Final Notes on Neurotransmitter Networks and LSDS - PDF

# Final Notes Lectures 12-22 ## Thursday 7:00 pm - 9:00 pm ## Final Exam: Dec 5, 20** # Lecture 12: Neurotransmitter Network **Recap** * Neurons aid in information flow in the nervous system (designed for information flow and speed). * Neurons are built to signal specific target cells with a spe...

# Final Notes Lectures 12-22 ## Thursday 7:00 pm - 9:00 pm ## Final Exam: Dec 5, 20** # Lecture 12: Neurotransmitter Network **Recap** * Neurons aid in information flow in the nervous system (designed for information flow and speed). * Neurons are built to signal specific target cells with a specific neurotransmitter. * Myelination occurs in both PNS and CNS and is done to increase electrical impulse speed. * Astrocytes are very important for communication (CNS). * BBB = Blood Brain Barrier * PET = Positron Emission Tomography. * GABA = Gamma-Aminobutyric Acid. The BBB protects our brain from bacteria and toxins, but remains semi-selective to certain essential compounds and some drugs. ## Phineas P. Gage 1823-1860 * Case displayed early evidence that different areas of the brain are networked to create our personality. * Most of his frontal lobe was destroyed. * He recovered, but his personality changed for the worse. * The brain is networked in a way that makes it responsible for creating emergent properties such as personality, rational decision and the processing of emotion. ## Imaging Techniques * **PET** - tracks glucose uptake * **fMRI** - tracks blood flow (deoxygenated magnesis) Unpaired electrons are weakly attracted to the magnetic field. Areas of activity can stretch across different regions of the brain. ## Phenylalanine Hydroxylase Pathway (PAH) Normally: * Converts phenylalanine to tyrosine. * Removes excess phenylalanine and enables tyrosine production. Affects 1 in 12,000 infants in Canada. **PKU:** A mutation in the PAH gene reduces the amount of the enzyme which converts phenylalanine to tyrosine. This leads to decreased dopamine and serotonin in the brain. ## Health Implications of Altering the PAH Pathway **Dopamine ↓** **Behavioral symptoms:** * ADHD * Anxiety * Impulsivity * Low motivation and self-esteem **Serotonin ↓** * Mental illness. **Treatments for PKU:** * Diet with low phenylalanine intake. ## Neurotransmitter-Driven Networks Networks are identified by neurons using the same neurotransmitter. * **Norepinephrine network** * Modulates: * Attention * Memory * Pain * Arousal * Sleep-wake * Anxiety * Mood * Learning * Psychostimulants include: * Methamphetamine * Ritalin (similar to Adderall) "smart drugs" nootropics, ADHD * Caffeine * **Serotonin network** * Modulates: * Pain * Sleep-wake cycle (melatonin is its derivative) * Emotion * Contributor to feelings of well-being and happiness. * Antidepressants increase serotonin levels. * Low serotonin associated with migraines. * **Acetylcholine Network** * Modulates: * Arousal * Memory * Sleep-wake * Sensory information * Learning * Cholinesterase inhibitors used for Alzheimer's disease. * Enzyme that rapidly breaks down acetylcholine in the synapse. * **Dopamine Network** * Modulates: * Motor control * Reward/pleasure centers * Amygdala, prefrontal cortex * Feel-good/pleasure network. * Associated with addictions. * Can be increased by drugs such as cocaine. * Increased by natural endorphins. Exercise, high food? **Massive loss of cholinergic neurons** * Low acetylcholine levels. * Loss of dopamine network occurs in advancing Parkinson's. * Dopamine agonists are used to increase the lifespan of individuals with Parkinson's. * Too much medication can cause hypersexuality and problems controlling impulses. **GABA is inhibitory, turns off the signal before it reaches the post-synaptic cleft, meaning dopamine keeps being released.** * Inhibited by heroin or morphine. * Drugs: * Heroin/morphine: * Inhibit GABA - dopamine signals continue to be sent past homeostatic levels (rush). * Bind to GABA receptors, preventing GABA's inhibition of dopamine. * Cocaine: * Causes the release of dopamine. * Blocks the reuptake of dopamine causing lasting effects. # Lecture 13: Endocrine System Overview **The Role of Hormones** Modulate: 1. Growth and development. 2. Homeostasis. 3. Reproduction. And many other things in the CCN, neurodev, and immunity. * Come from endocrine glands, nerves. * Target organs that produce hormones as a secondary function: * Adipose tissue. * Skeletal muscle. * Nervous system and endocrine system = foundation of CCN. ## Nerves Release Their Neurotransmitters Directly into the Bloodstream (Neurohormones) ## All Primary Endocrine Glands and Secondary Endocrine Tissue Are Innervated by Neurons of the Autonomic Nervous System. Neurotransmitters can modulate hormone secretion! * **Norepinephrine:** epinephrine & insulin. ## CNS and PNS Neurons Have Receptors for Many Hormones. * Insulin, estrogen, testosterone. ## Anterior Pituitary Hormones * Acts like a gland - contains endocrine cells that release many hormones. * Makes its own hormones, but the hypothalamus controls the release of them. **Anterior Pituitary Acts Like a Gland - Contains Endocrine Cells That Release Many Hormones** Stimulates release * **GHPH** * **PRH** * **PIH** * **TRH** * **CRH** * **GHRH** * **GHIH** * **GnRH** * **TSH** * **ACTH** * **GH** * **LH** * **FSH** * **EPO** ## EPO Causes ↑ RBC * Dehydration, causing thicker blood. * Performance enhancers, prohibited. ## NT's vs. NH's **Neurohormones:** NTs with downstream effects on hormone secretion. * **NTs:** * Chemical messengers released by neurons that transmit signals to adjacent cells(within the nervous system). * Act at synapses - the junctions between nerve cells and their target cells (neurons, muscle cells, or gland cells). * **NH's:** * NT's that are released into the bloodstream by neurons. * Travel to distant target cells or glands to exert their effects. * Act more broadly on the body. * Influence the endocrine gland function and the release of hormones. ## Posterior Pituitary Hormones Releases: **Oxytocin** * Made in the hypothalamus. * Not really an endocrine gland - more like a connection of nerve endings that release oxytocin and ADH into pituitary circulation (neuroendocrine). * Uterine contraction, milk ejection, positive mood (bliss). **ADH (Antidiuretic Hormone)** * Made in the hypothalamus. * Fluid retention by the kidney ## Oxytocin * Implicated in social cognition and behavior (low levels = autism). * Depression, anxiety, and stress = low oxytocin. * Levels increase to initiate milk ejection for breastfeeding. * Breastfeeding has a calming effect on the mother. * Low oxytocin = lower pain tolerance. ## ADH (Vasopressin) * Regulates BP and blood volume. * ↑ ADH release in response to severe blood loss or dehydration. * This is because you want to retain as much water in your body so your cells are hypertonic. * Hypovolemic shock is dehydration due to blood loss - the heart is unable to pump enough blood. * ↑ ADH release for heart failure (supporting BP in response to reduced blood flow) leads to water retention and fluid overload to help blood movement. * Can worsen heart failure symptoms. # Lecture 14: LSDS **Local Support and Defense System** ## First Line: Nonspecific Physical and Chemical Surface Barriers ## Second Line: Nonspecific Internal Cellular and Chemical Defense ## Third Line: Immune Response - Adaptive Immune System (Has a memory) * B-cell or B-cell response. * Cell-based defense - phagocytosis ## Phagocytes * **Neutrophils:** first responders - consume bacteria. * **Macrophages:** consume almost anything. ## Non-Phagocytes * Target pathogens/invading organisms that are too large for phagocytosis * Eosinophils: Discharge enzymes that digest foreign cells. * **Natural killer cells:** constantly circulate and "patrol" for non-self. Target cancer cells. * Release perforin and proteases to destroy cells. ## Inflammation * Immune system secretes histamine, leading to an inflammatory response. * Blood vessels widen (vasodilation) - increased blood flow, redness, warmth. * Heat travels to the surface - sweating. * Capillaries become more permeable. * **Swelling:** fluid containing defensive chemicals speeds up healing, reduces movement, allowing healing. To treat - think **RICE**: * **R**est * **I**ce * **C**ompression * **E**levate ## Complement Destroys Bacteria ## Phagocytes Engulf Bacteria ## Inflammation Occurs In Response To Tissue Damage & Stress * **Bruises:** torn tissue, delayed onset muscle soreness (acute inflammation) * **Disease states:** arthritis, obesity (chronic inflammation) ## Fever * Infection → Fever * Increase in body temperature to fight off foreign bodies. * Some fevers have unknown origins - endocrine disorders, cancer, drug use. ## Innate Immune System * Natural, not learned. ## Protein-Based Defense * Non-specific and specific systems. ## Complement System * **20+ proteins mainly synthesized in the liver (released in inactive forms).** * Deactivated by native proteins in the blood and the surface of the body's own cells. * Become activated by: 1. Polysaccharides on bacteria's surface. 2. Antigen/antibody complexes (adaptive immune response). * Promotes inflammation and attacks the pathogen's cell membrane. ## Defense - Lysis by the Complement System ## Functional Cells * **Parenchymal cells:** principal "functional portion" of the tissue. * **Most prominent cell type (the majority of mass).** ## Stromal Cells **Non-parenchymal cells** * Support parenchymal cells forming the LSDS. ## Examples * Neurons. * Astrocytes. * Gap junctions. ## LSDS Functions * LSDS is always on - watching and waiting. * Supports the parenchymal cells and communication and defense. * **Local tissue damage by processes that are not due to infectious pathogens.** * **Normal tissue turnover:** * Cell death. * Tissue repair, regeneration during wound healing. * **Looks out for appearance of transformed cell populations (cancer).** # Lecture 15: LSDS P.2 ## Displays Both Self and Non-Self Antigens * Used in recognition of pathogens. * Attacks in immune responses. ## Third Line of Defense: Adaptive Immune Response * **Proteins expressed on the surface of a cell.** * **Support:** A self MHC marker (labels the body's cells as self or "friend") * **Attack:** An antigen is a molecule, often on the surface of a pathogen. The immune system recognizes it as a specific "foe." ## Attack Process 1. Threat: Invader enters body - displays MHC with antigen on the surface. 2. Detection: Macrophage encounters the invader (antigen), engulfs and digests it. 3. Alert: Macrophage presents the antigen to a helper T-cell and secretes a chemical that activates the T-cell. * **Recognition** * **Verification (ensures it's not self)** ## Memory * Helper T cells (stored forever in the bone marrow and thymus) * Cytotoxic T cells * B cells ## Negative Feedback * Neutralize foreign proteins. * Trigger release of complement. * Attract macrophages. ## T Suppressor Cells: Suppress Activation of the Immune System * Production of the helper T-cells. * Allows tolerance to self-antigens. ## Too Little? * Autoimmune diseases, allergies, inflammation. ## Too Much? * Cancer? * Increased occurrence of infectious disease. ## Antibody Responses * B cells mature in bone marrow. * T cells mature in the thymus. ## The Threat * Antigen ## Detection * Engulfed by a macrophage. * The macrophage presents the antigen to identify the invader. ## Alert * The helper T cell divides. ## Effector Helper T-Cell * **Alarm** * **Building** * **Defense** ## Antibody Mediated Response * The naive B cell activates into a: * Plasma cell * Effector B cell * The plasma cell secretes antibodies. ## Cell Mediated Response * Naive cytotoxic T cell. * The naive cytotoxic T cell: * Divides - amplification * Activates into a memory cytotoxic T cell (more robust) * Activates an effector cytotoxic T cell. * The effector cytotoxic T cell doesn't engage with the antigens but causes the secretion of * Antibodies, which engage with the antigens. ## Pathogens or Foreign Toxins * Antibodies will bind to the specific antigens that initiate the above events. * Provide a quick response in future antigen encounters. ## Targets * Cells infected with intracellular pathogens. * Cancer cells * Organ transplant cells. ## Effector Cytotoxic T-Cells * Kill by chemical means, for example, perforins punch holes in the target cell membrane. # Lecture 16: Cardiovascular System Overview * Cardiovascular system: lymphatic (circulatory system) * Heart - muscular pump. * Blood vessels - conduits for blood flow. * Blood - Carries materials intercellularly. ## Communication * Lymph. * Cerebrospinal fluid (CSF). * Extracellular fluid. * RBC. ## Diseases * Heart attack. * Hypertension (high BP). * Myocarditis. * Stroke. ## Blood Vessels Conduct Blood in Continuous Loops * Deoxygenated blood returns to the right side of the heart (enters the right atrium) from venous circulation. * Atria receive blood. * The heart contracts, pumps blood to the ventricles. * Right ventricle - to the lungs! - to the left atrium! * Oxygenated blood leaves the left ventricle via the aorta. * Note the deoxygenated blood in the pulmonary artery and the oxygenated blood in the pulmonary vein. ## Pump Blood to Whole Body * Arteries (thickest) * Smooth muscle. * Handle pressure. * Away from the heart (deoxygenated). ## Atherosclerosis - Blockage (Plaque) ## Arterioles * Within arteries. * Pressure is less intense. * Regulate BP (vaso regulation). * Controlled, smooth muscle contraction. ## Capillaries (A Cell Thick) * No muscle. * No diameter control. * Cannot withstand ↑ pressures. ## Venules * Main lymphocyte cite crossing from blood to lymph nodes via lacteals. ## Veins * Bring blood from the body to the heart by a pressure gradient between both sides of the heart. * Easy expansion, fairly muscular. ## Facilitated by: * Movement of the thoracic cavity during breathing. * Contracting skeletal muscles. ## Valves (Preventing Backflow) * Varicose veins: * One-way valves malfunction. * Allow backflow, pooling in the vein. * Occurs in the saphenous vein. ## Basic Anatomy of the Heart * Myocardium - myogenic (doesn't need brain signals to operate). * Neural conduction: gap junctions - contracts as a unit (synced). ## Metabolism * Very high oxidative capacity. * High mitochondria content. * Fatigue resistant. ## Connection * High SA + small diameter = rapid conductance (aorta). * Large SA + low diameter (capillaries) = optimal exchange. ## Cardiac Output - Amount of Blood Pumped by Heart/Min. * Heart Rate x Stroke Volume ## Stenosis - Narrowing of a Valve * Calcification. * Scarring from rheumatic fever. * Congenital. * Causes fatigue and shortness of breath, exercise intolerance. ## Solutions * Can use pig heart valves. * Artificial valves - very durable (carbon, titanium). * Can cause clots. * Can get stuck. * Vulnerable to back-flow. ## Lecture 17: Cardiac Cycle ## Preload Initial stretch of the cardiac myocytes prior to systole (related to ventricular filling). ## Afterload Diastolic arterial pressure * The pressure the heart must work against to eject blood during systole. ## Neural and Endocrine Signals Control Strength and Rate of Contractions * Sympathetic: ↑ heart rate (epinephrine). * Parasympathetic: ↓ heart rate (acetylcholine). * Epinephrine ↑ strength of systole. ## Causes High BP and Stenosis * Causes inflammation (thickening of wall). * Leads to heart attacks and strokes. ## Athletes Heart * Higher endurance. ## Conduction through the Heart * Nodes: * SA node (heart's natural pacemaker). * AV node. * Nerves: * Connected by intercalated discs to work together. * Bundle of His. * Bundle branches. * Purkinje fibers. ## Hypertrophy - A Sign of Being Overworked (Too Jacked) * Endurance Athletes - mostly in LV chamber, ↑ in cardiac output. * Weight Lifters: LV wall and septum thickness - need to overcome afterload. # Lecture 18: Gastrointestinal Overview ## GI Tract * Oral cavity * Esophagus * Stomach * Small intestine * Colon (large intestine) * Rectum * Anal sphincter ## Sphincters Partially Segregate Function within the Tube * Upper esophageal sphincter. * Lower esophageal sphincter. * Pyloric sphincter. * Ileocecal sphincter. ## Greatly Exposed to External Factors * To fight this: * Vomit. * Diarrhea. * Localized tears in the intestinal mucosa. ## Basic Processes 1. **Motility** (through GI tract) 2. **Secretion** (enzymes) 3. **Digestion** 4. **Absorption** (water, nutrients) ## Properties * Super long. * Tons of villi and microvilli to increase surface area. * ↑ re-absorbable food holding time. * Gut microbiome protects against pathogens and toxins entering or inside the GI tract. * Intrinsic or enteric nervous system to control and coordinate functions. ## Cephaic Phase: Digestion and Absorption * Chemical and mechanical digestion (mouth) * Chewing (mastication). * Secretions are in response to sensory stimuli (see, smell, taste) prepares the GI tract for food processing. * Salivary secretion is under autonomic control (SNS and PNS). * Softens/lubricates food (bolus). * Carb and fat digestion (enzymes provided). Highest in infancy. ## Secretory Cells of the Gastric Mucosa ## CPNS Influence * Increase intestinal and gland activity. * Relaxes sphincter muscles. ## Acetylcholine * Plays a huge role in the GI tract. ## Small Intestine Accessory Organs * **Pancreas:** Main enzyme contributor for digestion. * Released in inactive form (ex: trypsinogen). * Activated in the small intestine by enterokinase in the *brush border* of the duodenum to form trypsin - for protein digestion. * **Gallbladder:** Stores bile produced by the liver (fat digestion). ## Absorption in Small Intestine * Secretions into the lumen of the small intestine upon the opening of the pyloric sphincter and chyme entering the upper duodenum. * Bicarbonate (intestinal epithelium/pancreas). * Digestive enzymes (pancreas). * Bile acids (liver/gallbladder). ## Digestive Enzymes Anchored on the Luminal Surface of the Small Intestinal Epithelial Cells: 1. Dissachrides. 2. Amino peptidase. # Lecture 19: P.2 ## Lactose Deficiency Causes Lactose Intolerance ## Carbohydrate Absorption and Transport * Maltose, sucrose (glucose + fructose), and lactose (glucose + galactose). ## Glucose and Galactose are Absorbed by Active Transport ## Fructose is Absorbed by Facilitated Transport * Through the villi (brush border) * Through the intestinal portal vein into the hepatic liver. ## Proteins on the Other Hand... Do Not Normally Get Absorbed into the Hepatic Portal Vein ## Only Time It Would Get Absorbed * Leaky gut (prominently manifest with obesity). ## Problem with Tight Junctions * Protein would get into the bloodstream - body labels it foreign, and then the immune system responds. ## Large Intestine: Digestion & Absorption * Ilial chyme comes in from the ileocecal valve. ## Large Intestine Parts 1. Caecum. 2. Ascending colon. 3. Transverse colon. 4. Descending colon. 5. Sigmoid colon. 6. Rectum. ## Absorbs: * Water. * Any unabsorbed nutrients. * Hormones and chemical messengers (biotic). * Double fiber (prebiotic) & digested - insoluble fiber. * Microbes (probiotics). * Cellular debris. * Excretion from the liver. ## Microbes Digest and Absorb What Prebiotics They Can * In a process called fermentation, produces short-chain fatty acids. * Microbes produce vitamins as a metabolic byproduct (hormone like activity). * Produce gases. * Multiply (microbes). ## Lecture 20: Energy Distribution Overview ## Energy * The capacity to do work. ## ATP * The medium of energy exchange (energy currency). ## Facts * Acetyl-CoA leads to the production of ATP. * Glucose and fatty acid metabolism generate most of the ATP. * Some ATP by glycolysis and Krebs. * Krebs uses amnio acids and produces reducing equivalents: NADH, FADH2. * Glycolysis, beta-oxidation, and Krebs produce reducing equivalents: NADH, FADH2. ## Anaerobic Respiration Generates ATP (less) without O2 via phosphocreatine: * PCr + ADP + H+ → ATP + Cr. * Breakdown through glycolysis → pyruvate → lactate → lactic acid - Inefficient, but fast! ## Energy Storage * **Fat** - mostly stored as triglycerides in our adipocytes. * **Carbs** - glycogen: * Liver (most concentrated) * Blood (least). * **Protein** - large potential energy source. * **Protected but used in caloric restriction or starvation.** ## Absorptive State: 3-4 Hours After Meal * Anabolic state. * Macronutrients are stored (anabolism). * Extra calories in the form of glucose and amino acids can get converted to fat. ## Extra Calories are Stored as: 1. Glycogen: Liver (muscles) 2. Triglycerides: Adipose tissue, liver/muscle ## Post-Absorptive State (Metabolism for Energy - Catabolism) * Stored macros are metabolized for energy (catabolism). * Glucose is spared for the nervous system. ## Glucose Regulation via Insulin (After a Meal - Blood Glucose ↑) ## Plasma Glucose ## B-Cells In Pancreas ## Insulin ## Liver ## Muscle ## Adipose Tissue ## Negative Feedback ## Also Glucagon Since ↑ in Insulin ## Lipolysis ## More Glucose is Stored, Less Glycogen is Broken Down into Glucose ## Catabolic State ## Glucose Regulation via Glucagon (Fasting - Blood Glucose ↓) ## Plasma Glucose ## Alpha Cells In Pancreas ## Glucagon ## Liver ## Adipose Tissue ## Negative Feedback ## ↓ Insulin Since ↑ Glucagon ## Glycogenolysis ## Lipolysis ## Breaks Down Triglycerides ## Supply ATP for Nervous System ## ↑ Plasma Fatty Acids ## Glucose Spared # Lecture 21: P.2 ## Regulation of Blood Glucose Levels * Normal glucose range is ~ 4-5.5 (very narrow). ## Fasting Hyperglycemia * Glucose > 7 mM. ## Fasting Hypoglycemia * Glucose ~ 3.5 mM. ## Maintenance * Many cells require glucose. * Maintain osmotic balance. * Hyperglycemia can cause glycosylation of amino acids in: * Kidneys. * Peripheral nerves. * Lens of eye, causing eye damage ## Challenge Energy Distribution: Exercise ## Low Intensity (Walking) * Blood glucose and fatty acids; muscle triglycerides and glycogen. ## Moderate Intensity (Cycling, Jogging) * Muscle glycogen & triglycerides; blood glucose and fatty acids. ## High Intensity (Sprinting) * Muscle glycogen, PCr. * Large anaerobic component. ## Cancer Cachexia * **Long-term fat loss (10-15%).** ## Cancer Cells Divide Rapidly, Causing a Tumor (No Apoptosis) * Tumor cells have high ATP demand to support rapid cell division. * Causes weight loss due to tissue catabolism for ATP. * Skeletal muscle + adipose tissue. # Lecture 22: Lifestyle, Aging, & Disease ## Age Due to Genes * Single nucleotide polymorphisms. * Each SNP represents a difference in a single DNA building block. * Not the only source of genetic variation. Major source that distinguishes one individual from another. ## Polymorphism * Common DNA sequence in the population. ## Age Can Be Due To Mitochondrial Damage * Due to ROS (free radicals, oxygen). * Peroxides. * Superoxide. * Hydroxyl radical. * Singlet oxygen. ## DNA Polymerase Gamma * Replicates and proofreads/repairs DNA. * Errors become more frequent with age, therefore, age. ## Drugs ↑ Insulin Sensitivity * Obesity → Insulin resistant muscles. * ↓ glucose reuptake from the blood. ## Mouse Genetic Model for Aging Based on Mitochondrial Mutations * Mice carry mutations in mtDNA polymerase gamma (POLG) - proofreading activity was lost. * Mt-DNA was error-prone. * Accelerated signs of aging. ## Causative Link Between MtDNA Mutations and Aging Phenotype.