Chemorecepce Všechny buňky a všichni živočichové jsou citliví na chemické složení jejich životního prostředí. To je důležité nejen při rozeznávání potravy, ale i při páření, vztazích matka-mládě, značení teritoria a při dalších případech sociálního chování. Citlivost na chemické signály je jedním z charakteristických rysů živých soustav. Využití membránové sensitivity ^----^^^ ve službách celku: \ VĚDOMI Kůra telence/ala PODVEDOMÍ Reflexní, Motorický NS Vegetativní NS Hormonální S automatické řízení *-y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y- Buněčná recepce a komunikace PM^PM ^ 7 apoptotický signál, ^—^ tah v membráně... "for their discoveries of odorant receptors and the organization of the olfactory system" Richard Axel 1/2 of the prize USA Columbia University New York, NY, USA; Howard Hughes Medical Institute Linda B. Buck 1/2 of the prize USA Fred Hutchinson Cancer Research Center Seattle, WA, USA; Howard Hughes Medical Institute b. 1946 b. 1947 Čich - Distanční chemorecepce Modelový objekt pro mnoho dalších signálových drah 7TM receptory Metabotropní signalizace prostřednictvím G proteinů ný systém podobný imunitnímu ást (4%) genomu věnovaná čichovým receptorům Sensory stimulus Odorant Light Na+ Ca2+ Effector ^V^" molecule Receptor GTP G protein GTP GTP "* Second messenger Savci: 1000 genů pro čichové receptory - největší genová rodina Člověk: 350 funkčních genů Drosophila: 62 A (Repellant) B (Attractant) Periplasmic space Inner membráno ■ Ter [I W J Cytoplasm Flagellar motor anticlockwise motion Figure 10.6 Molecular signalling in the E. cofr'chemosensory system, (a) The Tsr receptor-transducer protein accepts a repellant molecule (Leu). CheW and CheA are activated. CheA accepts phosphate from ATP and passes it on CheY. CheY diffuses to the flagellar motor and induces a clockwise rotation and hence tumbling. CheY is eventually dephosphorylated by CheZ. (b) The Tsr receptor-transducer accepts an attractant molecule (Ser). The consequent conformational change Inactivates CheA and CheW so that CheY remains unphos-phorylated and consequently inactive. The flagellum resumes its anticlockwise motion and the bacterium swims smoothly forward. A = CheA; W=CheW; Y = CheY; Z = CheZ. Data from Bourrett, Borkovich and Simon, 1991 E.coli Zatímco u obratlovců jde o posuny filament proti sobě, u baktérií jde asi o jediný známý biologický případ rotačního pohybu. Konec bičíku na straně buňky rotuje asi lOOx za vteřinu mechanismem poháněným transmembránovým gradientem vodíku Cell wall Outer membrane Pozori Transe 2 paralelní lonvergence eukaryot: Hganizace čichové dráhy M0E 'stémy GCD lb (AOB). NO) jm (MOE) consists predominantly of ciliated olfactory Is), which project to the main olfactory bulb (MOB) bulbus oífactorius regto oífactoria Cich vzduch A. Nosní dutina a čichový orgán vůně vrstva hlenu kati on to vý kanál offactoria B, Čichový epitel (podle Andresa) čichový podnet* :2? 200- d CD I o 10CM 0) r- Cl ■h fD 0- -i 5 čas po začátku podnátu [s] C. Transdukce čichového podnětu D. Adaptace cíchu Čichové buňky savců jsou bipolární, primární r., je jich 6-10 milionů, dendrit má na konci 5-20 vlásků - cilií, řasinek. Figure 7.7 Olfactory epithelium (A) Schematic cross section of olfactory epithelium. (B) Scanning micrograph of a dendritic knob and dendrites of a human olfactory receptor neuron. Magnification: 18,500x. (From Morrison and Costanzo, 1990.) Čichový lalok - součást koncového mozku Sädjr view Hľ-Iľjui V i ľ* Human Čichový lalok - součást koncového mozku ľľiILi.im viuw 6 Gary G. Matthews Univerzální receptor G prot signální dráhy 7TM a-helix receptor GPCR - G prot. coupled rec. s jedinou zvláštností: velmi dlouhou druhou extracelulární smyčkou. Možná nejzajímavější je hypervariabilní oblast na 3., 4. a 5. transmembránové doméně. Na prostorových modelech se tyto oblasti přikládají k sobě a vytváří jakousi kapsu. Ta je pravděpodobným místem pro vazbu těkavých ligandů . Figure 2 Odorant receptors are the Jewel of olfactory research In the past 1 □ years. The odorant receptors comprise the largest family of GPCRs. In mammals, odour receptors are represented by as many as 1,000 genes and may account for as m uch as 2% of the genome, Sequence compa rlson across the receptors has revealed many regions of conservation and variability that may he related to function, a, In a 'snake' diagram showing the amino adds for a particular receptor (M71), those residues that are most highly conserved a re shown In shades of blue and those that are most variable are shown In shades of red. The seven a-hellcal regions (boxed) are connected by Intracellular and extracellular loops, b, A schematic view of the proposed three-d Imenslona I structure of the receptor based on the recently solved structure of rhodopsln. Each of the transmembrane regions Is numbered according to that model. The conserved (blue) and variable (red) regions are sketched onto this qualitative view and suggest tret a llgand-blndlng region may be at least partially formed by thevarlable regions of the receptor, c, Mammalian odour receptors are related phylogenetlcally to other chemosensory receptors. In the tree depicted herethe numbers refer to the approximate num ber of receptors In each family OR, Odorant receptors; T1R, T2R, taste receptors; V3R, vomeronsal recepmrs;DOR,DGR. DmopMa odour and gustatory receptors: worm refers to C. elsgans, Tre scale bar Is a graphical distance equal to 10K seguence divergence. Hypervariabi oblast J □OR 61 DGR -GO H —1 T1 1 Univerzální mechanismy transdukce Cl ionty také depolarizují - výjimka kvůli vysoké koncentraci uvnitř Ca ionty i adaptační význam ío) Increase in cAMP Extracellular fluid (it) Increase in IP3 Extracellular fluid Zesílení, max. 4.10"15g/l Adaptace (Ca), terminace a Adenylyl cyclase (ill) modulace Cyclic nucleotide's-^, gated channel Ca' ci- T Calcíum-dependcnt chloride channel Snížení afinity k cAMP cAMP Specializace receptoru Kombinace cca 350 receptoru 3.000-100.000 vůní (?) Odor ants Receptors AAA Pattern of peripheral activation □ Although there are some 1,000 ORs, detecting the enormous, repertoire of odours requires a combinatorial strategy. Most odour molecules are recognized by more than one receptor (perhaps by dozens) and most receptors recognize several odours, probably related by chemical property. The scheme in the figure represents a current consensus model. There are numerous molecular features, two of which are represented here by colour and shape. Receptors are able to recognize different features of molecules, and a particular odour compound may also consist of a number of these 'epitopes' or 'determinants' that possess some of these features. Thus the recognition of an odorant molecule depends on which receptors are activated and to what extent, as shown by the shade of colour (black represents no colour or shape match and thus no activation). Four odour compounds are depicted with the specific array of receptors each would activate. Note that there are best receptors (for example, red square), but also other receptors that are able to recognize some feature of the molecule (for example, any square) and would participate in the discrimination of that compound. In the olfactory bulb there seem to be wide areas of sensitivity to different features (for example, functional group or molecular length). This model is based on current experimental evidence, but is likely to undergo considerable revision as more data become available. Olfactory Bulb Odoríints Receptors AAA Pattern of peripheral activation ..na j a □ Olfactory Bulb Although there are some 1,000 ORs, detecting the enormous, repertoire of odours requires a combinatorial strategy. Most odour molecules are recognized by more than one receptor (perhaps by dozens) and most receptors recognize several odours, probably related by chemical property. The scheme in the figure represents a current consensus model. There are numerous molecular features, two of which are represented here by colour and shape. Receptors are able to recognize different features of molecules, and a particular odour compound may also consist of a number of these 'epitopes' or 'determinants' that possess some of these features. Thus the recognition of an odorant molecule depends on which receptors are activated and to what extent, as shown by the shade of colour (black represents no colour or shape match Většina vůní je rozeznávána více než jedním typem receptoru a většina receptorů rozeznává více vůní. Informace o určité vůni je kódována vzájemným poměrem vzruchových aktivit jednotlivých výstupů různě specializovaných čichových buněk. Zajímavé je, že určité vůně jsou stále stejně cítit při 5 řádovém rozdílu intenzit -přitom se přece zapojují i ne úplně naladěné receptory a tedy i receptory pro jiné vůně. Patrně budou existovat široce naladěné receptory měřící pouze intenzitu. Periferie čichové dráhy Rozlišování chem. Struktury Laterální inhibice Kontrastování Eferentní inhibice |— A. Olfactory pathway and olfactory sensor specificity 1 Nasal cavity Olfactory bulb IBta olfactoria Olfactory region Granular celt 2 Olfactory pathway Chomáčková b. Bristle cells 3 Sensor specificity (example) to u -a CT e ■v ortho meta ch3 CHi J_l_l ........ ........ Oh ........ ........ ........ ........ CH, CH-j ........ ........ \f........ ........ (After K.Katoh eta!.) Všechny neurony exprimující určitý receptor, bez ohledu na to, kde je umístěn, na sliznici konvergují na jeden jediné místo na čichovém laloku. Těmito místy jsou glomeruly, kulovité shluky šedé hmoty, asi 50-1000 mikrometrů, sestávající z přicházejících axonů z receptoru a z dendritů mitrálních buněk. V jednom zvlášť extrémním případě konverguje několik tisíc smyslových neuronů na asi 10 mitrálních buněk, což je v nervovém systému rekord. Podobnost architektury sensorických obvodů a drah LMfjcivny iic.......s * "■ "i iili U ll h. Mural lX'ILi { Pcriglomerulur cells Pcrigloriwruljtr eclh b NEUROBIOLOGY Gary G. Matthews Lirsiiijlij iv IL (J|-.:]iiijle t>jlL To öICKiöry «MTBJC Konvergence na příslušný glomerulus (100 - 1000/1) Mapa vůní - vzorec aktivovaných Glomerulů čichového laloku Specifická „mozaika" aktivace pro konkrétní vůni Konvergence neprostorového parametru na prostorový Glomeruli Ant en rial lobe Inhibitory neurons Higher processi rig centres Olfactory epithelium * Olfactory bulb Odour molecules Olfactory sensory neurons Odour molecules 0 0 0 Figure 11 Odour images in the olfactory glomerular layer, ai, Diagram showing the relationship between the olfactory receptor cell sheet in the nose and the glomeruli of the olfactory bulb""3, b, fMRI images of die different but overlapping activity patterns seen in the glomerular layer of the olfactory bulb of a mouse exposed to members of the straight-chain aldehyde series, varying from four to six carbon atoms. The lower part of the image in the left panel corresponds to the image on the medial side of the olfactory glomerular layer as shown in a (see asterisk). (Image in a adapted, with permission, from ref. 53; image in b adapted, with permission, from ref. 10.) Podobnost architektury sensorických obvodů a drah Olfactory bulb Glomerulus Forebrain Olfactory tract (OT) Olfactory nerve (ON) fibres Cribriform plate Olfactory epithelium Olfactory receptor cell (ORC) Centrifugal fibre ~~ OT GRL MCL EPL GL ONL Olfactory epithelium Figure 13.7 Olfactory bulb, (a) The figure shows olfactory axons passing through the cribriform plate to end in glomeruli in the olfactory bulb, (b) Basic circuit of the mammalian olfactory bulb. Layers: EPL = external plexiform layer; GL = glomerular layer; GRL = granule cell layer; OT — olfactory tract; MCL = mitral cell layer. Cells: Gd — deep granule cell; G,, = superficial granule cell; M = mitral cell; PG = periglomerular cell; T = tufted cell. Inhibitory ceils stippled. Simplified from Podobnost architektury sensorických obvodů a drah Olfactory bulb Glomerulus Forebrain Olfactory tract (OT) Olfactory nerve (ON) fibres Cribriform plate Olfactory epithelium Olfactory receptor cell (ORC) Centrifugal fibre ~~ OT GRL MCL EPL GL ONL Olfactory epithelium Figure 13.7 Olfactory bulb, (a) The figure shows olfactory axons passing through the cribriform plate to end in glomeruli in the olfactory bulb, (b) Basic circuit of the mammalian olfactory bulb. Layers: EPL = external plexiform layer; GL = glomerular layer; GRL = granule cell layer; OT — olfactory tract; MCL = mitral cell layer. Cells: Gd — deep granule cell; G,, = superficial granule cell; M = mitral cell; PG = periglomerular cell; T = tufted cell. Inhibitory ceils stippled. Simplified from HuĽUfiiur UpcA Rüppurr ljpu ü Hüt^pfttc C Ríícyptir lypu D Adaptace: Některé receptorové buňky reagují trvale nebo jen s malou adaptaci na trvalé dráždění. To je ale v kontrastu se zkušeností velmi rychlé adaptace subjektivního počitku. Příčina je ve vyšších neurálních obvodech čichové dráhy. Citlivost: Práh čichové citlivosti může být u živočichů podle behaviorálních pokusů dokonce nižší než u jednotlivých receptoru elektrofyziologicky měřený. Jedním důvodem je právě konvergence na glomerulární buňky, dovolující mitrálním buňkám sbírat vstupy z velké populace identicky naladěných primárních neuronů a posílajících tak i velmi slabé signály do mozku. Systém také někdy zvyšuje citlivost na úkor rychlosti (časového rozlišení), která u čichu nehraje tak životně důležitou roli jako u zraku nebo sluchu. Časové parametry čichání At the level of the olfactory bulb (OB) odor information is contained in the spike patterns of mitral/tufted (M/T) cells. Today it is generally assumed that in addition to the identity of the activated M/T cells, the temporal patterns of their responses are important for olfactory coding (Friedrich and Laurent, 2001; Laurent et al., 2001; Schaefer and Margrie, 2007). In mammals, every sniff evokes a precise, odour-specific sequence of activity across olfactory neurons Distributed representations reflecting different features of a stimulus can therefore occur in the same circuit at different epochs of a response. Spatial coding and temporal coding are not mutually exclusive, and may instead exhibit synergy in numerous ways. We speculate that time comparisons across glomeruli give a concentration-invariant readout for odour identity, whereas temporal comparison to an internal representation of the sniff yields information about odour concentration. Such a coding scheme can rapidly resolve ambiguities that arise as odour identity and intensity change. Extracting both parameters on a sniff-by-sniff basis may help animals locate and identify odour sources in natural olfactory scenes. doi:10.1038/naturel0521 Lateralizace čich With the smells that were either neutral or ones that dogs liked (food, lemon, vaginal secretion and cotton swab), the first time dogs sniffed them, they did so with their right nostrils. However, as time went on and they encountered the smells more, they then switched to their left nostrils The fact that dogs smell with their right nostril first implies that the right side of the brain is involved first. This is thought to be because the right-hand side of the brain deals with novel information (in this case, a new smell), and then once the dog has become accustomed to the smell the left side of the brain takes over more, as this side handles more familiar stimuli. of the b However, for the other two smells (the vet's sweat and adrenaline), that perhaps may not be quite as welcome to a dog, the dogs always smelled them with their right nostril. Even though the smell of the vet would be as familiar to the dogs as ngnt nostril, bven tnougn tne smell or tne vet would oe as raminar to tne aogs as perhaps dog food or the smell from a female dog, it must have been more stressful to the dogs (as any person who owns a dog knows, taking it to the vet's generally isn't a relaxing event for anyone involved). The fight-or-flight response is mainly dealt with by the right side of the brain. Therefore, even though these smells became as familiar as the other ones did, they elicited enough strong emotions like fear to continue being processed by the right-side of the b right nostril) (and therefore the doi:10.1016/j.anbehav.2011.05.0 Centrální části čichové dráhy 1. Čichový lalok 2. Piriformní kůra 3. Orbitofrontální kůra Orbitofrontalni kura Piriformní kůra Má vztah k silné emocionální složce čichových vjemů a ukládání paměťových stop. I i i IlUKMIlirlĽXfr t ibUťkMJh ílIhalulIUbJ T (|i*|cixiisrtex I t T fPlfnuiĽirT Ľpii-iL-liinr- Antennal morphology diversity Response specificity to size and composition of odorant molecule Olfactory receptor neurons respond to odorants bombycol stimulus _u_sensory neurons I Mil 11II I IH II BHr--«1111 Mil- H II I fclH-1—H-H^i Antennal olfactory receptor neurons terminate in antennal lobe glomeruli Antennal lobe: two major classes of neurons f , hp ) pc / ^^^^^ p^1^^ ^\____pn / local interneuron projection neuron Inhibition 'sharpens' the PN response (temporal and odor discrimination) control 2s bicjcculin (GABA antagon nlilL ISQ--n cholinergic sensory a ff e rents bicuculline - sensitive receptors v bicuculline - insensitive excitatory pathway GABAergic PN LNs erminace odpovědi nezbytná pro časovou rozlišitelnost signálů. Odor is discontinuously distributed in air Even when following an odor trace, perception is discontinuous Temporal resolution is limited Antennal nerve electrical stimulus J_JOUUl LLLUEJL1JLL, 0\-\y _n n n n n [JMÜJLU_J1L 3(-|t n n n n n iilülJllIWJLiJU. -JilLU A\-\~* n n n n n C1 J -— n n n n n 5Hz-"—n—"—11—11- mnmsL_ _jji_Li_iiiii -| OH"7 n M rLn n pheromone stimuli PNs, temporal resolution lomerun responses reflect odorants' structural properties (chain length, residues, polarity etc.): odor map Apis me!Hfera, 11 ™ antenna I lobe carbon chain length L □ 20 40 60 BO 1LHJ-- rcsponse Intensity (sex) pheromones and 6 ordinary' odors are processed by two different pathways _ Olfactory receptors SPACE/* * I j_ J- I- J MACROGLOMERULAR COMPLEX ANTENNA AMTENNAL LOBE output mechonoeensoiv Input neurons PROTOCEREBRUM MOTOR SYSTEM 4> Hildebr; PNs may have narrower response spectra than receptor neurons L ORCl 4 4 ORGS onc3 44 PN1 G2 4 ORC4 4 ORG response PN2 AAA G3 ft OBC i ORC2 ORC3 OAC4 PN3 a odor ligandt PN respon&a PN1 ~ PN2 A PN3 specialist 'ordinary PNs {e.g. pheromone) a odor llgands 2 J.G. Hildebrand 1996 Podobnost mezi hmyzem a obratlovci přece jen omezená Claas Receptors Uganda Olirjameric state Localization Vertebrates GPCRs OR Odours Monomer Main olfactory epithelium. Cruncher g ganglion, vomeronasal organ and exogenic: expression TAAR Amines Monomer Main olfactory epithelium and GriJneberg ganglion FPR Pathogen-and inflammation-lelated compounds Unknown Apical layer of vomeronasa! organ VÍR Small volatile molecules and sulphated steroids Monomer Apical layer of vomeronasal organ and main olfactory epithelium V2R rfeptidestfSPl arid MHC peptides), MUPs and sulphated steroids M 01 11) r r le i h i h i 1 i e 1 e i or i hj r v: i 1 \ i H 2 - M v protei ns a nd B2M Basal layer of vomeronasal organ and Gruneberg ganglion Min lot opic: receptors (RTKtype) CCD t"xl racellulm: ui or, jnariylin rir n i guanyLn Intracellular: bicarbonate, Ca*" and ncurocalcin-G Dimer M air i »1 lad ory epi 1 i lelii ji ri GCC Unknown Unknown Gruneberg ganglion insects kino! ropu:'7-1 M' receptora OR hoi id odours and pherornones Helemdlmer (OrX-Or83h) Antenna (iiasiconic:, Iricdiuid arid coelocoiiiL" sensilla} and maxillaiy palp GR HoterodimcrfGrZlj G rttfa) Antenna (bosiconic scnsilla) lonotropic "glutamate* receptors IR Ammon ia.amines. water vapour and alcohols Multi merle Antenna (coeloconic sensitla) B2M, f>? microglobulin; FSP1, exocrine gland-secreting pepTirtp 1; FPR, formyl pppride receptors; CjCD and ftCX\, gu any Sate cyclase Type D and G; CIPCR, Ci protein-coupled receptor; CR. gustatory receptor; la and CIrfi"la. Drasaphin mplanaqastcr gustatory receptors 71a and b'ia; H7~Mv, non-rlassical clans 1 major histocompatibility yenes, IR, jurirjli rjpiu iccepLur, MHC, major bislotumpatibility complex; MUR 111joi urinary pry lsin: OR. odoianl receptor; RTK. i tueploj tyrusin« kinase; OiX 0i$3b, helerumeiic D. rjieiuriutjuste; odoidril receplor comuoied of Or83bdnd another 0R(OrX);TAAR, trdce amine associated receptor; /-1M, seven-transmemorane; Vt R and V7R, vomeronasal receptors type 1 and 7._ Podle: Čich hmyz a obratlovci, 2010 Podobnost mezi hmyzem a obratlovci jen omezená Table 2 | Commonalities and differences of olfactory receptors in vertebrates and insects Characteristic Vertebrates 1 nsects Class GPCR Non-GPCR Repertoire Large, variable Smaller, constant Topology Heptahelical Inverse heptahelical Activation Metabotropic lonotropic Pseudogene fraction High None to low Stoichiometry Monomers Heteromers One receptor-one neuron rule Yes Yes* Gene selection Stochastic Deterministic Expression pattern Zonal and random Zonal and random Instructive role Yes Unknown Ectopic expression Yes Unknown Inhibitory action of odorants Rare Common Convergence of axons to glomeruli Yes Yes Glomeruli per receptor type Variable, <2 up to 20 GPCR, G protein-coupled receptor. *There are notable exceptions to this ru le, which have been excluded from this table for clarity. Box 11 Amplification and sensitivity of olfactory signalling Vertebrates In general, G protein-coupled receptor (GPCR) signalling, such as that mediated by photoreceptors, amplifies a signal135. However, the principles governing olfactory signalling are quite different. Owing to the relatively low binding affinity of many odorants (micromolar range), the lifetime of the receptor-ligand complex is brief. Consequently, the probability that a receptor-ligand complex will meet a G protein and catalyse GDP-GTP exchange is low72. Why do most olfactory neurons not require high amplification at the receptor level? At micromolar odorant concentrations, more than 20 million odorant molecules arrive at a cilium every second139. Thus, although the probability that a single odorant molecule will activate the signalling pathway is minuscule, it is likely that a few odorant molecules will successfully evoke a response. By contrast, at low light levels, at which only a few photons reach the eye, amplification allows rod photoreceptors to detect and respond to single photons. In the vomeronasal organ, concentrations of pheromone molecules above 0.1 pM can elicit a response140141. At these low concentrations, only a few molecules per second are captured by a cilium. What are the biophysical requirements for such exquisite sensitivity? Receptors must bind the ligand with high affinity, increasing the lifetime of the ligand-receptor complex (seconds to minutes). During this time, the receptor may activate many hundreds of G proteins. However, active mechanisms are required to disable such stable ligand-receptor complexes. Receptor phosphorylation and (3-arrestin capping may be an important route for response termination. In other cases, there may be no need for rapid inactivation, because temporal coding of successive stimuli does not matter. Insects Similar to vertebrate neurons, insect olfactory receptor neurons (ORNs) can be very sensitive, responding to the binding of a single molecule of a sex pheromone142. Insect ORNs, which have an ionotropic mechanism of action, also lack the amplification provided at the receptor and G protein level. How then can a single pheromone molecule activate an insect neuron? The open probability (P ) of a ligand-gated channel is determined by its affinity for the ligand and, for nanomolar binding affinities, may reach unity on a timescale of seconds. Depending on the single-channel conductance, a single channel may readily carry currents in the order of a few picoamperes. The input resistance of vertebrate ORNs is high (2-8 Gfi) and a few picoamperes of inward current produce a voltage response that is sufficient to reach the threshold for triggering an action potential143. Similar mechanisms are seen in rod photoreceptors and sperm, which detect single photons and single molecules, respectively103144145. Feromony u obratlovců Interindividuální komunikace -Spouštěče: vyvolávají okamžitý behaviorální projev -Primery: pomalejší změny vývoje nebo metabolismu -Modulátory (?): ovlivňující emoce, náladu lidí Chemické složení: velikost, polarita, těkavost: Atraktanty nebo poplachové feromony - malé a těkavé (alkoholy) Individuální feromony - netěkavé (proteiny) Dva chemosensitivní systémy savců Hlavní čichový epitel (MOE): ciliátní čichové buňky Projekce do čichového laloku Každá buňka exprimuje jediný typ receptoru (1300 u myši) Proud vzduchu při nadechování (a vydechování) Identifikace potravy, kořisti, predátora, značení teritoria Otevřený systém vybudovaný na předpokladu, že není možné předvídat, se kterou molekulou se potká. Vomeronasální orgán (VNO): Slepá dutinka pod hlavní čichovou sliznicí Mikrovilární morfologie Projekce do přídavného čichového laloku (AOB) 2 třídy receptoru (G protein, ale málo příbuzné čichovým;^ > asi 200 celkem), velmi citlivé a specifické 1 V ! Vzduch přichází „pumpováním" při vzrušení (spíše ^ry přímým kontaktem) i'V'SÍ Nezbytný pro paletu chování spojených s pohlavím a 43 rozmnožováním, výchovou potomstva, nástupu pohl. dospívání, blokování těchotentsví, obrany a rozeznávání mláďat, mateřského chování, páření a vnitrodruhové agrese. Citlivost je vysoká, pro feromony myši až 10-10M. Axony jsou mezi čichovými laloky a vstupují do přídatných čichových laloků. Zde najdeme podobně jako v hlavní dráze specificky naladěné glomeruli (přijímají vstupy jen z buněk exprimujících jeden typ receptoru). Projekce pak nevedou ani tak do čichového kortexu, ale spíše do amygdaly a hypotalamu limbického systému, kde vyvolávají nevědomé odpovědi. Izolace dvou feromonů: Mužského z potu, ženského z moči MRI a PET ukázaly „rozsvícena čichové kůry Žen u ženského f. a hypotalamu u mužského f. Muži reagovali opačně. Gayové jako ženy. Hjernen Lugtkolben MHC nepříbuznost detekovaná čichem? MHC molekuly ovlivňují složení těkavých látek moči a Potu = Individualita na dálku Volba partnera, afrodiziaka, parfémy... Aroma, příchuť - kromě orthonasálního ještě i retronasální olfaktorický vjem FIGURE 14.1 Molecules released into the air inside our mouths as we chew and swallow food travel up through the retronasal passage into the nose, where they then move upward and contact the olfactory epithelium. Olfactory epithelium Table 11 The dual olfactory system Operations Orthonasal olfaction Retronasal olfaction Orthonasa olfaction Stimulation route Through the external nares From the back of the mouth through the nasopharynx Stimuli Floral scents Perfumes Smoke Food aromas Prey/predator smells Social odors Phcromones MHC molecules Food vola til es Processed by Olfactory pathway influenced by the visual pathway Olfactory pathway combined with pathways for taste, touch, sound and active sensing by proprioception form a'flavour system' Note the interesting contrast, that orthonasal olfactory perception involves a wide range of types of odors processed through only the olfactory pathway, in com pari son with retronasal olfactory perception which involves onlyfood volatiles but processed in combination with many brain pathways. (a) Olfactory epithelium Olfeictory receptors Vomeroria&at V2Rs + MHC V1Rs T1Rs T2RS Olfactory receptore Gustatory receptors The location of chemosensory organs in the mouse and Drosophila. (a) A sensory neuron in the olfactory epithelium of mice expresses one of about 1,000 olfactory receptors. Neurons in the apical and basal layers of the vomeronasal organ express distinct, unrelated classes of G-protein-coupled pheromone receptors (V1 Rs in the apical and V2Rs in the basal layer). In addition, a small family of MHC class I-like molecules is coexpressed with V2Rs in neurons of the basal layer. The taste cells in the tongue, palate and pharynx express other classes of GPCRs, one encoding sweet-taste receptors (T1Rs) and one encoding receptors for bitter compounds (T2Rs). Note that V1 Rs and T2Rs are related to each other, as are V2Rs and T1 Rs, respectively, (b) The olfactory neurons of Drosophila are located in two pairs of appendages in the head, the third antennal segment and the maxillary palps, and each neuron expresses very few, possibly just one, of the 61 olfactory receptor genes identified so far. The gustatory or taste sensory neurons are located in numerous organs, including the two labial palps on the head, internal sensory clusters in the pharynx (not shown), all the legs and the anterior wing margin. Each neuron expresses a few, possibly just one, gustatory receptor gene. A few gustatory receptor genes are also expressed in olfactory neurons of the antenna and maxillary palps. Čich a chuť spolupracují Chuť Chuť Na rozdíl od čichu je to smysl, kontaktní, méně citlivý, má mnohem -méně receptoru, ale překvapivě různá transdukční schémata. Čich rozeznává kapalnou fázi, chuť kapalnou. (b) One of the "facts" that experts have been unable to purge from many textbooks is the notion that sweet is perceived at the tip of the tongue, bitter at the back, sour on the sides, and salty all over. In the case of this myth, we know roughly when it began and we have some idea about what has maintained it in the face of determined efforts by experts to stamp it out. The origin is most likely a book written by Harvard University's Edwin Boring in 1942. Boring, in addition to his own work, chronicled the history of sensation and perception. He described a study conducted by Hanig in the laboratory of Wilhelm Wundt in 1901 (Hanig, 1901). Hanig wanted to show that the four basic tastes were mediated by different receptor mechanisms (something we take for granted today). He reasoned that if taste thresholds varied with tongue locus, then one would have to conclude that the receptor mechanisms varied as well. Hanig selected points on the oval distribution of taste buds around the perimeter of the tongue and laboriously measured thresholds for substances representing each of the four basic tastes. The variation in thresholds was small but the patterns across the four tastes were different; Hanig had made his point. Boring apparently misunderstood the concentration units in Hanig's study and failed to appreciate just how small the variations in thresholds really were. Thus, Hanig's result that sweet thresholds were slightly lower on the front of the tongue and bitter thresholds were slightly lower on the back was misconstrued and turned into the notion that we taste sweet on the front of our tongues, bitter on the back, etc. Since the tongue map became a common laboratory demonstration, generations of students have had reason to doubt the map. Asked why they could not observe it, one group of students said that they "must have done the experiment wrong." It is worth remembering that textbooks are not always correct. But you can believe us here: receptors for all four of the basic tastes are distributed over the entire tongue. References Boring, E. G. (1942). Sensation and Perception in the History of Experimental Psycho\ Appleton-Century-Crofts. Hanig, D. P. (1901). Zur Psychophysik des Gesch mackssinnes.P/7//osopfr/scfre Studien Receptory nejsou neurony, vznikají z epitelu pokožky, sekundární. Mikrovilli. Chuťové, podpůrné a bazálni. . .. .■ -ÍJ£V \ Chutovy .Příkopy" ohranicunc< papiiy^ pohárek Žlézy vylučující sliz do „přikopu" ohranifruticl papily v „ptikopcch" obVUipujicLíJi jcjiíh ceiKrllní val, reaguji na chilli hořké. Mezery me« papilami zvlhtuje slií. vylučovaný iliiijirii umístěnými nii bázi čichlo rueíer. Chutově molekuly sc mu*1 v lomu vlhkém jirosiíedl nejprve rozptýlil, a teprve pote je mohou ehuťov* poháfky detekoval. Afmeieferiá tfiaň UtOVÝ PO H A Apikálni (hrotový) pór Bazálni buňka ŕ^Synapse se synaptick Selektivita omezená. Člověk může rozlišit 100 chuťových kvalit, přičemž jde asi opět o skládání 5 základních kvalit: sladké, slané, kyselé, hořké a UMAMI. Jedna chuťová buňka může reagovat na všechny čtyři základní chuťové kvality, ale na jeden typ odpovídá maximálním generátorovým potenciálem. Některé jsou více specialisté jiné generalisté. A.. SjJl-prelcrriůL Shnili lll-n EalE / S SvfľľC [liLlnr .S:iil Sum U i- Hirer 1 y liilŕ ■. I |_ I I : ■ ■ l^ie-ŕíll ímnf r ľc|I 1- Timc OFF i Jl i ■.....■ ŕ \^ Suwl lín .i ^—I—I-L ■ III! I itltcr b NEUROBIOLOGY Gary G. Matthews. Task: bud SENSORY PROCESSES 383 Transdukční schémata G-prot - gustducin fa) Salt intracellular fluid NaH Taste btiti cell membrane Amiloride-sensitive -cation channel Depo l ar i?, ati on Adenylyl cyclase Closed K* channel / H«2 G protein Cytoplasm id} Umami Réctíptor, Depolarization Bitter /Glutamate Closed K+ channel \ ; Bitter substance MB G protein Decrease in cAMP Increase in Ca2 K+ De polarization Phos? G protein Increased transmitter release qute 13.34 Taste-transduction mechanisms differ for different iste qualities All transduction mechanisms except the IP3 action in Jlead to depolarization, which spreads to the basal end of the cell id opens voltage-gated Ca2+ channels to allow Ca2" entry and trans-litter release, (a) For salt taste, sodium ions enter a taste bud ceil irough amiioride-sensitive cation channels, directly depolarizing the ?1I, fb) In sour taste, either H+ ions enter the cell through amiloride-snsitive cation channels, or they close K+ channels to produce depo-irizatlon. ic> Sweet taste Is most commonly mediated by the binding fsugars to a G protein-coupled receptor, which acts via a G protein to ttivate adenylyl cyclase and produce cyclic AMP, Cyclic AMP then actT-3tes protein kinase A (PKA) to close a K~ channel [by phosphoryfating Endoplasmic reticulum it), producing depolarization, (d) The amino acid glutamate (monosodi-um glutamate, MSG) stimulates the taste quality umami (a savory or meaty quality). Glutamate binds to a G protein-coupled receptor (related to synaptic metabotropic glutamate receptors) to activate a phosphodiesterase (PDE) and decrease the concentration of cAMP.The decrease in cAMP leads to an increase in intracellular Ca2+ concentration, (e) Bitter taste mechanisms can involve a G protein-coupled receptor for bitter substances that acts via a G protein and phospholi-pase C to produce 1P3. IP3 liberates Ca2+ ions from intracellular stores, eliciting transmitter release without requiring depolarization.Other bitter substances bind to K+ channels and close them to depolarize the cell. Nu Transdukcni schemata A. Salt 4. ShuJiuici L'hjnnul } ToflCOCll V pIllMIM J II i.Til'i-.ll-k.' I^tw 1 Ijcw Na /-v Ěni [ ]ii;r.L: libra [ ^ [ | B. Suiir SufiJLV ihl li-niifUL b FywHfllmi ■r iii Pivftm Vti..... L'lUiiiilCl I'll opus I TbMcccII > ,i i- . 1 ■ i'A ChaJinel pH hoicked Ii.--: -.1 ■ pl.l-.ll-l \ \ filvr Nurinal NEUROBIOLOGY Gary G. Matthews crfi y "\ LLLL Ii li K: W liKi Transdukční schémata Uzavření K kanálu Sweet i\ KrliŕlI^t I rJírSirMpJiiMykiKeJ K+chunncJ — (vperu Pt|ii-iphnrjl .: i:"ii S?Vi vi M \t G-„ ■ OTP Acnturion at udcnvl>l cycluurt Autivuticiri (ifpnwiD kJiunc A. Píiii.phi.ri, l.iiiil k," ĺ hiinnrl m b Crow dccticin ví a. IufIe resefilor eefcJ HEUFtOBfOLOGY Gary G. Matth*sw& Neselektivni kationtovy kanal se otevira —-1. i - ■ i iii-.Uh.uk Sweet 2 Cyclic nudrcvlide bouraJL - ll'. -11 ■1 ■ . Imxi-iI Mn1 Cyclic nwlorfidc n*k Niu-nit: ........:"l cNMP NMP \-lUi.jlistD ill pCMmpniudichleni CTwbV rcuLlcuLjik? k-nrfi Ju.ll. CT>vlii/ iiu-uIl-il; \c Tii£ipri.-\trrJ LTUIlQcl i.irXTJIS Tattle In-^iiV i. rO b NEUROBfOLOGY Gary G. Matthews Hořká chuť Velká řada ligandů Caffeine Theophylline Cycloheximide Nicotine, Strichnine Quinine, Denatonium Others R jaxxxxxxxxxxxxxx) cGMP, transient increase a cAMP, cGMP transient decrease J Continuous source? ßy IP3 transient increase t3 DAG Figure 3 Transduction of bitter taste as elicited by a variety of ligands. Rsr multiple GPCRs of the T2R family, coupled to the G protein gustducin4749; a, a-subunit of gustducin657; G-protein subunits |33 and 7I3 (refs 60-62); PLCf32, phospholipase Csubtype61; lns(1,4,5)P3, inositol- 1,4,5-trisphosphate59; PDE, taste-specific phosphodiesterase58; cAMP, cyclic adenosine monophosphate59; cGMR cyclic guanosine monophosphate59; sGC, soluble guanylate cyclase55; NOr nitric oxide55; NOS, NO synthase56. For second-messenger kinetics, see refs 55,59,63,64, Zatímco sladká, umami, slaná (a tučná) chuť poskytují příjemné vjemy, hořká a kyselá chrání před příjmem potenciálně toxických látek a silných kyselin. ATP jako mediátor TASTE IN THE MOUTH Taste-bud receptors, primarily on the tongue, sense the qualities of salty, sour, bitter, sweet, and umami (the taste of glutamate). While sweet, umami, and salty foods provide pleasurable sensations that drive the intake of carbohydrates, amino acids, and sodium, the tastes of bitter and sour inhibit intake of potentially toxic substances and strong acids. Sweet or glutamate' rich foods THE TASTE SIGNALING CASCADE IN THE MOUTH The binding of molecular components of sweet or glutamate-rich foods to T1R-class receptors and bitter substances to T2R receptors stimulates the release of Ca2+ into thecytosol from the endoplasmic reticulum (ER) via G protein signaling and the second messenger molecule inositol trisphosphate (IP,) ©■ The Ca2* activates the TrpMS channel to allow the entry of sodium ions (Na+), depolarizing the cell ^. The combination of depolarization resulting from the influx of Na+ and rise in intracellular Ca2+ opens pannexin channels in the taste-cell membrane, releasing ATP from the cell This in turn activates purinergic receptors on the sensory nerve fibers innervating the taste buds, thereby sending a signal to the brain Q. Chuť ve střevě? TASTE IN THE GUT In contrast to taste receptors in the mouth, Tift and T2R receptors in the gut do not induce sensations of taste, but rather initiate molecular pathways that help guide the digestion or rejection of food substances traveling through the intestines. The underlying pathways, however, have many similarities. POODS IN THE GUT © Special l»d endocrine cells of the smal I Intest Ine, known as entGroendocrhiG calls, display T2R bitter receptors on their col I membranes. When bitter compounds bind to the T2R receptors, the cells release the peptide hormone cholecystDklnln (CCK), which acts on CCK2 receptors located on antarocytes, or Intestinal absorptive cells. This Increases the expression of the transporter ABCB1, which pumps toxins or unwanted substances out of the eel I and back Into the Intestlna I I u men. CCKalsoblndstoOCKI receptors on sensory fibers of the vagus nerve, sending signals to the brain to cease food Intake. © TIR-class receptors on enteroendocdne cells lining the small Intestine detect sweet substances and respond by secreting 1 he glucagon-like peptide GLP-1. GLP-1 then travels to the pancreas via the bloodstream, where It boosts the release of Insulin from pancreatic p-celts, promoting the uptake of glucose by diverse tissues. Additionally, GLP-1 diffuses to neighboring enberocyte cells In the small Intestine, driving the I nsertlon of the gl ucose transporters SGLT-1 and G LUT2, which facilitates the uptake of glucose from the Intestines. @ In the colon, bitter llgands bind to T2R receptors on epithelial cells, where they Induce the secretion of anions and water, which leads to fluid rushing Into thelntestlne, resultl ng I n d larrhea t hat flushes out the colon. Vagus nerve Potenciálně toxické (hořké) substance T2R receptor Kýchání, pohyb řasinek Plíce - dolní cd. TASTE IN THE AIRWAYS Scientists have also recently identified the existence of taste pathways in human airway cells, where they likely mediate defensive responses to inhaled foreign and potentially toxic substances. IN THE UPPER AIRWAY In the upper airways (nasal passages and trachea), T2R receptors on chemo sensory cells sense bitter com pounds, re lea sing secondary messengers that spur the release of Ca2* from the EH. The increase in cytoplasmic Ca**■ activates the TrpM5 transduction channel, allowing the Influx of Na+ and the depolarization of the cell. This in turn activates voltage-gated Ca2* channels, which permit even more Ca2+to flood into the cell. This initiates the fusion of synaptic vesicles with the plasma membrane, releasing the neurotransmitter acetylcholine to activate nearby nerve fibers and induce protective reflexes such as sneezing o IM cc LU CD LU > LU 2 ji LU CC a < IN THE LOWER AIRWAY In airway smooth muscle cells of the lungs, the same T2R pathway is initiated by the binding of bitter compounds. Increases in cytoplasmic Ca2* likely cause nearby calcium-activated potassium channels to open, allowing the outflow of K+, which causes hyper polarization and subsequent relaxation of the muscle cells Also in the lungs, T2R receptors on ciliated airway epithelial cells bind bitter compounds, initiating the same G protein-mediated pathway that results in the release of Ca2* from Intracellular stores and thereby an Increase in ciliary beat frequency, which researchers suspect serves to sweep irritants away from the surface of the cell Bitter foods Cilia on airway epithelial cells Si_► causes cílil to move I _m II^IIILIII IIUIIIMIUMll'lllllllllllU Nosohltan a trachea - horní cd. Sensing fat? CAN WE TASTE FATS? Although gusfi'n and TAS2R38 contribute to the supertaster phenotype and may contribute to the perception of fat texture, researchers are still looking for a receptor directly triggered by fat. One promising candidate is the protein CD36, which binds long-chain fatty acids in mice, and is expressed on taste buds. The mechanism by which the CD36 carrier protein initiates a neural signal is poorly understood. CD36 may serve as a carrier protein that transfers the fatty acid to another receptor or it may activate an ion channel that alters the excitability of taste cells. Fatty acids DETECTING FATTY ACIDS Although CD3& binds long-chain free fatty acids, most of the fat we eat Is composed of triglycerides (three fatty acids bound to a glycerol backbone), which CD36 cannot bind. However, lingual lipase, an enzyme that humans secrete In small quantities, breaks down triglycerides into free fatty acids, producing low levels of fatty acids that bind to CD36 in animals and may affect fat preference. Lingual lipase HOW DOES THIS LEAD TO OBESITY? Recent work has shown that people who had a particular single nucleotide difference In their CD36 gene perceived high levels of creaminess in foods regardless of the fat level. These individuals, showed high preferences for creamy, usually fattier, foods, Although the mechanism remains unclear, this finding raises the possibility that disruptions in this gene lead to both persistently high responsiveness to the oral sensation of fat and an elevated preference for fat which could lead to obesity over time. CD 36- gene (ability to "taste" fat) Güstin gene and PROP tasting (ability to detect fat "texture") I Preference for fatty taxis Increased fat intake Obesity and chronic disease risk 2 názory na kódování chutí: A) labeled lineš (analogie sluchu) - jeden nerv, jedna nemíchaná chuť, nepřekrývají se ani buňky ani dráhy, nebo: B) specifické vzorce aktivity (analogie b.vidění nebo čichu - jeden receptor o výsledné kvalitě nic neříká a až směs dvou dává třetí kvalitu) Labelled-line model Across-fibre models Figure 2 | Encoding of taste qualities at the periphery. There are two opposing views of how taste qualities are encoded in the periphery. a. In the labelled-line model, receptor cells are tuned to respond to single taste modalities — sweet, bitter, sour, salty or umami — and are innervated by individually tuned nerve fibres. In tliis case, each taste quality is specified by the activity of non-overlapping cells and fibres, b, c. Two contrasting models of what is known as the ^across-fibre pattern'. This states that either individual TRCs are tuned to multiple taste qualities (indicated by various tones of grey and multicoloured stippled nuclei), and consequently the same afferent fibre carries information for more than one taste modality (b), or that TRCs are still tuned to single taste qualities but the same afferent fibre carries information for more than one taste modality (c). In these two models, the specification of any one taste quality is embedded in a complex pattern of activity across various lines. Recent molecular and functional studies in mice have demonstrated that different TRCs define the different taste modalities, and that activation of a single type of TRC is sufficient to encode taste quality, strongly supporting the la belled-line model. Transgenní myši s přehozenými receptory Bitter receptor Bitter tastant Itltlifr B'rtter receptor .*••'****'** in sweet cells .I-"" ......I--" íä"*1""**"*'**,*Si* Wild-type control 1......iii *+ í"*'**.....^ Bitter receptor .........H" in bitter cells i i 11-1-1—i—i—i—i i i j-1-1—i—i—i—i 11 0.1 1 10 Bitter tastant (mM) Vnímání sladkého ne receptorových buněk chuťových molekul draží aktivaci jen i la vlastnosti recep Každou jednotlivou chuť rozeznáme i ve směsi chutí - ochrana. Nevytváří se tedy mícháním chutní chuti nové. Labelled-line model A cross-fibre i i IV, ■ Bitter □ salty I Sweet J Umám I Sour Figure 2 | Encoding of taste qualities at the periphery. There are two opposin»iews of how taste qualities are encoded in the^keriphery. a, In the labelled-line model, receptor cells are tuned to respond to single taste modalities — sweeV bitter, sour, salty or umami — and are innernttjl by individually tuned nerve fibres. In tliis case, each taste quality is specified by the activity of non-overmpping cells and fibres, b, c. Two contrasting mndels of what is known as the ^across-fibre pattern'. This states that either individual TRCs are tuned to mult ire taste qualities (indicated by various tones ofgkey and multicoloured stippled nuclei), and consequently the same afferent fibre carries information for mow than one taste modality (b), or that TRCs are\till tuned to single taste qualities but the same afferent fibre carries information for more than one taste Modality (c). In these two models, the specificatAu of any one taste quality is embedded in a complex pattern of activity across various lines. Recent mWecular and functional studies in mice have demonstrated tliat different TRCs define the different taste modalities, and that activation of a single type or\RC is sufficient to encode taste quality, strong^supporting the la belled-line model. Axony patří pseudounipolárním neuronům, jejichž těla leží v gangliích VIL, IX. a X. hlavového nervu. Přes nižší mozková centra můžeme sledovat cestu chuťové informace ke dvěma kôrových chuťovým oblastem. První asi hraje roli při vnímání prostorového rozmístění chuťových počitků na jazyku a druhá je zodpovědná za vnímání vlastní kvality chuti. Najdeme také významnou projekci do limbického systému a hypotalamu. Uvedené spoje jsou morfologickým substrátem významné emocionální komponenty, která vždy doprovází určitý chuťový vjem a pojí se paměťovými stopami - rozlišování vhodné a nevhodné potravy už od mládí. Zřejmě také zprostředkovávají autonomní reflexní reakce při příjmu potravy (sekrece slin, žaludeční šťávy apod.). Příjemné tóny sladkého a umami signalizují kalorické stravitelné jídlo. Hořká chuť má nízký práh při vyvolávání dávivého reflexu, jde o varování před obvykle jedovatými látkami. r— C. Gustatory pathways Nucleus tractus solitaril N. petrosus major Chorda tympani Insula Thalamus: Nucleus ventralis posteromediaiis Hypothalamus See D. Palate fThroat Tongue Itiiikantm: -t b Gary G. Matthövi'e CľILHHiL HjlLTJh I3! i'-lL^nCrjl £trüi Turliilp- HUťlĽlflŕMJIIWIfy ■(.hídícn fonpn ťllLľJTIIll vi-JW I NEUROBIOLOGY Gary G. Matih«w£ Potěšení z chutí - vrozené prospěšné reflexy. Zvýšená chuť na chybějící složku. 100 r- t_> d o" s o c o t; 50 "Dry receptor' ^^^^^ "Moist receptor" 100% -1——I-1-1— 40 50 60 70 Time (sec) 100% 0% 0% RH r o 10 20 30 80 90 100 FIGURE 7-18 The "cold-moist-dry" triad sensory sensillum of the cockroach contains three bipolar sensory neurons; one neuron of the hygroreceptor responds to high humidity ("moist" receptor) and one to low humidity ("dry" receptor). The receptor cavity of the poreless sensillum is filled with a dense secretion. (Modified from Yokohari and Tateda 1976; Schaller 1978.) Termorecepce a Spinal cord and dorsal root ganglion b Skin Low-threshold mecha noreceptors Temperature and pain receptors \fentral horn /fibres^, ^ Efferent' fibres Merkel cells Meissners corpuscle Pacinian — corpuscle Epidermis { Dermis < Hair-root plexus Ruffini's endings Free nerve endings Hair follicle c Histological section Skeletal muscle Epidermis Dermis Figure 1 | Anatomic and functional organization of touch, a | Spinal nerves Formed by the joining of afferent (sensory) and efferent (motor) roots provide peripheral innervation to skin, skeletal muscle, viscera and glands. Arrows denote the direction of incoming sensory and outgoing motor impulses. The cell bodies oF motor neurons are located within the ventral horn (laminae VII—IX) of the spinal cord. Cell bodies oFsensory neurons are located in the dorsal root ganglia (DRG). Within the DRG there are subclasses of sensory neurons known as proprioceptive (blue), low-threshold mechanosensitive (red) and temperature- and pain-sensing neurons (green). These neurons project centrally to dorsal horn interneurons (laminae I—VI of the spinal cord) and peripherally to target tissues. Proprioceptive neurons (blue fibre) project to specialized structures within target tissues such as muscle, and sense musde stretch, b | Low-threshold mechanosensitive neurons J"ed Wares) project to end organs that transmit mechanical stimuli. Five types of mechanosensitive assemblies have been described and are illustrated in the figure. Temperature and pain sensing neurons (green) do not project to specialized end organs; instead they terminate as free nerve endings in all layers of the skin, and near blood vessels and hair follicles, c | Section of skin showing Free nerve endings (green fibres) stained with the pan-neuronal marker PGF>9.5. The nudei of skin cells are stained (blue) with 4,6-diamidino-2-phenylindole (DAPI). Free nerve endings are found in both the epidermal and dermal layers. Olfactory epithelium * Olfactory bulb Odour molecules Olfactory sensory neurons Odour molecules OOO Figure 11 Odour images in the olfactory glomerular layer, a, Diagram showing the relations hip between the olfactory receptor cell sheet in the nose and the glomeruli of the olfactory bull/3, b, fMRI images of the different but overlapping activity patterns seen in the glomerular layer of the olfactory bulb of a mouse exposed to members of the straight- chain aldehyde series, varying from four to six carbon atoms, The lower part of the image in the left panel corresponds to the image on the medial side of the olfactory glomerular layer as shown in a (see asterisk). (Image in a adapted, with permission, from ref. 53; image in b adapted, with permission, from ref 10,) Tabid 1 The dual olfactory system Operations Orthonasal olfaction Retronasal olfaction Stimulation route Through the external nares From the back of the mouth through thenaso pharynx Stimuli Floral stents Perfumes Smoke Food aromas Prey/predator smells Social odors Pheromones MHC molecules Food volatiles Proces^ed by Olfactory pathway influenced by the visual pathway Olfactory pathway combined with pathways for taste, touchy sound and active sensing by proprioception form a 'flavour system' tote tne i riteresti ng contrast that ortho nasa I o Ifacto ly r^rceptio n i nvol ves a wide range of types of odors processed through on ly the olfactory pathway, in comparison with retronasal olfactory perceptionwhichi nvol onlyfbodvolatilesbutp recessed i n comb i nation with ma ny b ra in path way s. Figure ZI The dua I olfactory system. a, Brain systems involved in smell perception during orthonasal olfaction (sniffing in), b, Brain systems involved in smell perception during retronasal olfaction (breathing out), witli food in the oral cavity. Air flows indicated by dashed and dotted lines; dotted lines indicate air carrying odour molecules. ACC, accumbens; AM, amygdala; AVI, anterior ventral insular cortex; DI, dorsal insular cortex; LH, lateral hypothalamus; LOFC, lateral orbitofrontal cortex; MOFC, medial orbitofrontalcortex;NST, nucleus of the solitary tract; OB, olfactory bulb; OC, olfactory cortex; OE, olfactory epithelium; PPC, posterior parietal cortex; SOM, somatosensory cortex; V, VII, IX, X, cranial nerves; VC, primary visual cortex; VPM, ventral posteromedial thalamic nucleus. Sensory modalities Vision Colour Shape Sound Frequency Somatosensory Temperature Deep touch A stringency Light touch Creaminess Pain Taste Sweet Umami Salt Sour Bitter Smell Pattern Primate neocortex Conscious Flavour perception Circuits Human neocortex Language circuits ippoca mpus, olfactory* a nd limbic systems) Gut Autonomic and metabolic properties Hypothalamus Feeding circuits Amygdala systems Emotion circuits 1 Motivation circuits Craving circuits Figure 3 I The human brai n flavour systems that eval uate and regulate food intake. The diagram shows the areas involved in the perceptual, emotional, memory-related, motivational and linguistic aspects of food evaluation mediated by flavour input s3i41,54'55. Left, different sensory modalities and submodalities that contribute to flavour perception. Middle and right, brain flavour system that evaluates and regulates food intake. Red regions mediate conscious sensory perception; thicker outlines indicate their greater importance in humans and other primates. Green regions mediate subconscious feeding regulation. Deficiencies in essential amino acids are sensed by the anterior olfactory cortex (asterisk).