Final exam Flashcards
What are the functions of the GI system?
- digestion - break macromolecules (nutrients) into forms that can be transported across the epithelium
- absorption - transport nutrients, water, ions, vitamins across epithelium
- secretion - release of enzymes into the gut lumen (heavily regulated)
- motility - keep the gut contents moving (heavily regulated)
- maintain water balance - balance between secretion and reabsorption
What are some problems faced by the GI tract regarding its function?
- need to digest marcomolecules but not itself
-break down of barriers? -> peptic, duodenal ulcers - needs to allow entry of digested nutrients but not pathogens
-GI lining is largest area of contact between internal and external environments
-protection from pathogens mediated by:
+ epithelial barrier
+ mucus
+ digestive enzymes
+ acid
+ gut associated lymphoid tissue (GALT) - needs to react to pathogens but not foreign proteins associated with food
Anatomy
- stomach
- small intestine - duodenum, jejunum, ileum
- large intestine - colon, rectum
Muscosal surface anatomy
- mucosa - epithelium, lamina propria, muscularis mucosa
- submucosa - Meissner’s (Submucosal) plexus
- smooth muscle layers - circular muscle, auerbach’s (myenteric) plexus, longitudinal muscle
- serosa
Differences between small intestine and stomach anatomy?
stomach:
-gastric glands
-oblique muscle
small intestine:
-villi, crypt
-Peyer’s patch (in mucosa)
What features increase surface area?
stomach - gastric glands
small intestine - crypts
What are the 2 major patterns of contraction for gut motility?
- peristalis - moving food from mouth to anus (forward movement)
- segmental contractions - mixing/churning, maximizes exposure to digestive enzymes and epithelium (little or no net forward movement)
these occur during/after a meal
Tonic vs. phasic contractions
-most gut muscle is a single unit smooth muscle, connected by gap junctions
-certain regions are tonically contracted for minutes to hours
+ smooth muscle sphincters
+ anterior part of the stomach (keeps food from moving backwards)
-other regions undergo phasic contractions
+ posterior stomach
+ small intestine
Migrating motor complexes
-a series of contractions that begin in the empty stomach and end in the large intestine (~90 minutes)
-“house keeping” function -> sweeps food remnants and bacteria out of GI tract and into the large intestine
-between meals
Slow wave potentials
-slow waves similar to pacemaker potentials in cardiac muscle except much less frequent, and do not necessarily reach threshold
+ below threshold = no contraction
+ above threshold = opening of voltage-gated Na+ channels -> action potentials -> contraction
-degree of contraction is graded according to amount of Ca2+ that enters
+ longer wave = more time for Ca2+ to enter = larger contraction
+ amplitude and duration of contraction influenced by: neurotransmitters (autonomic input), hormones, paracrine factors
Interstitial cells of cajal
-slow wave frequency varies in different regions of the tract
+ more frequent in duodenum vs. stomach
+ set by ‘pacemaker cells’ between smooth muscle layers “interstitial cells of Cajal”
What is secreted?
-water and ions (secreted into lumen then reabsorbed)
-enzymes
-mucus
-bile (from liver)
-saliva
How are water and ions secreted?
-mostly via membrane transporters
-water follows osmotic gradient
-water and ions in some regions can also pass between cells (paracellular pathway)
-similar channels/transports to kidney
transporters:
Na/K ATPase, NKCC cotransporter, Cl/CHO exchanger, Na/H+ exchanger, H/K exchanger
ion channels:
-ENaC, K+ channels, Cl channels (including CFTR)
How is acid secreted?
-secreted by parietal cells
1. CA forms bicarb in pariteal cells
2. basolateral side: HCO3- out and Cl- in
3. apical side: H+ out and K+ in (H+/K+ATPase), Cl- out via Cl- channel
bicarb moving out is absorbed in blood - ‘alkaline tide’ can be measured after a meal
How is bicarb secreted?
-secreted from epithelial cells lining ducts of pancreas -> duodenum to neutralize stomach acid
1. CA (H20 + CO2 -> HCO3- + H+) creates bicarb inside cells
2. basolateral side: Cl- in via NKCC transporter
3. apical side: bicarb secreted via Cl-/HCO3- exchanger, Cl- out via CFTR channel and reenters via Cl-/HCO3- exchanger
How is NaCl secreted?
-secreted from small intestine, colon, salivary glands
1) Na+, K+, 2 Cl- enter via NKCC transporter (basolateral side)
2) Cl- enters lumen through CFTR channel (apical side)
3) Na+ is reabsorbed (Na+/K+ ATPase) (basolateral side)
4) Negative Cl- in lumen attracts Na+ by paracellular pathway and water follows (from basolateral -> apical)
-crypt cells in small intestine and colon secrete ‘isotonicsaline’ that mixes with mucus secreted by goblet cells to lubricate gut contents
How does Cystic Fibrosis effect the pancreas?
-mutation in gene that encodes the CFTR channel
-leads to defects in Cl- (and water) transport
-named for changes in the pancreas
+ fluid-filled cysts and fibrosis (scarring)
mechanism:
1) Cl- not transported into ducts
2) various effects including decreased Na+ and water transport into ducts
3) mucus still produced but greatly thickened due to lack of water
4) blockage of pancreatic ducts
5) exocrine secretions of pancreas not released (bicarb, enzymes)
6) back pressure/inflammation -> damage to pancreas
How are enzymes secreted?
-enzymes secreted by either exocrine glands (pancreas, salviary) or epithelial cells of stomach and small intestine
+ synthesized by rough ER, packed by Golgi into vesicles, stored in cell under signal for release by exocytosis
-enzymes sometimes remain linked to apical membranes by protein or lipid ‘stalks’ (‘‘brush border’ enzyme)
-often released as inactive precursors (zymogens) to prevent auto-digestion
-secretion regulated by neural, hormonal, paracrine signals
+ usually stimulated by PNS stimulation (via vagus)
How is mucus secreted?
-mucus consists primarily of ‘mucins’ -> mixture of glycoproteins
-produced by exocrine cells
+ serous cells in salivary glands
+ mucous cells in stomach
+ goblet cells in intestine
-signals for secretion:
+ PNS stimulation
+ various neuropeptides (of enteric nervous system)
+ cytokines (from immune cells)
-infection and inflammation increase mucus secretion
How is saliva secreted?
secreted by acinar cells
-as it passes through ducts, epithelial cells take back Na+ and secrete K+, so that it eventually resembles intracellular fluid
-ducts have low water permeability, so water remains in saliva -> hypo-osmotic
-signals for secretion:
+ stimulated by Parasympathetic NS, inhibited by Sympathetic NS
Organization of hepatic lobule (bile flow)
How is bile secreted?
hepatocytes -> bile caniculi -> bile ductiles -> common hepatic duct (+ gall bladder) -> common bile duct -> duodenum
How does blood flow work in the liver?
-most absorbed nutrients fromGI system enter capillaries then into hepatic portal vein (fat go into lymphatic system rather than blood)
-xenobiotics (foreign substances) must first pass through the liver before reaching systemic circulation
25% hepatic artery + 75% hepatic portal vein -> sinusoids -> central vein -> hepatic vein
What are the key components of bile?
-bile salts (facilitate fat digetion)
-bile pigments (eg. bilirubin, from Hb breakdown)
-cholesterol
also:
-drugs and other xenobiotics being processed in liver and excreted in feces
Iron and RBC turnover: bilirubin
1) Fe+ from diet
2) Fe+ absorbed by active transport
3) bone marrow uses Fe+ to make hemoglobin (Hb)
4) spleen converts Hb to bilirubin
5) excess Fe+ stored in liver as ferritin
6) liver metabolizes bilirubin and excretes it in bile
7) bilirubin metabolites excreted in urine and feces
-bilirubin or its metabolites are responsible for:
+ normal colour of feces
+ normal colour of urine
-indicators of injury/pathology
+ yellow phase of bruises
+ yellow pigmentation of jaundice (hyper bilirubin anemia)
What is digestion?
combination of mechanical and enzymatic processes
-occurs in mouth, stomach, small intestine
-chewing, ‘churning’ -> expose more surface area to enzymes
+ emulsification via bile -> exposes more surface area for lipid digestion
What is absorption?
crossing the gut epithelium
-mostly in small intestine (some ions/water absorbed in the large intestine)
-use many of the same transporters as the kidney
+ exception: fat enters lymph vessels (lacteals)
Are digestion and absorption related?
not directly related
-influenced by motility and secretion, which are regulated
How does absorption in the small intestine occur?
lumen -> apical membrane -> epithelial cell (enterocyte) -> basolateral membrane -> interstitium -> capillary OR lymph
Carbohydrates
-constitute ~50% caloric intake (mostly starch, sucrose)
-can only be absorbed via a membrane transporter
+ we only have membrane transporters for MONOsaccharides
-artificial sweeteners: typically interact, in some way, with ‘sweet’ receptors, but cannot be digested to a form that can cross enterocytes
How are carbohydrates digested?
glucose polymers - (amylase) -> dissarcharides -> monosaccharides
How are carbohydrates absorbed?
1) glucose/galactose enter with Na+ on SGLT (apical side) and exits on GLUT2 (basolateral side)
2) fructose enters on GLUT5 (apical side) and exits on GLUT2 (basolateral side)
How is protein digested?
1) endopeptidases (aka proteases) digests internal peptide bonds of polypeptides - making smaller peptides
- example of endopeptidases: pepsin (stomach), trypsin, chymotrypsin (small intestine)
2) exopeptidases digest terminal peptide bonds to release amino acids
-examples of exopeptidases: aminopeptidase (from brush border), carboxypeptidase (from pancreas)
products of protein digestion = amino acids, di=peptides, tripeptides
How is protein absorbed?
proteins broken down into peptides
-di and tripeptides cotransport with H+
-amino acids cotransport with Na+
-small peptides are carried intact across the cell by transcytosis
+ normally only occurs in first few hours to days of life prior to ‘gut closure’
Fats
triglycerides (most fat calories are in this form, major lipid in plants and animals)
cholesterol, phospholipids, long chain fatty acids, fat soluble vitamins
-digestion complicated by solubility issues
-leave stomach as large droplets mixed with aqueous chyme
+ low surface area available to interact with enzymes
-broken down into smaller particles through action of bile salts
+ bile salts are derivatives of cholesterol ‘amphipathic’
Bile salts (bile acids)
primary bile acid
modified by gut bacteria -> secondary bile acid-> conjugated in liver -> conjugated bile acid
OR
conjugated in liver -> conjugated bile acid
How is fat digested? (part 1)
-bile salts coat lipids to make emulsions of large droplets
+ hydrophobic side associates with lipids
+ polar side chains (hydrophilic side) associates with water
-pancreatic lipases can act on triglycerides in droplets, aided by colipase from pancreas (break don into monoglyceride and free fatty acids)
How is fat digested? (part 2)
formation of micelles
-all fat is digested in smaller components except cholesterol
-micelles can then move close to the surface of enterocytes (epilthelial cells of SI) and lipids can diffuse across apical membrane into cells
How is fat absorbed?
1) bile salts coat fat droplets
2) pancreatic lipase and colipase break down fats into monoglycerides and free fatty acids stored in micelles
3a) monoglycerides and fatty acids diffuse from micelles across apical membrane into cells
3b) cholesterol is transported into cells
4) absorbed fats combine with cholesterol and proteins in intestinal cells to form chylomicrons
5) chylomicrons removed by lymphatic systems
more details:
-monoglycerides and fatty acids reform into triglycerides in smooth ER
-triglycerides, cholesterol, proteins form chylomicrons, which are packed into vesicles and exocytosed (short fatty acids can travel solo, entering capillaries rather than lymph)
How are nucleic acids digested and absorbed?
digested into nucleotides, then bases and monosaccharides
-bases -membrane transporters
-sugars -same transporters as other monosaccharides
How are vitamins digested and absorbed?
fat soluble (A, D, E, K)
-absorbed in small intestine along with fats
water soluble (C, most Bs)
-typically absorbed in small intestine via membrane transporters
exception: B12 (cobalamin) -participates in metabolic pathways in every single cell, particularly important in RBC synthesis
*absorption (in ileum) requires protein secreted by gastric parietal cells (‘intrinsic factor’)
*deficiency of intrinsic factor leads to deficiency of B12 that cannot be corrected by oral B12 supplementation
How are water and ions absorbed?
absorbed by small and large intestine
1) Na+ enters by multiple pathways
2) the Na+/K+ ATPase pumps Na+ into ECF
3) water and K+ move through paracellular pathway
in general: ions (espNa+) moves across apical side (various transporters); main driver on basolateral side is Na+/K+-ATPase; water follows by osmosis
How are iron and calcium absorbed?
two of the few substances for which intestinal absorption is regulated
-decreased levels -> detector -> signal -> increased intestinal uptake
iron:
-Fe2+ and H+ contransported across apical membrane by DMT1
-heme also transported across apical membrane
-heme broken down (polypherin + Fe2+)
-Fe2+ transported across basolateral membrane by ferroportin (regulated)
calcium:
-paracellular absorption not regulated
-Ca2+ crosses apical membrane via Ca2+ channel
-transport of Ca2+ across basolateral membrane regulated by vitamin D3
Describe long reflexes
integrated in CNS
-sensory info from GI tract to CNS
-‘feedforward’ reflexes that originate outside GI tract
+ include cephalic reflexes in response to sight, smell, thought of food, effects of emotion
-efferent limb always autonomic
+ parasympathetic = excitatory
+ sympathetic = generally inhibitory
Describe short reflexes
integrated in gut in ‘enteric nervous system’ (gut brain)
-neurons in submucosal plexus receive signals from lumen, regulate secretion
-neurons in myenteric plexus regulate motility
Describe reflexes involving gut peptides
-can act locally (paracrine) or travel via blood (endocrine)
+ effects on motility - altered peristalsis, gastric emptying
+ effects on both exocrine and endocrine secretion
-some gut peptides can also act on brain (some even produced there)
What are the similarities between the enteric and central nervous system?
-has intrinsic neurons that lie entirely within the gut (similar to interneurons in CNS)
-releases more than 30 different neurotransmitters and neuromodulators (not epi,NE,ACh but similar molecules used in CNS)
-has glial supported cells (similar to astrocytes of CNS)
-diffusion barrier -> capillaries surrounding ganglia are not very permeable (similar to blood-brain barrier)
-acts as integrating center (gut function can be regulated without CNS)
What was Pavlov’s contribution to the history of gut hormones?
-acid chyme passing into duodenum -> pancretic juice secreted
mechanism?
-vagus afferents from duodenum to brain -> vagal efferents from brain to pancreas -> pancreatic juice secreted into duodenum
-pancreatic secretion was thought to be controlled only by vagus nerve
What was Bayliss and Starling’s contribution to the history of gut hormones?
-carefully dissected away all nerves surrounding pancreas and duodenum
+ put acid in duodenum
+ pancreas still secreted
-hypothesis: acid caused release of signal from duodenum into blood
-tested hypothesis:
+ collected lining of duodenum
+ added acid to it
+ injected it intravenously
+ resulted in pancreatic secretion
-factor from duodenum that stimulated pancreatic secretion = secretin
-general term for blood-borne regulators: hormones
What are the families of gut hormones?
1) gastrin family
-includes gastrin, CCK
-major target are stomach (gastrin), intestine, and accessory organs (CCK)
2) secretin family
-secretin, vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1)
-both endocrine and exocrine targets
3) motilin
-acts on gut smooth muscle
-regulates migrating motor complexes
How does the mouth initiate digestion?
-saliva -> secretion under autonomic control
+ softens and lubricates food
+ digestion: salivary amylase, some lipase
+ antimicrobial: lysozyme, immunoglobins
-chewing (mastication)
-transfer to stomach (deglutition = swallowing)
Describe the swallowing reflex
1) tongue pushes bolous against soft palate and back of mouth, triggers swallowing reflex
2) breathing inhibited as bolous passes closed airway
3) food moves downward into esophagus, propelled by peristalic waves and aided by gravity
-swallowing reflex integrated in medulla
-sensory afferents in cranial nerve IX an somatic motor and autonomic neurons mediate reflex
Transition into the stomach
-lower esophageal sphincter guards entry into stomach
-if LES not closed acid from stomach can splash up into lower esophagus
+ during respiration (when intrathoracic pressure drops)
+ during churning of the stomach = gastroesophageal reflux disease (GERD) ‘heartburn’
Cephalic phase (neural control)
initiated with long vagal reflexe
anticipation/presence of food in mouth -> activation of neurons in medulla -> efferent signals to salivary glands, autonomic signals via vagus to enteric nervous system (gut brain) -> increase motility and secretion in stomach, intestine, and accessory organs
Gastric phase (neural control)
once food enters stomach, series of short reflexes
distention (stretching) or peptides and amino acids -> sensory signal to enteric nervous system -> increased motility and secretion in
stomach, intestine, accessory organs
What are the 3 functions of the stomach?
- storage - neurally mediated ‘receptive relaxation’ of upper stomach
-importance of storage function has been more apparent as gastric surgeries have become more popular
*‘gastric dumping syndrome’ - digestion - mechanical and chemical processing into chyme
-secretions begin before food arrives …
*enzymes, acid, hormones - protection - against microbes -> acid
-self-protection -> mucus-bicarbonate barrier
Functions of gastric secretory products
- parietal cells -> acid
-activates pepsin
-denatures proteins (more accessible to pepsin)
-anti-microbial - chief cells -> pepsin
-endopeptidase (particularly affective on collagen=meat digestion) - chief cells -> gastric lipase
-minor contribution to fat digestion (co-secreted with pepsin) - ECLs -> histamine
-binds to H2 receptors on parietal cells and stimulates acid secretion - G cells -> gastrin
-triggered by long and short reflexes
multiple roles - D cells -> stomatostatin
-stops secretion of acid and pepsin (negative regulator)
Integration of cephalic and gastric phases
1) food or cephalic reflexes initiate gastric secretion
2) gastrin stimulates acid secretion by direct action on parietal cells or indirectly through histamine
3) acid stimulates short reflex secretion of pepsin
4) somatostatin release by H+ is feedback signal that modulates acid and pepsin release
What is the purpose of mucus in the stomach?
bicarbonate barrier - protects itself from acid
breakdown of mucus-bicarb barrier = peptic ulcer
-acid and pepsin damage mucosal surface, creating holes that extend into submucosa and muscularis layers
Prevention/treatment of peptic ulcers
-main treatment was ‘antiacids’
+ substances that neutralized stomach acid
-more modern approaches include
+H2 receptors antagonists -> block histamine
+proton pump inhibitors -> block Na/K ATPase
How are parietal cells stimulated? (acid secretion)
-gastrin, histamine, and ACh (PNS stim) cause H+/K+ATPase expression on parietal cells
Intestinal phase
-stomach produces chyme by actions of acid, pepsin, perastalsis
-intestinal phase begins with controlled entry of chyme into small intestine
-sensors in duodenum feed back to stomach to control delivery of chyme, feed forward to intestine to promote digestion, motility and nutrient utilization
Enteroheptatic circulation of bile salts
bile salts are released into duodenum, absorbed in terminal ileum, enter portal circulation, travel back to liver
-recycled several times during a meal
How are pancreatic zymogens activated?
- pancreatic secretions (including zymogens and trypsinogen) enter lumen of small intestine
- enteropeptidase in brush border activates trypsin (trypsinogen -> trypsin)
- trypsin activates zymogens (zymogens -> activated enzymes)
How does absorption in the small intestine work?
most fluid is absorbed in small intestine
-transport of organic nutrients and ions creates osmotic gradient
-most absorbed nutrients move into capillaries in villi, then into hepatic portal vein
*fats go into lymphatic system rather than blood
xenobiotics (foregin body substances) must first pass through liver before reaching systemic circulation
What is the role of the large intestine?
-removes most of the remaining water -> forms feces
motility:
-ileocecal valve relaxes each time a peristalic wave reaches it (also relaxes when food leaves the stomach- gastroileal reflex)
-segmental contractions with little forward movement except when mass movements occur 3-4 times/day (wave of contractions that send bolus forward trigger distension of rectum -> defecation reflex)
What is diarrhea?
imbalance between intestinal absorption and secretion
- osmotic diarrhea= unabsorbed osmotically active solutes
- secretory diarrhea= bacterial toxins increase CL- secretion eg. cholera
-can be adaptive (flushing out toxin) but can also lead to dehydration and metabolic acidosis
Intracellular trafficking of cholera toxin
-enters cell via pentameric B subunits
-travels in retrograde direction through golgi
-mimics a misfolded protein and gets dumped into the cytosol (normally to be degraded)
-instead A1 subunit (enyzme) modifies Galpha subunit -remains bound to GTP
-constant activation of AC
-persistent elevation on cAMP
-sustained activation of CFTR channel
Why is the frequency of cystic fibrosis so high?
suggestion:
*CF heterozygotes have some advantage over `non-CF’ homozygotes
-heterozygotes have ~ 50% functional CFTRs
*enough for normal function but allows them to resist death by cholera due to reduced Cl-secretion during infection?
*survive to pass on the gene to offspring??
BUT:
*cholera epidemics did not strike Northern Europe until 19th century
RESPONSE:
*CFTR channels involved in other diseases that were around earlier
-bronchial asthma, typhoid fever, …
Homeostatic vs. non-homeostatic eating
homesostatic:
-eating when energy fuels are depleted (metabolically driven)
non-homeostatic:
-eating in absense of hunger
-eating despite large fat reserves
(involves cognitive, reward, emotion factors)
(has neural similarities to addiction = hedonic eating)
Models for regulation of homeostatic eating
2 centres in hypothalamus: ‘hunger/feeding’ centre and ‘satiety’ centre
glucostatic theory:
*intake regulated by glucose levels, monitored by centres in the hypothalamus
-plasma glucose low -> satiety centre suppressed -> feeding centre dominant
lipostatic theory:
*signal from fat stores to brain modulates eating behaviour
1994: discovery of protein hormone synthesized in white adipose tissue = leptin
Leptin and mice
ob/ob mouse = mutation in leptin product
db/db mouse = mutation in leptin receptor
both cause mice to be obese and eat a lot
What signals from gut cause increased appetite?
stomach:
increased ghrelin - secreted by cells of empty stomach
What signals from gut cause decreased appetite?
stomach:
-increased stretch or increased acid
upper small intestine:
-increased CCK (in response to protein/fat)
-increased glucose in lumen
lower small intestine/colon:
-increased peptide YY (PYY)
-increased GLP1
(both triggered by macronutrients in lumen and also neural reflex from upper small intestine)
What is the key neurotransmitter in stimulation of appetite?
neuropeptide Y
What is metabolic rate?
C6H12O6+ O2+ ADP + Pi -> CO2+ H2O + ATP + heat
rate of oxygen consumption?
rate of CO2 production?
-But ratio of CO2produced / O2consumed is different for macronutrients other than glucose
What are the factors that affect metabolic rate?
*age, sex
*lean muscle mass -muscle has higher O2consumption than adipose even at rest
*activity level
*diet (heat production increases after eating, extent depends on what was eaten)
*hormones,gut peptides
*genetics
What are the 3 possible fates of ingested biomolecules?
- metabolized to provide energy to fuel mechanical work = oxodize
2.used in synthesis reactions for growth and maintenance of tissues = build
3.stored as glycogen (liver, skeletal muscles) or fat= store
What are the 2 states of metabolism?
- fed/absorptive state = anabolic, products of digestion being absorbed and used/stored
- fasted/postabsorptive state = catabolic, body taps into stores
What are the nutrient pools available for immediate use?
usually in plasma:
-free fatty acid pool
-glucose pool
-amino acid pool
How do enzymes control direction of metabolism?
- no regulation = pathway cycles bath and forth, no net synthesis of glucose or glycogen
- fed-state metabolism under the influence of insulin = glucose to glycogen reaction increases, enzymes for glycogen breakdown inhibited = net glycogen synthesis
- fasted state metabolism under the influence of glucagon = enzymes that break down glycogen are more active and enzymes that synthesize glycogen are inhibited = not glucose synthesis
What happens to carbs in fed state?
absorbed glucose travels to liver
-70% passes through to other tissues
-30% moves into hepatic cells
+ enters glycolysis (ATP synthesis or stored as glycogen or fat)
What happens to amino acids in fed state?
absorbed amino acids travel to the liver
-some pass through liver (used for synthesis)
-some move out of sinusoids into hepatic cells (for synthesis of liver proteins, enzymes)
if not used for protein synthesis AAs can be deaminated and and their carbon skeletons re-deployed
-converted to metabolites that can be used to generate glucose
-converted to acetoacetate to make fatty acids (ketogenic AAs)
What is a chylomicron?
formed in enterocyte
-cholesterol, TGs, phospholipid plus lipid-binding proteins (apoproteins)
-enter lymphatic drainage, eventually enter circulation
-acted upon by lipases in capillary endothelium
+FFA can be oxidized for energy (most cells)
+FFA plus glycerol can be re-esterified and stored as TG (adipose)
+remaining particles (HDL, chylomicron remnants) taken up by liver
What can the liver do with fat?
-break down fat (βoxidation of FAs)
-store fat (as TGs)
-use cholesterol to form bile salts (release into gut lumen)
-package FAs and cholesterol as LDL particles (release into circulation as sources of cholesterol and FAs)
+ can only be taken into cells by receptor-mediated endocytosis
*protein components (apoproteins) interact with receptors
How is fat synthesized?
1.Glycerol can be made from glucose through glycolysis.
2.Fatty acids made when 2-carbon acyl units from acetyl CoA linked together.
3.One glycerol plus 3 fatty acids = triglyceride (happens in smooth ER).
4.Even with zero dietary cholesterol, cholesterol can and will be synthesized from acetyl CoA
What is the goal of fasted state metabolism?
maintain plasma glucose levels
-achieved through pathways that yield glucose or ATP:
glycogenolysis
lipolysis
oxidation of amino acids
gluconeogenesis
Overview of fasted state metabolism (what happens in each cell type?)
1) liver glycogen -> glucose
2) TGs in adipose -> glycerol + FFAs -> enter blood
3) muscle uses glycogen for energy and also uses fatty acids and break down their proteins to amino
acids that enter blood.
4) brain only uses glucose and ketone bodies for energy
Glycogenolysis
breakdown of glycogen
most glycogen becomes glucose 6 phosphate:
-splitting off glucose by addition of Pi (most)
+ only liver can remove Pi to create free glucose
-splitting off glucose then spending an ATP to phosphorylate
*muscle can contribute to plasma glucose only indirectly by exporting pyruvate or lactate
Amino acid catabolism
-free amino acid pool is usually used for ATP production during fasted state (proteolysis- break down of proteins only occurs during extended fasts)
-amino acids are deaminated and create intermediates that can:
+ directly enter glycolysis or krebs cycle
+ be sent to the liver to be converted into glucose (gluconeogenesis)
How does lipolysis work? (fat breakdown)
1) lipases digest TGs into glycerol and FFAs
2) glycerol becomes a glycolysis substrate
3) B-oxidation chops 2 acyl units off FA
4) acyl units become acetyl CoA and can be used in krebs cycle
What is ketogenesis?
formation of ketone bodies
-occurs when lipids are broken down faster than acetyl CoA can be used in krebs cycle
-can enter blood and provide brain with energy during times of starvation
-typically generated by low carb, high protein/fat diets
ketogenesis can be dangerous
-certain ketone bodies are strong acids that can disrupt acid-base balance (ketoacidosis)
What does homesostatic regulation of metabolism mean?
whether transformations of energy substrates (carbs, fats, proteins) are biased toward storage/ anabolism or breakdown/ catabolism
How is metabolism regulated?
endocrine -primary role
-products of endocrine pancreas
*insulin/glucagon ratio
neural -regulation of food intake
-endocrine pancreas also innervated (autonomic)
What are Islets of Langerhans?
little islands of endocrine cells within exocrine cells of pancreas
-majority of pancreas is exocrine
Insulin vs. glucose in fed state
more insulin =
increase glucose oxidation
increase glycogen synthesis
increase fat synthesis
Insulin vs. glucose in fasted state
more glucagon =
increased glycogenolysis
increased gluconeogenesis
increased ketogenesis
What is gluconeogenesis?
creating glucose from substrates
What causes insulin to be released?
increased plasma glucose
increased plasma amino acids
increased GLP1, GIP
increased PNS stimulation
What are the targets of insulin?
striated muscle, adipose (expressing glut4 transporter)
liver
What are the actions of insulin?
-increased transport into glut4 expressing target cells
-increased glucose metabolism
-increased glycogenesis
-increased fat synthesis, increased protein synthesis
What are the features of Beta cells involved in glucose monitoring and insulin release?
-GLUT2 transporters -move glucose into beta cells by facilitated diffusion
- K+leak channels -usually open, closes when ATP binds to it “ATP-gated K+channel”
- voltage-gated Ca2+ channels
- secretory vesicles of insulin waiting for release signal
Describe a beta cell at rest
low blood glucose -> metabolism slows -> decreased ATP -> KATP channels open (leaking) -> cell at resting Em = no insulin released
(voltage gated Ca2+ channels closed)
KATP channels open, cell at RMP, no insulin released
Describe a beta cell during high blood glucose
high blood glucose -> increased metabolism -> increased ATP -> KATP channels close -> cell depolarizes -> voltage gated Ca2+ channels open -> insulin released
closure of K+ATP channels depolarizes cell, opening of Ca2+channels, exocytosis
How does the insulin receptor work?
-enzyme coupled, receptor, tyrosine kinase (RTK)
+ 2 alpha subunits, extracellular, insulin binds here
+ 2 beta subunits penetrate through the plasma membrane
-when activated, RTKs transfer phosphate groups from ATP to tyrosine residues on target proteins
insulin binds -> B subunits phosphorylate themselves -> activated RTK phosphorylates target proteins -> (altered protein/enzyme activity) -> cell responses
Insulin effects in muscle and adipose
fasted state = no insulin = no GLUT4 transporters on membrane
fed state = insulin signalling = GLUT4 inserted into membrane = glucose enters cell
Insulin effects in hepatocytes
fasted state = low blood glucose, low insulin
-hepatocytes make glucose and export it via GLUT2 transporters
fed state = high blood glucose, high insulin
-gradient favours glucose import via GLUT2
-insulin signalling activates hexokinase which:
glucose -> glucose 6 phophate ->….
(keeps free glucose low in cell)
How is insulin anabolic?
activates enzymes that enhance:
-glycolysis (glucose oxidation)
-glycogenesis (storage)
-AA utilization/protein synthesis
-lipogenesis
inhibits enzymes that enhance:
-gluconeogenesis
-glycogenolysis
-proteolysis
-lipolysis
-B oxidation of fatty acids
How does glucagon antagonize actions of insulin?
-produced by alpha cells of pancreas
-member of secretin family of peptides
-main trigger is low blood glucose
-main target is liver
-activates GPCR, cAMP
-main function is to prevent hypoglycemia
+ during overnight fast, ~75% of the glucose from the liver comes from glycogenolysis, ~25% from gluconeogenesis
What is diabetes mellitus?
group of diseases characterized by elevated blood glucose (hyperglycemia) resulting from:
-inadequate insulin secretion (Type 1)
-abnormal target cell responsiveness or both (Type 2)
Type 2 diabetes
*accounts for ~90% of diabetes
-was once called “mature onset” diabetes (versus “juvenile”)
*typically there is “insulin resistance”, with delayed response to a glucose ‘challenge’ (oral glucose tolerance test)
-can be coupled with low, normal or high insulin secretion
*acute symptoms not as severe as Type 1, but metabolism is not normal
*Type 2 diabetes, atherosclerosis and hypertension often occur together, typically in association with obesity ‘Metabolic Syndrome’
Why does obesity occur?
*larger animals (such as humans) have significant energy stores so can go without food for relatively long periods
-but food restriction and fat depletion eventually lead to ‘hungry brain’
*powerful effector mechanisms that are adaptable, flexible, learn from experience
*major force ‘designing’ the system was the constant struggle throughout evolution to find enough food for survival
-resulted in very strong defence of the lower limits of adiposity
Why is obesity an issue for modern humans?
*modern environment acts on higher brain regions to over-stimulate food intake
-advertising, social cues, stress vulnerability, …
*procuring food is no longer demanding or dangerous
*exceeding the upper limits of body weight is no longer a disadvantage in terms of predator-prey relationships
-little or no selection pressure for leanness
*many obese humans become ‘leptin-resistant’
-also happens in lab animals when exposed to ‘human’ diets
-makes sense in the wild in seasonal animals
*elevated leptindoesn’t curb appetite in summer when food abundant (building up stores), leptinsensitivity restored in winter
-modern humans in perpetual ‘summer’
Are there leptin deficiencies in humans?
yes - few reported cases
Describe the adrenal gland
-located on top of the kidneys
-adrenal cortex (outside) secretes hormones:
aldosterone
catecholamines (mostly epi)
sex hormones
cortisol
-inside is neural
What are the targets of cortisol?
liver -> glucogenesis
muscle -> protein catabolism
adipose -> lipolysis
*team glucagon = break down to get glucose
also:
immune system -> supression
How is cortisol secreted?
in a circadian rhythm
What are the targets of glucocortisoids (cortisol)?
*receptors expressed by all nucleated cells!
*mostly longer-term (genomic) effects -classic steroid
-increased expression of enzymes
-“of receptors for other regulatory hormones
effects in general:
1. prevention of hypoglycemia
-adipose -> lipolysis -> FAs for energy, glycerol
-muscle -> proteolysis -> AAs
-liver -> gluconeogenesis
*permissive for full effects of glucagon and epinephrine
2. suppress immune response
Who is Hans Selye?
*built on work of Claude Bernard, Walter Cannon (homeostasis)
-developed concept that a wide variety of ‘stressors’ (harmless, noxious, positive, negative) caused a generic response:
*adrenal hypertrophy
*atrophy of thymus / lymph nodes
*GI ulcers
-failure to cope with / adapt to stresses caused diseases of adaptation (ulcers, hypertension, etc)
*led to many breakthroughs in hypothalamic-pituitary axis
Epinephrine and fight or flight response
*norepinephrine from sympathetic post-ganglionic neurons
*epinephrine from adrenal medulla
-rapid effects but very short half life (2 minutes)
*various effects throughout body
*metabolic effects: mobilize energy substrates
-↓ insulin release, ↑ glucagon release
-adipose -> lipolysis -> FAs for energy, glycerol
-muscle -> glycogenolysis
-liver -> glycogenolysis, gluconeogenesis
-effects similar to glucagon but receptors expressed on a broader range of target cells
Synergistic effects on blood glucose?
epinephrine and glucagon and cortisol together greatly increase blood glucose levels
What is hypercortisolism?
aka. Cushing’s syndrome
*primary -cortisol-secreting adrenal tumors (not regulated by ACTH)
*secondary -pituitary tumor that over-secretes ACTH “adenoma”
*iatrogenic -secondary to cortisol therapy for other conditions “doctor’s fault”
would circulating ACTH be lower, higher, or normal?
What is hypocortisolism?
-primary- adrenal insufficiency (Addison’s disease)
*adrenal gland does not develop normally
*mutations in key steroidogenicenzymes
*adrenal gland damaged / destroyed (autoimmune)
-secondary -lack of ACTH
would circulating ACTH be lower, higher, or normal?
What is thyroid hormone?
*amino acid derivative (from tyrosine), containing iodine
-only known use of iodine in body
*mechanism of action more like steroids
-binds to nuclear receptor
*lipophilic, travels in circulation bound to thyroid-binding globulin
T4-main circulating form
T3-most active form, converted at target cell by deiodinases
What are the actions of thyroid hormone?
*essential for normal growth / development, esp nervous system
-thyroid hormone levels checked in all newborns in Canada
*in adults, not essential, but affects quality of life
*main function is to provide substrates for oxidative metabolism
-increase oxygen consumption and generation of heat (thermogenesis) in most tissues ‘basal metabolic rate’
*increase activity of Na+/K+-ATPase
-interact with other hormones to modulate carbohydrate, protein and lipid metabolism
What is hypothyroidism?
-decreased oxygen consumption, decreased metabolic rate (cold intolerant)
-neurological effects, fatigue
-effects on skin, hair, nails
most common cause is iodine deficiency -> enlarged thyroid gland ‘goitre’
What is hyperthyroidism?
-increased oxygen consumption, increased heart production (intolerant of heat)
-muscle weakness (protein catabolism)
-neurological, cardiac effects
-exophthalmos (protruding eyes)
most common cause is graves disease -> autoantibodies that resemble TSH overstimulate thyroid gland (not subject to negative feedback regulation)
Growth Hormone (GH, Somatotropin)
control of growth depends on many factors:
*GH, plus many other hormones playing direct and permissive roles
-insulin, thyroid hormone, sex steroids
*adequate nutrition
*absence of chronic stress
*genetics
*released throughout life but much more important during childhood
*effects can be direct -
-target cells express GH receptor
*or indirect -
-mediated by insulin-like growth factors (IGFs = somatomedins) produced by liver or target cells themselves
*growth effects and metabolic effects
What are the actions of growth hormone?
1) metabolic
-carbohydrate -indirect effects lead to increased plasma glucose
-fat -increased lipolysis, increased oxidation
+ catabolic with respect to CHOs and fat, ‘anti-insulin’
protein -increased AA uptake, increased protein synthesis, decreased oxidation for energy
+ anabolic with respect to proteins, ‘pro-insulin’
2) growth
-increased proliferation and differentiation of chondrocytes -> cartilage and bone growth
-increased muscle growth (see metabolic effects)
-increased growth of other soft tissues
Growth hormone deficiency
due to GH hyposecretion, GH-receptor mutations … dwarfism (though GH issues are not a common cause)
Excess growth hormone
depends on whether excess secretion is before or after closure of growth plates of long bones
-before -giantism
-after -acromegaly
Where is calcium located?
component of extracellular matrix of bones and teeth
-bone is largest reservoir of calcium but very little of it is ionized and available for exchange
What does calcium do?
*extracellular calcium involved in …
-secretion / exocytosis (neurotransmitters, secretory products)
-contraction of cardiac and smooth muscle
-clotting cascade
*intracellular calcium in SR, cytosol, mitochondria
-involved in muscle contraction, signalling pathways
Composition of bone
compact bone - dense, used for support
spongy bone - forms calcified lattice
How do bones grow?
- proliferating columns of chondrocytes at epiphyseal plate secrete collagen and other extracellular matrix components
- older chondrocytes degenerate, leaving spaces
- osteoblastsinvade spaces, lay down Ca-PO4matrix on cartilage base
- osteoblasts revert to less active form (osteocytes)
What are osteoclasts?
large, multinucleate cells derived from hematopoietic stem cells
-breaks down bone for reabsorption
Where does Ca2+ come from?
only about 1/3 ingested calcium is absorbed
-by paracellular and transcellular routes
-absorption via transcellular route is hormonally regulated
Where does Ca2+ output occur?
-primarily via kidneys -freely filtered, most reabsorbed
*hormonally controlled reabsorption at distal nephron only
What is the main regulator of plasma Ca2+?
parathyroid hormone
What does parathyroid hormone do?
PTH released in response to ↓ plasma Ca++
kidney:
↑ Ca++ reabsorption
bone:
↑ osteoclastactivity -> ↑ bone resorption
small intestine:
↑ Ca++ absorption (via transcellular route)
Vitamin D
*refers to group of fat soluble vitamins
*forms from diet and UV-induced conversion of dermal precursors not biologically active until hydroxylation steps in liver and kidney
What is hycocalemia?
too much calcium
How do you defend against hypocalcemia?
PTH from parathyroid gland
Vitamin D
What is physiology?
the science of the function of living systems
What is homeostasis?
the maintenance of a relatively stable internal environment (especially ECF)
-oscillation around a set point
Who is Walter Cannon?
the father of physiology
coined the term “homeostasis”
What is the difference between local and reflex control?
Local control = cells near site of change initiate response
Reflex control = cells at a distant site control response
What is negative feedback?
stabilizes variable (correction in opposite direction of change)
What is feedforward mechanism?
control anticipates change
What is positive feedback?
reinforces stimulus (NOT homeostatic)
What are the 3 ways cells can communicate long range?
- endocrine - chemical released in blood and distributed throughout the body
- neural - electrical signal travels down neuron then becomes chemical which travels to target cell
- neuroendocrine - electrical signal travels travel down neuron then becomes chemical signal that is secreted into the blood
What determines what type of receptors ligands will interact with?
chemical properties of the ligands
surface receptor = hydrophillic/lipophobic/water soluble
intracellular receptor = hydrophobic/lipophillic/water insoluble
How can cells change their response to different signals?
change receptor number or sensitivity
increase = increase expression of gene that codes for receptor or increase expression of receptor proteins on cell surface
decrease = internalize surface receptors
change receptor sensitivity = phosphorylation
How is a GPCR activated?
-signal molecule binds to receptor and causes conformational change
-activates G protein by exchanging GDP for GTP
-when GTp binds alpha subunit+GTP dissociates from the B and gamma subunits
-G alpha subunit turns itself off by hydrolizing GTP
What affect does Cholera Toxin have on the inactivation of G alpha subunit?
-blocks GTP hydrolysis (GTPase activity)
-results in persistent activation of adenylate cyclase
What are Cannon’s Postulates?
-the nervous system has a role in maintaining the ‘fitness’ of the internal environment
-some systems under tonic control
-some systems are under antagonistic control
-one chemical signal can have different effects in different tissues
Specificity of neural vs. endocrine control
neural = single target cell or limited number of adjacent target cells
endocrine = exposed to all cells but only those which receptors respond
Nature of signal for neural vs. endocrine control
neural = electrical signal that turns chemical (neurotransmitter)
endocrine = chemical signals
Speed of neural vs. endocrine control
neural = very rapid
endocrine = much slower than neural responses
Duration of action in neural vs. endocrine control
neural = usually very short
endocrine = longer than neural responses
Coding for stimulus intensity in neural vs endocrine control
neural = each signal is identical in strength. Increase intensity by increasing frequency
endocrine = intensity proportional to amount of hormone secreted
What are the evolutionary trends in the nervous system?
bilateral symmetry -> cephalization -> consolidation of PNS -> nerves -> ventral nerve cord -> dorsal nerve cord -> spinal cord -> increasing role of forebrain
Describe the development of the Human CNS
4 weeks: anterior end of neural tube specialized into 3 regions (forebrain, midbrain, hindbrain) and spinal cord
6 weeks: neural tube differentiates into major brain regions present at birth
forebrain -> diencephalon, cerebrum
midbrain
hindbrain -> medulla oblongata, cerebellum, and pons
11 weeks: growth of cerebrum much more rapid than that of other regions
birth: cerebrum covers most of other brain regions; convoluted surface due to rapid growth in confined space
What structures provide protection and support for CNS?
-surrounded by bony cage: cranium
-3 layers of connective tissues: meninges
-fluid between layer: cerebrospinal fluid
What are the meninges?
layers of connective tissue that surround the brain and spinal cord
dura mater = outermost layer
arachnoid mater = middle layer
pia mater = innermost layer
Describe the fluid filled cavities in the CNS
-ventricles within the brain and hollow central canal within the spinal cord
-2 lateral ventricles and 2 descending ventricles that extend through in brain stem
-CSF in ventricles continuous with fluid in central canal of spinal cord
-CSF is secreted by the choroid plexus within each ventricle (choroid plexuses produce ~500mL of CSF/day)
Extracellular fluids of the CNS
- interstitial fluid - surrounds neurons and glial cells
- plasma - within cerebral blood vessels
- cerebrospinal fluid - within ventricular system and bathes external surfaces of the brain between meninges (removed and replaced ~4 times per day)
Plasma vs. CSF
CSF has:
- lower K+, Ca2+, HCO3-, glucose, pH
-similar Na+
-very low protein, no blood cells (presence of elevated protein or blood cells collected from CSF indicates infection)
Glial cells of the CNS
- oligodendrocytes - form myelin sheaths within CNS “white matter”
- microglia - immune cell lineage
- astrocytes - regulate local ECF by releasing chemicals (numerous in the brain)
- ependymal cells - creates barrier between compartments (decide what ends up in CSF)
What are the special features of the cerebral vasculature?
- astrocyte foot processes- secrete paracrine factors that promote tight junction formation
- tight junctions- prevent solute movement between endothelial cells
Describe the blood-brain ‘barrier’
-lipid soluble molecules cross readily (o2, co2)
-hydrophillic substances (ions, amino acids, peptides, proteins) will only cross if specific transporters/carriers are present in endothelial cells of capillaries within CNS
-considerations for drugs that are and are not wanted to reach the CNS: antihistamines and treating diseases of the CNS
What are the metabolic needs of the CNS?
- oxygen requirement- neurons are “obligate aerobes’ (require O2 to functions) so O2 readily crosses the blood brain barrier
- glucose requirement- capillaries of CNS express high levels of glucose transporters to provide adequate levels of glucose (brain responsible for 1/2 body’s glucose consumption)
- vaculature to deliever O2 and glucose- approximately 15% of cardiac output received by the brain
Describe the spinal cord
-major path for information flow between CNS, skin, joints and muscles
-contains neural networks involved in locomotion
-divided into 4 regions (cervical, thoracic, lumbar, sacral) each of which is divided into 4 segments
-each segment gives rise to a pair of spinal nerves
Describe the segments of the spinal cord
- white matter (myelinated axons) - consists of ascending and descending tracts
-ascending tracts: dorsal columns (fine touch, proprioception, vibration) or spinothalamic (pain,temp, crude touch)
-descending tracts: corticospinal tracts (voluntary movement) - grey matter (synapse + cell bodies) - consists of sensory and motor nuclei
Where does sensory info enter spinal cord?
dorsal root -> dorsal horn gray matter
Where does motor (efferent) info leave the spinal cord?
ventral horn gray matter -> ventral root
What is a spinal reflex?
-spinal reflex initiates response without input from the brain (integrating center within spinal cord)
-still sends feedback to the brain
Describe the brain stem
-medulla pons and midbrain
-oldest most primitive part of the brain
-organized much like the spinal cord (most cranial nerves originate here)
-contains nuclei associated with reticular formation (diffuse network of neurons involved in processes such as arousal/sleep, muscle tone, coordination of breathing, blood pressure)
What is the function of the midbrain?
coordination of eye movement, visual and auditory reflexes
What is the function of the medulla?
- gray matter involved in control of many involuntary functions (blood pressure, breathing, swallowing, vomiting)
- white matter - ascending somatosensory tracts, descending corticospinal tracts
- site of deccusation for most neurons in corticospinal tract
What is the function of the pons?
relay station between cerebrum and cerebellum (also works with medulla to coordinate breathing)
Describe the cerebellum
2nd largest structure in the brain
coordinates movement
Describe the diencephalon
located between brain stem and cerebrum
1. thalamus - relays and integrates sensory info from lower parts of the CNS, ears, eyes, motor info from cerebellum
2. hypothalamus - homeostasis: contain centers that drive behavior related to hunger, thirst and influences autonomic responses, endocrine systems
3. pituitary gland - regulated by hypothalamus
4. pineal gland - secretes hormone melatonin (involved in circadian and seasonal rhythms)
Describe the cerebrum
-site of higher brain functions
-each cerebral hemisphere divided into 4 lobes (parietal, temporal, frontal, occipital)
-groove = sulcus
-convolution = gyrus (raised parts)
-degree of folding not related to higher processing
How is the cerebrum organized?
3 regions of cerebral gray matter:
1. basal ganglia - coordination of movement
2. limbic system - linking emotion/fear with higher cognitive functions
3. cerebral cortex
What are the functional areas of the cerebral cortex
- sensory areas - sensory input translated into perception (awareness)
2 motor areas - control skeletal muscles - association areas - integrate info from sensory and motor areas
Describe the primary motor cortex
-on ridge just anterior to central sulcus
-cell bodies of descending ‘upper’ or ‘first order’ motor neurons
Describe the primary somatosensory cortex
-on ridges just posterior to central sulcus
-terminals of ascending sensory pathways from skin, musculoskeletal system, viscera (info about touch, pain, pressure, temperature, body position)
Where are cortex’s for special senses?
special senses have devoted regions (ex. visual cortex, auditory cortex)
Who is Wilder Penfield?
developed the Montreal procedure
-having patient lay awake and probed different area of their brain (mapped the brain)
-burnt toast
How does information travel on sensory pathway?
stimulus -> receptor tranduces stimulus into intracellular signal (usually change in Em) -> APs travel along afferent neuron -> info reaches subcorticol integrating/relay centres (thalamus, medulla) -> information reaches appropriate regions in cortex (only becomes conscious when processing reaches cortex)
How do sensory receptors vary?
- free nerve endings - cutaneous receptors for pain, temp, crude touch
- receptors with nerve endings enclosed in connective tissue capsules - Pacinian corpuscle (vibration)
- specialized receptor cell that release neurotransmitter onto sensory neuron - special senses, hair cell in inner ear
What are the different types of sensory receptors?
chemoreceptors - O2, pH, glucose, smell, taste
mechanoreceptors - pressure (baroreecptors), cell stretch (osmoreceptors), vibration, acceleration, sound, touch
photoreceptors - photons of light
thermoreceptors - varying degrees of heat
What is are the adequate stimuli of each receptor type?
each sensory receptor has an adequate stimulus… type of energy to which it best responds
thermo - increased temp
mechano - deformations of membrane that open ion channels
photoreceptors - light
What is receptor potential?
change in membrane potential
Describe receptive fields
-somatosensory and visual neurons are activated by stimuli that fall within a certain physical area
-at least 2 afferent neurons in pathway to CNS
1. first order (primary) sensory neuron - directly associated with stimuli
2. second order (secondary) sensory neuron - relays info from first neuron
-receptive fields often determined by neurons further up the pathway (sensory input can then be gathered by more than one primary sensory neuron)
-several primary neurons converge into a secondary neuron
-convergence allows summation (creates larger receptive fields)
What is the problem with convergence of sensory neurons?
no 2-point discrimination:
-2 stimuli fall within same receptive field and only 1 signal goes to the brain = perceived as a single point
-smaller receptive fields = better 2 point discrimination (activate different pathways to the brain and perceived as distinct stimuli)
How is sensory info integrated in the CNS?
-olfactory pathways from nose projected through olfactory bulb to olfactory cortex
-most sensory pathways (hearing, taste, vision, somatic) project to thalamus which modifies and relays info to cortical centres
-equilibrium pathways project primarily to the cerebellum (some to thalamus)
-visceral sensory info most integrated in brain stem and spinal cord (usually does not reach conscious processing)
How are different sensations distinguished if all stimuli are converted to APs?
CNS must be able to decode:
-type of stimulus: modality
-location
-intensity
-duration
What is labelled line coding?
adequate stimulus for that receptor type -> brain associates information from that receptor type with that modality
ex. touch receptors - perceived as touch
How is location of sensory stimulus coded for?
-location is coded according to which receptive fields are activated (touch receptors in specific part of body project to certain area in somatosensory cortex)
-special senses are different (ex. hair cells respond to different frequencies but no receptive fields relating to location of sound source)
What is lateral inhibition?
-primary neuron response is proportional to stimulus strength
-pathway closest to the stimulus inhibits neighbours
-inhibition of lateral neurons enhances perception of stimulus (better localization)
How is stimulus intensity coded for?
- # of receptors activated (population coding)-different thresholds for stimulation among groups of receptors
-with low intensity stimulus most sensitive (lowest threshold) receptor recruited first
-as stimulus intensifies, more receptors activated - frequency of APs coming from individual receptor cells
-frequency of APs increases with stimulus intensity until a max. is reached
How is stimulus intensity and duration coded for?
-receptor potential strength and duration vary with stimulus
-receptor potential is integrated at the trigger zones
-duration of a series of APs is proportional to duration of the stimulus
-neurotransmitter release varies with pattern of APs arriving at the axon terminal
-some receptors adapt to sustained stimuli
1. tonic receptors - slowly adapting, respond throughout stimulus
2. phasic receptors - rapidly adapt to a sustained stimulus and turn off
Merkel’s disk
cutaneous sensory receptor
location: superficial
receptive field: small
adaptation: slow (tonic)
function: sustained touch/pressure, texture
Meissner’s corpuscle
cutaneous sensory receptor
location: superficial
receptive field: small
adaptation: fast (phasic)
function: beginning and end of fine touch/pressure
Ruffini’s corpuscle
cutaneous sensory receptor
location: deep
receptive field: large
adaptation: slow (tonic)
function: sustained gross touch/vibration/stretch
Pacinian corpuscle
cutaneous sensory receptor
location: deep
receptive field: large
adaptation: fast (phasic)
function: beginning and end of gross touch/vibration
Free Nerve Endings
cutaneous sensory receptor
location: variable
receptive field: variable
adaptation: variable
function: pain, temperature, hair movement
Nociception
-found in many tissues (not just skin)
-“pain” is a sensation rather than a stimulus
-nociception is mediated by free nerve endings expressing ion channels that respond to a variety of strong stimuli (chemical/mechanical/thermal)
-pain (eg. due to tissue injury) is mediated via release of local chemicals (K+, histamine, prostaglandins, serotonin, substance P): can either directly activate nociceptors or sensitize them (inflammation)
-mediated by Transient Receptor Potential (TRP) channels
Transient Receptor Protein (TRP) channels
-mediate a wide variety of sensations including pain, heat/warmth, cold, some tastes, pressure, vision, osmotic pressure, stretch
-relatively non-selective ion channels
Somatic pain
-information from nociceptors can follow many different pathways
1. spinal reflexes
2. ascending pathways to cerebral cortex (info also sent to limbic system and hypothalamus)
*emotional reactions
*autonomic responses (sweating, vomiting, nausea)
-different types of pain travel on different fibre types
Describe the conduction velocities of different fibre types
- alpha motor neurons = fastest
-myelinated
-diameter = largest
-function: innervates extrafusal muscle fibres, afferent from muscle spindle, afferent from Golgi tendon organ - cutaneous mechanoreceptors (fine touch)
-myelinated
-diameter = medium - free nerve endings of crude touch/pressure, fast pain, temp and innervates intrafusal muscle fibres (gamma)
-myelinated
-diameter = small - slowest = slow pain, itch, temp
-unmyelinated
-diameter = small
How are neural reflexes classified?
- according to effector
-skeletal muscle (controlled by somatic motor neurons)
-smooth and cardiac muscle, glands, adipose tissue (controlled by autonomic neurons) - according to integrating centre
-spinal reflexes, ‘cranial’ reflexes - innate (inborn) vs. conditioned (learned)
- number of neurons in pathway
-monosypnaptic (only afferent and efferent neurons): somatic motor reflexes only
-polysynaptic (eg. autonomic reflexes, involving interneurons)
Autonomic (visceral) reflexes
-some are spinal reflexes (can often be modulated via signals from higher centers and inhibition by higher centres can be a learned response)
-others integrated in the brain (hypothalamus, thalamus, brain stem)
-emotional stimuli can be converted into visceral responses
Skeletal muscle reflexes
-monitor: proprioception (position of limbs in space relative to other body parts) and effort exerted in lifiting/holding objects
-integrating centre = CNS (via networks of excitatory or inhibitory neurons)
-efferent pathway: somatic motor neurons (alpha motor neurons)
-effectors: contractile skeletal muscle fibres (extrafusal muscle fibres)
Proprioceptors
-receptors that sense changes in joint movements, muscle length, muscle tension, and send info the CNS
-depending on appropriate response, CNS activates motor neurons to make motor units contract or activates inhibitory interneurons to make muscles relax
-examples of proprioceptors: muscle spindles (muscle stretch), Golgi tendon organs (muscle tension), joint receptors (distortions as bones are repositioned)
Muscle spindles
-each spindle consists of 3-12 intrafusal muscle fibres (arranged in parallel to extrafusal muscle fibres)
-most sensitive to muscle stretch (increased length)
-tonically active, sending stream of APs even at rest
-mediate stretch reflexes (introduces contraction when muscle is stretched, tends to maintain muscle at constant length)
-unloaded when muscle shortens unless tightened up by intrafusal muscle fibres (alpha-gamma coactivation)
-alpha MN innervates extrafusal
-gamma MN innervates intrafusal
Explain how a stretch reflex works
-muscle stretched
-increased firing from sensory neuron associated with spindle
-increased firing of alpha motor neuron to biceps
-biceps contracts
-increased firing of inhibitory interneuron
-decreased firing of alpha motor neuron to triceps (reciprocal inhibition)
-antagonist muscle relaxes
Golgi Tendon Organ
-between fibres and tendon (in series with muscle fibres)
-whether isotonic or isometric, contraction of muscle causes tendon and GTO to stretch (most sensitive to isometric contraction)
-relatively insensitive to muscle stretch
-monitors tension (force of contraction)
What are the purposes of skeletal muscle reflexes?
- stretch reflex (sensor: muscle spindle - change in length)
-maintenance of posture
-positional info to CNS (usually includes reciprocal inhibition) - monitoring muscle tension (sensor: Golgi tendon organ)
-eg. maintaining constant grip on a paper cup - withdrawal reflex (sensor: pain receptors)
-get away from pain, ideally while maintaining posture and balance (usually involves reciprocal inhibition and crossed extensor reflex)
How is control of movement integrated?
- muscle reflex
-primarily driven by external stimuli
-inherent (vs. learned), rapid
-mostly handled at the level of the spinal cord and brain stem with modulation by higher centres - voluntary movement
-most complex, integrated in cerebral cortex
-learned movements can improve with practice (become subconscious)
How are voluntary movements coordinated?
- sensory inputs- sensory cortex, motor cortex
- planning and decision making- prefrontal cortex, motor association areas, basal ganglia, thalamus
- coordination and timing- input from cerebellum
- execution- corticospinal tract to skeletal muscles
- execution- brain stem, spinal cord
- continuous feedback to sensory cortex
