- Email: [email protected]
Olfactory Neuroscience: Beyond the Bulb
Current Biology Vol 21 No 11 R438
this remains to be proven. It is worth noting that these results implicating PPA and RSC in the coding of spatial information do not exclude the possibility that these regions might also encode nonspatial information, such as color, texture, or statistical summaries of visual features, which might give important cues for scene recognition. Nor do they preclude the possibility that PPA and RSC might encode a broader set of spatial relationships that would fall under the more general rubric of ‘‘contextual associations’’ rather than just spatial layout alone [18]. Finally, an especially intriguing aspect of the current findings is the observation of scene-selective responses in blind subjects, including three participants blind from birth. These subjects have never perceived a scene through sight, so they must have become accustomed to learning about scene geometry through other routes. Do blind navigators use auditory cues to perceive the structure of a room? Or do they use idiothetic cues to keep track of locations within the room, building up a representation of spatial layout over time [19,20]? Answering these questions is important not only for understanding navigation in the blind, but also
for understanding the spatial representations common to blind and sighted navigators. References 1. Epstein, R.A. (2008). Parahippocampal and retrosplenial contributions to human spatial navigation. Trends Cogn. Sci. 12, 388–396. 2. Aguirre, G.K., Zarahn, E., and D’Esposito, M. (1998). An area within human ventral cortex sensitive to ‘‘building’’ stimuli: Evidence and implications. Neuron 21, 373–383. 3. Janzen, G., and van Turennout, M. (2004). Selective neural representation of objects relevant for navigation. Nat. Neurosci. 7, 673–677. 4. Aguirre, G.K., and D’Esposito, M. (1999). Topographical disorientation: a synthesis and taxonomy. Brain 122, 1613–1628. 5. Epstein, R., and Kanwisher, N. (1998). A cortical representation of the local visual environment. Nature 392, 598–601. 6. Epstein, R., Harris, A., Stanley, D., and Kanwisher, N. (1999). The parahippocampal place area: Recognition, navigation, or encoding? Neuron 23, 115–125. 7. Wolbers, T., Klatzky, R.L., Loomis, J.M., Wutte, M.G., and Giudice, N.A. (2011). Modality-independent coding of spatial layout in the human brain. Curr. Biol. 21, 984–989. 8. Kravitz, D.J., Peng, C.S., and Baker, C.I. (2011). Real-world scene representations in high-level visual cortex — it’s the spaces more than the places. J. Neurosci., in press. 9. Park, S., Brady, T.F., Greene, M.R., and Oliva, A. (2011). Disentangling scene content from spatial boundary: complementary roles for the parahippocampal place area and lateral occipital complex in representing real-world scenes. J. Neurosci. 31, 1333–1340. 10. Park, S., Intraub, H., Yi, D.J., Widders, D., and Chun, M.M. (2007). Beyond the edges of a view: boundary extension in human scene-selective visual cortex. Neuron 54, 335–342.
Olfactory Neuroscience: Beyond the Bulb High-resolution tracing of projections from the olfactory bulb to its cortical targets revealed coarse topography and stereotopy in some areas but highly distributed, combinatorial connectivity in others. These results provide a basis for understanding innate and associative olfactory processing and perception. Rainer W. Friedrich Although the cerebral cortex is overwhelmingly complex, many sensory cortices are spatially organized by simple topographic principles. The mammalian visual cortex, for example, contains a map of visual space that is established through a series of precise topographic connections from the eye. Similarly, orderly projections set up maps of stimulus features in other sensory cortices. However, topographic maps are not omnipresent — the visual
cortex of turtles, for example, lacks a precise two-dimensional map of visual space [1]. Four recent studies [2–5] now report that topography is not a prominent feature of projections from the first processing center in the olfactory system, the olfactory bulb, to higher brain areas in the mouse. Projections to two cortical targets, the anterior olfactory nucleus (AON) and the cortical amygdala, are topographically organized at coarse, but not at fine, spatial scales. No topography whatsoever was found in projections to piriform cortex, the
11. Intraub, H., and Richardson, M. (1989). Wide-angle memories of close-up scenes. J. Exp. Psychol. Learn. Mem. Cogn. 15, 179–187. 12. Intraub, H. (2004). Anticipatory spatial representation of 3D regions explored by sighted observers and a deaf-and-blindobserver. Cognition 94, 19–37. 13. Cate, A.D., Goodale, M.A., and Kohler, S. (2011). The role of apparent size in building- and object-specific regions of ventral visual cortex. Brain Res. 1388, 109–122. 14. Amit, E., Trope, Y., and Yovel, G. (2008). A distance principle of organization of the ventral visual stream. J. Vision 8, 329. 15. Takahashi, N., Kawamura, M., Shiota, J., Kasahata, N., and Hirayama, K. (1997). Pure topographic disorientation due to right retrosplenial lesion. Neurology 49, 464–469. 16. Epstein, R.A., Parker, W.E., and Feiler, A.M. (2007). Where am I now? Distinct roles for parahippocampal and retrosplenial cortices in place recognition. J. Neurosci. 27, 6141–6149. 17. Baumann, O., and Mattingley, J.B. (2010). Medial parietal cortex encodes perceived heading direction in humans. J. Neurosci. 30, 12897–12901. 18. Bar, M. (2004). Visual objects in context. Nat. Rev. Neurosci. 5, 617–629. 19. Loomis, J.M., Klatzky, R.L., Golledge, R.G., Cicinelli, J.G., Pellegrino, J.W., and Fry, P.A. (1993). Nonvisual navigation by blind and sighted: assessment of path integration ability. J. Exp. Psychol. Gen. 122, 73–91. 20. Landau, B., Spelke, E., and Gleitman, H. (1984). Spatial knowledge in a young blind child. Cognition 16, 225–260.
Department of Psychology, University of Pennsylvania, 3720 Walnut Street, Philadelphia, PA 19104, USA. E-mail: [email protected]
DOI: 10.1016/j.cub.2011.04.037
largest target area. These results provide a hard anatomical foundation for understanding the organization of higher olfactory brain areas — and ample food for thought. From the Olfactory Bulb to Higher Brain Areas Input to the olfactory bulb from the nose terminates in a stereotyped array of glomeruli. Within each of the approximately 2000 glomeruli of the rodent olfactory bulb, thousands of sensory neurons expressing the same odorant receptor converge onto approximately 20–50 principal neurons, the mitral/tufted (MT) cells. Odors are represented by the activation of distributed combinations of glomeruli. Glomerular activation patterns can be biased towards subregions of the olfactory bulb by particular molecular features, but nearby glomeruli frequently respond to chemically different sets of odorants
Dispatch R439
[6,7]. Odor representations, therefore, show only a loose topographic organization with respect to chemical space already at the first processing stage in the olfactory bulb. Neuronal circuits within the olfactory bulb reorganize activity across MT cells in space and time and diversify odor-encoding activity patterns. However, excitatory convergence of multiple processing channels, which is thought to mediate associations between molecular features of olfactory objects, appears to occur mainly in higher brain areas [8,9]. How are odor-encoding activity patterns transmitted from the olfactory bulb to higher brain areas? Individual MT-cell axons diffusely innervate multiple target areas, including the AON, cortical amygdala, and piriform cortex [9], but a precise understanding of these projections has been lacking. In particular, it has been unclear whether MT-cell projections are determined by the identity of their home glomeruli. Three recent studies [2–4] have succeeded in following small cohorts of MT-cell axons from identified glomeruli to their targets by electroporation or viral expression of fluorescent tracers. A fourth study [5] traced MT cells connected to small populations of cortical neurons back to the olfactory bulb. This was accomplished by an elegant combination of conditional gene expression methods and a transsynaptic viral tracer that crosses only one synapse [10]. Results from these studies now provide a detailed picture of the anatomical relationships between the array of glomeruli and higher brain areas. Coarse Topography and Stereotopy Projections from the olfactory bulb to the AON were found to preserve the dorsoventral, but not the anterior-posterior, axis of the olfactory bulb (Figure 1) [5]. Consistent with previous studies, topographic projections were also found to the pars externa, a distinct subdivision of the AON that mediates topographic communication between the two olfactory bulbs. However, projections of individual axons were diffuse and overlapping, indicating that topography is not maintained at finer scales [3]. Point-to-point topography was also not found in MT-cell projections to the cortical amygdala. However, MT cells
Glomeruli
Anterior olfactory nucleus
Piriform cortex
Amygdala Current Biology
Figure 1. Projections from the olfactory bulb to cortical target areas. Schematic summary of some results obtained by antograde tracing of MT cells associated with individual glomeruli and retrograde tracing of MT inputs to small groups of cortical neurons. MT cell projections from glomeruli in the olfactory bulb to the anterior olfactory nucleus are not point-to-point, but preserve dorso-ventral topography. Projections from individual glomeruli to the cortical amygdala have overlapping, yet circumscribed, terminal fields. The location of terminal fields is stereotyped and depends on the glomerulus. Projections to piriform cortex show no topography. Individual MT cells have varicose branches throughout piriform cortex. Branching patterns of sister MT cells from the same glomerulus (red vs. pink) were no more similar than those of heterotypic MT cells (red vs. blue).
from identified glomeruli projected to overlapping, yet spatially restricted, terminal fields with stereotyped positions in different animals (Figure 1), implying that projections are coarsely topographic and depend on the identity of the glomerulus [4]. Moreover, MT cells projecting to the cortical amygdala were found predominantly, but not exclusively, in the dorsal olfactory bulb [5]. The cortical amygdala has been implicated in innate olfactory behaviors and conveys output, via additional relays, to the hypothalamus. Genetic ablation of sensory input to the dorsal olfactory bulb abolished innate aversive responses to defined odors, but not the detection of these odors per se [11]. Topographic projections to the cortical amygdala may, therefore, be part of hard-wired circuits that mediate stereotyped olfactory responses. Similarly, innate olfactory responses of insects involve stereotyped projections from the antennal lobe, a brain area corresponding to the olfactory bulb, to the lateral horn, one of its two targets [12]. Distributed Combinatorial Connectivity No spatial organization at all was found in MT projections to the piriform
cortex — a paleocortical area that is thought to be involved in associative olfactory processing and memory (Figure 1). Small, local groups of piriform cortex neurons received input from MT cells throughout the olfactory bulb [5], and individual MT cells projected varicose axon collaterals throughout piriform cortex [2–4]. No obvious similarities were observed between projections of sister MT cells originating from the same glomerulus. These striking findings are consistent with previous studies that found no apparent chemotopic organization of odor-evoked activity patterns in the piriform cortex [13,14]. Indeed, a study in zebrafish directly demonstrated that the coarse chemotopy of odor representations in the olfactory bulb is not preserved in the target area homologous to olfactory cortex [15]. Selective responses to odorant mixtures, as well as recent opto- and electrophysiological results, indicate that piriform cortex neurons detect combinatorial activity patterns across MT cells [8,13,15–17]. The direct convergence of functionally different MT inputs onto the piriform cortex neurons could be one mechanism by which this pattern detection is accomplished. In addition, pattern detection is likely to involve the
Current Biology Vol 21 No 11 R440
extensive association fiber system that sparsely connects principal neurons throughout the piriform cortex [9]. Transsynaptic viral tracing demonstrated that the average number of presynaptic MT cells is at least six-fold higher for superficial GABAergic interneurons in the piriform cortex than for pyramidal target cells [5]. This finding is consistent with physiological data and may explain why inhibition in piriform cortex is more broadly tuned than excitation [18]. Although estimates of convergence ratios represent a lower bound, the number of MT inputs to individual piriform cortex neurons is likely to be small compared to the total number of MT cells or glomeruli. This contrasts with insects, where Kenyon cells in a higher associative center, the mushroom body, receive input from up to 50% of the projection neurons in the antennal lobe [12,19]. Unlike Kenyon cells, individual piriform-cortex neurons may therefore analyze activity across small ensembles of inputs, which is likely to have important consequences for olfactory coding. Anatomy of Higher Brain Functions The observed projection patterns in the piriform cortex argue not only that connectivity of MT cells is independent of their spatial coordinates, but connectivity could even be independent of MT cell identity. Indeed, odor responses of genetically identified Kenyon cells in Drosophila melanogaster differ substantially within and between individuals, indicating that connectivity between projection neurons and Kenyon cells is highly variable [20]. Obviously, variable — or even stochastic — connectivity generates a high diversity of input combinations converging onto higher-order neurons. This is consistent with the assumption that the piriform cortex is an associative area that detects combinations of molecular features,
forms and refines representations of olfactory objects, and stores odor representations in memory [8,9]. Essentially all humans agree that rotten fish stinks, or that the smell of certain flowers is pleasant. This consistency of basic odor perception would be difficult to reconcile with stochastic connectivity alone, suggesting that it involves stereotyped circuits. Future experiments may thus test the hypothesis that areas such as the piriform cortex are primarily involved in fine odor discrimination and/or memory whereas basic perceptions are mediated by more stereotyped areas such as the cortical amygdala. However, this hypothesis may also be too simple, considering that higher olfactory brain areas are heavily connected to each other and to the olfactory bulb. It is, therefore, possible that different olfactory computations are not carried out independently in distinct areas, but distributed across a large-scale network [9]. High-resolution, quantitative studies of connectivity are essential steps towards understanding such networks in the olfactory system and elsewhere. References 1. Mulligan, K.A., and Ulinski, P.S. (1990). Organization of geniculocortical projections in turtles: isoazimuth lamellae in the visual cortex. J. Comp. Neurol. 296, 531–547. 2. Nagayama, S., Enerva, A., Fletcher, M.L., Masurkar, A.V., Igarashi, K.M., Mori, K., and Chen, W.R. (2010). Differential axonal projection of mitral and tufted cells in the mouse main olfactory system. Front. Neural Circuits 4, 120. 3. Ghosh, S., Larson, S.D., Hefzi, H., Marnoy, Z., Cutforth, T., Dokka, K., and Baldwin, K.K. (2011). Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons. Nature 472, 217–220. 4. Sosulski, D.L., Lissitsyna Bloom, M., Cutforth, T., Axel, R., and Datta, S.R. (2011). Distinct representations of olfactory information in different cortical centres. Nature 472, 213–216. 5. Miyamichi, K., Amat, F., Moussavi, F., Wang, C., Wickersham, I., Wall, N.R., Taniguchi, H., Tasic, B., Huang, Z.J., He, Z., et al. (2011). Cortical representations of olfactory input by trans-synaptic tracing. Nature 472, 191–196.
6. Friedrich, R.W., and Korsching, S.I. (1997). Combinatorial and chemotopic odorant coding in the zebrafish olfactory bulb visualized by optical imaging. Neuron 18, 737–752. 7. Soucy, E.R., Albeanu, D.F., Fantana, A.L., Murthy, V.N., and Meister, M. (2009). Precision and diversity in an odor map on the olfactory bulb. Nat. Neurosci. 12, 210–220. 8. Wilson, D.A., and Stevenson, R.J. (2003). The fundamental role of memory in olfactory perception. Trends Neurosci. 26, 243–247. 9. Haberly, L.B. (2001). Parallel-distributed processing in olfactory cortex: new insights from morphological and physiological analysis of neuronal circuitry. Chem. Senses 26, 551–576. 10. Wickersham, I.R., Lyon, D.C., Barnard, R.J., Mori, T., Finke, S., Conzelmann, K.K., Young, J.A., and Callaway, E.M. (2007). Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53, 639–647. 11. Kobayakawa, K., Kobayakawa, R., Matsumoto, H., Oka, Y., Imai, T., Ikawa, M., Okabe, M., Ikeda, T., Itohara, S., Kikusui, T., et al. (2007). Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508. 12. Masse, N.Y., Turner, G.C., and Jefferis, G.S. (2009). Olfactory information processing in Drosophila. Curr. Biol. 19, R700–R713. 13. Stettler, D.D., and Axel, R. (2009). Representations of odor in the piriform cortex. Neuron 63, 854–864. 14. Illig, K.R., and Haberly, L.B. (2003). Odor-evoked activity is spatially distributed in piriform cortex. J. Comp. Neurol. 457, 361–373. 15. Yaksi, E., von Saint Paul, F., Niessing, J., Bundschuh, S.T., and Friedrich, R.W. (2009). Transformation of odor representations in target areas of the olfactory bulb. Nat. Neurosci. 12, 474–482. 16. Yoshida, I., and Mori, K. (2007). Odorant category profile selectivity of olfactory cortex neurons. J. Neurosci. 27, 9105–9114. 17. Davison, I.G., and Ehlers, M.D. (2011). Neural circuit mechanisms for pattern detection and feature combination in olfactory cortex. Neuron 70, 82–94. 18. Poo, C., and Isaacson, J.S. (2009). Odor representations in olfactory cortex: ‘‘sparse’’ coding, global inhibition, and oscillations. Neuron 62, 850–861. 19. Jortner, R.A., Farivar, S.S., and Laurent, G. (2007). A simple connectivity scheme for sparse coding in an olfactory system. J. Neurosci. 27, 1659–1669. 20. Murthy, M., Fiete, I., and Laurent, G. (2008). Testing odor response stereotypy in the Drosophila mushroom body. Neuron 59, 1009–1023.
Friedrich Miescher Institute for Biomedical Research and University of Basel, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. E-mail: [email protected] DOI: 10.1016/j.cub.2011.04.036
this remains to be proven. It is worth noting that these results implicating PPA and RSC in the coding of spatial information do not exclude the possibility that these regions might also encode nonspatial information, such as color, texture, or statistical summaries of visual features, which might give important cues for scene recognition. Nor do they preclude the possibility that PPA and RSC might encode a broader set of spatial relationships that would fall under the more general rubric of ‘‘contextual associations’’ rather than just spatial layout alone [18]. Finally, an especially intriguing aspect of the current findings is the observation of scene-selective responses in blind subjects, including three participants blind from birth. These subjects have never perceived a scene through sight, so they must have become accustomed to learning about scene geometry through other routes. Do blind navigators use auditory cues to perceive the structure of a room? Or do they use idiothetic cues to keep track of locations within the room, building up a representation of spatial layout over time [19,20]? Answering these questions is important not only for understanding navigation in the blind, but also
for understanding the spatial representations common to blind and sighted navigators. References 1. Epstein, R.A. (2008). Parahippocampal and retrosplenial contributions to human spatial navigation. Trends Cogn. Sci. 12, 388–396. 2. Aguirre, G.K., Zarahn, E., and D’Esposito, M. (1998). An area within human ventral cortex sensitive to ‘‘building’’ stimuli: Evidence and implications. Neuron 21, 373–383. 3. Janzen, G., and van Turennout, M. (2004). Selective neural representation of objects relevant for navigation. Nat. Neurosci. 7, 673–677. 4. Aguirre, G.K., and D’Esposito, M. (1999). Topographical disorientation: a synthesis and taxonomy. Brain 122, 1613–1628. 5. Epstein, R., and Kanwisher, N. (1998). A cortical representation of the local visual environment. Nature 392, 598–601. 6. Epstein, R., Harris, A., Stanley, D., and Kanwisher, N. (1999). The parahippocampal place area: Recognition, navigation, or encoding? Neuron 23, 115–125. 7. Wolbers, T., Klatzky, R.L., Loomis, J.M., Wutte, M.G., and Giudice, N.A. (2011). Modality-independent coding of spatial layout in the human brain. Curr. Biol. 21, 984–989. 8. Kravitz, D.J., Peng, C.S., and Baker, C.I. (2011). Real-world scene representations in high-level visual cortex — it’s the spaces more than the places. J. Neurosci., in press. 9. Park, S., Brady, T.F., Greene, M.R., and Oliva, A. (2011). Disentangling scene content from spatial boundary: complementary roles for the parahippocampal place area and lateral occipital complex in representing real-world scenes. J. Neurosci. 31, 1333–1340. 10. Park, S., Intraub, H., Yi, D.J., Widders, D., and Chun, M.M. (2007). Beyond the edges of a view: boundary extension in human scene-selective visual cortex. Neuron 54, 335–342.
Olfactory Neuroscience: Beyond the Bulb High-resolution tracing of projections from the olfactory bulb to its cortical targets revealed coarse topography and stereotopy in some areas but highly distributed, combinatorial connectivity in others. These results provide a basis for understanding innate and associative olfactory processing and perception. Rainer W. Friedrich Although the cerebral cortex is overwhelmingly complex, many sensory cortices are spatially organized by simple topographic principles. The mammalian visual cortex, for example, contains a map of visual space that is established through a series of precise topographic connections from the eye. Similarly, orderly projections set up maps of stimulus features in other sensory cortices. However, topographic maps are not omnipresent — the visual
cortex of turtles, for example, lacks a precise two-dimensional map of visual space [1]. Four recent studies [2–5] now report that topography is not a prominent feature of projections from the first processing center in the olfactory system, the olfactory bulb, to higher brain areas in the mouse. Projections to two cortical targets, the anterior olfactory nucleus (AON) and the cortical amygdala, are topographically organized at coarse, but not at fine, spatial scales. No topography whatsoever was found in projections to piriform cortex, the
11. Intraub, H., and Richardson, M. (1989). Wide-angle memories of close-up scenes. J. Exp. Psychol. Learn. Mem. Cogn. 15, 179–187. 12. Intraub, H. (2004). Anticipatory spatial representation of 3D regions explored by sighted observers and a deaf-and-blindobserver. Cognition 94, 19–37. 13. Cate, A.D., Goodale, M.A., and Kohler, S. (2011). The role of apparent size in building- and object-specific regions of ventral visual cortex. Brain Res. 1388, 109–122. 14. Amit, E., Trope, Y., and Yovel, G. (2008). A distance principle of organization of the ventral visual stream. J. Vision 8, 329. 15. Takahashi, N., Kawamura, M., Shiota, J., Kasahata, N., and Hirayama, K. (1997). Pure topographic disorientation due to right retrosplenial lesion. Neurology 49, 464–469. 16. Epstein, R.A., Parker, W.E., and Feiler, A.M. (2007). Where am I now? Distinct roles for parahippocampal and retrosplenial cortices in place recognition. J. Neurosci. 27, 6141–6149. 17. Baumann, O., and Mattingley, J.B. (2010). Medial parietal cortex encodes perceived heading direction in humans. J. Neurosci. 30, 12897–12901. 18. Bar, M. (2004). Visual objects in context. Nat. Rev. Neurosci. 5, 617–629. 19. Loomis, J.M., Klatzky, R.L., Golledge, R.G., Cicinelli, J.G., Pellegrino, J.W., and Fry, P.A. (1993). Nonvisual navigation by blind and sighted: assessment of path integration ability. J. Exp. Psychol. Gen. 122, 73–91. 20. Landau, B., Spelke, E., and Gleitman, H. (1984). Spatial knowledge in a young blind child. Cognition 16, 225–260.
Department of Psychology, University of Pennsylvania, 3720 Walnut Street, Philadelphia, PA 19104, USA. E-mail: [email protected]
DOI: 10.1016/j.cub.2011.04.037
largest target area. These results provide a hard anatomical foundation for understanding the organization of higher olfactory brain areas — and ample food for thought. From the Olfactory Bulb to Higher Brain Areas Input to the olfactory bulb from the nose terminates in a stereotyped array of glomeruli. Within each of the approximately 2000 glomeruli of the rodent olfactory bulb, thousands of sensory neurons expressing the same odorant receptor converge onto approximately 20–50 principal neurons, the mitral/tufted (MT) cells. Odors are represented by the activation of distributed combinations of glomeruli. Glomerular activation patterns can be biased towards subregions of the olfactory bulb by particular molecular features, but nearby glomeruli frequently respond to chemically different sets of odorants
Dispatch R439
[6,7]. Odor representations, therefore, show only a loose topographic organization with respect to chemical space already at the first processing stage in the olfactory bulb. Neuronal circuits within the olfactory bulb reorganize activity across MT cells in space and time and diversify odor-encoding activity patterns. However, excitatory convergence of multiple processing channels, which is thought to mediate associations between molecular features of olfactory objects, appears to occur mainly in higher brain areas [8,9]. How are odor-encoding activity patterns transmitted from the olfactory bulb to higher brain areas? Individual MT-cell axons diffusely innervate multiple target areas, including the AON, cortical amygdala, and piriform cortex [9], but a precise understanding of these projections has been lacking. In particular, it has been unclear whether MT-cell projections are determined by the identity of their home glomeruli. Three recent studies [2–4] have succeeded in following small cohorts of MT-cell axons from identified glomeruli to their targets by electroporation or viral expression of fluorescent tracers. A fourth study [5] traced MT cells connected to small populations of cortical neurons back to the olfactory bulb. This was accomplished by an elegant combination of conditional gene expression methods and a transsynaptic viral tracer that crosses only one synapse [10]. Results from these studies now provide a detailed picture of the anatomical relationships between the array of glomeruli and higher brain areas. Coarse Topography and Stereotopy Projections from the olfactory bulb to the AON were found to preserve the dorsoventral, but not the anterior-posterior, axis of the olfactory bulb (Figure 1) [5]. Consistent with previous studies, topographic projections were also found to the pars externa, a distinct subdivision of the AON that mediates topographic communication between the two olfactory bulbs. However, projections of individual axons were diffuse and overlapping, indicating that topography is not maintained at finer scales [3]. Point-to-point topography was also not found in MT-cell projections to the cortical amygdala. However, MT cells
Glomeruli
Anterior olfactory nucleus
Piriform cortex
Amygdala Current Biology
Figure 1. Projections from the olfactory bulb to cortical target areas. Schematic summary of some results obtained by antograde tracing of MT cells associated with individual glomeruli and retrograde tracing of MT inputs to small groups of cortical neurons. MT cell projections from glomeruli in the olfactory bulb to the anterior olfactory nucleus are not point-to-point, but preserve dorso-ventral topography. Projections from individual glomeruli to the cortical amygdala have overlapping, yet circumscribed, terminal fields. The location of terminal fields is stereotyped and depends on the glomerulus. Projections to piriform cortex show no topography. Individual MT cells have varicose branches throughout piriform cortex. Branching patterns of sister MT cells from the same glomerulus (red vs. pink) were no more similar than those of heterotypic MT cells (red vs. blue).
from identified glomeruli projected to overlapping, yet spatially restricted, terminal fields with stereotyped positions in different animals (Figure 1), implying that projections are coarsely topographic and depend on the identity of the glomerulus [4]. Moreover, MT cells projecting to the cortical amygdala were found predominantly, but not exclusively, in the dorsal olfactory bulb [5]. The cortical amygdala has been implicated in innate olfactory behaviors and conveys output, via additional relays, to the hypothalamus. Genetic ablation of sensory input to the dorsal olfactory bulb abolished innate aversive responses to defined odors, but not the detection of these odors per se [11]. Topographic projections to the cortical amygdala may, therefore, be part of hard-wired circuits that mediate stereotyped olfactory responses. Similarly, innate olfactory responses of insects involve stereotyped projections from the antennal lobe, a brain area corresponding to the olfactory bulb, to the lateral horn, one of its two targets [12]. Distributed Combinatorial Connectivity No spatial organization at all was found in MT projections to the piriform
cortex — a paleocortical area that is thought to be involved in associative olfactory processing and memory (Figure 1). Small, local groups of piriform cortex neurons received input from MT cells throughout the olfactory bulb [5], and individual MT cells projected varicose axon collaterals throughout piriform cortex [2–4]. No obvious similarities were observed between projections of sister MT cells originating from the same glomerulus. These striking findings are consistent with previous studies that found no apparent chemotopic organization of odor-evoked activity patterns in the piriform cortex [13,14]. Indeed, a study in zebrafish directly demonstrated that the coarse chemotopy of odor representations in the olfactory bulb is not preserved in the target area homologous to olfactory cortex [15]. Selective responses to odorant mixtures, as well as recent opto- and electrophysiological results, indicate that piriform cortex neurons detect combinatorial activity patterns across MT cells [8,13,15–17]. The direct convergence of functionally different MT inputs onto the piriform cortex neurons could be one mechanism by which this pattern detection is accomplished. In addition, pattern detection is likely to involve the
Current Biology Vol 21 No 11 R440
extensive association fiber system that sparsely connects principal neurons throughout the piriform cortex [9]. Transsynaptic viral tracing demonstrated that the average number of presynaptic MT cells is at least six-fold higher for superficial GABAergic interneurons in the piriform cortex than for pyramidal target cells [5]. This finding is consistent with physiological data and may explain why inhibition in piriform cortex is more broadly tuned than excitation [18]. Although estimates of convergence ratios represent a lower bound, the number of MT inputs to individual piriform cortex neurons is likely to be small compared to the total number of MT cells or glomeruli. This contrasts with insects, where Kenyon cells in a higher associative center, the mushroom body, receive input from up to 50% of the projection neurons in the antennal lobe [12,19]. Unlike Kenyon cells, individual piriform-cortex neurons may therefore analyze activity across small ensembles of inputs, which is likely to have important consequences for olfactory coding. Anatomy of Higher Brain Functions The observed projection patterns in the piriform cortex argue not only that connectivity of MT cells is independent of their spatial coordinates, but connectivity could even be independent of MT cell identity. Indeed, odor responses of genetically identified Kenyon cells in Drosophila melanogaster differ substantially within and between individuals, indicating that connectivity between projection neurons and Kenyon cells is highly variable [20]. Obviously, variable — or even stochastic — connectivity generates a high diversity of input combinations converging onto higher-order neurons. This is consistent with the assumption that the piriform cortex is an associative area that detects combinations of molecular features,
forms and refines representations of olfactory objects, and stores odor representations in memory [8,9]. Essentially all humans agree that rotten fish stinks, or that the smell of certain flowers is pleasant. This consistency of basic odor perception would be difficult to reconcile with stochastic connectivity alone, suggesting that it involves stereotyped circuits. Future experiments may thus test the hypothesis that areas such as the piriform cortex are primarily involved in fine odor discrimination and/or memory whereas basic perceptions are mediated by more stereotyped areas such as the cortical amygdala. However, this hypothesis may also be too simple, considering that higher olfactory brain areas are heavily connected to each other and to the olfactory bulb. It is, therefore, possible that different olfactory computations are not carried out independently in distinct areas, but distributed across a large-scale network [9]. High-resolution, quantitative studies of connectivity are essential steps towards understanding such networks in the olfactory system and elsewhere. References 1. Mulligan, K.A., and Ulinski, P.S. (1990). Organization of geniculocortical projections in turtles: isoazimuth lamellae in the visual cortex. J. Comp. Neurol. 296, 531–547. 2. Nagayama, S., Enerva, A., Fletcher, M.L., Masurkar, A.V., Igarashi, K.M., Mori, K., and Chen, W.R. (2010). Differential axonal projection of mitral and tufted cells in the mouse main olfactory system. Front. Neural Circuits 4, 120. 3. Ghosh, S., Larson, S.D., Hefzi, H., Marnoy, Z., Cutforth, T., Dokka, K., and Baldwin, K.K. (2011). Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons. Nature 472, 217–220. 4. Sosulski, D.L., Lissitsyna Bloom, M., Cutforth, T., Axel, R., and Datta, S.R. (2011). Distinct representations of olfactory information in different cortical centres. Nature 472, 213–216. 5. Miyamichi, K., Amat, F., Moussavi, F., Wang, C., Wickersham, I., Wall, N.R., Taniguchi, H., Tasic, B., Huang, Z.J., He, Z., et al. (2011). Cortical representations of olfactory input by trans-synaptic tracing. Nature 472, 191–196.
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Friedrich Miescher Institute for Biomedical Research and University of Basel, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. E-mail: [email protected] DOI: 10.1016/j.cub.2011.04.036