Sensation and Sensory Processing: Perceiving the world Module 404 Sean Sweeney
Sensation and Sensory Processing: Perceiving the world Module 404 Sean Sweeney.
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Transcript of Sensation and Sensory Processing: Perceiving the world Module 404 Sean Sweeney.
Sensation and Sensory Processing: Perceiving the world
Module 404
Sean Sweeney
Learning Outcomes:
Understand the purpose of the sensory system to an organism
Differentiate between different sensory ‘modalities’
Understand that the sensory system is organised in a logicalmanner, tuned to life strategy
Understand that sensory stimuli are transduced, encoded andfinally perceived
Understand the basis of light perception in the insect eye
Appreciate the different organisation between the insect andmammalian olfactory and gustatory systems while also appreciating that the systems follow a similar logic forcoding and perception
Sensation involves the ability to transduce, encode andperceive information generated by stimuli arising fromboth the external and internal environment.
Questions:1) How is the stimulus detected (at a molecular level)?
2) How is the stimulus transduced and encoded?
3) How does the CNS perceive the incoming information?
for 2) and 3), how is the wiring diagram organised?
4) How can qualitative and quantitative information aboutthe stimuli be represented?
5) for some modalities, how can location be represented
The stimuli
touchmovement mechanosensationimbalancesoundtemperature thermosensation (Pain!)light photoreceptionpain nociceptiontastesmell chemoceptionmoisture
Monitoring the internal environment for homeostatic regulation
?
internalor external?
The anatomy of detection
touch body surfacemovement body surface, muscle spindles, chordotonal
organsimbalance auditory organsound auditory organtemperature body surface, hypothalamus, gustatory systemlight eye/photoreceptive organpain body surface, internal pain receptorstaste integrated w/ the gustatory system (gut?)smell olfactory organ, body surface?moisture body surface? gustatory system?
Dedicated Organs v Dispersed Receptors
The detection and transduction of the stimuli
The TRP receptor paradigm
Superfamily of channels (found in yeast to humans)
Six transmembrane domains (with varying degrees of homology)
Permeability to cations (varying cation selectivity)
A single channel can be activated by disparate mechanisms
TRP channels play critical roles in responses to all major classesof external stimuli.
TRP channels work as heteromultimers in supramolecularcomplexes
Channel Pca:Pna modulation
TRPC1 nonselective store depletion, stretchconformational coupling
TRPC2 2.7 DAGTRPC3 1.6 store depletion, DAG
conformational couplingexocytosis
TRPV1 3.8(heat) Heat (43oC), vanilloids9.6(vanilloids) anandamide, camphor
piperine, allacin, EtOHproinflammatory cytokinesnicotine, protons, PIP2
TRPV2 3 Heat (53oC), osmotic cellswelling, exocytosis
TRPV3 2.6 PUFAs, menthol, compounds from oregano, cloves, thyme
The capsaicin receptor capsaicin, the active ingredient ofcapiscum or chili peppers
Strength measured in ‘Scoville Units’(Wilbur Scoville, 1912)
Jalapeño, 5000 Scoville units
Habañero, 300,000 Scoville units
Expression cloning of the receptor TRPV1:Caterina et al., (1997) Nature 389: 816-24
In vivo function of the receptor (KO mice):Caterina et al., (2000) Science 288: 306-313
TRPV1 activated by capsaicin, anandamide,heat (>43oC), camphor, piperine, garlic
Mice lacking TRPV1 are deficient for vanilloidellicited pain, thermal sensation, and tissueinjury-induced thermal hyperalgesia
Known sensory modalities mediated by TRP channels:KO organisms, experimental evidence
Chemosensationosm-9, ocr-2 (C. elegans) TRPV response to odorants
(and other modalities)TRPM5 (mammals) TRPM sweet, bitter and a.a. tasteTRPC2 (mouse!!) TRPC pheromone (in VNO!!)
Thermosensation/nociceptionTRPV1 (mouse) TRPV >43oCTRPV2 (mouse) TRPV >52oCTRPV3 (mouse) TRPV >30-39oCTRPV4 (mouse) TRPV ~25-34oCTRPM8 (mouse) TRPM <28oCTRPA1 (mouse) TRPA ??dTRPA1 (Drosophila) TRPA >35-41oC painless (Drosophila) TRPA >39-41oCpyrexia (Drosophila) TRPA >39oC
ThermoTRPs are also required for response to chemical stimuli
MechanosensationTRPV4 (mouse) TRPV hypotonicityosm-9 TRPV osmotic changeocr-2 TRPV osmotic changeTRPY (yeast) hyperosmotic conditionsTRPA1 (mouse) TRPA hearing????TRPML3 (mouse) TRPML hearing?TRPN1 (mouse zebrafish) TRPN hearing?NOMPC (Drosophila) TRPN hearing, mechanosensationNanchung (Drosophila) TRPV hearing, hygrosensationInactive (Drosophila) TRPV hearing, proprioception?TRP-4 (C. elegans) TRPN mechanosensation
water witch (Drosophila) TRPML hygrosensation (moist air)
PhototransductionTRP (Drosophila) TRPC phototransductionTRPL (Drosophila) TRPC phototransductionTRP (Drosophila) TRPC phototransductionTRPC3 (mouse) TRPC phototransduction????
The tuned sensitivity of TRP channels to ranges of temperatures ensuresefficient detection across a range of temperatures for thermosensation/nociception
TRP channels transduce many environmental signals into a physiological response.
Responses may be specific or may be multi-modal depending on the activatoror (possibly) the heteromultimerisation of the channel subunits or the sensory neurons in which the receptors are expressed (?).
The original Transient Receptor Potential: Drosophila phototransductionseven rhabdomeres per ommatidium, some are sensitive to different wavelengths
SMC:submicrovillarcisternae
ROS: Rod outersegments
Rhodopsin, the light sensing molecule (ancient!)
Whole cell patch clamp
1 photon generates 1 ‘quantum bump’
~20ms duration, ~10pA amplitude (in Ca2+) = opening of ~15 TRP channels within one villusShort latency (20-100ms) - time for DAG to accumulate and activate TRP channels
The Drosophila Signalplex
1) Photoisomeration of rhodopsin to meta-rhodopsin activates heterotimeric Gq - releasesGq
2) Gq activates phospholipase C generatingInsP3 and DAG from PIP2. DAG also releasesPUFAs by activation of DAG lipase
3) TRP and TRPL activated by PUFAs (?) and/orDAG. TRPs, PKC, PLC organised in a complexby inaD (5x PDZ domains)
4) SMC (submicrovillar cisternae) Ca2+ stores?Insp3 gated?
5) DAG converted to PA via DAG kinase andCDP-DAG by CD synthase, PI regeneratedAnd transported back to microvillar membraneBy PI transfer protein and converted to PIP2
Things that go ‘bump’: a) 20ms after absorbtion of photonmetarhodopsin activates G-protein, activating PLC generating membrane 2nd messenger (red) - thresholdfor activating one channel is reached
b) Ca2+ influx sensitises other channels - rising phase of bump
c) Ca2+ floods microvillus (>200µM) leading to rapid inactivation and refractory period, Ca2+ returns to resting levels (~150nM) within ~100ms. M, Gq and PLC aredeactivated and PIP2 resynthesised.
The Ca2+/Na+ exchanger Calx extrudes Ca2+
The human eye
Retinaouter segmentof rod
light sensitiveprotein
Rhodopsin catalyses the only light sensitive step in vision. 11-cis-retinal chromophore lies in a pocket of the protein and is isomerised to all-trans retinal when light is absorbed. The isomerisation of retinal leads to a change of the shape of rhodopsin which triggers a cascade of reactions which lead to a nerve impulse which is transmitted to the brain by the optical nerve.
TRPless vision: the mammalian phototransduction cascade
Rods (100 million) detect degree of lightnessbleached by light sensitivity determined by amount of rhodopsin Low sensitivity
Cones (3 million) sensitive to light but retainfunction in high illumination, use pigmentiodopsin
red green blue
Activated rhodopsin binds to transducin (a trimeric G-protein), activated -transducinremoves the inhibitory subunit of phosphodiesterase EPDE hydrolyses cGMP to GMPDark - cGMP high cGMP binds to cyclic nucleotide gated channels (CNG)‘dark current’ flows releasing glutamate to the horizontal and bipolar cells
In light, cGMP is hydrolysed by PDE, the CNG channelcloses, inhibiting glutamaterelease, bipolar cells relaythis to ganglion cells
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Invertebrate photoreception uses the phosphoinositide pathwayBest characterised genetic model of this pathway!
vertebrate rods use the phosphodiesterase pathway.
Both G-protein signal transduction methods employ arrestin to terminatethe signal, also rhodopsin kinase arrests rhodopsin function.
Invertebrates activate TRP channels to activate an electrical response
Vertebrates inactivate CNG channels, inhibiting glutamate release toactivate an appropriate response
Invertebrates employ a highly structured signalling complex
Vertebrates employ a diffusion process
Olfactory and gustatory processing
Single cell prokaryotes can orient towards and move up a gradient towardsnutrients: chemical sensing
Plants can orient towards air-borne chemicals allowing growth to food sources
Smell and taste guide food and mate selection, danger, nutritive value, poison
‘Flavour’ is a fusion of taste and odour
Olfaction: detection of chemicals at a distance
Gustation: requires direct contact with relevant chemical
Sugars are appetitive: important nutrients
bitter or sour elicit rejection: bitter compounds often toxic
Olfaction: optimised for combinatorial detection of vast numbers of odorants
Gustation: organised to categorise tastants into defined non-overlapping modalities (sweet, bitter, sour, salty, umami)
Flies can taste the world with more than their ‘tongue’and ‘nose’.
Drosophila olfactory receptors (OR)and gustatory receptors (GR)
cloned by expression
G-protein coupled????7 transmembraneinverse comformation to mammalianORs
ORs, GRs: one large family
Obligate heterodimer
62 ORs in Drosophila (60 genes)79 ORs in Mosquito157 ORs in Honeybee
68 GRs (60 genes)
Or83b mutant flies are anosmic
two receptors perchemosensory neuron, OR83b + 2nd
CO2!!!!
some ORs v. specific for one chemicalsome broadly tuned for class
Black = posterior, grey intermediate, white posterior
sensilla from similar anatomical regions send projections to closely associated glomeruli
glomeruli are dendrites for the projection neurons(PNs)PNs then project to the Mushroom body calyxand lateral horn
OR67d responds to 11,cis-vaccenyl-acetatethe glomeruli are fruitless positive and sexuallydimorphic
Each OR target a unique and sterotyped glomerulus
Transgenic reporters uncover the odour code
GRs project to the suboesophageal ganglion(somatotopy?)
The mammalian olfactory system:
Closely linked with the respiratory and gustatory apparatusAided by turbulent air eddies
The mammalian olfactory epithelia
lines the nasal cavity - allows direct access to odorant moleculesmucus protects, neurons are turned over
Each olfactory sensory neuron expresses only one type of olfactory receptorORs in human: 950ORs in mouse 1500
Mammalian Odorant receptorsIdentified 1991: Buck and Axel, Cell, 65 175-187G-protein coupled receptors, 7 transmembrane.
1000s of ORs expressed in millions of neurons projecting to 2000 glomeruli
ORs are involved in regulating axon guidance and glomerular targeting
cAMP gates the Ca2+/Na+ channel, depolarisation aided by the Ca2+-gated Cl- channel. rectified by Ca2+/Na+
exchanger
Gustatory Transduction in Mammals:
No Taste map!!
T1R receptors: GPCRs - sweet and umamiT1R1 + T1R3 - umamiT1R2 + T1R3 - sweetT1R3 - common receptor
T2R receptors: GPCRs - bitter
PKD1L3 + PKD2L1: TRP receptors - sour
Two models of taste perception: the ‘labeled line’ and ‘across fibre’ models
Expressing the bitter receptor in the ‘sweet’ cells generates an attractive responseto a bitter tastant : favours the labelled line model
Conclusions:
Insects and vertebrates employ remarkably similar strategies for sensory transductionand coding suggesting ancient origins for sensory systems
Sensory transduction is mediated by ‘molecular sensors’ which detect specific sensory stimuli and transduce this signal to a generate a neuronal code
The neuronal code is processed in secondary and tertiary order neurons
Questions
How are strength, quality and direction of sensory cues transduced and detected?
How are these properties of the sensory cue coded?