Another Remembered Present Kaspar Meyer Science 335, 415 (2012); DOI: 10.1126/science.

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PERSPECTIVES
NEUROSCIENCE

Another Remembered Present

Kaspar Meyer

Could conscious perception reect a memory process?

CREDIT: Y. HAMMOND/SCIENCE

ntuition tells us that perceptual experiencethe seamless flow of conscious images of vision, sound, touch, and so forthreects the external world. Accordingly, information flow along the brains sensory pathways has been thought to follow a caudo-rostral direction, away from the ports of entry, toward integrative cortices in the anterior parts of the frontal and temporal lobes. However, this view of a unidirectional, bottom-up processing cascade is challenged by findings which suggest that there is also information transfer in the opposite, top-down direction, from association areas toward early sensory cortices. A particularly intriguing observation is that while the initial bottomup activation sweep along the sensory pathways can accomplish stimulus processing of considerable complexity and yield certain automated behaviors, conscious awareness of a sensory object appears to depend on topdown signals (13), as observed in the visual (4), auditory (5), and somatosensory (6) systems. Why is this the case? Bidirectional signaling figures prominently in two influential theories of consciousness. According to the dynamic core hypothesis, two fundamental characteristics of consciousness are differentiation and integration (7). The high differentiation of a conscious state is evident from the fact that we can imagine a practically unlimited number of such states without any two of them being identical. Integration, on the other hand, refers to the observation that a conscious state cannot be decomposed into independent constituents: We see a red rose, rather than a colorless shape paired with a shapeless color. Computer stimulations suggest that the amount of integrated information (and, therefore, consciousness) that a system can generate is greater when information ow among the systems elements is bidirectional than when it is strictly feed-forward. Although fronto-parietal association cortices, rather than the early sensory relays,
Brain and Creativity Institute, University of Southern California, Los Angeles, CA 90089, USA. E-mail: kaspar. meyer@usc.edu

are considered most crucial for information integration, the dynamic core hypothesis could, in principle, offer an explanation for the importance of top-down signals in conscious perception. According to the global neuronal workspace model, there are two distinct computational spaces in the brain (8). The rst space consists of a collection of separate and anatomically conned processors, each of which is specialized in a particular function (e.g., visual motion processing). These functions are carried out nonconsciously. The second space consists of a network of global workspace neurons that distinguish themselves from the local processors by their reciprocal, long-range anatomical interconnections. Information encoded in the workspace therefore is available to many brain regions at once, including those responsible for motor behavior or verbal report. According to the model, this global availability of information () is what we subjectively experience as a conscious state (9). The model suggests the global workspace to comprise prefrontal, cingulate, and parietal cortices, in particular, but attributes high importance to top-down signals from these regions to the individual processors located in lower-level cortices. The top-down signals would act as generators of diversity, dynamically selecting the brain networks that participate in a conscious state at any given moment.

A third, somewhat less prominent hypothesis that implicates top-down signals along the sensory pathways is the model of multiregional retroactivation (10). This model emphasizes that perception and memory recall are inseparable processes. Any sensory object we perceive automatically triggers the re-experience of associated images, in both the same and other modalities: Reading the word mother may evoke a visual image of your mothers face, an auditory image of her voice, etc. These associated images are stored in dispositional form in socalled convergence-divergence zones (CDZs) in the association cortices. To be consciously re-experienced, the images have to be reconverted to their explicit form by being reconstructed, via top-down signals, in the early sensory cortices. A loose analogy would be that of a movie which may be stored on a chip (the CDZs) but, to be watched, must be projected onto a screen (the early sensory cortices). Multiregional retroactivation offers a possible explanation for the importance of top-down signals for conscious perception if we assume that all the images we experience (and not just those manifestly triggered by association) are reconstructed based on records held in CDZs. The stream of consciousness would be nothing other than a remembered present (11). Intriguingly, the idea that perceptual images are not a direct reection of the environment has precedence. Consciousness has been described as an intrinsic property arising from the expression of existing dispositions of the brain to be active in certain ways. It is a close kin to dreaming, where sensory input by constraining the intrinsic functional states species, rather than informs, the brain of those properties of external reality that are important for survival (12). Along similar lines, it was suggested that from a top-down perspective, feedback is provided by the bottomup stream (6). Taking this view of conscious perception, the images we experience would result from signals that descend through the sensory systems, just as behavior results from signals that descend along the motor pathways.

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PERSPECTIVES
Neuroanatomical and neurophysiological ndings from animal studies are generally compatible with this view. Connectivity along the sensory pathways is reciprocal at all levels and in all modalities, perhaps even dominated by top-down projections (13). Top-down signals can excite pyramidal neurons located as deep as layer V in their target area, although they contact mainly apical dendrites in the most supercial cortical layers (6). Top-down projections target almost exclusively pyramidal cells and induce an excitatory postsynaptic potential with little or no subsequent inhibition, whereas the fraction of terminals on inhibitory interneurons is considerably greater for bottom-up projections, and the excitation they induce is followed by an inhibitory hyperpolarization (6, 14, 15). Furthermore, neuroimaging studies show that nonstimulated regions of V1 contain information about stimuli presented elsewhere in the visual eld, and that these activity patterns are induced via cortico-cortical top-down projections, rather than lateral projections within V1 (16, 17). Along the same lines, purely visual stimuli that imply sound or touch induce content-specic neural patterns in the early auditory and somatosensory cortices, respectively, in the absence of any direct stimulation in those modalities (18, 19). Taken together, such data suggest that top-down signals, contrary to their common designation as feedback signals, have more than a modulatory function: They can reconstruct neural representations of considerable resolution in the early sensory cortices. Why would the conscious mind be grounded in dispositional records held in CDZs, rather than the raw version of reality initially established in the early sensory cortices through bottom-up signals from the thalamus? One potential answer is tied to prediction: The brain constantly and internally [generates] varieties of hypotheses and [tests] them upon the outside world, instead of having the environment impose (instruct) solutions directly upon the internal structure of the brain (20).
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. D. A. Pollen, Cereb. Cortex 9, 4 (1999). V. A. F. Lamme, Brain Mind 1, 385 (2000). J. Bullier, Trends Cogn. Sci. 5, 369 (2001). T. Ro, B. Breitmeyer, P. Burton, N. S. Singhal, D. Lane, Curr. Biol. 13, 1038 (2003). M. Boly et al., Science 332, 858 (2011). L. Cauller, Behav. Brain Res. 71, 163 (1995). G. Tononi, G. M. Edelman, Science 282, 1846 (1998). S. Dehaene, J.-P. Changeux, in Cognitive Neurosciences, M. S. Gazzaniga, Ed. (MIT Press, Cambridge, MA, ed. 3, 2004). S. Dehaene, J.-P. Changeux, Neuron 70, 200 (2011). A. R. Damasio, Cognition 33, 25 (1989). G. Edelman, Ann. N. Y. Acad. Sci. 929, 111 (2001). R. R. Llins, D. Par, Neurosci. 44, 521 (1991). P.-A. Salin, J. Bullier, Physiol. Rev. 75, 107 (1995). R. R. Johnson, A. Burkhalter, J. Comp. Neurol. 368, 383 (1996). Z. Shao, A. Burkhalter, J. Neurosci. 16, 7353 (1996). M. A. Williams et al., Nat. Neurosci. 11, 1439 (2008). F. W. Smith, L. Muckli, Proc. Natl. Acad. Sci. U.S.A. 107, 20099 (2010). K. Meyer et al., Nat. Neurosci. 13, 667 (2010). K. Meyer, J. T. Kaplan, R. Essex, H. Damasio, A. Damasio, Cereb. Cortex 21, 2113 (2011). J.-P. Changeux, S. Dehaene, Cognition 33, 63 (1989). This work was supported by the Mathers Foundation and by the NIH (NIH/NINDS 5P50NS019632). 10.1126/science.1214652

References and Notes

STRUCTURAL BIOLOGY

The Inner Workings of a Dynamic Duo

Hanne Poulsen and Poul Nissen

Structures of twopore domain potassium channels reveal key differences from the more widely found tetrameric channels.

ore than 60 years ago, Hodgkin and Huxley showed that neurons maintain their negative resting membrane potential by leaking potassium ions (1). In most cells, the Na+- and K +-dependent adenosine triphosphatase (Na+, K+-ATPase) builds up high concentrations of extracellular sodium and intracellular potassium, and because the membrane is more permeable to potassium, there is a net ow of positive ions out of the cell. The channels responsible for the permeability were much later identied to be the two pore domain potassium (K2P) channels (2). On pages 432 and 436 of this issue, Miller and Long (3) and Brohawn et al. (4) report the structures of the human K2P channels TWIK-1 and TRAAK. Most potassium channels are tetrameric, but K2Ps are dimers with four transmemCentre for Membrane Pumps in Cells and DiseasePumpkin, Danish National Research Foundation, and Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark. E-mail: hp@ mb.au.dk, pn@mb.au.dk

brane helices and two pore domains per subunit (see the gure, panel A). The new structures may suggest a structural basis for how K2Ps, in addition to their role as leak channels, can be regulated by a wide variety of stimuli including pH, membrane stretch, and anesthetics (5). The rst ion channel visualized at high resolution was the tetrameric bacterial homolog of mammalian potassium channels, KcsA. The KcsA structure revealed how exquisite ion selectivity is achieved by a membraneembedded lter formed by four symmetrically arranged hairpins, with backbone oxygens lining a channel. Because the potassium ions are optimally coordinated by the backbone oxygens, they can become dehydrated as they pass (6). A highly conserved feature of tetrameric potassium channels is the selectivity filter sequence Thr-X-Gly-Tyr-Gly-Asp (where X denotes a hydrophobic residue). In K2P channels, only threonine and the first glycine are strictly conserved, but the new structures (3, 4) show that the K2P selectivity l-

ter approaches four-fold symmetry, and K+ is coordinated in the same way as in the tetrameric potassium channels. The sequence variation of the two lters in each subunit offers a way to tweak the K2P pore. For example, TWIK-1 becomes Na+-permeable at low extracellular K+ levels, a characteristic that depends on a threonine residue after the conserved threonine residue in the rst pore domain (7). Two recent studies have suggested that opening and closing of K2Ps depend mainly or solely on the pore and its vicinity (8, 9). The diversity in the lter motifs may thus reect variations in gating. Both of the new structures show a potassium-conducting channel with the intracellular gate open, but the two inner helices forming the gate from each K2P subunit differ markedly from those of the tetrameric channels (see the gure, panel B): The M2 helix is longer and bends in the middle of the membrane; M4 is shorter and more perpendicular to the membrane plane. The C-terminal part of either M2 (in TRAAK) or M4 (in TWIK-1) localizes to the cytosolic membrane interface.

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