami- Dorsal and ventral
Roots
One way streets
Sensory (dorsal) info towards the spinal cord [AFFERENT]
Motor (ventral) info towards the periphery [EFFERENT]
**Dorsal root ganglia helps with orientation
Trunk and Rami
2 way traffic
Rami- sensory and motor info
Dorsal rami- shorter one, serve DEEP back muscles and skin on back
Ventral rami- serve body wall and limbs
- cervical plexus (neck/head)
- brachial plexus (shoulder/upper limbs)
- intercostals (easy, segmental body plan, serves trunk)
- lumbar and sacral plexi (groin and lower limbs)
Dermatomes
regions of skin that correspond to a given spinal cord level (sensory)
C2-occipital proterbance C4-collar [spinal cord/nerve level around collar] C5- shoulder C6- thumb C7- middle finger C8- pinky T1- medial elbow [spinal cord/nerve level around first rib] T4-nipple (teat pore) T7-xiphoid process T10- umbilicus (belly button)
Myotomes
Muscles that correspond to a given spinal cord level (movements)
C5-shoulder abduction
C6- elbow flexion, wrist extension
C7- elbow extension
Autonomic Nervous System
Sympathetic: fight or flight (smooth muscle of vessels)
Parasympathetic: rest and digest (smooth muscle of digestive system/ visceral organs)
ANS 2 neuron pathway
CNS [preganglionic neuron]–> autonomic ganglion [post ganglionic neuron]–> target organ
Basis for both S/PS
Preganglionic Sympathetics
ORIGINATE: T1-L2 spinal cord levels
Preganglionic sympathetics- sympathetic innervation of pupil, heart, bronchial tree, hepatic artery, adrenal medulla, genitals, or sweat glands
Preganglionic Parasympathetic
ORIGINATE: Brainstem (cranial nerves 3, 7, 9, 10) or S2-4 spinal cord levels
Preganglionic parasympathetics- parasympathetic innervation of the pupil, heart, bronchial tree, stomach, genitals, or bladder
Brainstem- everything except what S2-4 levels innervate
S2-4- hindgut (descending colon to anus), pelvic organs and perinuem
Post ganglionic neurons embryo story
X section through developing embryo: neural tube, neural crest cells [face; other tissues, BECOME PERIPHERAL NERVE GANGLIA in PNS], somites [muscles], notochord (intervertebral disc, vertebrae body) Dorsal aorta, IVC, gut tube
Neural Crest Cells
BECOME PERIPHERAL NERVE GANGLIA in PNS
1. Dorsal root ganglia (sensory neurons- somatic and visceral)
NC cell migration
2. In front of notochord
SYMPATHETIC CHAIN with sympathetic ganglia
(Paravertebral ganglia) ; postganglionic sympathetic neurons ; Blood vessels or sweat glands
NC cell migration
3. In front of aorta
PREAORTIC GANGLIA (prevertebral ganglia); postganglionic sympathetic neurons;
NC cell migration
4. Into the viscera
INTRAMURAL GANGLIA
postganglionic parasympathetic neurons; embedded in tissues/target organs
Sympathetic pathways
Sympathetic ganglion, sympathetic internodal fiber, sympathetic chain,
white ramus communicans (PREGANGLIONIC SYMPATHETICS TRAVELING THE SPINAL CORD AND THE CHAIN),
grey ramus communicans (PRE AND POSTGANGLIONIC SYMPATHETICS TRAVELING TO THE PERIPHERY),
splanchnic nerve (PREGANGLIONIC SYMPATHETICS TRAVELING TO PREAORTIC GANGLIA, INNERVATES GI TRACT)
preaortic ganglion
GO TO APPROPRIATE LEVEL TO SYNAPSE
Connective Tissue
Loose CT, Dense CT (regular, irregular), Cartilage (hyaline, fibrocartilage, elastic) bone, blood
Cartilage
Composed of cells (CHONDROCYTES) embedded in jelly-like matrix of ground substance containing various fibrous molecules
STRUCTURALLY DESIGNED TO : withstand tension/compression, provides low friction surface at joints, provide support for soft tissue, provide a framework for long bone osteogenesis (during development)
skeleton initially made of cartilage/fibrous membrane- mostly replaced by bone
- chondroblasts produce new collagen matrix until skeleton stops growing; the few cartilages that remain in adults are found mainly in regions where FLEXIBLE CT is needed
DIFFER FROM BONE:
More flexible, avascular (less blood supply, thus heals very slowly), less organized structure, no nerve fibers, composed of up to 80% water
Nutrients come via diffusion through PERICHONDRIUM
(FIBROUS CT SHEATH; surrounds cartilage and acts like a girdle to resist outward expansion when compressed and CONTAINS: Type 1 collagen (denser, provides structural strength), vascular supply to cartilage, chondrogenic cells (capable of differentiating into chondroblasts [immature] and chondrocytes [mature), not present in all types of cartilage
Cartilage of the human skeleton
- Hyaline 2. Fibrous 3. Elastic
Have same basic structure but differ in cell distribution and/or number, and the type of fibers in the matrix
Components of Cartilage
CELLS (Immature are chondroblasts which secrete ground substance matrix/fibers and mature are chondrocytes which are less active and enclosed in lacunae)
FIBERS (provide structural support ex:
- Collagen: strongest (even than steel), thin fibers:Hyaline (finer Type 2 only) , thick fibers:fibrocartilage (Type 1 & 2)
- Elastic: gives tissue elasticity ex: elastic c.(elastic fibers + Type 2)
GROUND SUBSTANCE: gel like interstitial fluid filling the space between cells; composed of water, glycosaminoglycans, proteoglycans [aggregates of CHONDROITIN SULFATE +hyaluronic acid] , and glycoproteins; The tightly packed and highly charged proteoglycan sulfate groups generate electrostatic repulsion that provides much of the resistance to compression. loss of chondroitin sulfate in cartilage is a major cause of OSTEOARTHRITIS
Proteoglycan Repulsion
Cartilage is composed of cross linked type II collagen fibers bond to proteoglycan aggregates made up of chondroitin sulfate (forming glycosaminoglycan molecules) linked to hyaluronic acid
Proteoglycan consists of a protein core with one or more negatively charged covalently attached glycosaminoglycan chains
PROTEOGLYCAN REPULSIONS OCCURS BETWEEN ADJACENT NEGATIVELY FIXED CHARGES OF ADJACENT GLYCOSAMINOGLYCAN MOLECULES
Hyaline Cartilage ***
MOST widespread type of collagen, ABSORBS mild compression, provides SUPPORT, FLEXIBILITY & RESILIENCE. WEAKEST of the 3, resembles frosted glass;
COMPOSITION: has perichondrium, spherical chondrocytes, Type 2 collagen fibers, and no nerves or blood vessels
LOCATION: Articular cartilages (end of most long bones at movable joints), costal cartilages (rib to sternum connection), respiratory cartilages (skeleton of larynx, reinforce respiratory passageway and tracheal rings), and nasal cartilages (support external nose)
In embryo, bone begins as hyaline- ossification occurs as chondroblasts die and replaced by osteoblasts clustered in OSSIFICATION CENTERS. bone formation proceeds from these centers
Fibrocartilage **
STRONGEST; alternating parallel layers, matrix has ROWS OF CHONDROCYTES, THICK COLLAGEN FIBERS oriented in direction of functional stress
only type that has BOTH Type 1 & 2 collagen fibers (more fibers, fewer cells than others); only type that LACKS perichondrium (SLOWEST to heal)
HIGHLY COMPRESSIBLE- great tensile strength, able to withstand high pressure and high stretch sites
LOCATION: menisci of knee, intervertebral disc, pubic symphysis
Elastic Cartilage **
resembles hyaline but MORE SPRINGY (intermediate), able to stand up to repeated bending
Has PERICHONDRIUM, chondrocytes are in a threadlike network of ELASTIC FIBERS and Type 2 collagen fibers within the matrix (provides strength, elasticity, and maintains shape)
LOCATION: external ear, epiglottis (covers larynx during swallowing)
Axial vs Appendicular
Axial- the central axis- skull, ribs, vertebral column, sternum
Appendicular- limbs and girdles (pelvic and pectoral)
Functions of Bone **
SUPPORT (structural framework for body, attachment for muscles) PROTECTION (of internal organs) ASSISTING MOVEMENT (musculoskeletal system) MINERAL HOMEOSTASIS (store of Ca and Pi) BLOOD CELL PRODUCTION (hematopoesis in bone marrow)
Bone vs Cartilage
Both have living cells which occupy lacunae
- Bone (osteocytes) cartilage (chondrocytes)
Both have fibrous CT covering
-bone (periosteum) cartilage(perichondrium)
Bone is HIGH VASCULARIZED unlike cartilage
Bone intracellular matrix has MORE COLLAGEN than cartilage (greater tensile strength, more than steel) heavily MINERALIZED with Ca salts, osteocytes UNABLE DIVIDE hence all bone growth is by APPOSITION (deposition of bone on preexisting surfaces)
Adult bone structure **
All adult bone is composed of LAMELLAE (layers of mineralized bone matrix that make up mature bone)
they are arranged to for 2 structures:
- COMPACT (cortical) bone- makes outer layer of most bones (regular pattern) ~80% of bone in body
-TRABECULAR (spongy) bone- inside compact (irregular pattern) ~20% of bone in body
Lamellae make osteon with central (Haversian canal) and canaliculi are channels that link lacunae
Protein in bone matrix is over 90% type I collagen, which is also major structural protein in tendons and skin (weight by weight as strong as steel)
Bone remodeling **
Throughout life bone is constantly being turned, resorbed, and new bone formed
REMODELING STAGES:
- bone resorption (breakdown) by osteoclasts (erode and absorb bone)
- bone formation b osteoblasts (modified fibroblasts that lay Type i collagen and form new bone matrix (osteoid) at or near where osteoclasts resorbed it
Osteocytes are mature bone cells (from osteoblasts maturing and being surrounded by bone matrix)
Osteoclasts
Multinucleated cells; Attach to bone via integrins at isolated areas called SEALING ZONES; H dependent ATPases then move from endosomes and acidify the compartment to ~pH 4; the acidic pH dissolves HYDROXYAPATITE and collagen, forming a shallow depression in bone (release of Ca/Pi in blood); the digested products are endocytosed and move across osteoclast by transcytosis, with release into interstitial fluid
Hormonal Regulation of Remodeling
Parathyroid hormone (PTH) and 1,25 (OH)2 VIt D (activated form) both promote healthy remodeling and maintain bone homeostasis
Direct effects on osteoblasts and osteoclasts (rapid)
indirect effect on osteoid accumulation on osteoclasts is slower (stimulate expression of RANK ligand receptor to activate osteoclasts)
Ca and Phosphate Homeostasis Importance **
Homeostasis is a property of an organism or system to maintain its parameters within a normal range of values
Ca is a vital 2nd messenger needed for blood coagulation, muscle contraction and nerve function (if too low- cardiac condition- hypocalcemic tentany)
Phosphate homeostasis is also critical to normal body function: part of ATP, biological buffer, protein regulation via phosphorylation and dephosphorylation
Bone Ca Homeostasis**
Humans contain~ 1100 g (27.5 mol) of Ca about which 99% is stored in bones
Bone is available from 2 reservoir: bone and ECG or glomerular filtrate?
Vast majority of bone Ca is in a stable reservoir that only slowly exchanges with the ECF (accretion/ reabsorbtion)
Phosphorous Homeostasis
Bone contains 85% of the total body phosphorus
The kidney is the main regulator of the human phosphate homeostasis
Hormones that regulate Ca Homeostasis **
PARATHYROID HORMONE (PTH)- secreted by CHIEF CELLS of the PARATHYROID GLANDS- mobilize Ca from bone, increases urinary phosphate excretion
1,25 DIHYDROXYCHOLECALCIFEROL is a steroid hormone formed from VIT D IN SKIN (SUN) and successive hydroxylation in the LIVER AND KIDNEYS- INCREASES Ca absorption from the intestine, INCREASES Ca in bone
CALCITONIN, a Ca lowering hormone secreted by the PARAFOLLICULAR CELLS (C- cells) in the THYROID GLAND- inhibits bone resportion (chewing up of bone by osteoclasts)
Hormonal regulation of Ca Homeostasis
PTH and Calcitonin interact to maintain Ca levels within a narrow range:
PTH increases blood levels of Ca when plasma levels are too low
Calcitonin decreases blood levels of Ca when plasma levels get too high
Regulatory feedback between Vit D and PTH: PTH helps activate Vit D to 1,25 dihydroxycholecalciferol in kidney which can then downregulate PTH release
When Ca is TOO HIGH in plasma, Calcitonin is secreted from parafollicular cells of thyroid to inhibit Ca resorption from bone (inhibits osteoclastic break up)
When Ca decreases in the blood, PTH is secreted by parathyroid and stimulates Ca release from bone into blood, Ca reabsorption in kidney, and activation of Vit D, which further increases Ca reuptake in the intestine, to turn off PTH
Sources of VIt D
Vit D is a group of closely related sterols produced by the action of UV from the sun on certain provitamins
Can be found in small amounts in fatty fish (herring, mackerel, sardines, and tuna) added to dairy products, juices and cereals
Most vit D (~90% of what body gets) is obtained through exposure to sunlight
1,25 DIHYDROXYCHOLECALCIFEROL aka Calcitriol ACTIVE FORM
PTH Effects
Increases bone resorption (chewing of bone) and mobilizes Ca to plasma
Increases reabsorption of Ca in the kidney and phosphate excretion in the urine (increasing plasma Ca while lowering plasma phosphate levels; PTH strongly inhibits the transporter mediated reabsorption of Pi in the proximal tubules of kidney)
Increases plasma 1,25 dihydroxycholecalciferol levels, which in turn increases gut Ca absorption. ( Calcitriol [activated vit D] then feedback inhibits PTH release)
Calcitonin
Secreted by PARAFOLLICULAR CELLS OF THE THYROID
G protein coupled receptors for calcitonin are found in both bones (on osteoclasts) and in the kidneys.
Calcitonin LOWERS Ca levels (opposing effects of PTH): Inhibits Ca absorption in intestines, inhibits osteoclast activity in bones, stimulates osteoblastic activity in bones, inhibits renal tubular cell reabsorption of Ca allowing it to be excreted in the urine
May be used therapeutically for treatment of hypercalcemia or osteoporosis (anti- resorptive meds) thus lowering risk of breaking bones
Other hormones that impact Ca metabolism
GLUCOCORTICOIDS (steriods like prednisone)- weaken bones/lower plasma Ca levels by inhibiting osteoclast formation and activity
GROWTH HORMONE- increases Ca excretion in the urine, but also increases intestinal absorption of Ca, and this effect may be greater than the effect on excretion, with a resultant positive Ca balance (indirectly stimulates protein synthesis in bone)
ESTROGEN- prevents osteoporosis by inhibiting the stimulatory effects of cytokines on osteoclasts. Also prevents osteoblast apoptosis by blocking osteoblast’s synthesis of interleukin 6 and antagonizing the interleukin 6 receptors.
INSULIN- increases bone formation, and there is significant bone loss in untreated diabetes.
Bone disease **
Rickets (kids) or Osteomalacia (adults)-Defective bone matrix calcification due to Vit D and/or Ca deficiency
In children this results in weakness and bowing of weight-bearing bones, dental defects and hypocalcemia.
In adults, symptoms include muscle weakness and achy bone pain. (Enamel hypoplasia and incomplete mineralization of teeth on dental exam)
Treatment for osteomalacia involves replenishing low levels of vitamin D and calcium and treating any underlying disorders that may be causing the deficiencies.
Osteopetrosis- Osteoclasts are defective and unable to resorb bone so osteoblasts operate unopposed
Bone density increases and growth becomes distorted (bulbous) with few foramina for nerves to pass through
Osteoperosis- Relative excess of osteoclast function results in loss of bone matrix and high risk of bone fractures
Involutional osteoporosis- as age increases, bone loss increases. Increased dietary intake of Ca and exercise may slow progression
Treatment: Bisphosphonate (alendronate or Fosamax) inhibit osteoclasts, preventing resorbtion and increasing mineral content of bone
Bisphosphonate Therapy
For osteopetrosis
Bisphosphonate Therapy Associated Osteonecrosis of Jaw (ONJ)- disfiguring jaw condition that includes serious infection and osteopetrosis, an abnormal build up of fragile bone.
Preventative Care Prior to bisphosphonate initiation:
Patients already receiving bisphosphonates should:
Electrical Signaling
Benefits: Covers long distances with minimal loss of signal, rapid, quickly repeated, information can be conveyed in patterns
Limitations: Binary (all or none), difficulty to modify, energy intensive ( a lot of movement of ions/ concentration gradients), microenvironment dependent
Resting Membrane Potential **
The potential energy in the electrical gradient formed across the plasma membrane
Basis for neuron electrical activity
Formed by opposition between concentration (move out) electrical gradients (move in)
Separation of charge across the membrane (-) internal membrane (+) external membrane
caused by: 1. formation of a K concentration gradient (high inside cell and low outside cell) 2. Permeability of the membrane to K (forms an electrical gradient by moving out, negative charge inside and positive charge outside)
Presence of different ions increase/decrease the resting membrane potential
Necessary for the AP to occur
Ohm’s Law
V=IR
V=voltage= potential difference between 2 points [plasma membrane- capacitor]
I= Current= flow of electrical energy between 2 points
R= Resistance- opposition to the flow of electrical energy [ex. ion channels]
we create electrical energy by slow movement of K and separates pos. and neg. charge; potential can be changed
Diffusion drives EC equilibrium
When the concentration and electrical gradients for an ion are in balance
When concentrations are equal, no net flux of K, no potential energy in system
When concentration on inside is increased, Net flow of K from inside to outside
At electrochemical equilibrium, there is not an electrical potential separation of charge; Flux of K from inside to outside is balanced by the opposing membrane potential V=-58mV
Ion transporters and channels maintain resting membrane potential
active transporters- actively move selected ions against concentration gradient, create ion concentration gradients Ex Na/K ATPase- establishes Na and K gradients across neuron membrane (uses ATP) moves Na out of neuron and K in, moving against concentration gradients
Ion channels- allow ions to diffuse down their concentration gradient; are selectively permeable to certain ions ex. K, Na, Ca, Cl channels; open and close due to different stimuli
The Neuron Membrane at Rest
Interior of neuron is negatively charged, the separation and slow flow of K ions across the plasma membrane creates membrane potential (more neg. inside and more pos, ions outside) , Na/K ATPase activity maintains electrochemical gradients, other ions influence membrane potential
Membrane potentials allow neurons electrical activity; separation of ions needed to have an energy store (charge buildup)
Nernst Equation
Calculate Membrane potential; equilibrium potential of an individual ion
Goldman Equation
Calculate membrane potential; equilibrium potential of the entire plasma membrane
The Neuron Passive Electrical State
Cytoplasm is electrically resistant; Neurons electrically inert at rest, passive current rapidly decays over space and time, active current flow allows neuron electrical information transfer
Passive Current Flow
Current decays, cytoplasmic resistance (to the ions), relative to distance
Actually occurs: axons without channels and cell bodies
Active Current Flow
Current constant over time, current repropagated, active process, relative to distance
Actually occurs: axons
The Action Potential Overview
Rapid change in membrane potential (from negative to positive, then back to negative), caused by the sequential opening of Na and K channels in a voltage and time dependent manner; requires Na (high outside) and K (high inside) gradients This is the electrical event that carries information throughout neurons and the nervous system
Ion Channels create dynamic potentials
Passive movement along concentration gradients
- Leakage- small tunnel/pores; establish resting membrane potential; constant ion flow along a gradient
- Voltage gated- respond to changes in membrane potential (allow AP to occur)
- Ligand Gated- Respond to ligand binding (create a conformational change in channel structure and opens so ions can move) ex. Neurotransmitters, proteins, ions, lipids
- Physically Gated- Respond to other physical stimuli(moving or stretching of membrane) Mechanical, temperature, light
Transporters create dynamic potentials
Active movement of ions and proteins against concentration gradients
- ATPase Pumps- use ATP to move one or more substrates
- Ion Exchangers- Energy from moving one or more ion(s) along a concentration gradient moves other ion(s) against a gradient, opposite ion direction
- Co- transporters- One or more ions moves another ion (one aong and one against), same direction
- Multiple Transporter Systems- multiple transporters working together to move a substrate
Voltage Gated Ion Channel
Physical conformation changes with membrane polarization; time and charge dependent, ions move along their gradients, passive, refractory period (channel closed and can’t open again until changes conformational state)
ex. voltage gated K channel- as internal membrane becomes more pos. changes conformational structure of transporter and allows flow of K
Ligand Gated Ion Channel
Ligand binding changes the conformation to allow ion movement; diversity of ligand (neurotransmitter, ions, proteins, intracellular signaling proteins, lipids) ions move along concentration gradients, passive, open in presence of sufficient ligand and appropriate environmental state
Na/K ATPase pumps
- Na binding inside of cell 2. Phosphorylation 3. Conformational change causes Na release and K binding outside of cell 4. Dephosphorylation- induced conformational change leads to K release into cell
The action potential **
NEGATIVE RESTING POTENTIAL
potential changes and once reaches threshold–> depolarization (from negative to very positive) then reverts itself (positive –> more negative than originally) –> goes back to original negative
ex. electrical activity changes state of presynaptic neuron–> release of NT–> carry info to target
- Resting Phase (a lot of K in, and a lot of Na out) K moving toward electrochemical equilibrium through LEAKAGE K CHANNELS
- Activation Phase (stimulus induced (gated) Na channels open and flow into cell which is negative)
3 Rising Phase- more Na in and hit threshold potential–> voltage gated ion channels open and massive amount of Na flows in (external becomes negative and internal positive) [OVERSHOOT} K voltage gated channels begin to open - Falling Phase- Voltage gated Na channels close and Voltage gated K channels open (moving along concentration gradient) leave negative inside, K moves toward equilibrium potential (leakage also still open)
- Undershoot phase- Refractory period where voltage gated Na channels can’t open and where K voltage gated K channels close [can’t have another AP]
- Recovery Phase- Na/K ATPase re-establishes membrane potential and Leak K Channels help re-establish resting potential
AP vary across Species
Same general shape, but vary in size, width etc.
AP are initiated at axon hillock (trigger zone)
Where the axon meets the cell body; Na voltage gated channel dense region, relatively low membrane threshold, postsynaptic membrane potentials are summated
AP in cell body are passive–> currents get added up (if pass threshold, create AP)
Axonal Conduction of an AP
Anterograde (toward presynaptic terminal); undirection
Increasing AP Conductance
- Increase Axon Caliber
- reduce internal resistance, energy intensive, physically restrictive - Insulate axon- prevent current leakage, requires glial support, oligodendrocytes (CNS) and Schwann cells (PNS)
Saltatory Conduction speeds AP velocity
due to myelination; electrical signal moves rapidly by jumping between myelination; Node of Ranvier (concentration of Na channels)
unmyelinated= 0.5-10m/s myelinated= 150 m/s
demyelination- causes MS, stress, oxidative stress, neurons not set up to deal with energy expenditure, and slower signal
Neurons Communicate at Synapses to form networks
connect to target tissue; AP must be converted to a chemical signal (Nt or neuropeptide)
NS collects info–> sends to CNS–> processing, execution –> AP–> chemical signal at synapse
Chemical Synapse Structure
Axon, synaptic vesicle pool, Active zone, in presynaptic terminal–> synapse–> postsynaptic terminal
benefit of not being continuous: point where you can modify signal
Neurotransmitter
Small molecules
- aa or derivatives, synthesized in the presynaptic terminal, stored in small (clear) synaptic vesicles ( ~40-60nm in size ), released from the presynaptic terminal; cross synapse
ex. Glutamate (primary excitatory NS), GABA (primary inhibitor NS), ACh (sympathetic NS), Serotonin, Glycine, Norepi, Dopamine, Histamine, Epi
neuropeptides
- proteins (or small peptide chains), synthesized in the cell body, stored in large (dense core) vesicles ~80-150nm in size; released both pre- and post-synaptically, can be released into extracellular environment (affect multiple cells)
Synaptic Transmission Overview **
- AP
- Ca2+ depolarization
- Ca2+ influx (messenger)
- Synaptic vesicle fusion
- NT release into synaptic cleft
- NT receptor activation (post and presynaptically)
- NT reuptake (by adjacent glial cells or neurons)
- NT sequestration (put back into synaptic vesicle)/ metabolism (broken up)
AP cause presynpatic Ca Influx
AP depolarize the presynaptic membrane (becomes positive), Voltage gated Ca channels open, increase intracellular Ca drives vesicle release
In absence of AP, voltage gated channels can be opened by ligand
Synaptic Vesicle Resides in 3 Distinct pools
- Readily releasable pool 2. Recycling pool 3. Reserve pool
Classic model- physical segregation into 3 different pools; active zone (dense in proteins that will pull vesicles to membrane) as pools depleted, reservoir pool
Current model- some vesicles free to move and others are not; set of stages of release as above so we don’t run out
Every neuron in our body is constantly firing at some degree using it in different ways
SNARE Complex Proteins allow vesicle release
Synpatic vesicles can tether to SNARE, SNAP 25 binds to both Syntaxin on presynaptic plasma membrane and Synaptobrevin on synaptic vesicle membrane
Botox causes change- cleaves SNARE proteins
Neurotransmitter Release **
- vesicle docks
- SNARE Complexes form to pull membrane together (Synaptobrevin, Syntaxin, SNAP 25)
- Entering Ca2+ binds to synaptotagmin
- Ca2+ bound synaptotagmin catalyzes membrane fusion by binding to SNAREs and the plasma membrane
- release of NT
Models of Membrane Reuptake and Vesicle Reformation
Membrane needs to be pulled off to retain size
Classic Synaptic Vesicle Cycle: Endosome–> budding–> Docking–> priming–> fusion (Ca- 1 ms)–> exocytosis (1 min)–> endocytosis (10-20s)–> budding–> endosome
Ultrafast Synaptic Vesicle Cycle [more likely]has to cycle or won't work Ultrafast endocytosis (100ms)--> large endocytic vesicle--> synaptic endosome (1 s) --> clathrin coat (3 s)--> synaptic vesicles (5s)--> exocytosis
Neurotransmitter Receptor Type
Ionotropic (ligand gated ion channels)
Metabotropic (G protein coupled receptor) can affect ionic conduction not just moving ion
Ionotropic NT receptor
ligand binding opens ion channel, variable selectively for ions, not necessarily unidirectional, directly involved in creating post synaptic electrical current and changing membrane potential, excitatory (depolarizing- Na) or inhibitory (hyperpolarizing (Cl)
FAST (ms)
Metabotropic NT Receptor
G protein coupled intracellular signals, relatively slow activation time (s), prolonged signal duration, signals modify the activity of ionotropic receptors, ion channels and transporters; signals alter terminal structure and function
NT receptor change postsynpatic membrane potential
Excitatory Postsynaptic Potential (EPSP)- Depolarization of the postsynaptic membrane through its own cell body ex. Na, Ca
Inhibitory Postsynaptic potential (IPSP)- Hyperpolarization of postsynaptic membrane
ex. influx of Cl, efflux of K
Location influences Synaptic Input strength
Synapse Location matters; membrane potentials decay, proximity to the trigger zone dictates the relative influence of a synaptic input, decay over space/time
Postsynaptic Potential Summation
Summation- the total change in membrane potential based on the spatial (location) and temporal (frequency) aggregation of postsynaptic potentials
Sufficient depolarization triggers an AP, axon hillock
signals are summed; pass threshold–> AP (axon)–> second neuron
Inhibitory signal can play a role (subtracted)–> smaller signal that prevent firing to reach axon hillock
Neurons create complex networks
Neurons organize complex networks and form discrete structures; networks are established early in life, information processing is dictated by network connectivity, brain structure have vast, but specific connectivity, Within structural confines, networks are highly plastic (malleable- can be shaped, changed) throughout life
Cerebral cortex is a large network that gives rise to discrete brain structures that perform function but ALL connected to each other; conductivity is pretty conserved (connections) but broad range of variability in plasticity
Networks acquire information, process information and execute behaviors
Afferent (internal and external environment)–> sensory receptors, sensory ganglia and nerves –> Brain (analysis and integration of sensory and motor information)–> Visceral (autonomic ganglia and nerves) and Somatic motor systems (motor nerves) –> effectors
Neuronal Networks map external and internal environments in the brain **
All senses are mapped to discrete regions of the cortex (ex. somatosensory cortex), emotional and abstract (short term memory, emotions, thoughts) states are mapped in deep brain areas, maps are overlaid and compared in association cortices
Senses are segregated but are dependent and interact with each other which leads to decision making and behaviors
Simple Networks can perform simple behaviors **
Spinal reflexes- sensory and motor loops that function independent of descending brain control
NS is not a summation of reflexes;
descending control (brain has a lot of impact on how these reflexes occur- modified in context of environment);
measure of network health and connectivity (if damage, will not see these reflexes)
Many oral reflexes ex gag reflex
Reflex protect muscles and prevent excessive pulling; can induce this
Hebbian Theory
Networks change
Neuronal networks undergo activity-dependent plasticity throughout life
Activity drives neural network consolidation, while inactivity leads to decay
Synapse pruning occurs during development (also adult pruning- selecting only important connections- critical period)
Long term potentiation (increase) (LTP) and Long term depression (decrease) (LTD) occur during adulthood: strengthening of connections, number of connections, In depression, inefficiency in info transfer, reduction in connection, higher threshold needed to be passed within network to be passed on to target
Changes at Synaptic Terminals drive neuronal plasticity
The NS is constantly changing in response to activity and inactivity- whatever you spend your time doing, you will get better at
Increased/decreased synaptic vesicle release, increased/decreased receptor density, changes in receptor sensitivity and conductance, changes in receptor subtype expression, sprouting of new synapses, formation of new connections
ex. muscle memory
Touch: The basic somatosensory circuit **
3 neurons communicate peripheral sensation to the brain:
1st order: mechanosensory neuron –> brainstem (medulla)
2nd order: Brainstem (medulla) –> thalamus (distribution center of brain) [DECUSSATE- cross the midline at the level of the medulla)
3rd order: Thalamus–> somatosensory cortex
Information is processed contralaterally (opposite side of where it was perceived) within brain [ info at right side of body is perceived on left side of body]
The body is segregated into dermatomes
Dermatomes are cutaneous division of simal nerve innervation; organized rostrally to caudally , dermatomes overlap, varying degrees of innervation and number of sensory fields (what sit in dermatomes and send info to brain)
Sensory field Dermatomes
Discrete areas of touch discrimination; sensory fields overlap, size of a field is determined by (the number of neurons innervating a dermatome, the degree of neuronal arborization) highly variable in size
more sensitive more neurons
Physical Distortion activates mechanosensory neurons **
Mechanosensory neurons are pseudounipolar neurons that detect touch (dendrite to axon tree)
Plasma membrane movement opens Na channels–> electrical signal; AP NOT initiated at cell body; pain (nocioceptors) and temperature neurons (thermoreceptors) have free nerve endings- explicit receptors for particular pain
somatosensory neurons involved in touch are encapsulated by mechanoreceptor cells
Mechanoreceptor cells encase mechanosensory nerve endings **
- Merkel cells (discs)- movement/depression of ridge
- Meissner Corpuscle- compression
- Ruffini endings- sensation of stretching of skin, sustained pressure, perception of heat
- Pacinian Corpuscle- vibration/pressure
Detect and transfer different types of skin distortion information, senstivity, response time, and duration of activation vary, a single neuron innervates a single mechanoreceptor cell type, nocioceptors and thermoreceptors have free nerve endings (temp/pain)
Mechanosensation in the face and oral cavity
Oral dermatomes and oral somatosensation networks
mouth, head, neck innervated by cranial nerves ex. trigeminal and vagus, facial nerve
Somatosensory cortex is in brain
The somatosensory cortex maps the body’s surface
Physical representation of peripheral somatosensation (mechanoreceptors, pain, temp); cortical area is dictated by the density of peripheral innervation and extent of synapse formation; Sensory information is passed along:
- secondary somatosensory cortex; associated cortices, premotor cortex (plans activity), limbic cortex ( perceive and respond to emotion) and frontal cortex ( executive function)
Homonculus- represents the number of mechanosensory neurons for certain parts of body (finger neurons have less arborization- closer together)
Sensory fields are organized in the Somatosensory cortex
Very organized distribution per stimulus coming in
The somatosensory cortex is plastic **
Cortical regions expand and contract in size (less stimulus for activation, sensitivity, information transfer) use increases connectivity (sensitivity) while disuse decreases connectivity
Neuronal networks are less plastic with age; network perceives world around you-map
Pain is not a uniform signal
- Somatic- pain perceived from peripheral cutaneous perception (thermal, mechanical, chemical- what touches skin)
- Visceral- pain perceived from internal organ systems (referred, perceived as peripheral ex. heart attack)
- Neuropathic- pain caused by damage to PNS and CNS neurons is perceived as a burning or shocking pain (most of it is peripheral, brain has no pain receptors so no capacity to detect a painful stimlulus)
Pain protects us- stop use of a damaged system, consequence of damage/injury, OR not associated with disorder/infection
Pain is perceived by nocioceptors **
Nociceptors- neurons with free nerve endings containing receptors that perceive a specific pain stimulus
Thermal nociceptors- temp. extremes (> 45 C or
Pain signaling- Initiation
Cutaneous nociceptors activated, inflammation releases modulatory signals (prostoglandins, thromboxanes, leuotrines, neuropeptides); inflammatory molecules (drive inflammation, sensitize nociceptors [more sensitive to thermal/mechanical change] , directly activated nociceptors; Non- steroidal inflammatory drugs (NSAIDs) treat somatic pain (aspirin, IBU, acetomenophin); Block COX 1/2 activity (produce prostaglandins, thromboxanes from arachnoid acid )
Pain signaling- afferent connections **
1st, 2nd and 3rd order neurons; somatosensory cortex destination, first order neurons synapse in the spinal cord, second order neurons decussate (cross) in the spinal cord; pain can be gated (affected within) at the spinal cord
visceral–> perceived by somatic nociceptors (organ referred pain)
pain/touch split which way up spinal cord- can lose perception of touch but not of pain if damage one side
Silent Nociceptors refer pain
They synapse onto the same second order neurons as peripheral nociceptors ; ex. heart attack- pain on left arm
Pain is gated at the spinal cord**
Gate theory of pain
Pain is gated and regulated at the level of the spinal cord (hurt knee, then hold it) ; nociceptors and second order connection
peripheral touch inhibits nociceptor, no descending (brain) signaling required, descending signals can influence spinal gating
Descending serotonin neurons activate Enkephalin-releasing interneuron–> neuropeptide–> interact with pre and post–> inhibit perception of pain [brain can send signals that inhibit perception of pain- disrupts first order to second order connection]
sensitive to opioid drugs
Opiates
Interact with central pain receptors (brain and spinal cord) to block the transmission of nociceptive stimuli to the somatosensory cortex ; cause IPSP-presence of stimulus and reduces perception [plasticity exists- sensitization can occur]
increase sensitivity of terminals- more synaptic vesicles, voltage gated channels; compensation from lack of perception of pain–> when opiate removed, greater sensitivity of pain at second order neuron
Drugs can inhibit pain peripherally and centrally**
NSAIDs Prevent pain peripherally- stop nociceptors from perceiving pain, inhibit COX 1/2, reduce the production of pro-inflammatory lipids, reduce inflammation, prevent nociceptor sensitization, common drugs (Acetlysalicylic acid (Aspirin) Ibuprofen (Advil, Midol) Acetaminophen (Tylenol) Naproxen (Aleve))
Opiates
Prevent pain centrally- ability to signal to next neuron in chain is blocked, inhibit nociceptor to second order neuron transmission, abuse potential (pleasurable aspect of reward encoded by endogenous opiates), tolerance, scheduled- most pain meds are schedule 2; 1 (high abuse potential, no therapeutic use)-5
Common drugs (Morphine (Avinza, Duramorph)
Oxycodone (Oxycontin)
Fentanyl (Duragesic, Abstral))
