Reviews

5.Fearmemoriesrequireproteinsynthesisintheamygdalaforreconsolidationafterretrieval.pdf

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sites in each county, depending on the popularity of a given mixture with farmers. Plots ranged from 100 to 450 m2 each, depending on ®eld size.

Survey plots were assessed in late August for the severity of blast symptoms, expressed as the percentage of panicle branches that were necrotic due to the effects of M. grisea. Disease was assessed at ®ve sampling points in each plot, distributed in a uniform pattern. Twenty hills resulting from the transplanting process were evaluated at each sampling point, with each hill containing about 10 panicles per hill, to give a total of approximately 1,000 panicles evaluated per plot. Each sampled panicle was visually examined by experienced personnel to estimate the percentage of branches that were necrotic due to infection by M. grisea. Each panicle was given a rating29 from 0 to 5, where 0 is no disease; 1 is less than 5% of panicle branches necrotic; 2 is 5±30% necrotic; 3 is 30±50% necrotic; 4 is greater than 50% necrotic; and 5 is 100% necrotic. Disease severity was summarized within each plot as {��n1 3 1� � �n2 3 2� � �n3 3 3� � �n4 3 4� � �n5 3 5��=Sn0 ¼n5 } 3 100, where n0...n5 is the number of culms in each of the respective disease categories. Thus, a disease severity of 0% would indicate no disease and 100% would indicate that 100% of panicle branches were necrotic.

Yield evaluation

Plots were hand-harvested, threshed and weighed to determine grain yield. Individual varieties were evaluated separately in mixtures. Land equivalent ratios22 were calculated as (yield ha-1 of variety A in mixture/yield ha-1of variety A in monoculture) + (yield ha-1 of variety B in mixture/yield ha-1 of variety B in monoculture).

Statistical analyses

Each survey plot was considered to be an experimental unit, and analyses were based on mean disease severities and grain yield for each plot. Statistical analyses were conducted separately by year and county owing to differences in disease level. One-tailed t-tests were used to determine if blast severity for each of the two varieties in each of the four mixtures differed signi®cantly from its corresponding monoculture control.

Received 18 April; accepted 30 June 2000.

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(1999).

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The dynamics of spatially subsidized food webs. Annu. Rev. Ecol. Syst. 28, 289±316 (1997).

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properties. Science 277, 504±508 (1997).

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12. International Rice Research Institute. IRRI Rice Facts (International Rice Research Institute, Manila,

1997).

13. Baker, B., Zambryski, P., Staskawicz & Dinesh-Kumar, S. P. Signaling in plant-microbe interactions.

Science 276, 726±733 (1997).

14. Staskawicz, B. J., Ausubel, F. M., Baker, B. J., Ellis, J. G. & Jones, J. D. G. Molecular genetics of plant

disease resistance. Science 268, 661±667 (1995).

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187 (1980).

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Phytopathol. 30, 507± 528 (1992).

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18. Boudreau, M. A. & Mundt, C. C. in Environmentally Safe Approaches to Disease Control (eds Rechcigl,

J. & Rechcigl, N.) 33± 62 (CRC, Boca Raton, 1997).

19. Chin, K. M. & Wolfe, M. S. Selection on Erysiphe graminis in pure and mixed stands of barley. Plant

Pathol. 33, 89±100 (1984).

20. Calonnec, A., Goyeau, H. & de Vallavieille-Pope, C. Effects of induced resistance on infection

ef®ciency and sporulation of Puccinia striiformis on seedlings in varietal mixtures and on ®eld

epidemics in pure stands. Eur. J. Plant Pathol. 102, 733±741 (1996).

21. George, M. L., Nelson, R. J., Zeigler, R. S. & Leung, H. Rapid population analysis of Magnaporthe grisea

by using rep-PCR and endogenous repetitive DNA sequences. Phytopathology 88, 223±229 (1998).

22. Francis, C. A. in Multiple Cropping Systems (ed. Francis, C. A.) 1±19 (MacMillan, New York, 1986).

23. Mundt, C. C. in Plant Disease Epidemiology (eds Leonard, K. J. & Fry, W. E.) 150±181 (McGraw-Hill,

1989).

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T.) 37±46 (Blackwell, Oxford, 1981).

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28. Schmidt, R. A. in Plant Disease: An Advanced Treatise (eds Horsfall, J. G & Cowling, E. B.) 287±315

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Press, Beijing, 1996).

Acknowledgements

This work was supported by the Asian Development Bank, the Yunnan Province Government, The Ministry of Science and Technology of China, the International Rice Research Institute (IRRI), and a scienti®c agreement between IRRI and Oregon State University. We thank the personnel of the provincial and county Plant Protection Stations and participating farmers for their contributions to this project, and M. Hoffer for computer assistance and graphics.

Correspondence and requests for materials should be addressed to C.C.M. (e-mail: [email protected]).

................................................................. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval Karim Nader, Glenn E. Schafe & Joseph E. Le Doux

W. M. Keck Foundation Laboratory of Neurobiology, Center for Neural Science,

New York University, New York, New York 10003, USA

..............................................................................................................................................

`New' memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories1 ± 5. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons6 ±9. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning10. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents

L C

–2.8

–3.8

L C

–3.3

B C

–2.3

Figure 1 Schematic representation of the amygdala at four different rostral±caudal

planes. The numbers represent the posterior coordinate from bregma. Injector

placements in the LBA are represented by the ®lled symbols; black ®lled squares

represent ASCF group placements, grey ®lled triangles represent the low-dose

anisomycin, and black ®lled circles represent high-dose group. L, lateral nucleus; B, basal

nucleus; C, central nucleus. The placements for subsequent experiments all demonstrate

similar distributions as in this experiment and therefore are not shown.

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consolidation of fear memories11. Here we show that consolidated fear memories, when reactivated during retrieval, return to a labile state in which infusion of anisomycin shortly after memory reactivation produces amnesia on later tests, regardless of whether reactivation was performed 1 or 14 days after condition- ing. The same treatment with anisomycin, in the absence of memory reactivation, left memory intact. Consistent with a time-limited role for protein synthesis production in consolida- tion, delay of the infusion until six hours after memory reactiva- tion produced no amnesia. Our data show that consolidated fear memories, when reactivated, return to a labile state that requires de novo protein synthesis for reconsolidation. These ®ndings are not predicted by traditional theories of memory consolidation.

The idea that new memories go through an initial labile period before being consolidated into stable long-term memories is an entrenched part of psychological and neurobiological models of memory12. For example, there is considerable evidence that the formation of a long-term memory can be disrupted by certain treatments, such as systemic drug injections or electroconvulsive shock, given shortly after training, but that the same treatments given several hours or days later have no effect. One of the most commonly used drug manipulations involves the administration of drugs that block the translation of RNA into protein. Studies of this type indicate that memory consolidation involves protein synthesis5±9.

It has also been reported that electroconvulsive shock or systemic drug administration given after memory reactivation (retrieval) can cause an amnesia for the original learning13±16, which indicates that consolidated memories might become labile when retrieved, and might even require reconsolidation. Here we examine whether reconsolidation involving protein synthesis is required for retrieved memories to persist. We use a behavioural paradigm, auditory fear conditioning, for which the neural circuit underlying memory formation is well characterized17±19. This allows us to manipulate

memory at its presumed locus of storage, in contrast to past studies in which drugs were administered systemically. Speci®cally, we target infusions of anisomycin, an inhibitor of protein synthesis, to the LBA, a region implicated in fear learning by lesion, pharma- cological and physiological ®ndings17±19. Previously, we showed that infusions of anisomycin given after training block long-term but not short-term memory of auditory fear conditioning11. Here we examine the effects of similar manipulations administered after retrieval.

Rats were given a single pairing of a tone (conditioned stimulus, CS) and foot-shock (unconditioned stimulus, US). On test days, immobility (freezing) was used as an index of fear learning20. Twenty-four hours later, the rats received a single CS presentation (test 1) immediately followed by bilateral infusions of anisomycin or vehicle (arti®cial cerebrospinal ¯uid; ACSF) into the LBA. Freezing in test 1 was speci®c to the CS and comparable across groups. An analysis of variance (ANOVA) that compared freezing during the pre-CS or CS periods across groups indicated that there was no interaction between these two variables (F�2; 18� � 1:6), nor an effect of group (F�2; 18� � 1:4). However, there was a signi®cant effect of period (F�1; 18� � 160, P , 0:01). Twenty-four hours after test 1, the rats were presented with three CSs (test 2). Anisomycin produced a dose-dependent decrease in freezing in response to the CS in test 2 (Figs 1, 2a±c). An ANOVA revealed a main effect of group (F�2; 18� � 12, P , 0:01). A Newman±Keuls post hoc test revealed that the low-dose anisomycin and ACSF groups were similar to each other (P . 0:05), but both were signi®cantly different from the high-dose group (P values , 0:01). Extinction was observed over the three CS presentations (main effect of trial (F�2; 36� � 7, P , 0:01), but there was no interaction between trials and group (F , 1). This effect of anisomycin requires that the memory be actively retrieved, as omission of the CS before aniso- mycin infusion in test 1 led to normal conditioned fear responses in test 2 (Fig. 2d, e; no main effect of group (F , 1). The latter ®nding

Figure 2 A test of whether consolidated fear memories can become labile when

reactivated. a, The behavioural procedure used for experiment 1A. b, Freezing to the CS

on test 1 was comparable across groups and was speci®c to the CS. c, Intra-LBA

anisomycin infusions after reactivation of a consolidated fear memory produce amnesia

for the original learning, as measured on test 2. d, e, Rats demonstrated normal memory if

the CS was omitted before anisomycin. d, The behavioural procedure used for experiment

1B. Rats were placed in the test chamber and received infusions of anisomycin. e, Percent

freezing on test 2. Figure legend is applicable to both c and e. Vertical open-headed

arrows represent infusions. All data points represent group means 6 s.e.m.

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rules out the possibility that the de®cit we observed is due to a disruption of late waves of protein synthesis21 that may be necessary for the consolidation of the original learning, or to nonspeci®c effects such as damage to the amygdala by the drug. It is unlikely that the high dose of anisomycin damaged the amygdala after CS transmission, as there was no histological evidence of amygdala damage. Furthermore, rats relearn fear conditioning normally when the same dose of anisomycin is infused into the amygdala after initial learning. The fact that anisomycin infusions after reactivation of the fear memory produced amnesia for the original learning indicates that reactivation of a consolidation fear memory may place it in a labile state, one that has to be reconsolidated by protein synthesis to remain usable to the organism in future situations.

Protein synthesis inhibitors typically impair the consolidation of new memories when they are administered during a speci®c time window (which varies from minutes to hours) after learning8. Administration of such drugs after this time window does not affect memory. We next asked whether a time window also exists for reconsolidation, by delaying anisomycin infusions for 6 h after retrieval. Freezing in test 1 was speci®c to the CS and comparable across groups. ANOVAs revealed no period ´ group interaction (F , 1) and no effect of group (F � 1) but a signi®cant effect of period (F�1; 13� � 124, P , 0:01). In contrast to anisomycin infu- sion immediately after retrieval, infusion 6 h after retrieval had no effect (Fig. 3). ANOVAs revealed that in test 2 there was no main effect of group (F�1; 13� � 4), no trial ´ group interaction (F�2; 26� � 2:7) and no main effect of trial (F�2; 26� � 3). Note that the nonsigni®cant impairment produced by delaying anisomy- cin is much smaller than that seen when anisomycin is given immediately after CS reactivation (compare with Fig. 2c). Thus, both consolidation and reconsolidation have time windows within which protein synthesis is required if a memory is to persist.

In all of the previous experiments, the time between training and CS presentation for test 1 was about 24 h. We next investigated whether reconsolidation has a temporal gradient. For example, older memories may be more thoroughly consolidated and thus may be resistant to becoming unstable when retrieved. To test this, we waited for 14 days between conditioning and test 1 (Fig. 4).

Postponing test 1 by 14 days produced an incubation effect22 such that freezing in test 1 was higher than in the previous experiment. Freezing during test 1 was speci®c to the CS and was comparable across groups. There was no period ´ group interaction (F�1; 9� � 1:1) and no effect of group (F � 1), but a signi®cant effect of period (F�1; 9� � 440, P , 0:01). However, the performance of the groups in test 2 divergedÐthe group receiving intra-LBA infusions of anisomycin showed signi®cantly less freezing than the controls. ANOVAs revealed a main effect of group (F�1; 9� � 20:6, P , 0:01) and trials (F�2; 18� � 7, P , 0:01), but no interaction between these variables (F , 1). Thus, blockade of protein synthesis in the LBA after memory reactivation caused amnesia of the original learning, even though the learning took place 14 days before the reactivation and drug treatment. Even well consolidated memories are labile and subject to disruption when reactivated.

Although anisomycin blocks reconsolidation, it is possible that the impairment is due to nonspeci®c effects that render the amygdala temporarily dysfunctional for reasons other than protein synthesis inhibition. To provide compelling evidence that any manipulation acts speci®cally on the molecular mechanisms medi- ating consolidation, as opposed to producing nonspeci®c effects, at a minimum it is necessary to show that memory is intact shortly after training but impaired later23±26. For example, rats freeze normally 4 h but are impaired 24 h after receiving intra-LBA anisomycin infusions immediately after training11. Using the same logic and applying it to reconsolidation, if the effects of anisomycin infused into the LBA shortly after memory reactivation are speci®c to reconsolidation, then freezing should be normal at 4 h, but impaired at 24 h, after CS presentation. We refer to these two time points are post-reactivation short-term memory (PR-STM) and post-reactivation long-term memory (PR-LTM), respectively.

The two groups exhibited comparable freezing during test 1

Figure 3 Intact memory if anisomycin infusions are delayed by 6 h. a, The behavioural

procedure used for experiment 2. Vertical open-headed arrows represent infusions.

b, Freezing on test 1 was speci®c to the CS and comparable across groups. c, Percent

freezing during test 2. The groups are not signi®cantly different. All data points represent

group means 6 s.e.m.

Figure 4 Fourteen days after training, anisomycin infusions after reactivation of the

memory still produce amnesia. a, The behavioural procedure used for experiment 3.

Vertical open-headed arrows represent infusions. b, Freezing during test 1 was speci®c to

the CS and was comparable across groups. c, Percent freezing on test 2. All data points

represent group means 6 s.e.m.

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(Fig. 5). An ANOVA revealed a signi®cant effect of period (F�1; 10� � 147, P , 0:01), no effect of group (F , 1) and no interaction between these two variables (F , 1). Rats treated with anisomycin immediately after test 1 exhibited intact PR-STM but de®cient PR-LTM. ANOVAs on the scores of the PR-STM test showed that there was no main effect of group (F , 1), no inter- action between trial ´ group (F , 1) and no effect of trial (F , 1). Conversely, a similar analysis on the PR-LTM scores did reveal a signi®cant effect of group (F�1; 14� � 14, P , 0:01). Furthermore, there was no interaction between group and trial (F , 1) but there was a main effect of trial (F�2; 28� � 5, P , 0:05). The fact that animals can accurately perceive, evaluate and respond to the CS 4 h after anisomycin infusion shows that the amygdala is functionally intact at the time of the PR-STM test, and thus that anisomycin did not affect reconsolidation by producing nonspeci®c effects. This pattern of ®ndings, intact PR-STM and impaired PR-LTM, localizes the effects of anisomycin on fear behaviour to the molecular processes mediating reconsolidation.

The conventional view of memory consolidation predicts that blockade of protein synthesis should block new learning in test 1 of these experiments, which is an extinction test. The only new learning that occurs is about the failure of the CS to predict the US. Blockade of protein synthesis should therefore block extinction, and thus enhance memory, according to the conventional view. In contrast, however, blockade of protein synthesis had the opposite effectÐit eliminated the memory rather than making it stronger.

These results provide evidence that fear memories, once retrieved, must undergo protein-synthesis-dependent reconsolida- tion in the LBA or nearby areas to remain accessible at later times. The full implications of this ®nding for fear and other memories are not understood at present. It is possible that not all memories require reconsolidation. There may be a range of parameters within which reactivation of a memory converts it into a labile state, possibly involving the extent of experience with the particular

learning situation, the kind of learning system engaged and the motivational state of the subject at the time of learning and retrieval.

Reconsolidation may re¯ect the dynamic nature of the process by which new information is added to existing stores. It has long been believed that memory retrieval is an active or constructive process by which old information is integrated with the current knowledge base of the organism27. Reconsolidation may be part of the neural mechanism through which constructed memories are stored for later constructions.

Current models of learning propose that the production of new proteins is necessary for structural encoding of recent experiences in long-term memory6±9. In addition, it now appears that new proteins are also required to maintain memories that have been reactivated. It seems unlikely that retrieval reverses the structural changes induced by original learning. Rather, some property of retrieval may destabilize the structural changes such that they now have to be reconsolidated with the aid of new proteins. The fact that animals demonstrate intact freezing 4 h after anisomycin indicates that the structural changes may remain functional for at least 4 h. Particularly important for future work will be the clari®cation of the physiological basis of memory lability during retrieval and the requirement for reconsolidation. It is possible that some modi®cation of the synap- tic tagging hypothesis28,29, which proposes that active synapses are given molecular markers that help stabilize synapses by capturing proteins made in the cell nucleus, might account for lability and reconsolidation, although this remains to be seen.

We have shown that reactivation changes the status of a con- solidated fear memory to a labile one that must be reconsolidated using de novo protein synthesis to persist. Like consolidation itself, reconsolidation has a temporal window during which blockade of protein synthesis is effective, and beyond which it is not. Further- more the reconsolidation process, like the consolidation process, has a short-term phase that is not dependent on protein synthesis. A de®nition of consolidation based on `new' memories is insuf®- ciently broad to describe these data. We propose, in keeping with the original suggestion by Misanin et al.13, that as a ®rst approxima- tion `active' rather than `new' memories be viewed as labile, subject to disruption, and requiring protein-synthesis-dependent consolidation processes. M

Methods Subjects

Subjects were adult male Sprague±Dawley rats from Hilltop Labs. Rats were housed individually in plastic Nalgene cages and maintained on a 12/12 h light/dark cycle. Food and water were provided ad libitum.

Surgery and histology

Under Nembutal anaesthesia (45 mg kg-1), rats were implanted bilaterally with 22-gauge stainless steel cannulas into the lateral amygdata. Coordinates were 3.0 mm posterior to bregma, 5.3 mm lateral to the midline and 8.0 mm ventral to the skull surface. Rats were given at least 5 days to recover before experimental procedures. All procedures were in accordance with the NIH Guide, and were approved by the NYU Animal Care and Use Committee. At the end of the experiment, using standard histological methods, animals were perfused and their brains sectioned at 50 mm thickness. The sections were stained using cresyl violet and examined by light microscopy for cannula penetration into the LBA.

Intra-LBA infusions

Drugs were infused slowly using an infusion pump into the LBA at 0.25 ml min-1. Following drug infusion, cannulas were left in place for an additional minute to allow diffusion of the drug away from the cannula tip. Anisomycin (Sigma) was dissolved in equimolar HCl, diluted with ACSF and adjusted to pH 7.4 with NaOH. Although the lateral nucleus was the main target, the 0.5-ml infusions also probably affected the adjacent basal nucleus. We therefore refer to the affected area as the lateral and basal amygdala (LBA).

Apparatus

Conditioning and tone testing were conducted in different chambers. For conditioning, rats were placed in a Plexiglas rodent conditioning chamber (chamber A) with a metal grid ¯oor (Model E10-10, Coulbourn Instruments) that was enclosed within a sound attenuating chamber (Model E10-20). The chamber was dimly illuminated by a single house light. For tone testing, rats were placed in a different Plexiglas chamber (ENV-001,

Figure 5 Amnesia following anisomycin is not due to nonspeci®c effects. a, The

behavioural procedure used for experiment 4. Vertical open-headed arrows represent

infusions. Anisomycin infusions impaired post-reactivation long-term memory (PR-LTM),

but had no effect on post-reactivation short-term memory (PR-STM). b, All rats

demonstrated comparable freezing scores on test 1. c, Scores on the PR-STM test 4 h

after reactivation and anisomycin. d, Scores on the PR-LTM test 24 h after reactivation

and anisomycin. The key is applicable to both c and d. All data points represent group

means 6 s.e.m.

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726 NATURE | VOL 406 | 17 AUGUST 2000 | www.nature.com

MedAssociates), which has been shown to minimize generalization from the conditioning environment11. The tone-testing chamber (chamber B) was brightly lit with three house lights and contained a ¯at black Formica ¯oor that had been washed with peppermint soap. A micro-video camera was mounted at the top of the chamber so that rats could be videotaped during testing.

General behavioural procedures

Rats were placed in chamber A and after a 5-min acclimatizing period, given a single conditioning trial consisting of a 30-s presentation of a 5-kHz, 75-dB tone CS that ended at the same time as a 2.0-mA, 1-s food shock US. Rats were then returned to their home cages. The next day, 24 h later, rats were placed in chamber B and given a single 30-s CS presentation (test 1) to reactivate the memory. Twenty-four hours after test 1, rats were returned to chamber B and given three CS presentations (test 2).

Experiment 1A

Rats were infused with either 62.5 mg per 0.5 ml per side (n � 8) or 6.2 mg per 0.5 ml per side (n � 7) anisomycin or ACSF (n � 6) immediately after CS termination during test 1. The highest dose of anisomycin was chosen based on a previous study showing .90% suppression of protein synthesis in cortex using this concentration30. Previous data have shown that post-training intra-LBA infusions of the high but not low dose blocked consolidation of fear conditioning11.

Experiment 1B

During test 1 no CS was presented while the animals explored chamber B, but rats still received an infusion of vehicle (n � 6) or the high dose of anisomycin (n � 7) at the end of the exposure to chamber B.

Experiment 2

High-dose anisomycin (n � 8) or vehicle (n � 7) infusions were performed 6 h after test 1. Animals were transported to the infusion room, received the infusion and were then returned to their home cage.

Experiment 3

Fourteen days were inserted between conditioning and test 1. After CS reactivation, rats received either high-dose anisomycin (n � 6) or vehicle (n � 5) infusion.

Experiment 4

After test 1 animals received either vehicle (n � 8) or high-dose anisomycin (n � 8) infusions into the LBA. An extra test was inserted 4 h after test 1 (post-reactivation short- term memory, PR-STM) during which animals received three CS presentations. Test 2 was performed as described above, 24 h after reactivation (post-reactivation long-term memory, PR-LTM). These time points were chosen based on the ®ndings that freezing is intact 4 h, but impaired 24 h, after conditioning11.

Received 3 April; accepted 18 May 2000.

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Acknowledgements

This research was supported in part by NIMH grants to J.E.L. and a HFSF grant to K.N. The work was also supported by a grant from the W. M. Keck Foundation to N.Y.U. The authors thank A. Schoute for technical assistance.

Correspondence and requests for materials should be addressed to K.N. (e-mail: [email protected]).

................................................................. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex Takuji Iwasato*, Akash Datwani², Alexander M. Wolf³, Hiroshi Nishiyama*§, Yusuke Taguchi*, Susumu Tonegawak, Thomas KnoÈ pfel³, Reha S. Erzurumlu² & Shigeyoshi Itohara*

* Laboratory for Behavioral Genetics, Brain Science Institute (BSI), RIKEN,

2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan ² Department of Cell Biology and Anatomy and Neuroscience Center, LSUHSC, New Orleans, Louisiana 70112, USA ³ Laboratory for Neuronal Circuit Dynamics, Brain Science Institute (BSI),

RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan § Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

k Howard Hughes Medical Institute, Center for Learning & Memory, RIKEN-MIT Neuroscience Research Center, Department of Biology, MIT,

77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA ..............................................................................................................................................

In the rodent primary somatosensory cortex, the con®guration of whiskers and sinus hairs on the snout and of receptor-dense zones on the paws is topographically represented as discrete modules of layer IV granule cells (barrels) and thalamocortical afferent terminals1,2. The role of neural activity, particularly activity mediated by NMDARs (N-methyl-D-aspartate receptors), in pat- terning of the somatosensory cortex has been a subject of debate3 ±6. We have generated mice in which deletion of the NMDAR1 (NR1) gene is restricted to excitatory cortical neurons, and here we show that sensory periphery-related patterns develop normally in the brainstem and thalamic somatosensory relay stations of these mice. In the somatosensory cortex, thalamocor- tical afferents corresponding to large whiskers form patterns and display critical period plasticity, but their patterning is not as distinct as that seen in the cortex of normal mice. Other thala- mocortical patterns corresponding to sinus hairs and digits are mostly absent. The cellular aggregates known as barrels and barrel boundaries do not develop even at sites where thalamocor- tical afferents cluster. Our ®ndings indicate that cortical NMDARs