Centripetal and Centrifugal Reorganizations of Frequency Map of Auditory Cortex in Gerbils

Centripetal and centrifugal reorganizations of frequency map of auditory cortex in gerbils

Masashi Sakai and Nobuo Suga*

Department of Biology, Washington University, One Brookings Drive, St. Louis, MO 63130

Contributed by Nobuo Suga, March 21, 2002 As repetitive acoustic stimulation and auditory conditioning do, sound-duration tuning (15) of collicular neurons. Therefore, the electric stimulation of the primary auditory cortex (AI) evokes corticofugal system modulates the functional organization of the reorganization of the frequency map of AI, as well as of the IC not only in the frequency domain but also in the time domain. subcortical auditory nuclei. The reorganization is caused by shifts Centripetal reorganization is assumed to be widely shared with in best frequencies (BFs) of neurons either toward (centripetal) or mammalian sensory systems. away from (centrifugal) the BF of stimulated cortical neurons. In AI Reorganization of the frequency map is, however, different of the Mongolian gerbil, we found that focal electrical stimulation between specialized and nonspecialized areas of the auditory evoked a centripetal BF shift in an elliptical area centered at cortex of the mustached bat (11, 18). The Doppler-shifted the stimulated neurons and a centrifugal BF shift in a zone constant frequency (DSCF) and frequency modulation surrounding it. The 1.9-mm long major and 1.1-mm long minor axes (FM)–FM areas of the auditory cortex of the mustached bat are of the elliptical area were parallel and orthogonal to the frequency specialized for processing either velocity and relative size infor- axis, respectively. The width of the surrounding zone was 0.2–0.3 mation carried by Ϸ61 kHz sound (21) or target-distance mm. Such ‘‘center-surround’’ reorganization has not yet been information carried by a pair of FM sounds (23, 24), respectively. found in any sensory cortex except AI of the gerbil. The ellipse is Focal electric stimulation of the DSCF or FM–FM area revokes similar to the arborization pattern of pyramidal neurons, the major centrifugal shift in the BFs of collicular, thalamic, (16, 25) and source of excitatory horizontal connections in AI, whereas the cortical (11) DSCF neurons or in the best delays of collicular and surrounding zone is compatible to the arborization range of small thalamic FM–FM neurons (26), respectively. The direction of basket cells (inhibitory neurons) in AI. these shifts in BF and best delay is opposite to that in BF observed in the posterior division of AI of the mustached bat frequency tuning ͉ hearing ͉ plasticity ͉ tonotopic map (11). Such a difference appears to be related to corticofugal facilitation and lateral inhibition of auditory responses of sub- he response properties of frequency-tuned neurons and͞or cortical auditory neurons, so that the following working hypoth- Tthe cochleotopic (frequency) map of the primary auditory esis has been proposed (18). If the positive feedback evoking cortex (AI) can be changed by repetitive acoustic stimulation (1, facilitation is strong and widespread to neighboring neurons and 2), auditory conditioning (3–9), learning of a discrimination task negative feedback evoking lateral inhibition is weak, a focal (10), focal electric stimulation of AI (1, 2, 11), or electric activation of the auditory cortex evokes a prominent centripetal stimulation of the basal forebrain paired with acoustic stimula- BF shift in a large area that is surrounded by a narrow zone of tion (6, 12). centrifugal BF shift. On the contrary, if the positive feedback is The response properties of frequency-tuned neurons and the highly focused and negative feedback is strong and widespread cochleotopic map of the inferior colliculus (IC) also can be to neighboring neurons, a focal activation of the auditory cortex changed by repetitive acoustic stimulation (2, 13, 14), auditory evokes a prominent centrifugal BF shift in a large area sur- conditioning (8, 9, 14), or focal electric stimulation of AI (2, 13, rounding a narrow zone where a small centripetal BF shift is 15, 17). evoked. In AI, there are excitatory neurons for horizontal In the big brown bat, Eptesicus fuscus, cortical and collicular connections and inhibitory neurons for local connections (27, changes in the cochleotopic map are caused by the shift in best 28), so that facilitation and inhibition for BF shifts may also frequency (BF) of single neurons toward the frequency of a occur. repetitively delivered acoustic stimulus (1, 13, 14), the frequency If the corticofugal system evokes facilitation and inhibition of of a conditioned sound (8, 9, 14), or the BF of electrically subcortical neurons for processing auditory information and stimulated AI neurons (1, 11, 13, 15). BF shifts resulting in reorganizing the central auditory system, reorganization of AI of reorganization of the frequency map are basically the same the Mongolian gerbil may consist of two types of areas: an area regardless of the means that evoked them and are attributable to for centripetal BF shift at the center and an area for centrifugal activity within the corticofugal system (8, 9, 14). This means that BF shift in the surround. The aim of the current article is to focal electric stimulation of AI activates the essential portion of report the data showing such a center-surround reorganization the neural mechanism for reorganization (plasticity) of the of the gerbil’s AI. central auditory system and that it can be an appropriate method Materials and Methods for the exploration of the plasticity of neurons in the IC, medial geniculate body, and AI (18). BF shifts toward and away from Animal preparation and experimental procedures were exactly the BF of electrically stimulated cortical neurons or the fre- the same as those in our previous article (11). Eleven adult Mongolian gerbils (Meriones unguiculatus; 65.2 Ϯ 1.8 g body quency of a repetitively delivered tone burst are called ‘‘cen- ͞ tripetal’’ and ‘‘centrifugal’’ BF shifts, respectively (18). weight) were used. Under anesthesia with ketamine (40 mg kg A centripetal BF shift evoked by focal electric stimulation of

AI has been found not only in the big brown bat, but also in the Abbreviations: AI, primary auditory cortex; BF, best frequency; IC, inferior colliculus; DSCF, posterior division (nonspecialized portion) of AI of the mus- Doppler-shifted constant frequency; FM, frequency modulation. tached bat and AI of the Mongolian gerbil (11). Furthermore, *To whom reprint requests should be addressed. E-mail: [email protected]. centripetal shift of the receptive fields of neurons in the somato- The publication costs of this article were defrayed in part by page charge payment. This sensory cortex has been found in monkeys (19) and cats (20). article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Focal electric stimulation of AI also evokes centripetal shift in §1734 solely to indicate this fact.

7108–7112 ͉ PNAS ͉ May 14, 2002 ͉ vol. 99 ͉ no. 10 www.pnas.org͞cgi͞doi͞10.1073͞pnas.102165399 Downloaded by guest on September 29, 2021 body weight) and meditomidine (0.26 mg͞kg body weight), the dorsal surface of the animal’s skull was exposed, and four plastic sockets (1.5 mm in diameter and 2.0 mm in length) were attached onto the lateral sides of the skull with glue and dental cement. After the surgery (5–7 d), the animal was lightly anesthetized with the above drugs and placed in a polyethylene-foam body- mold suspended by an elastic band at the center of a soundproof room. The animal’s head was immobilized by inserting metal rods into the sockets and adjusted to face directly at a loudspeaker located 74 cm away. Holes (50–100 ␮m in diameter) were made on the skull covering AI. Tungsten-wire electrodes (Ϸ7 ␮m in tip diameter) for electric stimulation or recording action potentials were orthogonally inserted into AI through the holes. The protocol of our research was approved by the Animal Studies Committee of Washington University. A tone burst (20 ms-long, 0.5-ms rise͞decay time) was delivered at a rate of 5͞s from the loudspeaker. The BF, minimum Fig. 1. Frequency map of the AI of the Mongolian gerbil. Dashed lines: iso-BF threshold, and frequency-tuning curve of a single neuron were lines [based on Thomas et al. (29)]. Electric stimulation was delivered to first measured audiovisually. A computer-controlled frequency cortical neurons within the shaded area. (Inset) Dorsolateral view of the gerbil brain. The auditory cortex (AC) consists of seven areas. The black area is the AI. scan (22 time blocks, 200 ms long for each) was then delivered, in which the frequency of the tone burst was shifted in steps of a given frequency (0.04–0.5 kHz) across the BF of the neuron. kHz, respectively (Fig. 2Ba1), the electric stimulation suppressed The amplitude of tone bursts in the scan was set at 10 dB above response of the recorded neuron at 1.45 kHz (Fig. 2Bb2) and the minimum threshold of a given neuron. Identical frequency ͞ facilitated its response at 1.65 kHz (Fig. 2Bc2). As a result, the scans were repeated at a rate of 1 5s. BF and frequency-response curve of the neuron shifted away A pair of tungsten-wire microelectrodes (Ϸ7 ␮m in tip diameter; 150-␮m apart, one proximal to the other) was inserted into cortical layer V (700–800 ␮m in depth). Action potentials originating from 2–3 single neurons were recorded and the BFs of the neurons were measured. Then they were electrically stimulated through the pair of electrodes. The electric stimulation was a 6.2-ms long train of four monophasic electric pulses (100 nA, 0.2-ms duration, 2.0-ms intervals). The train was delivered at a rate of 10͞s for 30 min. Action potentials of a single cortical neuron were selected with an amplitude-window discriminator (BAK Electronic, Rockville, MD; model DLS-1), and an action potential of the neuron was stored on the screen of a digital storage oscilloscope at the beginning of data acquisition. The responses of a cortical neuron to 50 identical frequency scans were displayed as an array of peri-stimulus-time histograms as a function of frequency. Ac- quisition of peri-stimulus-time histograms was continued as long as action potentials visually matched the template, the stored action potential of the neuron. Data were stored on a computer hard drive and analyzed off-line for BF shifts. If a shifted BF and frequency-response curve did not shift back by more than 50% of the change, the data were excluded from the analysis. In stable recordings, all BFs and curves shifted by the electric stimulation recovered by Ͼ50%. This recovery itself helped to prove that the shift was significant. Results In AI of the gerbil, frequencies between 0.2 and 43 kHz are systematically mapped along the caudo-rostral axis, and frequencies from 0.5 to 5 kHz are over-represented (ref. 29; Fig. 1). The BFs of electrically stimulated cortical neurons ranged between 0.88 and 1.2 kHz (mean Ϯ SE: 1.10 Ϯ 0.09 kHz, n ϭ 97) and those of recorded cortical neurons ranged between 0.1 and 37.0 kHz Fig. 2. Shifts in frequency-response curve evoked by cortical electric stimu- Ϯ ϭ lation. (Aa and Ba) Array of peristimulus-time cumulative histograms repre- (4.62 3.8 kHz, n 338). Electric stimulation of cortical NEUROBIOLOGY neurons evoked a BF shift of other cortical neurons located near senting frequency-response curves. (Ab, Ac, Bb, and Bc) Peristimulus-time those stimulated. When stimulated and recorded neurons were histograms representing responses at BF in the control (BFc) or shifted (BFs) tuned to 1.00 and 1.60 kHz, respectively (Fig. 2Aa1), electric condition. (A) The BF at 1.60 kHz shifted toward the 1.00 kHz BF of the stimulation suppressed the response of the recorded neuron at stimulated cortical neurons (centripetal BF shift). (B) The BF at 1.45 kHz shifted away from the 1.10-kHz BF of the stimulated cortical neurons (centrifugal BF 1.60 kHz (Fig. 2Ab2) and facilitated its response at 1.20 kHz (Fig. shift). (Aa2 and Ba2, arrow) The BF of the stimulated cortical neurons. (Aa and 2Ac2). As a result, the BF and the frequency-response curve of Ba) The BFs of the recorded cortical neuron in the control F, shifted ϫ, and the neuron shifted toward the BF of the stimulated neurons (Fig. recovered E conditions, respectively. 1–4: The data obtained before, and 30, 2Aa2). In other words, centripetal BF shift was evoked. When 80, and 180 min after the onset of electric stimulation. The horizontal bars at stimulated and recorded neurons were tuned to 1.10 and 1.45 the bottom of b and c represent 20 ms-long tone bursts.

Sakai and Suga PNAS ͉ May 14, 2002 ͉ vol. 99 ͉ no. 10 ͉ 7109 Downloaded by guest on September 29, 2021 Fig. 3. Distributions of cortical neurons that exhibited centripetal or centrifugal BF shift. (A) Centripetal BF shift, F.(B) Centrifugal BF shift, Œ and no BF shift, ϫ. Locations of recorded neurons along the cortical surface are plotted relative to that of stimulated cortical neurons at the origin of the Fig. 4. Amount of BF shift in a zone parallel or orthogonal to the frequency coordinates. x and y axes, directions parallel or orthogonal to the frequency axis of the AI. (A) Conﬁdence ellipses for neurons that showed centripetal axis of the AI. Data are pooled from 16 hemispheres of 11 animals. BF ,BFof e (open area) or centrifugal BF shift (shaded area) (see Fig. 3). The directions and electrically stimulated cortical neurons. Ellipse, area for centripetal or centrif- amounts of BF shifts of neurons in the rostro-caudal (B) and dorso-ventral (C ugal BF shifts. and D) zones in A were respectively plotted in B–D as a function of distance along the cortical surface. BFe, BF of electrically stimulated cortical neuron and BF , BF of recorded cortical neuron. See Inset at the top right for symbols. from the BF of the stimulated neuron (Fig. 2Ba2). In other r words, centrifugal BF shift was evoked. The shifted BF and changed responses returned to the control condition 180 min difference in distance for evoking a BF shift between the rostral after the electric stimulation (a4, b4, and c4 in Fig. 2 A and B). and caudal sides (Fig. 4B). Whether a recorded neuron showed a centripetal or centrif- BF shifts measured within a 0.30-mm wide vertical zone ugal BF shift depended on the distance between the recorded caudal or rostral to the 1.1-kHz iso-BF line (C and D in Fig. 4A) and stimulated neurons along the surface of AI. Neurons were pooled because the edge of the ellipse in this zone was showing a centripetal BF shift were distributed in an elliptical Ϸ somewhat parallel to the frequency axis. The pooled data were area centered at the stimulated neurons that were tuned to 1.1 plotted as a function of distance between stimulated and re- kHz on the average (Fig. 3A). Their confidence ellipse (based on corded neurons along the 1.1-kHz iso-BF line. The amount of BF P Ͼ x Mahalanobis’s equation 0.95) crossed the rostro-caudal ( ) shift was larger on the rostral side of the 1.1-kHz iso-BF line (Fig. axis at approximately Ϯ0.56 mm and the 1.1-kHz iso-BF line (y) 4D) than on its caudal side (Fig. 4C). Centripetal and centrifugal axis at approximately Ϯ0.95 mm. On the other hand, neurons BF shifts both occurred symmetrically in amount on the dorsal showing centrifugal BF shift distributed in a zone surrounding and ventral sides of the stimulated cortical neurons. Within the elliptical area (Fig. 3B). The confidence ellipse crossed the Ϯ0.60 mm, the great majority of the neurons showed centripetal x axis at approximately Ϯ0.72 mm and the y axis at approximately BF shift, and there was a tendency that the farther the distance Ϯ1.23 mm. This surround was 0.20–0.30 mm wide. In this surrounding zone, many neurons (Ϸ57%) did not show a BF shift away from the stimulated neurons along the iso-BF line, the (see Discussion). smaller the centripetal BF shift. Large BF shifts (1.5–1.8 kHz) The amount of BF shift varied depending on the distance and occurred within 0.10 mm. This finding indicated that BF shift was the BF difference between recorded and stimulated neurons. BF the largest along the frequency axis crossing the electrically shifts measured in a 0.6-mm wide horizontal zone containing the stimulated cortical neurons. Centrifugal BF shift occurred at electrically stimulated neurons at its center (zone B in Fig. 4A) distances between 0.5 and 1.1 mm from the stimulated neurons were pooled because the edge of the ellipse in this zone was (Fig. 4 C and D). somewhat parallel to the 1.1-kHz iso-BF line. The pooled data In the normal (i.e., control) condition, a BF systematically were plotted as a function of the distance between stimulated increased from the caudal end to the rostral end of AI (Fig. 5A, E and recorded neurons along the frequency axis. The great ). There was no sign that 1.1 kHz was over-represented. majority of neurons within Ϯ0.45 mm from the 1.1-kHz iso-BF However, BF shift evoked by electric stimulation of 1.1-kHz- line showed centripetal BF shift, and the amounts of their BF tuned cortical neurons resulted in the prominent over- shifts were nonmonotonically related to the distance (Fig. 4B, representation of 1.1-kHz sound, so that the iso-1.1-kHz BF line circles). The largest negative centripetal BF shift occurred at changed into a 0.33-mm wide band (Fig. 5A, F). A small 0.21 mm rostral to the 1.1-kHz iso-BF line (corresponding to a under-representation also occurred for frequencies lower than BF 1.8 kHz higher than 1.1 kHz), whereas the largest positive 0.52 kHz and higher than 4.7 kHz (Fig. 5A, Œ). centripetal BF shift occurred at 0.27 mm caudal (corresponding Because a BF systematically changed along the caudo-rostral to a BF 0.36 kHz lower than 1.1 kHz). The largest positive axis of AI, the amount of BF shifts shown in Fig. 4B could be centrifugal BF shift occurred at 0.48 mm rostral to the 1.1-kHz expressed in mm (Fig. 5B). When expressed in this manner, the iso-BF line, whereas the largest negative centrifugal BF shift maximum amount of centripetal BF shift in mm was 0.21 or 0.22 occurred at 0.62 mm caudal (Fig. 4B, triangles). Both centripetal mm on the rostral side and on the caudal side, respectively. and centrifugal BF shifts were significantly larger on the rostral Therefore, the prominent asymmetrical BF shift in kHz (Fig. 4B) side than on the caudal side (P Ͻ 0.05). However, there was no was related to the nonlinear frequency axis in AI: a small BF

7110 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.102165399 Sakai and Suga Downloaded by guest on September 29, 2021 species of animals except the above two species of bats. In our previous studies of the gerbil AI (11), we found 65 centripetal BF shifts and two centrifugal BF shifts, so that center-surround reorganization was unclear. However, it became clear in our present detailed studies. Therefore, it is expected that center- surround reorganization will also be found in the auditory cortex of other species of animals by further studies. In rats, a train of tone bursts paired with electric stimulation of dopaminergic neurons in the ventral tegmental area evokes over-representation of the frequency of these tones and under-representation of frequencies lower or higher than that in AI (30). However, it has not yet been shown whether this under-representation is partly caused by centrifugal BF shifts. In a nonspecialized auditory cortex such as the gerbil’sAI, reorganization is predominantly based on centripetal BF shift. A centripetal BF shift would result in over-representation of a particular value of a parameter characterizing an acoustic signal (1, 2, 11, 13, 14). A specialized auditory cortex such as the DSCF area of the mustached bat over-represents particular values of frequency in a narrow range in the natural condition (21, 22). In the DSCF area, reorganization is predominantly based on centrifugal BF shift, which would increase contrast in neural representation of a particular value of frequency characterizing an acoustic signal (16, 25).

Receptive-Field Shift in Nonauditory Sensory Systems. In monkeys (19), excess stimulation of a digit evokes over-representation of that digit in the primary somatosensory cortex. This over- representation is caused by centripetal shift of the receptive fields of cortical neurons representing a cutaneous area around that digit. Thus far, centrifugal shift of a receptive field has not been reported for reorganization of the somatosensory system. In cats, electric stimulation of the primary visual cortex evokes Fig. 5. Change in the frequency axis (A) and amount of BF shift expressed in millimeters (B). (A) Over- (between the arrows) and under- (between the lateral inhibition associated with focused facilitation in the vertical lines) representations evoked by cortical electric stimulation. Distri- lateral geniculate nucleus (31) as in the auditory system of the bution of BFs along the caudo-rostral axis of the AI was studied before (E) and mustached bat (16, 25, 26). However, shift in receptive field has after (F and Œ) electric stimulation of 1.1-kHz-tuned cortical neurons. (B) not been reported. Distributions of centripetal (F) and centrifugal (Œ) BF shifts expressed in Neurons in the primary visual cortex have excitatory inputs millimeters along the caudo-rostral axis of the AI. surrounded by inhibitory inputs (32, 33). However, the diameter of the area for excitatory inputs (Ϸ0.25 mm) is almost one-half of the minor axis of the elliptical area for a centripetal BF shift ͞ ͞ change unit distance below 1.1 kHz and a large BF change unit in the gerbil’sAI(Ϸ0.60 mm). The estimated density of hori- distance above 1.1 kHz. zontal axon collaterals of pyramidal neurons in the visual cortex is approximately one-half of that in the auditory cortex (34). Discussion Because the most basic cortical neural circuit (27, 35) and the Centripetal and Centrifugal BF Shifts. The amount of BF shifts we corticothalamic feedback loop are presumably shared by the observed was related to differences in both distance and BF auditory (36), visual (37), and somatosensory (38) cortices, it is between recorded and stimulated cortical neurons. Iso-BF lines likely that center-surround reorganization also may be shared by are not necessarily parallel to each other and show some these sensory systems. variations among animals (22, 29). Accordingly, in our data pooled from 11 animals, the area for the centripetal BF shift Anatomical Correlates to Centripetal and Centrifugal BF Shifts. Axon overlapped with the surround for the centrifugal BF shift, and collaterals of pyramidal neurons in the primary auditory, so- neurons showing centrifugal BF shift were intermixed with those matosensory, visual, and motor cortices extend Ϸ1,500 ␮m (27) showing no BF shift. Irrespective of these overlap and intermix- for the integration of neural signals and the synchronization of ture, our present data clearly show center-surround reorganiza- the activities of distant neurons (39, 40). Horizontal excitatory tion and favor the hypothesis stating that facilitation and lateral connections are mostly under tonic inhibition produced by inhibition, respectively, evoke centripetal and centrifugal BF GABAergic interneurons (41). The balance between excitatory shifts (18). and inhibitory influences on single neurons is the primary

In AI of the big brown bat (1, 2) and the nonspecialized determinant of the representation of the somatosensory (42), NEUROBIOLOGY posterior division of AI of the mustached bat (11), cortical visual (40), and motor cortices (43). In the somatosensory cortex, electric stimulation evokes a centripetal BF shift around the expansion of representation of a body surface caused by training stimulated cortical neurons and a centrifugal BF shift at the (10) or cortical electric stimulation (19), especially its rapid rostral or caudal edge of the centripetal BF shift area. However, change, is the result of unmasking, i.e., conversion of subthresh- in previous studies, the number of neurons showing centrifugal old excitatory-horizontal connections to suprathreshold connec- BF shift was so small that the center-surround reorganization tions. In a slice preparation of AI, synaptic efficiency between was not clear. In rats (12), electric stimulation of the basal horizontal fibers is highly modifiable (44). In the bat’s AI, BF forebrain paired with an acoustic stimulus evokes a centripetal shifts evoked by cortical electric stimulation occur within several BF shift. Centrifugal BF shift has not been reported in any minutes and disappears within 180 min after the cessation of the

Sakai and Suga PNAS ͉ May 14, 2002 ͉ vol. 99 ͉ no. 10 ͉ 7111 Downloaded by guest on September 29, 2021 stimulation (Fig. 2; 1, 2). This short-term plasticity is probably (9, 13, 14, 18), the recurrent circuit within AI and the corticofu- not caused by to a morphological change such as axonal sprout- gal feedback loop both presumably play an important role in ing or dendritic spine proliferation, but by a change in efficiency cortical plasticity. of existing synapses. The recurrent fibers of pyramidal neurons spread over 0.6 to Horizontal arborizations of pyramidal neurons for excitation several millimeters within the cortex and form minute connec- are classified into short- and long-range projections. The former tions with inhibitory interneurons. Most inhibitory interneurons is up to 0.6 mm long and omnidirectional, whereas the latter is (small basket cells) in AI radially project 0.2–0.3 mm, forming several millimeters long and preferentially parallel to iso-BF uniformly dense arbors (28, 49). The surrounding zone for contour lines (45–48). The minor and major axes of the ellipse centrifugal BF shift was 0.56–0.95 mm away from the stimulated for centripetal BF shift may, respectively, be related to the short- cortical neurons and 0.15–0.30 mm wide. Therefore, the inhib- and long-range projections. The recurrent fibers of pyramidal itory interneurons activated by the recurrent fibers may produce lateral inhibition that evokes a centrifugal BF shift. neurons form an intracortical positive feedback loop. In the big brown bat, electric stimulation of AI evokes a BF shift in the IC, We thank N. Laleman and K. K. Ohlemiller for comments on the which is very similar to cortical BF shift (2), and the cortical BF manuscript. Our research has been supported by a research grant from shift greatly depends on the collicular BF shift (8, 9). Because the National Institute on Deafness and Other Communicative Disorders centripetal BF shift in the IC is evoked by the corticofugal system (DC 00175).

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