BME 621 Midterm (All Slides) PDF

BME 621 –Advanced Human Anatomy and Physiology for Biomedical Engineers Course Co-ordinator: Marilee Stephens Anatomy: – study of structure of body: the branch of science that studies the physical structure of animals, plants, and other organisms (Encarta World Eng...

BME 621 –Advanced Human Anatomy and Physiology for Biomedical Engineers Course Co-ordinator: Marilee Stephens Anatomy: – study of structure of body: the branch of science that studies the physical structure of animals, plants, and other organisms (Encarta World English Dictionary) It’s the “what” of the human body Physiology: – study of functioning of living things: the branch of biology that deals with the internal workings of living things, including functions such as metabolism, respiration, and reproduction, rather than with their shape or structure It’s the “how” of the human body – body's internal processes: the way a particular body or organism works (Encarta World English Dictionary)  In a lot of ways, humans are just really intricate machines: – Have to obey the laws of physics. – Have a variety of different materials structured in a way that allows them to work together to do a number of processes… etc. – But we do differ in a couple of ways: Very self-adapting to different environments and situations Have self-repair mechanisms (though these are limited to a certain extant) – (Then there’s the whole “sentience” thing… but we’re not going to get into that right now…)  Fundamentals of Anatomy and Physiology Text Book: Martini, Nath and Bartholomew 8th, 9th, 10th or 11th ed. Course Grading: 1 mid-term (Oct. 23rd) worth 35 % of final mark, covering first 11 lectures of course – in class - 80 minutes long. 1 term paper worth 30% of course – Due November 27th. 1 final exam/2nd midterm - (Date: Tentative – Dec. 16th, at 8:30 am) worth 35% of final grade, covering lecture #12 and lectures #14-24 of course – 90 minutes Grading Scheme: Note: Course is *not* graded on a curve. What you earn is what you get. 90 – 100%: A+ 85 – 89.99%: A 80 – 84.99%: A- 77 – 79.99%: B+ 73 – 76.99%: B 70 – 72.99%: B- 67 – 69.99%: C+ 63 – 66.99%: C 60 – 62.99%: C- 55 – 59.99%: D+ 50 – 54.99%: D < 50%: F Cellular Level of Organization: Martini and Nath and Bartholomew: Chapter 3 One thing in common – All composed of a cell/cells Cells are the smallest units of life. They can exist by themselves, or working as a “collective”. But they all have the same 4 things in common: 1. Cells – building blocks for all plants/animals 2. Come from division of pre-existing cells 3. Smallest units that perform all the vital physiological functions 4. Each cells maintains Homeostasis on the cellular level. How do cells accomplish this? Cells have to have the ability to be self-contained and self-maintaining. – Need to be able to take in nutrients to produce energy required for physiological functions and release wastes – Need to be able reproduce when necessary – Need to have the all the information necessary to carry out above functions Multicellular organisms need to have the ability to communicate with each other to co-ordinate activities. – Cells can become highly specialized as the organism becomes more complex.  So why aren’t Viruses considered as alive when Bacteria are? Bacteria, for the most part, are single-cell organisms, that are generally structured like the cells in your body. They can take in fuel, eject waste and most importantly, replicate themselves, without the aid of another organism. Viruses, on the other hand, can’t replicate themselves, but have to use host cells to provide them with the mechanism for replication. As a result, they reside in a “gray area” where they contain a lot of the same material seen in living cells (DNA/RNA, protein, sometimes fat), but are not cells, as they can’t reproduce themselves and need a host cell to live.  Human Cells: 2 Types: Sex and Somatic: How many chromosomes do each of the two types have? Sex: Somatic:  Stem Cells: Stem Cells are early stages of cells that have the ability to develop/differentiate into several different types of cells. 2 Main Types: Pluripotent: early mammalian embryos have these cells, which can differentiate into a variety of different cells and subsequent tissue types. Adult: Stem cells found located in tissues that can help with the repair of that tissue if damaged via “wear-n-tear”, injury or disease. Location specific for the most part, and can stay “quiet”/dormant until needed.  Stem Cells: Unique Properties of Stem Cells: 1. Have the ability to self-renew: Some mature cells can’t replicate themselves (neurons, blood cells, muscle cells). Stem cells have the ability to replicate several times. When they divide, the result could lead to 2 daughter cells that are: 1. Both stem cells 2. 1 stem cell and 1 differentiated cell 3. 2 differentiated cells 2. Stem cells have the ability to create functional tissues: Pluripotent stem cells are undifferentiated and do not have any tissue-specific characteristics for performing specialized functions. But they create all of the differentiated cells in the body, such as heart muscle cells, blood cells, and nerve cells. Adult stem cells differentiate to yield the specialized cell types of the tissue or organ in which they reside. Different types of stems cells have varying degrees of potency (the number of different cell types that they can form, which can take several steps, specializing more each step). We are beginning to understand the signals that trigger each step of the differentiation process. Signals for cell differentiation include factors secreted by other cells, physical contact with neighboring cells, and certain molecules in the microenvironment.  Stem Cells: Interesting Applications Reversing from Adult to Stem Cell: In 1998, a method was found to derive stem cells from what is known as Inner Cell Mass (cells in the blastocyte stage that will become eventually become all the cells and tissues of the body), by taking pre-implantation human embryos and grow Human embryonic stem cells (hESC’s) in the laboratory. In 2006, a method was found that could take adult cells (such as skin cells) and reverse them into an embryonic stem-cell like state. These cells are known as iPSC’s (induced pluripotent stem cells). Stem Cells: Interesting Applications These cells could then possibly be used in Tissue Engineering, to allow for these pluripotent cells to be used to grow a variety of different tissues and organs that could then be used for transplantion purposes. Given the lack of organs for transplant via donation, this could be a method to create a greater supply. However, currently, the only FDA-approved stem cell-based products are related to blood, from blood-forming stem cells found in umbilical cord blood. There are several steps that need to be considered to making these tissues – ability to make enough cells to replace lost cells and tissues; get desired cell types (via the culture medium and factors); ability to survive in patient after transplant and integrate with other tissues; avoid rejection by immune system and then survive and function for rest of patient’s life. Anatomy of a Cell: Similar to Figure 3-1 in textbook Components of a Cell: 1. Cell membrane and processes 2. Cytoplasm – Contents of cell (Cytosol and Organelles) - Cytosol (soup?) - the above structures will be present in all cells. 3. Organelles: Variety of different ones. Different Cells Types will have different types of organelles and different numbers of the organelles present. 1. The Plasma Membrane Structure: Fluid Mosaic Model: Explanation of structure of Plasma Membrane, proposed by Singer and Nicolson, 1972. - states plasma membranes are dynamic structures, composed of “a mosaic of components”, including cholesterol, phospholipids, proteins, and carbohydrates, which give membrane a fluid character (not stiff or solid), and elasticity. The components are constantly moving, being added or being removed (as needed). The Plasma Membrane: Functions -Also known as the Cell Membrane or Plasmalemma - 4 Main Functions: -Physical Isolation – physical barrier that in general keeps the contents of the cell separate from the surround extracellular fluid. Conditions between the two can be very different and must be maintained for Homeostasis. -Regulation of Exchange with the Environment – the plasma membrane controls the entry of ions and nutrients, the release of wastes and the release of secretions -Sensitivity to the Environment – 1st part of cell affected by changes to the external environment, ie. pH, composition of extracellular fluid or changes in concentrations of substances in extracellular fluid. -Structural Support – Specialized connections between plasma membranes or other external materials, give tissues stability  1. The Plasma Membrane Structure: Components - Lipids - Form most of the surface of the cell membrane (only 42% of weight). - Proteins - Denser than Lipids, makes up 55% of membrane weight, though less in volume. - Carbohydrates - smallest element of the plasma membrane, accounts for 3% of weight.  The Plasma Membrane Structure: Membrane Lipids - Make up the Phospholipid Bilayer; – viscose and individual phospholipid molecules can move in membrane - Bilayer - Phosphate “heads” which are hydrophilic (like water). Lipid “tails” that are hydrophobic (dislike water). Thus the philic heads are in contact with the aqueous solutions on either side of the membrane. Molecules that are both hydrophilic and hydrophobic: Amphipathic - Ions and water soluble compounds can’t enter the lipid bilayer as the hydrophobic tails will not “associate” with water and won’t allow it to pass. This allows for isolation of the cytosol from the extracellular fluid, a necessity for Homeostasis. Certain mechanisms are required to get materials in and out of the cell. Cholesterol gives some stability to membrane. The Plasma Membrane Structure: Membrane Proteins Two types of membrane proteins exist: Integral Proteins are also know as transmembrane proteins and span the width of the membrane at least once, if not more. Peripheral Proteins are bound to the outer or inner surface of the membrane.  The Plasma Membrane Structure: Membrane Carbohydrates The carbohydrates found in the membrane are part of large molecules such as glycoproteins (and subclass – proteoglycans), and glycolipids. The carbohydrate part of these molecules extend out the plasma membrane, forming a layer called the Glycocalyx (also known as pericellular matrix). Functions of the Glycocalyx: - Lubrication and Protection - Anchoring and Locomotion - Specificity in Binding - Recognition  Cell Membrane Functions: Transport Mechanisms Through Plasma Membrane The plasma membrane is a physical barrier between the cytosol and the extracellular fluid. However, the cell needs to get both nutrients in and wastes out of the cell. This is done through a variety of methods: Diffusion (passive and channel- mediated) Carrier Mediated Transport: Facilitated Diffusion Active Transport Secondary Active Transport Vesicular Transport Endocytosis Exocytosis  Transport Mechanisms Through Plasma Membrane: Diffusion Diffusion: - Distribution process of ions and molecules, usually down a concentration gradient, eventually removing that gradient. Important in body fluids, as eliminates local concentration gradients: CO2 moves freely through plasma membrane, and is highest in the cell, then the extracellular fluid, and then the circulating blood. As the cell produces CO2 as waste, it readily moves out to the blood, to eventually go to the lungs for expiration. Factors affecting Diffusion Rates: - Distance (shorter – quicker concentration gradients eliminated) - Molecule size: Ions and smaller molecules diffuse faster - Temperature: Higher the temperature, faster the diffusion rate - Gradient Size: Larger the concentration gradient, the faster the diffusion. - Electrical Forces: Interior of Cell –ve, pulls +ve ions in.  Transport Mechanisms Through Plasma Membrane: Diffusion Diffusion: 3 types across Plasma Membranes Simple Diffusion Channel-Mediated Diffusion Osmosis Simple Diffusion: Occurs with substances that can easily pass through the plasma membrane, as they can diffuse through the lipid bilayer. - Include: Alcohol, Fatty Acids and Steroids. - Dissolved gases: O2 and CO2 - Lipid-Soluble Drugs: THC, Warfarin, Vit. A,D, E, K Channel-Mediated Diffusion: Small channels (0.8 nm in diameter) exist in the membrane. Small ions and molecules may diffuse through via these channels. Factors such as size and charge of ion, size of hydration sphere and interactions between the ion and channel wall will determine the rate of diffusion  Transport Mechanisms Through Plasma Membrane: Diffusion - Osmosis - Movement of water molecules across selectively permeable membrane from low to higher concentration - Total solute concentration is osmotic concentration - Isotonic – ‘same tension’; hypotonic, hypertonic Crenation  Transport Mechanisms Through Plasma Membrane: Carrier-Mediated Transport – Facilitated Diffusion - Extracellular molecule binds to receptor site on a carrier protein - The binding alters shape of protein - Molecule is released to diffuse into cytoplasm - No energy used, but does need concentration gradient Transport Mechanisms Through Plasma Membrane: Carrier-Mediated Transport – Active Transport - Principal cations in body fluids are sodium and potassium (Gatorade) - Na: high in ECF, low cytoplasm - K: low in ECF, high cytoplasm - Ions slowly diffuse in and out - Homeostasis – need to rebalance loss via leak channels and other movements of ions - Uses energy  Transport Mechanisms Through Plasma Membrane: Carrier-Mediated Transport – Secondary Active Transport - Glucose transfer only occurs after binding with sodium - Glucose AND sodium brought into cell - Sodium pumped out of cell  Transport Mechanisms Through Plasma Membrane: Vesicular Transport - Endocytosis In Vesicular Transport, materials move in and out of Cell via small membranous sacs called Vesicles. Receptor- Mediated Endocytosis: - Extracellular materials packaged in vesicles at cell surface and brought into cell. Selective process to bring into cell a specific target molecule by binding molecule to receptor.  Pinocytosis - Cell drinking - Endosomes bring in ECF Phagocytosis and Exocytosis - Cell eating 2. Cytoplasm: all the material inside a cell; cytosol; organelles 2. Cytosol: intracellular fluid; contains dissolved nutrients, ions, proteins and waste. Cytosol differs from Extracellular Fluid (ECF): - K+ ions high concentration in Cytosol; ECF has high concentration of Na+ ions – potential gradients - contains high concentration of dissolved and suspended proteins – many of which are enzymes used in metabolic functions. - small quantities of Carbohydrates (energy) and large amounts of amino acids (proteins) and lipids (energy). Used as reserves, whereas ECF has no reserves. 3. Organelles: types and numbers vary with cell type. 2 Classifications: Nonmembranous and membranous Nonmembranous – not completely enclosed by membranes and has some contact with Cytosol Membranous – Isolated from Cytosol by phopholipid membranes Nonmembranous Membranous Cytoskeleton Endoplasmic Reticulum Microvilli Golgi apparatus Centrioles Lysosomes Cilia Peroxisomes Ribosomes Mitochrondria Proteasomes Nucleus Non-Membraneous: The Cytoskeleton: Functions as the cell’s skeleton; provides internal protein framework. The Cytoskeleton. Microfilaments: - smallest of cytoskeletal elements - composed of protein actin - usually found at periphery of cell - terminal web in some cells Functions: 1. Anchors cytoskeleton to Integral proteins in plasma membrane 2. Acts with other proteins to determine consistency of cytoplasm 3. Actin acts with Myosin to produce active movement of a portion of the cell. Thick Filaments: Intermediate Filaments: - composed of protein Myosin - protein composition varies with cell type - range from 15 nm in size - range from 7-11 nm in size - only found in muscle cells. Functions: 1. Strengthens cell and helps Functions: 1. Interact with Actin to generate maintain shape muscle contractions. 2. Stabilizes the position of organelles Actin 3. Stabilize the position of the Myosin cell with respect to other cells via specialized attachments  The Cytoskeleton. Microtubules: - hollow tubes formed by protein Tubulin - largest components of cytoskeleton – 25 nm - extend from Centrosome near nucleus to periphery of cell – distribution changes with time Functions: - Gives cell strength and rigidity, anchors position of major organelles. - Can change shape of cell by dissembling microtubules - Monorail, molecular motors: can move vesicles and organelles around cell - Mitosis – form spindle apparatus - form structural components of organelles such as centrioles and cilia Centrosome with microtubules radiating from it. Non-Membranous: Microvilli: Increases the surface area of the cell exposed to extracellular environment. - small, finger-shaped projections on cell surface - greatly increase surface area exposed - actively absorbing material – GI tract - connects to cytoskeleton by microfilaments Non-Membranous: Centrioles: - All animal cells capable of division contain a pair of centrioles - Cylindrical, made of short microtubules - 9 groups, 3 in each group; called “9 + 0 array” - In mitosis, form spindles for DNA strands - No centrioles = no division: RBC, skeletal muscle, cardiac, typical neurons - Associated with the centrosome (cytoplasm surrounding centriole) – heart of cytoskeletal system  Non-Membranous: Cilia (-um) - Long, slender extensions of cell membrane - Found in the respiratory tract, reproductive tract - 9 (pairs) of microtubules are arranged around a central pair (9 + 2 array) - Anchored to basal body found just beneath the cell’s surface which has a 9 (triplets) + 0 array arrangement - “Beat” rhythmically – move fluids, secretions across the cell’s surface - stiff during the power stroke, and flexible during return stroke -Smoking: damages/immobilizes Cilia - can’t clear irritants away Non-Membranous: Proteasomes: Organelles that remove proteins from cytoplasm - Free Ribosomes produce proteins within the cytoplasm, while smaller Proteasomes remove them. - They contain an assortment of protein- digesting enzymes (Proteases) - Cytoplasmic enzymes attach a “tag”, Ubiquitin, to proteins that are to be Top View of a Proteasome “recycled” - These tagged proteins are transported to the Proteasome, where when inside, they are broken down into amino acids and small peptides – these are then released back into the cytoplasm. - Therefore, these organelles are responsible for removing and recycling damaged or denatured proteins, and breaking down abnormal proteins. Non-Membranous: Ribosomes: Organelles responsible for Protein Synthesis: - Proteins produced in cells using information from DNA - # Ribosomes found in a cell varies type of cell and with demand for new proteins -Liver versus Fat cell - Appear in Electron microscope as dense granules about 25 nm in diameter - Roughly 60% RNA and 40% protein - Two sub units - small and large ribosomal units - Contain special proteins and ribosomal RNA (rRNA) - Small and large subunit must combine with a strand of mRNA to produce protein Ribosomes: Two Types: Fixed Ribosomes - Attached to Endoplasmic Reticulum - Proteins enter lumen where they are modified and packaged for export Free Ribosomes - Scattered throughout cytoplasm - Proteins manufactured by them remain in cytosol  Membranous Organelles - Organelles that are completely surrounded by a phospholipid bilayer similar to cell membrane - Separates contents from cytosol - Allows for manufacture and storage of material that could affect cytosol Membranous: Nucleus – Control Centre of the Cell: Control Centre for the cell as stores the “blueprints” for synthesizing more than 100 000 different proteins. - determines the structure of the cell and what functions it can perform by controlling what proteins produced For a cell to have a prolonged life-span, must have a nucleus. - cells without one, ie. Red Blood Cells, “dies” within 3-4 months  Nucleus – Control Centre of the Cell: Structure Several Components: Nuclear Envelope: - separates nucleus from Cytosol. - consists of a double-layer Membrane, where 2 layers are separated by a Perinuclear Space. Nucleolus: - Dark-stained areas; Transient nuclear organelles that Synthesize ribosomal RNA Nucleoplasm: - fluid contents of the nucleus – contains the nuclear matrix Nuclear Pore: - channels between nucleus and cytosol to allow for exchange of ions and Small molecules – allows for communication of conditions outside the nucleus.  Nucleus – Information Storage: Information storage is done by DNA (Deoxyribonucleic Acid). DNA combine with Histones to form a complex known as a Nucleosome – allows for a lot of information to be Stored in a small Space. When not reproducing, strands are loosely coiled (Chromatin). Just before cell division, coils up tighter (Chromosomes). Gene – Functional unit of heredity: - contains all the DNA triplets needed to produce specific proteins. Not all DNA molecules carry instructions for proteins; some control synthesis of transfer or ribosomal RNA, some have regulatory function and some we’re not sure what they do (no apparent function) Nucleus – mRNA Transcription http://www.youtube.com/watch?v=zr_O8aJKHnI http://www.youtube.com/watch?v=ztPkv7wc3yU&feature=related  Nucleus – mRNA Transcription - Information is stored in sequence of bases along DNA strand - A,C,T,G - Triplet code – 3 bases specify single amino acid – read in groups of 3 - TGT codes for the amno acid cysteine; TGC also codes for cysteine - The two DNA strands are complementary - Coding strand contains triplets that specify sequence of amino acids in polypeptide - Template strand complementary triplets used as template for mRNA production Nucleus – mRNA Transcription Step 1 Step 2 Step 3 - DNA strands - RNA poly moves - at stop signal RNA separate along poly and mRNA strand - RNA polymerase - complementray RNA detach binds to promotor nucleotides are added - two DNA strands - RNA poly strings to reassociate form mRNA strand Protein Synthesis: mRNA Translation http://www.youtube.com/watch?v=KIOKenqiRhk https://www.youtube.com/watch?v=TfYf_rPWUdY Role of Aminoacyl tRNA Synthetase in attaching tRNA to correct Amino Acid - Enzymes - 20 types of aminoacyl tRNA synthetases exist – 1 for every type of amino acid. - tRNA molecules that code of that amino acid (have the anticodon for the amino acid) will be the only tRNA molecules the will “fit” that particular aminoacyl tRNA synthetase enzyme.  Protein Synthesis: mRNA Translation Translation: - Protein synthesis is the assembling of polypeptides in cytoplasm - Translation – formation of a linear chain of amino acids using information from mRNA - Each mRNA codon specifies particular amino acid to be incorporated into polyp chain - Amino acids provided by tRNA – binds and delivers specific amino acid - Anticodon – identifies specific amino acid; connects with mRNA and adds amino acid Protein Synthesis: mRNA Translation Protein Synthesis: mRNA Translation Nucleus – Controls Cell’s Structure and Function By controlling Protein Synthesis, DNA from the nucleus regulates the functions and structure of the cell: 2 Methods: Direct Control – synthesizes structural proteins, ie membrane proteins, receptors, cytoskeletal components and secretory products. - changing instructions, via mRNA, allows the nucleus to alter the structure of the cell, sensitivity to environment, and secretory functions Indirect Control – as enzymes are proteins, but regulating the synthesis of enzymes, the nucleus has control over other aspects of cellular Metabolism, as it can increase or decrease production of certain enzymes as required.  Membranous: Endoplasmic reticulum (ER) - Network of intra cellular membranes connected to nuclear envelop - Composed of hollow tubes, flattened sheets, cisternae (chambers) - Functions: - Synthesizes proteins, carbohydrates, lipids - Stores synthesized molecules or materials absorbed from cytosol without interrupting other cell functions. - Allows for transport of materials within ER - Detoxification: Drugs, toxins absorbed by ER and neutralized by enzymes stored within it. Endoplasmic reticulum (ER): Two Types Rough ER Smooth ER - Works as combination of workshop and - Has no ribosomes attached to it. shipping depot - Functions: - Contains fixed ribosomes: looks beady or - Synthesis of lipids and carbohydrates grainy. In several places, connects to needed for maintenance and growth of nuclear envelope membranes - Polypeptide chains produced at fixed - Synthesis of steroid hormones ribosomes enter cisternae, where modified - Synthesis and storage of glycerides, into secondary and tertiary structures, or glycogen have carbohydrates attached - storage of calcium ions, removal and - Most proteins and glycoproteins are inactivation of toxins packaged into small sacs – transported to Golgi Apparatus Rough ER Function: Membranous: Golgi - Transport vesicle with new protein in it that is to be Apparatus (Complex): exported from cell goes from ER to Golgi - Consists of 5 or 6 flattened membranes (cisternae) - Often several Golgi near nucleus of cell - Functions: - Modifies and packages secretions (exocytosis) - Renews or modifies plasma membranes - Packages special enzymes for use in cytosol  Golgi Apparatus (Complex): Packaging Vesicles 1. Proteins and Glycoproteins delivered from RER to Golgi Apparatus via Transport Vesicles which fuse with Golgi on its forming (cis) face 2. Enzymes within Golgi modify the proteins, etc. into desired product as they move up the cisterna (transferred between cisterna by small vesicles) 3. Product arrives at maturing (trans) face and packaged into 3 types of vesicles: 1. Secretory Vesicles: Contains secretions to be discharged from cells (exocytosis) 2. Membrane Renewal Vesicles: Adds new lipids and proteins to plasma membrane while other areas of membrane are being removed – allows for changes in properties of the membrane 3. Lysosomes: Contain digestive enzymes (see next slide). Membranous: Lysosomes: Organelles that break down larger cell structures Cells have to be able to break down and recycle large molecules/organelles - Use powerful enzymes for this - Lysosomes: - Special Vesicles - Produced by Golgi apparatus - Are most important, as they are filled with digestive enzymes Functions: 1. Primary Lysosomes are filled with inactive enzymes, that when fused with damaged organelles, become active and form secondary lysosomes, which proceed to break down contents, with the cytosol reabsorbing nutrients and the rest being expelled. 2. Act to destroy bacteria that enter cell from extracellular fluid. 3. Cleanup and recycling functions inside cell, as well as sometimes destroying damaged or dead cells Membranous: Peroxisomes: Organelles that break down organic compounds Peroxisomes are smaller than lysosomes - Are considered a “semi-autonomous organelle” as they reproduce themselves, as well as functioning independently within the cell, - Carry a different group of enzymes - New ones produced by growth and subdivision of older ones - Enzymes contained within produced by free ribosomes, then transported by carrier proteins to the peroxisome - Functions: Absorb and break down fatty acids and other organic compounds, which results in hydrogen peroxide (H2O2) being produced (A Crystalline core (not always present) is made of Urate Oxidase, an enzyme that free radical that can be damaging to the cell). helps break down Uric Acid (by-product of - Other enzymes in the peroxisome then break metabolism of purine nucleotides – part of down the H2O2, leaving oxygen and water DNA and RNA) as well as other enzymes. - Thus the cell is protected from the protentially damaging effects of the free radicals that are produced during catabolism Membranous: Mitochondrion (-a): Energy Producers for the Cell - Cells need to have energy produced to survive - Number of Mitochrondria varies with a type of cell’s energy demand (RBC?; muscle?) - It has an unusual double membrane: outer – surrounds; inner has numerous folds (cristae), which increases surface area exposed to the fluid contents (Matrix) of the Mitochrondria. - Reactions that RELEASE energy occur in mitochondria - Activities that REQUIRE energy occur in cytoplasm - Cells must store energy that can be moved from place to place – Usually done as High Energy Bonds (such as found in ATP) - Cells can then break these high-energy bonds, reconverting ATP to ADP + phosphate and releasing energy - Also considered a Semi-Autonomous Organelle (like Peroxisomes)  Mitochondrial Energy Production: - In the cytosol – glycolysis – glucose molecule to 2 molecules pyruvic acid - absorbed by mitochondria - In mitochondria, a CO2 molecule is removed from each pyruvic acid molecule - Remainder enters Tricarboxylic Acid Cycle (TCA or Krebs) – breaks down absorbed pyruvic acid in presence of oxygen - Remnants of pyruvic acid molecules contain C,H,O atoms - C and O released as CO2 which diffuses out of cell; hydrogen atoms delivered to cristae - Electrons from H added to ADP to create ATP - Uses oxygen – AEROBIC METABOLISM – produces 95% of ATP necessary to keep cell alive  Human Cells: Variations Red Blood Cell – No Nucleus Striated Muscle Cell – Multinucleated Columnar Epithelial Cell – Simple Shape Neurons – Highly Branched Cells are the smallest units of life- - In multi-cellular, more complex organisms, a variety of cell types will be arranged in various combinations to form Tissues. Tissues: Epithelial Connective Nervous Muscle Cytology – Study of cells Histology – Study of Tissues Tissue: an aggregate of cells usually of a particular kind together with their intercellular substance that form one of the structural materials of a plant or an animal and that in animals include connective tissue, epithelium, muscle tissue, and nerve tissue. Merriam–Webster Dictionary A group or layer of cells that work together to perform a specific function. National Cancer Institute in physiology, a level of organization in multicellular organisms; it consists of a group of structurally and functionally similar cells and their intercellular material. Britannica As seen from the above definitions, tissues are collections of a variety of cell types and extracellular material that carry out a particular function. Types of Tissues: 1. Epithelial 2. Connective 3. Muscle 4. Neural Type: Epithelial Connective Nervous Muscle Features Lines inner and Widest variety of Electro-chemical Connection outer surfaces of tissues, but have transmission of between proteins the body cells, ground information via actin and myosin substance, ion movement allow for extracellular contraction. proteins Cells Epidermis of Blood cells, bone Neurons, Glial Skeletal skin, lining cells cells, fat cells, cells myocytes, cardiac of digestive, immune cells, (Astrocytes, myocytes, smooth lungs, body fibrocytes, Oligodendro- myocytes cavities melanocytes cytes) Functions Protective Provides Makes up one Force Generation mechanisms, structural control system restricting support, of body – movement of transport, determines what substances insulation body will do Repair Substantial, via Substantial Neurons – No Via Stem cells Abilities stem cells, with very high turn Glial Cells - Yes over rates Epithelial Tissue: Functions of the Epithelial Tissue: 1. Provide Physical Protection: 2. Control Permeability: 3. Produce Specialized Secretions: Glands 4. Provide Sensation: Neuroepithelia – specialized to provide certain sensory functions: smell, taste, sight, hearing epithelial cells  Epithelial Tissue: Properties Cellularity: cells attached tightly to each other to not allow substances to move between them. Polarity: cells have a laterality to them – side facing open space – Apical - side attaching to underlying other tissues - Basal Attachment: Base of epithelial tissue attaches to underlying connective tissue via complex structure called “Basal Laminae” Avascularity: No direct blood supply to these cells (no blood vessels). Nutrients and oxygen move through underlying connective tissue to reach cells and waste goes in opposite direction. Regeneration: loss is constant. Stem cells present in tissue will constantly be replacing lost cells with new cells. Is seen in other tissue types but not to same rate as here. Some Locations of Epithelial Tissue: Epithelial Classification Categories: Can classify epithelial tissue based on two features: – Cell Shape: Squamous, Cuboidal, Columnar – # of Layers: Simple vs. Stratified  Connective Tissue: Connective Tissues can vary widely in appearance and Function but they have 3 Common features: 1. Specialized Cells 2. Extracellular Protein Fibers Matrix 3. Fluid known as Ground Substance Functions of Connective Tissue: 1. Establishing a framework for the body 2. Transporting fluids and dissolved materials 3. Protecting delicate organs 4. Supporting, surrounding and interconnecting other types of tissues 5. Storing energy reserves, especially in the forms of triglycerides 6. Defending the body from Invading microorganisms Classification of Connective Tissues: Three Classification Groups: 1. Connective Tissue Proper: - includes many types of cells and extracellular fibers in syrupy ground substance - Can have very different proportions in terms of # of cells and relative properties and amount of fibers to ground substance - Loose (ie. Adipose) vs. Dense (ie. Tendon) 2. Fluid Connective Tissues: - Distinctive proportions of cells in a watery matrix that contains dissolved proteins - Blood and Lymph 3. Supporting Connective Tissues: - Less diverse cell population and more densely packed fibers than seen in Connective Tissue Proper - Cartilage and Bone Section 2 – Regulatory Control Systems Control Systems: Nervous and Endocrine Control Systems are used to activate various physiological processes around the body. – Nervous System – Uses Electrochemical signals, generated and transmitted via neurons, to directly and quickly (ms-sec time frame) activate various systems. Chemicals used are called Neurotransmitters. Somatic – Voluntary control of Skeletal/Striated Muscle Autonomic – Involuntary control of Cardiac and Smooth Muscle, as well as Glands and Adipocytes (Fat Cells). – Endocrine System – Delivers chemicals called Hormones to the blood stream, where they eventually interact with cells that have receptors for those chemicals. Takes longer (sec. to minutes to hours), and chemicals can be released from various tissues. https://www.sciencesfp.com/the-endocrine-system.html Section 2: Nervous System  The Nervous System – Anatomical Organization Peripheral Nervous System (PNS): nerve bundles - outside of blood brain barrier - peripheral nerves can regenerate - carries sensory inputs to and motor commands from the CNS Central Nervous System (CNS): brain and spinal cord - Isolated from other tissues by blood brain barrier - poor regenerative capabilities - processes and executes commands for movement, emotions, thoughts, sensations, memories, etc. Blood Brain Barrier: Between the Blood and Neural Tissue, there is an extra layer of cells that regulate/prevent substances from moving out of the blood and into the nervous tissue’s environment. These include the projections from astrocytes, as well as another cell type, called pericytes. The purpose of the blood–brain barrier is to protect against circulating toxins or pathogens that could cause brain infections, while at the same time allowing vital nutrients to reach the brain. Its other function is to help maintain relatively constant levels of hormones, nutrients and water in the brain – fluctuations in which could disrupt the finely tuned environment. Blood Brain Barrier: Interestingly, it’s been found after chronic spinal cord injury, the pericytes can cause vasoconstriction of the capillaries of the spinal cord caudal (lower) than the injury. This causes hypoxia (low oxygen levels) and reduced function in these areas of the spinal cord, where the circuitry is intact, but function is compromised due to this hypoxia. Li, Y. et al. 2017, Nat Med. June; 23(6): 733–741 The Nervous System – Anatomical Organization - Macro Functional Overview of the Nervous System:  Neurons: Functional Classification  Sensory neurons: Somatic sensory neurons: monitor outside world Visceral sensory neurons: monitor internal conditions Receptors: Interoceptors/Exteroceptors/Proprioceptors  Motor neurons Somatic Visceral  Interneurons Nerve Structure: Functional Cells – Neurons: Structure – Micro - Overview Neurons: Structural Classification  Neuronal Structure: Cell body (soma): large, round nucleus Has a specialized perikaryon (cytoplasm) which as such structures as Nissl bodies (clumps of RER and free ribosomes that give gray colour to cell bodies) Has a cytoskeleton composed of Neurofilaments and Neurotubules; gives internal support to dendrites and axons. Neurofibrils are bundles of neurofilaments Dendrites: extend out from the cell body – Highly branched, with each branch having dendritic spines – Site for receiving info – Represent ~80-90% of total surface area of neuron  Neuronal Structure: Axons & Synapses Axon: long process capable of propagating electric pulse (action potential). Contains: Axoplasm: cytoplasm of axon Axolemma: surrounds axoplasm Initial segment: base of the axon, attached to the cell body through axon hillock Collaterals: side branches of axons Telodendria: fine extensions that end at synaptic terminals The Synapse: Presynaptic cell: releases signal (neurotransmitter, chemical, electrical) Postsynaptic cell: receives signal Special types: 1) Neuromuscular junction Neuron and muscle cell 2) Neuroglandular junction Neuron and gland (secretory) cell  Synaptic Knob and Transport: Synaptic knob formed if synapse is neuron-to-neuron  **Rabies, Polio, Tetanus: virus enters body, taken up at Contains mitochondria, ER, synaptic terminals. As a vesicles (NT) result of retrograde transport, virus travels to cell body and Breakdown of NT is reassembled at synaptic knob into CNS with fatal consequences Axoplasmic transport – Anterograde (cell body to axon) – done by kinesin motor molecules – Retrograde (axon to cell body) – done by dynein motor molecules https://www.youtube.com/watch?v=y-uuk4Pr2i8  Neural Circuits: Organization of Neuronal Connections: Spreading Brings multiple Positive feedback Simultaneous Sequential stimulation to types of mechanism of the processing of the processing of multiple neurons information and post-synaptic same information information within or neuronal pools effects onto single neurons or pools within multiple a group of neurons in CNS. Allows for neuron from onto the pre- neurons or or a neuronal pool rapid spread of multiple sources synaptic neurons neuronal pools information Supporting Cells: Neuroglia (Nerve Glue) PNS CNS - Originally thought to be inactive connective tissue Supporting Cells: Neuroglia (Nerve Glue) Supporting Cells: Neuroglia – Myelination: Oligodendrocytes vs Schwann Cells At the Neuron: Electrophysiology - Overview At the cell – a neuron having inputs from several different other neurons acting on it (a single neuron can have connections onto it from on average 7000 other neurons) These inputs consist of either changes in its cellular membrane that causes the neuron’s internal electrical potential to become more positive (depolarize) or become more negative. What causes these changes in largely due to chemicals (neurotransmitters) that interact with receptors on the neuron’s membrane, with the receptors mainly located on the dendrites of the neurons, or the cell body (soma). If enough depolarization occurs, at the axon, an Action Potential will be generated, and carry the signal to the cells that that neuron’s axon interacts with (other neurons, muscle cells, gland cells, even adipose (fat) cells). It will affect that cell’s activity by releasing neurotransmitter at the Synapse, which will interact with receptors on the receiving cell’s membrane.  Membrane Potentials: The membrane potential refers to the electrical “charge” on the plasma (cell) membrane of a neuron due to unequal electrical charges of the ions and molecules inside compared to outside the neuron. Resting Membrane Potential – Potential in the membrane when no activity is happening at the neuron. Sits at about -70 mV due to the fact that you compare the inside of the neuron to the outside, and there is more negatively charged proteins inside the neuron then outside. Graded Membrane Potential – Small change in local membrane potential on dendrite or cell body of neuron due to release of a transmitter, interacting with a receptor, that causes positive or negative charges to move into or out of the cell. Action Potential – Large change in membrane potential at axon of neuron, that travels down axon until reaches synaptic terminal  Changing Membrane Potential Membrane Channels (Ion channels) – 1) Passive channels (@rest) are always open – 2) Active channels (gated channels) Gated Channels: 3 states – 1) Closed, BUT capable of opening (De-activated) – 2) Open (Activated) – 3) Closed, AND incapable of opening (Inactivated)  Substances can’t move through plasma membrane. Channels are made up of Proteins, some of which travel across the plasma membrane (integral proteins). These chains of amino acids are structures in ways that allow for regulation of flow of ions along concentration gradients. Potassium (K+) ion channel Principles of Neural Science, 6th edition, Kandel et al. Channels tend to be made up of subunits of protein. Example of structure of Potassium channel (K+) seen in bacteria). Principles of Neural Science, 6th edition, Kandel et al. 1. Gated Channels – Chemically Regulated Channels: Most abundant on dendrites and cell bodies: most synaptic communication occurs here (Neurotransmitter) Neurotransmitters Whether a neurotransmitter (ligands in neural tissue) has an excitatory or inhibitory effect on a cell does *NOT* only depend on the neurotransmitter In a chemically-gated situation *depends on the properties of the receptors*, which may allow only certain ions to move. For example: Serotonin (5-HT) - 7 different postsynaptic receptors types 5HT2 receptors: excitatory; 5HT1 receptors: inhibitory Various NT’s and receptors.  2. Gated Channels – Voltage-Gated Channels: States of Voltage – Gated Sodium And Potassium Channels Most Important: Na+, K+ and Ca2+ Na channel: 2 gates that function independently: - one to open (Activation), - one to close (Inactivation) From Amerman E.C., Human Anatomy & Physiology, 2016 3. Gated Channels – Mechanically-Gated Channels: Important for sensory receptors, e.g. Touch, Pressure, Vibration Active Movement of Ions - Pumps Uses energy to move ions against concentration gradient. Classic – Sodium-Potassium pump, moves 3 Na+ ions out of cell and 2 K+ ions in, using 1 ATP molecule Summary: Types of Channels and Pumpsseen in Neural Tissue From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013 Electrophysiology: Resting Membrane Potential - Electrical potential of Neuron when there is no input onto the cell. Sits negative (-70 mv), though some ion movement through passive leak channels. Potential reset using Sodium-Potassium Pump) Generation and Maintenance of Resting MembranePotential From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013  Graded Potentials: Local Potentials Change in membrane potential, V, that does not spread very far Any stimulus opening an ion channel will result in a graded potential Effect spreads passively Stronger stimulus produces greater graded potential (spreads more)  Graded Potentials:  Graded potential resulting in more positive membrane potential=depolarization  Return to resting potential = repolarization  Potential resulting in more negative membrane potential = hyperpolarization From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013 Postsynaptic Potentials From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013  Summation of Postsynaptic Potentials Typical EPSP produces depolarization ~0.5mV Local currents must depolarize ~10mV to reach threshold for action potential Individual EPSPs combined through summation Two forms of summation: – 1) Temporal Summation – 2) Spatial Summation Temporal and Spatial Summation Temporal Summation: Addition of stimuli occurring in rapid succession Occurs at single synapse that is activated repeatedly Second EPSP arrives before effects of first EPSP have dissipated Allows neuron to reach threshold for action potential Spatial Summation: Simultanous stimuli at different locations have cumulative effect on membrane potential Multiple synapses that are active simultaneously Degree of depolarization depends on how many synapses are active  Action Potentials https://www.youtube.com/watch?v=plFOiU7sTO4  Action Potentials Propagated changes in membrane potential that affect entire membrane First step: opening of V-gated Na channels by graded potentials (@ axon hillock) Spreads depolarization to adjacent sections of membrane, activating more Na channels Impulse propagated along entire length of axon Action Potential: “All or None” Principle – Threshold: depolarized membrane potential that is large enough to open Na channels – Typically -60 to -55mV (10-15mV depolarization from resting membrane potential) – All stimuli that bring membrane to threshold trigger same action potential i.e. action potential from larger stimuli= AP from smaller stimuli if both above threshold  Distribution of Ion Channels Action Potential: Ion Channels and Pumps in a Neuron Ion Channels involved are: Voltage-gated Na Channel – Threshold for activation of Na Channel ~- 55mV – Na channel is activated by depolarization of membrane potential – Na channel becomes *inactivated* quickly (inactivation gate) – When cell repolarizes, inactivation gate is removed and cell is de-activated but ready to be activated at next depolarization Voltage-gated K Channel – Activated by depolarization membrane (@ higher potential than Na channel ~+30mV – Slower activation – No inactivation From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013 Action Potential Generation At axon hillock: Cell is at rest -70mV Purple: Na channels Orange: K channels Na activation gate closed K activation gate closed Step1: Depolarization to Threshold Axon hillock depolarized by graded depolarizing potentials from stimuli Membrane depolarized 10mV to -60mV Still not enough to result in opening of Na channels More depolarization needed to reach threshold Action Potential Generation: Steps 2 & 3 Membrane is depolarized more by further stimuli Membrane potential crosses threshold for activation of Na channels Action potential is triggered Na activation gate opens Na ions rush in Rapid depolarization of membrane Travels down axon of neuron Depolarization by Na ions spreads along axon, increasing membrane potential As a result: Na channels start inactivating (less Na in) through closing of inactivation gate K channels open (K out) through opening of activation gate Action Potential Generation: Step 4 As a result of less Na in, and more K out, cell becomes hyperpolarized (less positive) Phase is called repolarization because cell returns to resting potential (a little lower because K channels slow to de-activate so too much K leaves cell) Repolarization removes inactivation of Na channels, Na channels now de-activated (hyperpolarized cell) Summary of Action Potentials Events From Amerman E.C., Human Anatomy & Physiology, 2016  Refractory Periods: Absolute and Relative Period where membrane does not respond normally to further stimuli Once Na channels open until Na channel inactivation ends, further stimulation has no effect on membrane potential “Absolute Refractory Period”: 0.4-1.0ms Because all Na channels are either open or inactivated, so further depolarizations (stimuli) result in no further effect “Relative Refractory Period”: Begins when inactivation of Na channels is removed, and Na channels return to normal resting condition Another action potential is possible if membrane is sufficiently depolarized during this time Needs to overcome hyperpolarization seen due to K channels being open. From Amerman E.C., Human Anatomy & Physiology, 2016 Action Potential: Brief Summary https://www.youtube.com/watch?v=G3WUJ9XaZWc https://www.youtube.com/watch?v=8yC--NvBn_M  Propagation of Action Potentials: Continuous Propagation Continuous propagation: Unmyelinated Axon Propagation of Action Potentials: Continuous Propagation From Amerman E.C., Human Anatomy & From McKinley, O’Loughlin and Bidle, Anatomy Physiology, 2016 and Physiology, 2013  Propagation of Action Potentials: Saltatory Propagation Saltatory propagation: Myelinated Axon – Action occurs at Nodes of Ranvier  Saltatory Conduction From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013 Comparison of Saltatory and Continuous Conduction Saltatory is faster and uses less ATP From Amerman E.C., Human Anatomy & Physiology, 2016 At the Neuron (Synapse): Depending on the combination of neurotransmitters and receptors, you can have different results. Some neurotransmitters are generally considered excitatory (causing depolarization) – Acetylcholine (Ach) Some are considered generally inhibitory (causing hyperpolarization) – GABA (Gamma Aminobutyric Acid). Interestingly, recently, in the lab I work in, we found a location where GABA causes excitation, and not inhibition.  Connecting Cells - Chemical Synapses Arriving action potential may or may not release enough neurotransmitter to bring postsynaptic neuron to threshold ( if does so, ˜ 300 vesicles released per AP) Variety of factors can influence transmission to postsynaptic cell Most abundant synapses Use neurotransmitters to transmit signal – Most common is acetylcholine (ACh) at neuromuscular junctions – Excitatory neurotransmitters produce depolarization in postsynaptic cell and promote generation of action potentials (eg. noradrenaline, serotonin) – Inhibitory neurotransmitters cause hyperpolarization and suppress generation of action potentials (e.g. GABA, glycine)  Location of Synapses From Amerman E.C., Human Anatomy & Physiology, 2016 Summary of Synaptic Events From McKinley, O’Loughlin and Bidle, Anatomy and Physiology, 2013 Cholinergic Synapses Involve ACh as neurotransmitter Most wide-spread and best-studied 1) at neuromuscular junctions with skeletal fibers 2) many synapses in CNS 3) all neuron-neuron synapses in the PNS 4) all neuromuscular and neuroglandular junctions of parasympathetic division of ANS  Events at Cholinergic Synapse Depolarization of synaptic knob Activates V-gated Ca channels, allowing Ca to enter presynaptic cell Increased concentration of Ca inside the presynaptic neuron triggers exocytosis of vesicles containing ACh ACh is released into synaptic cleft ACh in synaptic cleft binds to ACh receptors on postsynaptic membrane Binding of ACh to these receptors causes depolarization of cell membrane (Na moves in) Depolarization is graded potential lasting 20ms If threshold is reached an action potential is generated in the postsynaptic neuron ACh is removed from the synaptic cleft through acetylcholinesterase (AChE) an enzyme that breaks ACh into acetate and choline Choline taken up into presynaptic cell to make more Ach through Coenzyme A  At the Neuron (Synapse) – GABA Synapses: On large, myelinated, sensory neurons, bringing in sensory information from the periphery of the body, there are several places where the axons branch, to make connections with other neurons – These are known as Branch Points. You can have branch point failure, where the action potential does not get past the branching. GABAergic neuron Hari, K. et al, 2022, Nature Neuroscience Oct., 25, 1288-1299 GABA-ergic neurons form synapses at these branch points, and releasing GABA here activates GABAA This depolarization is due to a unique receptors. These actually cause depolarization at scenario here in these axons, where these branch points, and allow the action potential to there is actually more Cl- inside the keep propagating along the axon. axon, and opening of Cl channels, allowing Cl to leave the axon, However, activation of GABAB receptors, down at the resulting in a more positively charged synapse to motorneurons, etc, still causes the internal environment, keeping the inhibition associated with GABA. axon closer to threshold. Hari, K. et al, 2022, Nat. Neuroscience Oct., 25, 1288-1299 Section 2 – Regulatory Control Systems Gray and White Matter In the Brain: Gray Matter: Neuronal Cell bodies. - About 40% of brain - Used for processing of information White Matter: Bundles of Axons emerging from the neuronal cells bodies - a number covered with myelin – causing white appearance - about 60% of brain. - allows for connections between various neurons – communication routes.  Three Types of White Matter Tracts in the Brain and Spinal Cord: 1. Association – Axons travel within the same hemisphere of the brain. 2. Commissural – Axons that travel between the two hemispheres of the brain. Two main pathways: - Corpus Callosum - Anterior Commissure 3. Projection – Axons travel vertically, usually down to lower components of the brain: Ie. projection fibres from the Primary Motor Cortex project down through the Internal Capsule into the Brain Stem and finally to the Spinal Cord.  Ventricles: - Contains Choroid Plexus (Ependymal Glial Cells). - Choroid Plexus makes CSF (see below) Three Layers of Meninges: Dura Arachnoid Pia CSF (Cerebrospinal Fluid): - Weak salt solution - Acts as: - Cushion for brain and spinal cord - Gives Buoyancy to brain - Helps prevent brain ischemia - Involved in immunological protection - Helps clear out wastes and metabolic toxins  Central Nervous System: 5 major components Cerebrum/Cerebral Cortex Diencephalon Spinal Cord Cerebellum Brain Stem  CNS - Portion 1: Cerebrum/Cerebral Cortex Cerebrum: Largest portion of the brain. Cerebral Cortex: Outer layer of gray matter of the cerebrum – place where conscious thought and perception occurs. Cerebral Cortex Gray Matter: 6 Cellular Layers – Thickness of each layer can vary depending on type of information processing occurring BRAIN STIMULATION Pennefield Video Four Main Lobes of each hemisphere of the Cerebrum Frontal Lobe motor planning and execution Parietal Lobe thinking, reasoning sensory processing, perception Occipital Lobe visual processing Temporal Lobe auditory and olfactory processing language centres Two areas heavily studied are the Motor and Sensory Cortices Somatotopic organization of the motor and sensory cortex Motor homunculus – first outlined by Wilder Penfield and colleagues. Sensory Motor Also seen in: Thalamus Basal Ganglia Cerebellum Localization/Lateralization of cortical function Idea of localization first came from language studies: - Aphasia – Language disruption - Broca – had patient who could understand language but could not speak due to stroke. Could move mouth fine (utter isolated words, whistle, etc.) but not form complete sentences. Aware that has problems and can become frustrated. - showed that damage was on left hemisphere in “Broca’s area”, near the posterior of the frontal lobe, just in front of primary motor cortex. - Wernicki found patients who could not comprehend speech, rather than not produce it (receptive versus expressive malfunction). Patients could form words and sentences, but could not comprehend speech. Lesion was in “Wernicki’s area”, located in the area where temporal/parietal/occipital lobes meet. Tends to produce a “word salad” in speaking. Often doesn’t appear to know that a problem is occurring. - Conclusion was that speech/language had both motor and sensory programs that were housed in different regions of the cortex. Motor (Broca’s area) was an association area conveniently located near the primary motor cortex, while Sensory (Wernicki’s area) was an association area located in the temporal-parietal, surrounded by the auditory cortex. Localization/Lateralization of cortical function: Speech Even different modes/tasks associated with speech are found in different areas of brain: Using PET scanning: Upper left: Reading of single word. Upper right: Hearing a word Lower left: Repeat a word presented though earphones Lower right: Hearing the word “brain”, responding with a corresponding verb (ie. “to think). http://www.d.umn.edu/~jfitzake/Lectures/DMED/SpeechLanguage/CorticalS_LAreas/CorticalLanguageAreas.html Localization of Cortical Function: http://www.neuromedia.ca/en/sante/cerveau2.asp Lateralization of cortical function: Special Functional Grouping: Basal Ganglia Functional grouping of nuclei deep in the brain. Nuclei associated with: Cortex/Cerebrum region - Caudate, Striatum - Putamen, - Globus pallidus (pallidum) – Internal and External, Diencephalon - Subthalamic nuclei Mescencephalon/Midbrain - Substantia nigra pars compacta (SNc) - - Substantia nigra pars reticulata (SNr)  Special Functional Grouping: Basal Ganglia Has connections with several different parts of the brain and has role in multiple functions. Engaged in 5 “Loops”, 3 of which are shown here. THE BASAL GANGLIA: Motor Circuit Functions: Subconscious control of muscle tone and coordination of learned movement patterns Motor problems with basal ganglia lesions: akinesia, rigidity & tremor (Parkinson's disease: degeneration of substania nigra) OR dyskinesia (athetosis, chorea, hemiballismus: damage to putamen, sub-thalamic nucleus or globus pallidus) i.e. either poverty of movement or involuntary movement CNS - Portion 2: Diencephalon (Thalamus, Hypothalamus)  Diencephalon Composed of the Epithalamus, Thalamus and Hypothalamus Helps integrate incoming sensory information with outgoing motor information at a subconscious level Epithalamus: Roof of Diencephalon. – Anterior – extensive part of choroid plexus (producer of Cerebral Spinal Fluid (CSF). – Posterior – contains Pineal Gland Endrocrine Gland that produces hormone Melatonin  Thalamus Thalamus: The thalamus is an olive shaped structure about one inch in length. It serves as a relay station for impulses traveling to and from the spinal cord, brain stem, cerebellum and cerebrum. It has an important function in directing sensory input to the appropriate place in the cerebral cortex. Sensory input from the body, the eyes, ears and other senses (except for smell) pass through the thalamus. Most of thalamic projections will remain ipsilateral, to respective cerebral cortex(except from Reticular Nucleus – Involved with modulating the information from other nuclei in the thalamus).  Hypothalamus Hypothalamus The hypothalamus is located below the thalamus. An important center for many critical internal body functions: Monitors: water concentration, hormone concentrations and body temperature. Associated with feelings of rage, aggression, hunger and thirst. Also plays an important role as an intermediary between the nervous system and the endocrine system (hormones). The hypothalamus has many connections with the pituitary gland and can produce and regulate hormones. CNS - Portion 3: The Cerebellum “little brain” CEREBELLUM Vestibulocerebellum (vestibular nucleus): balance & posture Vermis (fastigial nucleus): truncal and head movements Intermediate zone (interpositus nucleus): gait, feedback control of voluntary movements Lateral hemispheres (dentate nucleus): interact with "upstream" cortical areas; control of complex, adaptive hand & eye movements (most developed in primates). One Function - Cerebellum’s Role in Motor learning: generation of motor programs for acquired skills. Need to compare “Efference Copy” sent from Motor Cortex to Sensory input coming from the body. Cerebellum acts as a comparator to the two signals to detect error and adjust subsequent movement. Absence of motor learning in person with cerebellar lesion  Cerebellum’s Role as a Comparator in Motor learning: Efference Copy (done via brainstem nuclei) (sensory information back) https://www.brainkart.com/article/Motor-Functions--Motor-Areas-Of-The-Cerebral-Cortex,-Descending-tracts,- Cerebellum_21819/ CNS - Portion 4: The Brainstem Mescencephalon/ Superior portion of Brain Stem: Mid-brain - Involved with associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and temperature regulation. Cerebral Peduncle (Crus Cerebri) – Motor tracts descending from pyramidal system (motor cortex). Superior Cerebellar Peduncle: connects cerebellum to mid-brain. Substantia Nigra: Houses neurons that produce neurotransmitter Dopamine. Tegmentum: Contains Red Nucleus and Reticular Formation. Integrates information from Cerebrum and Cerebellum and issues involuntary commands to back musculature to maintain posture during standing, bending at the waist and walking. Nuclei for 2 cranial nerves (CN III- Ocularmotor) and CN IV (Trochlear) are located in the mid-brain Tectum: Contains Superior Colliculi (Visual Reflex Centres – help track moving objects, control turning of eyes/head to visual stimuli) and Inferior Colliculi (Auditory Reflex Centres – reflexive turning of head/eyes to loud sounds).  Pons 1. Sensory and Motor Nuclei of Cranial Nerves (V, VI, VII, VIII (in part)) 2. Nuclei involved in respiration (apneustic and pneumotaxic centres 3. Nuclei and tracts to and from Cerebellum (links cerebellum to brainstem, cerebrum and spinal cord 4. Ascending, Descending and Transverse Tracts (links nuclei in pons to cerebellum)  Medulla Oblongata 1. Reticular formation: Nuclei for controlling autonomic function like: Cardiovasular centre: (adjusts heart rate, strength of cardiac contractions, flow of blood Respiratory rhythmicity centre: sets the pace of breathing 2. Sensory and Motor Nuclei of Cranial Nerves (VIII (in part), IX, X, XI, XII) 3. Relay station along Sensory and Motor Pathways (gracilis and cuneatus nuclei, solitary nucleus (visceral), olivary (sensory inputs to cerebellum)  Cranial Nerves “Oh, Once One Takes The Anatomy Final, Very Good Vacations Are Heavenly” CNS– Portion 5: The Spinal Cord : Anatomy of the spinal cord Note a few things about The cord: - The cord itself ends at the level of L1- L2. (This is not the same in all animals) - The percentage of the transverse slices made up of grey matter versus white matter at the different sections of the cord (cervical, thoracic etc.) - The “shape” of the gray matter at each section. - Note the location of the dorsal root ganglion (this is where the cell bodies of the sensory afferent neurons are located). - The fact that while there is 7 cervical vertebrae, there is actually 8 cervical spinal roots. Organization of a Spinal Cord Segment: Afferent: Sensory input coming into the spinal cord and up to the brain. Efferent: Motor output coming from the brain and spinal cord and out to the periphery. Upper and Lower Motorneurons – Generating Movement Upper motor neuron also known as Pyramidal Tract Neuron (PTN). In CNS. Lower motor neuron also known as Alpha (α) motor neuron. Axons are in PNS.  Motor Unit and Lower Motor neurons - Motoneuron: final synapse from spinal cord to muscle/gland - Motor Unit = motoneuron and all the muscle fibers it innervates - Motoneurons organized in pools in spinal cord enlargement -Longitudinal -Organized by muscle they innervate - (Note, this work was done on cat spinal cord) Yakovenko S et al. J Neurophysiol 2002 Location of Different Types of Neurons in Gray Matter Somatotopic Organization Location of Different Types of Neurons in Gray Matter Rexed Lamina: I-VI – Dorsal Horn – Sensory/Pain VII, X – Intermediate Zone VIII – Motor Interneurons IX – Motor Neurons  Important Note: What is being presented in the next slides is a relatively simplistic view of the spinal cord, which makes it somewhat easier to comprehend. In truth, each neuron in the spinal cord will be receiving multiple inputs, from multiple places. An example, taken from D.A. Winter’s “Biomechanics and Motor Control of Human Movement” (Wiley, 2009) illustrates just how many inputs can affect a motor neuron’s output and where that then can go for voluntary movement. Spinal Pathways: Afferent and Efferent Nerve Fibre Size and Related Functions: Nerves from different receptors or to different effectors can be differentiated based on diameter, conduction speed and function. These differences in size, conduction velocity, myelination, etc. can affect how signals are transmitted to and from the spinal cord and up to the brain.  SPINAL CORD PATHWAYS central gray matter: motoneurons, interneurons, dendrites white matter: tracts, either descending (motor) or ascending (sensory). Sensory Motor ASCENDING TRACTS DESCENDING TRACTS Dorsal (posterior) columns: (Medial Leminiscal Pathway) Gracilis (from leg) Cuneate (from arm) Lateral (crossed) corticospinal (pyramidal) tract Spinocerebellar Rubrospinal tract tracts: from red nucleus in midbrain dorsal ventral Reticulospinal tracts from brainstem Vestibulospinal tract from brainstem Spinothalamic tract Anterior (direct) corticospinal Extrapyramidal Tracts for (Pain Pathway) (pyramidal) tract unconscious automatic movements Corticospinal Tract (used in the conscious generation of movement) Pyramidal Decussation at lower end of Medulla Proportions of different branches of tract Connections in the Brain Influencing Output to Spinal Cord The Primary Motor Cortex (PMC) receives input from many areas of the Brain that both in a feed forward and feedback manner that can influence the output to the spinal cord for generation of movement. These can include: Motor Association Areas (Supplementary and Premotor), Somatosensory Cortex, Visual Cortex, Cerebellum, Basal Ganglia, Prefrontal Cortex and Cerebellum, as well as others.  Transcranial Magnetic Stimulation (TMS) Motor Cortex Corticospinal peak Spinal Cord Tract 0.4 MEP (mV) 0.0 peak -0.4 0 50 100 Motoneurons Time (ms) Muscle TRANSCRANIAL MAGNETIC STIMULATION TMS Video Cutaneous and Musculo- Sensory Receptors: Different Sensory endings register different types of sensation: Free Nerve Endings: Touch and Pressure Meissner’s Corpuscle: Highly developed spatial decernment of touch/texture Merkel’s Disk: Continuous Touch Ruffini End Organs: Continuous Touch and Deep Pressure sensations Pacinian Corpuscles: Vibration Muscle Spindles: Length of Muscle and Rate of Change of length of Muscle. Golgi Tendon Organ: Force in Muscle Cutaneous Muscular Sensory Regions of the Body: Dermatones Sensory Nerves, carrying information from the various skin sensory receptors, tend to be carried to the spinal cord, via the dorsal root nerves, corresponding to different areas of the body. These regions are known as Dermatones. For the surface skin of the face, the sensory information is carried into the brain stem via the three branches of the Trigeminal Nerve (Cranial Nerve V) Figure 18-4 Dorsal Column-Medial Lemniscal Pathway: (touch, pressure, proprioception) DC-MLP: Large-diameter sensory afferents enter the ipsilateral dorsal column and without crossing ascend to the medulla where they end in the first relay station (1st order sensory neurons) Neurons from medulla relay station give rise to axons that cross over to other side of medulla and then synapse onto thalamus (second order sensory neurons) Neurons from thalamus then project to somatosensory cortex (layer 4) where stimulus is perceived (third order sensory neurons) Spinothalamic Pathway (pain and temperature) Small-diameter nociceptive afferents enter the spinal cord and synapse onto a relay station in the dorsal part of the spinal cord (1st order). Neurons from this spinal relay station cross over to the other side of the spinal cord within a segment or two and project to thalamus (2nd order). Like in the MLP, neurons from the thalamus then travel to layer 4 of the sensorimotor cortex (3rd order) Note: The cross-over at spinal level of pain/temperature pathways differs from the cross-over of dorsal column pressure/touch/kinesthesia pathways, which doesn’t occur till the medulla. This leads to important clinical differences. Spinothalamic Pathway (pain and temperature) Lissauer’s Tract Dorsal Root Substantia Ganglion Gelatinosa Dorsal Column-Medial Lemniscal Pathway vs. Spinothalamic Pathway Note: -Point of decussation -medulla vs spinal cord -Size of fibres -large vs small -Amount of myelination (speed) -Thick vs thin/none -Both to thalamus (sensory relay station) -Both to S1 (primary sensory cortex) and other sensory areas in brain -Spinothalamic also to insular cortex (perception, fear, emotion, memory)  Spinal Reflexes: Reflexes are fast, automatic responses to specific stimuli. Different stimuli can produce different responses. The components of a reflex consist of: A stimulus that activates a receptor (can be in skin, muscles, eyes, ears, nose, mouth, etc.) Activation of a sensory neuron by that receptor. Information Processing: This can occur in the spinal cord, or for some longer responses, up in the brain stem, and higher (difference between spinal reflexes and cranial (cortical) reflexes). The distance the signal has to travel Illustration of Descartes’ and the number of synapses it has to cross (dependent on concept of reflex activation the number of interneurons included in the reflex loop) will affect the timing of the reflex. Activation of a motor neuron. Response of a Peripheral Effector (muscle, gland).  The Stretch Reflex: Negative Feedback Pathway Dorsal Root Ganglion Monosynaptic Pathway – only 1 synapse in pathway Disynaptic Pathway – goes through Note: Both sensory axons interneuron, therefore 2 synapses to and motor axons could be cross traveling in same nerve (not shown in picture) Monosynaptic Tendon Tap versus Electrically stimulated Hoffman (H) reflex In Research Labs and Clinical facilities, there is a test for looking at the monosynaptic reflex loop that is a bit more precise. The H-reflex is generated by the electrical stimulation of afferent axons arising from muscle spindles. This is a synchronous activation of the axons, as opposed to the asynchronous activation that arises from a tendon tap. - Allows for a cleaner signal to be generated and examined. See a better indication of timing and amplitude of the reflex, than can be used for measure of various conditions in normal and pathological conditions. Note – M-wave listed on bottom figure is due to a stimulation of axons from the lower motor neurons in spinal cord – directly activating muscle fibers, and is not considered a reflex.  The Flexor-withdrawal reflex This reflex pathway affects muscles at multiple joints by synapsing on motor neurons at different levels of the spinal cord. The Crossed-Extensor Reflex: Spinal Reflexes not only can activate reflexively muscles of the same limb, but can also send information across (and up or down) the spinal cord into other limbs. Example: Crossed Extensor Reflex: While the flexor reflex is withdrawing the leg that has encountered the unknown or painful stimulus, the extensor muscles of the other leg are activated (about 0.2 to 0.5 sec after the flexor reflex is activated), to accept the weight of the body and keep the person upright, as well as to push the body away from the painful stimulus. Central Pattern Generators: - Group of Neurons in Spinal Cord that generate rhythmic, oscillating patterns of activity. - Seen for walking, swimming, breathing, etc. - For normal walking, seem to be activated by tonic input from Mescencephalic Locomotor Region (MLR) of Reticular Formation in Brain Stem. - Also receives input from sensory afferents to help control and modify pattern. Interneurons in spinal cord – for walking, distributed along spinal cord for coordination. Motor Neurons to muscles Walking in trained spinalized cat  Epidural stimulation of spinal cord to induce locomotion https://www.cnn.com/2022/02/07/health/spinal-cord- stimulation-study/index.html Limbic System and Emotion: Physiological responses that occur more or less unconsciously when the brain detects certain challenging situations. Automatic physiological responses that can involve changes in arousal levels, attention, memory processing and decision strategy in the brain, with changes in endocrine, autonomic and musculoskeletal responses in the body. Different from “feelings” (conscious experiences that may or may not accompany these bodily responses) Neural Control of Emotional Response: Sensory Emotion Hypothalamus Spinal Cord and Effector Emotional Systems Systems and Brain Stem Autonomic Ganglia Cells Responses Somatic Motor Nerve Skeletal Muscle Behaviour (freezing) Smooth or Cardiac Autonomic Muscle Nerve Autonomic Emotional Activity (rise Stimuli in blood pressure) Endocrine Gland Hormone Release (stress Pituitary hormones Blood Vessel Hormone Some of the responses associated with Fear Figure adapted from Kandel, E.R, Schwartz, J.H., Jessell, T. M., Siegelbaum, S. A., and Hudspeth, A.J., Principles of Neural Science, 5th Edition, 2013,.  The Limbic System: the “Motivational System” “Visceral Brain” made up of various areas in the medial parts of the frontal and temporal lobe. establishes emotional states links conscious/ intellectual functions of the cerebrum with unconscious/automatic functions of the brainstem facilitates memory storage and retrieval Cingulate gyrus: heart rate, BP, cognitive and attentional processing Fornix: connects hippocampus to mamillary body (memory function related to smell) Dentate gyrus: new memories, happiness Parahippocampal gyrus: formation of spatial memory Amygdala: Involved in motivationally Mamillary Body: process of recognition significant stimuli for reward and fear; also in memory. formation and consolidation of memories associated with emotional events. Memory: The Hippocampus – Where we attain and access memories from: The hippocampus is the part of the brain that is involved in memory forming, organizing, and storing. It is a limbic system structure that is particularly important in forming new memories and connecting emotions and senses, such as smell and sound, to memories. The hippocampus is a horseshoe shaped paired structure, with one hippocampus located in the left brain hemisphere and the other in the right hemisphere. The hippocampus acts as a memory indexer by sending memories out to the appropriate part of the cerebral hemisphere for long-term storage and retrieving them when necessary. The hippocampus is involved in several functions of the body including: Consolidation of New Memories Emotional Responses Navigation Spatial Orientation Long Term Potentiation (LTP): Cellul