The readings listed below are the foundation of this course. Where available, journal article abstracts from PubMed (an online database providing access to citations from biomedical literature) are included.


Bear, M., B. Connors, and M. Paradiso. Neuroscience, Exploring the Brain. Williams and Wilkens, 2000.

Synaptic Plasticity I

Albright, T. D., T. M. Jessell, E. R. Kandel, and M. I. Posner. "Neural science: a century of progress and the mysteries that remain." Neuron. 25, 2000, Suppl: S1-55.

Bear, M. F. "A synaptic basis for memory storage in the cerebral cortex." In Proc. Natl. Acad. Sci. 93, USA, 1996, 13453-13459.

PubMed abstract: A cardinal feature of neurons in the cerebral cortex is stimulus selectivity, and experience-dependent shifts in selectivity are a common correlate of memory formation. We have used a theoretical "learning rule," devised to account for experience-dependent shifts in neuronal selectivity, to guide experiments on the elementary mechanisms of synaptic plasticity in hippocampus and neocortex. These experiments reveal that many synapses in hippocampus and neocortex are bidirectionally modifiable, that the modifications persist long enough to contribute to long-term memory storage, and that key variables governing the sign of synaptic plasticity are the amount of NMDA receptor activation and the recent history of cortical activity.

Bi, G. Q., and M. M. Poo. "Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type." J Neurosci. 18, 24, 1998, 10464-72.

PubMed abstract: In cultures of dissociated rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking determined the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 msec after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 msec before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb's rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.

Bliss, T. V., and G. L. Collingridge. "A synaptic model of memory: long-term potentiation in the hippocampus." Nature. 361, 6407, 1993, 31-9.

PubMed abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

Lichtman, J. W., and H. Colman. "Synapse elimination and indelible Memory." Neuron. 25, 2, 2000, 269-78.

Malenka, R. C., and R. A. Nicoll. "Long-term potentiation--a decade of progress?" Science. 285, 1999, 1870-4.

PubMed abstract: Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.

Markram, H., J. Lubke, M. Frotscher, and B. Sakmann. "Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs." Science. 275, 5297, 1997, 213-5.

PubMed abstract: Activity-driven modifications in synaptic connections between neurons in the neocortex may occur during development and learning. In dual whole-cell voltage recordings from pyramidal neurons, the coincidence of postsynaptic action potentials (APs) and unitary excitatory postsynaptic potentials (EPSPs) was found to induce changes in EPSPs. Their average amplitudes were differentially up- or down-regulated, depending on the precise timing of postsynaptic APs relative to EPSPs. These observations suggest that APs propagating back into dendrites serve to modify single active synaptic connections, depending on the pattern of electrical activity in the pre- and postsynaptic neurons.

Sanes, J. R., and J. W. Lichtman. "Can molecules explain long-term potentiation?" In Nat Neurosci. 2, 1999, 597-604.

Zhang, L. I., H. W. Tao, et al. "Visual input induces long-term potentiation of developing retinotectal synapses." Nat Neurosci. 3, 7, 2000, 708-15.

PubMed abstract: Early visual experience is essential in the refinement of developing neural connections. In vivo whole-cell recording from the tectum of Xenopus tadpoles showed that repetitive dimming-light stimulation applied to the contralateral eye resulted in persistent enhancement of glutamatergic inputs, but not GABAergic or glycinergic inputs, on tectal neurons. This enhancement can be attributed to potentiation of retinotectal synapses. It required spiking of postsynaptic tectal cells as well as activation of NMDA receptors, and effectively occluded long-term potentiation (LTP) of retinotectal synapses induced by direct electrical stimulation of retinal ganglion cells. Thus, LTP-like synaptic modification can be induced by natural visual inputs and may be part of the underlying mechanism for the activity-dependent refinement of developing connections.

Zucker, R. S. "Calcium- and activity-dependent synaptic plasticity." Curr. Opin. Neurobiol. 9, 1999, 305-313.

PubMed abstract: Calcium ions play crucial signaling roles in many forms of activity-dependent synaptic plasticity. Recent presynaptic [Ca2+]i measurements and manipulation of presynaptic exogenous buffers reveal roles for residual [Ca2+]i following conditioning stimulation in all phases of short-term synaptic enhancement. Pharmacological manipulations implicate mitochondria in post-tetanic potentiation. New evidence supports an influence of Ca2+ in replacing depleted vesicles after synaptic depression. In addition, high-resolution measurements of [Ca2+]i in dendritic spines show how Ca2+ can encode the precise relative timing of presynaptic input and postsynaptic activity and generate long-term synaptic modifications of opposite polarity.

Synaptic Plasticity II

Liao, D., N. A. Hessler, et al. "Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice." Nature. 375, 6530, 1995, 400-4.

PubMed abstract: Long-term potentiation (LTP) is an enhancement of synaptic strength that can be produced by pairing of presynaptic activity with postsynaptic depolarization. LTP in the hippocampus has been extensively studied as a cellular model of learning and memory, but the nature of the underlying synaptic modification remains elusive, partly because our knowledge of central synapses is still limited. One proposal is that the modification is postsynaptic, and that synapses expressing only NMDA (N-methyl-D-aspartate) receptors before potentiation are induced by LTP to express functional AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors. Here we report that a high proportion of synapses in hippocampal area CA1 transmit with NMDA receptors but not AMPA receptors, making these synapses effectively non-functional at normal resting potentials. These silent synapses acquire AMPA-type responses following LTP induction. Our findings challenge the view that LTP in CA1 involves a presynaptic modification, and suggest instead a simple postsynaptic mechanism for both induction and expression of LTP.

Martin, K. C., M. Barad, and E. R. Kandel. "Local protein synthesis and its role in synapse-specific plasticity." Curr Opin Neurobiol. 10, 2000, 587-92.

PubMed abstract: Long-lasting forms of learning-related synaptic plasticity require transcription and yet occur in a synapse-specific manner, indicating that there are mechanisms to target the products of gene expression to some but not other synapses of a given cell. Studies in a variety of systems have indicated that mRNA localization and synaptically regulated local protein synthesis constitute one such mechanism. The cellular and molecular mechanisms underlying RNA localization and regulated translation in neurons are just beginning to be delineated, and appear to be similar to those used in asymmetric non-neuronal cells.

Renger, J. J., C. Egles, et al. "A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation." Neuron. 29, 2, 2001, 469- 84.

PubMed abstract: Formation of glutamatergic synapses entails development of "silent" immature contacts into mature functional synapses. To determine how this transformation occurs, we investigated the development of neurotransmission at single synapses in vitro. Maturation of presynaptic function, assayed with endocytotic markers, followed accumulation of synapsin I. During this period, synaptic transmission was primarily mediated by activation of NMDA receptors, suggesting that most synapses were functionally silent. However, local glutamate application to silent synapses indicated that these synapses contained functional AMPA receptors, suggesting a possible presynaptic locus for silent transmission. Interference with presynaptic vesicle fusion by exposure to tetanus toxin reverted functional to silent transmission, implicating SNARE-mediated fusion as a determinant of the ratio of NMDA:AMPA receptor activation. This work reveals that functional maturation of synaptic transmission involves transformation of presynaptic silent secretion into mature synaptic transmitter release.

Shi, S., Y. Hayashi, J. A. Esteban, and R. Malinow. "Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons." Cell. 105, 2001, 331-43.

PubMed abstract: To monitor changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, the AMPA receptor subunit GluR1 was tagged with green fluorescent protein (GFP). This protein (GluR1-GFP) was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with two-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites. These postsynaptic trafficking events required synaptic N-methyl-D-aspartate (NMDA) receptor activation and may contribute to the enhanced AMPA receptor-mediatedtransmission observed during long-term potentiation and activity-dependent synaptic maturation.

Shi, S. H., Y. Hayashi, R. S. Petralia, S. H. Zaman, R. J. Wenthold, K. Svoboda, and R. Malinow. "Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation." Science. 284, 1999, 1811-6.

PubMed abstract: To monitor changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, the AMPA receptor subunit GluR1 was tagged with green fluorescent protein (GFP). This protein (GluR1-GFP) was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with two-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites. These postsynaptic trafficking events required synaptic N-methyl-D-aspartate (NMDA) receptor activation and may contribute to the enhanced AMPA receptor-mediatedtransmission observed during long-term potentiation and activity-dependent synaptic maturation.

Stevens, C. F. "Quantal release of neurotransmitter and long-term potentiation." Cell. 72, 1993, Suppl: 55-63.

Learning and Memory in Aplysia

Carew, T. J., R. D. Hawkins, and E. R. Kandel. "Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica." Science. 219, 4583, 28 Jan. 1983, 397-400.

PubMed abstract: The defensive siphon and gill withdrawal reflex of Aplysia is a simple reflex mediated by a well-defined neural circuit. This reflex exhibits classical conditioning when a weak tactile stimulus to the siphon is used as a conditioned stimulus and a strong shock to the tail is used as an unconditioned stimulus. The siphon withdrawal component of this reflex can be differentially conditioned when stimuli applied to two different sites on the mantle skin (the mantle shelf and the siphon) are used as discriminative stimuli. The differential conditioning can be acquired in a single trial, is retained for more than 24 hours, and increases in strength with increased trials. Differential conditioning can also be produced within the field of innervation of a single cluster of sensory neurons (the LE cluster) since two separate sites on the siphon skin can serve as discriminative stimuli. The finding that two independent afferent inputs that activate a common set of interneurons and motor neurons can be differentially conditioned restricts the possible cellular loci involved in the associative learning.

Dash, P. K., B. Hochner, and E. R. Kandel. "Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation." Nature. 345, 6277, 21 Jun. 1990, 718-21.

PubMed abstract: In both vertebrates and invertebrates, long-term memory differs from short-term in requiring protein synthesis during training. Studies of the gill and siphon withdrawal reflex in Aplysia indicate that similar requirements can be demonstrated at the level of sensory and motor neurons which may participate in memory storage. A single application of serotonin, a transmitter that mediates sensitization, to individual sensory and motor cells in dissociated cell cultures leads to enhanced transmitter release from the sensory neurons that is independent of new macromolecular synthesis. Five applications of serotonin cause a long-term enhancement, lasting one or more days, which requires translation and transcription. Prolonged application or intracellular injection into the sensory neuron of cyclic AMP, a second messenger for the action of serotonin, also produce long-term increases in synaptic strength, suggesting that some of the gene products important for long-term facilitation are cAMP-inducible. In eukaryotic cells, most cAMP-inducible genes so far studied are activated by the cAMP-dependent protein kinase (A kinase), which phosphorylates transcription factors that bind the cAMP-responsive element TGACGTCA. The cAMP-responsive element (CRE) binds a protein dimer of relative molecular mass 43,000, the CRE-binding protein (CREBP), which has been purified and shown to increase transcription when phosphorylated by the A kinase. Here we show that extracts of the Aplysia central nervous system and extracts of sensory neurons contain a set of proteins, including one with properties similar to mammalian CREBPs, that specifically bind the mammalian CRE sequence. Microinjection of the CRE sequence into the nucleus of a sensory neuron selectively blocks the serotonin-induced long-term increase in synaptic strength, without affecting short-term facilitation. Taken together, these observations suggest that one or more CREB-like transcriptional activators are required for long-term facilitation.

Hawkins, R. D., T. W. Abrams, T. J. Carew, and E. R. Kandel. "A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation." Science. 219, 4583, 28 Jan. 1983, 400-5.

PubMed abstract: A training procedure analogous to differential classical conditioning produces differential facilitation of excitatory postsynaptic potentials (EPSP's) in the neuronal circuit for the siphon withdrawal reflex in Aplysia. Thus, tail shock (the unconditioned stimulus) produces greater facilitation of the monosynaptic EPSP from a siphon sensory neuron to a siphon motor neuron if the shock is preceded by spike activity in the sensory neuron than if the shock and spike activity occur in a specifically unpaired pattern or if the shock occurs alone. Further experiments indicate that this activity-dependent amplification of facilitation is presynaptic in origin and involves a differential increase in spike duration and thus in Ca2+ influx in paired versus unpaired sensory neurons. The results of these cellular experiments are quantitatively similar to the results of behavioral experiments with the same protocol and parameters, suggesting that activity-dependent amplification of presynaptic facilitation may make a significant contribution to classical conditioning of the withdrawal reflex.

Martin, K. C., A. Casadio, E. Y. Zhu H, J. C. Rose, M. Chen, C. H. Bailey, and E. R. Kandel. "Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage." Cell. 91, 7, 26 Dec. 1997, 927-38.

PubMed abstract: The requirement for transcription during long-lasting synaptic plasticity has raised the question of whether the cellular unit of synaptic plasticity is the soma and its nucleus or the synapse. To address this question, we cultured a single bifurcated Aplysia sensory neuron making synapses with two spatially separated motor neurons. By perfusing serotonin onto the synapses made onto one motor neuron, we found that a single axonal branch can undergo long-term branch-specific facilitation. This branch-specific facilitation depends on CREB-mediated transcription and involves the growth of new synaptic connections exclusively at the treated branch. Branch-specific long-term facilitation requires local protein synthesis in the presynaptic but not the postsynaptic cell. In fact, presynaptic sensory neuron axons deprived of their cell bodies are capable of protein synthesis, and this protein synthesis is stimulated 3-fold by exposure to serotonin.

Learning and Memory in Drosophila

Grotewiel, M. S., C. D. O. Beck, K. H. Wu, X-R. Zhu, and R. L. Davis. "Integrinmediated short-term memory in Drosophila." Nature. 391, 6666, 29 Jan. 1998, 455-60.

PubMed abstract: Volado is a new memory mutant of Drosophila. The locus encodes two isoforms of a new alpha-integrin, a molecule that dynamically mediates cell adhesion and signal transduction. The Volado gene is expressed preferentially in mushroom body cells, which are neurons known to mediate olfactory learning in insects. Volado proteins are concentrated in the mushroom body neuropil, brain areas that contain mushroom body processes in synaptic contact with other neurons. Volado mutants display impaired olfactory memories within 3 min of training, indicating that the integrin is required for short-term memory processes. Conditional expression of a Volado transgene during adulthood rescues the memory impairment. This rescue of memory is reversible, fading over time along with expression of the transgene. Thus the Volado integrin is essential for the physiological processes underlying memory. We propose a model in which integrins act as dynamic regulators of synapse structure or the signalling events underlying short-term memory formation.

Liu, L., R. Wolf, R. Ernst, and M. Heisenberg. "Context generalization in Drosophila visual learning requires the mushroom bodies." Nature. 400, 6746, 1999, 753-56.

PubMed abstract: The world is permanently changing. Laboratory experiments on learning and memory normally minimize this feature of reality, keeping all conditions except the conditioned and unconditioned stimuli as constant as possible. In the real world, however, animals need to extract from the universe of sensory signals the actual predictors of salient events by separating them from non-predictive stimuli (context). In principle, this can be achieved if only those sensory inputs that resemble the reinforcer in their temporal structure are taken as predictors. Here we study visual learning in the fly Drosophila melanogaster, using a flight simulator, and show that memory retrieval is, indeed, partially context-independent. Moreover, we show that the mushroom bodies, which are required for olfactory but not visual or tactile learning, effectively support context generalization. In visual learning in Drosophila, it appears that a facilitating effect of context cues for memory retrieval is the default state, whereas making recall context-independent requires additional processing.

Quinn, W. G., and T. Tully. "Classical conditioning and retention in normal and mutant Drosophila melanogaster." J Comp Physiol [A]. 1985 Sep;157(2):263-77.

PubMed abstract: By changing the conditioned discrimination paradigm of Quinn et al. (1974) from an instrumental procedure to a classical (Pavlovian) one, we have demonstrated strong learning in wildtype flies. About 150 flies were sequestered in a closed chamber and trained by exposing them sequentially to two odors in air currents. Flies received twelve electric shock pulses in the presence of the first odor (CS+) but not in the presence of the second odor (CS-). To test for conditioned avoidance responses, flies were transported to a T-maze choice point, between converging currents of the two odors. Typically, 95% of trained flies avoided the shock-associated odor (CS+). Acquisition of learning was a function of the number of shock pulses received during CS+ presentation and was asymptotic within one training cycle. Conditioned avoidance increased with increasing shock intensity or odor concentration and was very resistant to extinction. Learning was best when CS+ presentations overlap shock (delay conditioning) and then decreased with increasing CS-US interstimulus intervals. Shocking flies immediately before CS+ presentation (backward conditioning) produced no learning. Nonassociative control procedures (CS Alone, US Alone and Explicitly Unpaired) produced slight decreases in avoidance responses, but these affected both odors equally and did not alter our associative learning index (A). Memory in wild-type flies decayed gradually over the first seven hours after training and still was present 24 h later. The mutants amnesiac, rutabaga and dunce showed appreciable learning acquisition, but their memories decayed very rapidly during the first 30 min. After this, the rates of decay slowed sharply; conditioned avoidance still was measureable at least three hours after training.

Waddell, S., J. D. Armstrong, T. Kitamoto, K. Kaiser, and W. G. Quinn. "The amnesiac gene product is expressed in two neurons in the drosophila brain that are critical for Memory." Cell. 103, Nov. 2000, 805-813.

PubMed abstract: Mutations in the amnesiac gene in Drosophila affect both memory retention and ethanol sensitivity. The predicted amnesiac gene product, AMN, is an apparent preproneuropeptide, and previous studies suggest that it stimulates cAMP synthesis. Here we show that, unlike other learning-related Drosophila proteins, AMN is not preferentially expressed in mushroom bodies. Instead, it is strongly expressed in two large neurons that project over all the lobes of the mushroom bodies, a finding that suggests a modulatory role for AMN in memory formation. Genetically engineered blockade of vesicle recycling in these cells abbreviates memory as in the amnesiac mutant. Moreover, restoration of amn gene expression to these cells reestablishes normal olfactory memory in an amn deletion background. These results indicate that AMN neuropeptide release onto the mushroom bodies is critical for normal olfactory memory.

Hippocampus I

Frank, L. M., E. N. Brown, and M. Wilson. "Trajectory encoding in the hippocampus and entorhinal cortex." Neuron. 27, 1, Jul. 2000, 169-78.

PubMed abstract: We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences.

Mehta, M. R., M. C. Quirk, and M. A. Wilson. "Experience-dependent asymmetric shape of hippocampal receptive fields." Neuron. 25, 3, Mar. 2000, 707-15.

PubMed abstract: We propose a novel parameter, namely, the skewness, or asymmetry, of the shape of a receptive field to characterize two properties of hippocampal place fields. First, a majority of hippocampal receptive fields on linear tracks are negatively skewed, such that during a single pass the firing rate is low as the rat enters the field but high as it exits. Second, while the place fields are symmetric at the beginning of a session, they become highly asymmetric with experience. Further experiments suggest that these results are likely to arise due to synaptic plasticity during behavior. Using a purely feed forward neural network model, we show that following repeated directional activation, NMDA-dependent long-term potentiation/long-term depotentiation (LTP/LTD) could result in an experience-dependent asymmetrization of receptive fields.

Hippocampus II

Louie, K., and M. A. Wilson. "Temporally Structured Replay of Awake Hippocampal Ensemble Activity during Rapid Eye Movement Sleep." Neuron. 29 1, Jan. 2001, 145-156.

PubMed abstract: Human dreaming occurs during rapid eye movement (REM) sleep. To investigate the structure of neural activity during REM sleep, we simultaneously recorded the activity of multiple neurons in the rat hippocampus during both sleep and awake behavior. We show that temporally sequenced ensemble firing rate patterns reflecting tens of seconds to minutes of behavioral experience are reproduced during REM episodes at an equivalent timescale. Furthermore, within such REM episodes behavior-dependent modulation of the subcortically driven theta rhythm is also reproduced. These results demonstrate that long temporal sequences of patterned multineuronal activity suggestive of episodic memory traces are reactivated during REM sleep. Such reactivation may be important for memory processing and provides a basis for the electrophysiological examination of the content of dream states.

Wilson, M. A., and B. L. McNaughton. "Reactivation of hippocampal ensemble memories during sleep." Science. 265, 5172, 29 Jul. 1994, 676-9.

PubMed abstract: Simultaneous recordings were made from large ensembles of hippocampal "place cells" in three rats during spatial behavioral tasks and in slow-wave sleep preceding and following these behaviors. Cells that fired together when the animal occupied particular locations in the environment exhibited an increased tendency to fire together during subsequent sleep, in comparison to sleep episodes preceding the behavioral tasks. Cells that were inactive during behavior, or that were active but had non-overlapping spatial firing, did not show this increase. This effect, which declined gradually during each post-behavior sleep session, may result from synaptic modification during waking experience. Information acquired during active behavior is thus re-expressed in hippocampal circuits during sleep, as postulated by some theories of memory consolidation.

Learning and Memory in Rodents I

Gilbert, P. E., and R. P. Kesner. "Role of the rodent hippocampus in paired-associate learning involving associations between a stimulus and a spatial location." Behav Neurosci. 116, 1, Feb. 2002, 63-71.

PubMed abstract: The ability of rats with control or hippocampal lesions to learn an object-place, odor-place, or object-odor paired-associate task was assessed in a cheeseboard maze apparatus. The data indicate that rats with hippocampal lesions were significantly impaired, compared with controls, in learning both the object-place and the odor-place paired-associate tasks. However, rats with hippocampal lesions learned the object-odor paired-associate task as readily as did controls. The data suggest that the rodent hippocampus is involved in paired-associate learning when a stimulus must be associated with a spatial location. However, the hippocampus is not involved in paired-associate learning when the association does not involve a spatial component.

Lee, I., and R. P. Kesner. "Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory." Nat Neurosci. 5, 2, Feb. 2002, 162-8.

PubMed abstract: N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity in the mammalian hippocampus is essential for learning and memory. Although computational models and anatomical studies have emphasized functional differences among hippocampal subregions, subregional specificity of NMDA receptor function is largely unknown. Here we present evidence that NMDA receptors in CA3 are required in a situation in which spatial representation needs to be reorganized, whereas the NMDA receptors in CA1 and/or the dentate gyrus are more involved in acquiring memory that needs to be retrieved after a delay period exceeding a short-term range. Our data, with data from CA1-specific knockout mice, suggest the possibility of heterogeneous mnemonic function of NMDA receptors in different subregions of the hippocampus.

McGaugh, J. L. "Memory -- a Century of Consolidation." Science. 287, 5451, 14 Jan. 2000, 248-51.

PubMed abstract: The memory consolidation hypothesis proposed 100 years ago by Muller and Pilzecker continues to guide memory research. The hypothesis that new memories consolidate slowly over time has stimulated studies revealing the hormonal and neural influences regulating memory consolidation, as well as molecular and cellular mechanisms. This review examines the progress made over the century in understanding the time-dependent processes that create our lasting memories.

Learning and Memory in Rodents II

Day, M., and R. G. Morris. "Memory consolidation and NMDA receptors: discrepancy between genetic and pharmacological approaches." Science. 293, 5531, 3 Aug. 2001, 755.

Nader, K., G. E. Schafe, and J. E. LeDoux. "The labile nature of consolidation theory." Nat Rev Neurosci. 1, 3, Dec. 2000, 216-9.

PubMed abstract: 'Consolidation' has been used to describe distinct but related processes. In considering the implications of our recent findings on the lability of reactivated fear memories, we view consolidation and reconsolidation in terms of molecular events taking place within neurons as opposed to interactions between brain regions. Our findings open up a new dimension in the study of memory consolidation. We argue that consolidation is not a one-time event, but instead is reiterated with subsequent activation of the memories.

Nader, K., G. E. Schafe, and J. E. LeDoux. "Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval." Nature. 406, 6797, 2000, 722-6.

PubMed abstract: 'New' memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents consolidation of fear memories. 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 conditioning. 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 consolidation, delay of the infusion until six hours after memory reactivation 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 findings are not predicted by traditional theories of memory consolidation.

Shimizu, E., Y. P. Tang, C. Rampon, and J. Z. Tsien. "NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation." Science. 290, 5494, 2000, 1170-4.

PubMed abstract: The hippocampal CA1 region is crucial for converting new memories into long-term memories, a process believed to continue for week(s) after initial learning. By developing an inducible, reversible, and CA1-specific knockout technique, we could switch N-methyl-D-aspartate (NMDA) receptor function off or on in CA1 during the consolidation period. Our data indicate that memory consolidation depends on the reactivation of the NMDA receptor, possibly to reinforce site-specific synaptic modifications to consolidate memory traces. Such a synaptic reinforcement process may also serve as a cellular means by which the new memory is transferred from the hippocampus to the cortex for permanent storage.

Computational Modeling

Foster, D. J., R. G. Morris, and P. Dayan. "A model of hippocampally dependent navigation, using the temporal difference learning rule." Hippocampus. 10, 1, 2000, 1-16.

PubMed abstract: This paper presents a model of how hippocampal place cells might be used for spatial navigation in two watermaze tasks: the standard reference memory task and a delayed matching-to-place task. In the reference memory task, the escape platform occupies a single location and rats gradually learn relatively direct paths to the goal over the course of days, in each of which they perform a fixed number of trials. In the delayed matching-to-place task, the escape platform occupies a novel location on each day, and rats gradually acquire one-trial learning, i.e., direct paths on the second trial of each day. The model uses a local, incremental, and statistically efficient connectionist algorithm called temporal difference learning in two distinct components. The first is a reinforcement-based "actor-critic" network that is a general model of classical and instrumental conditioning. In this case, it is applied to navigation, using place cells to provide information about state. By itself, the actor-critic can learn the reference memory task, but this learning is inflexible to changes to the platform location. We argue that one-trial learning in the delayed matching-to-place task demands a goal-independent representation of space. This is provided by the second component of the model: a network that uses temporal difference learning and self-motion information to acquire consistent spatial coordinates in the environment. Each component of the model is necessary at a different stage of the task; the actor-critic provides a way of transferring control to the component that performs best. The model successfully captures gradual acquisition in both tasks, and, in particular, the ultimate development of one-trial learning in the delayed matching-to-place task. Place cells report a form of stable, allocentric information that is well-suited to the various kinds of learning in the model.

O'Reilly, R. C., and J. W. Rudy. "Computational principles of learning in the neocortex and hippocampus." Hippocampus. 10, 4, 2000, 389-97.

PubMed abstract: We present an overview of our computational approach towards understanding the different contributions of the neocortex and hippocampus in learning and memory. The approach is based on a set of principles derived from converging biological, psychological, and computational constraints. The most central principles are that the neocortex employs a slow learning rate and overlapping distributed representations to extract the general statistical structure of the environment, while the hippocampus learns rapidly, using separated representations to encode the details of specific events while suffering minimal interference. Additional principles concern the nature of learning (error-driven and Hebbian), and recall of information via pattern completion. We summarize the results of applying these principles to a wide range of phenomena in conditioning, habituation, contextual learning, recognition memory, recall, and retrograde amnesia, and we point to directions of current development.

Learning and Memory in Primates I

Tomita, H., M. Ohbayashi, K. Nakahara, I. Hasegawa, and Y. Miyashita. "Top-down signal from prefrontal cortex in executive control of memory retrieval." Nature. 401, 6754, 14 Oct. 1999, 699-703.

PubMed abstract: Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus-stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.

Wallis, J. D., K. C. Anderson, and E. K. Miller. "Single neurons in prefrontal cortex encode abstract rules." Nature. 411, 6840, 21 Jun. 2001, 953-6.

PubMed abstract: The ability to abstract principles or rules from direct experience allows behaviour to extend beyond specific circumstances to general situations. For example, we learn the 'rules' for restaurant dining from specific experiences and can then apply them in new restaurants. The use of such rules is thought to depend on the prefrontal cortex (PFC) because its damage often results in difficulty in following rules. Here we explore its neural basis by recording from single neurons in the PFC of monkeys trained to use two abstract rules. They were required to indicate whether two successively presented pictures were the same or different depending on which rule was currently in effect. The monkeys performed this task with new pictures, thus showing that they had learned two general principles that could be applied to stimuli that they had not yet experienced. The most prevalent neuronal activity observed in the PFC reflected the coding of these abstract rules.

Learning and Memory in Primates II

Bichot, N. P., J. D. Schall, and K. G. Thompson. "Visual feature selectivity in frontal eye fields induced by experience in mature macaques." Nature. 381, 6584, 20 Jun. 1996, 697-9.

PubMed abstract: When examining a complex image, the eye movements of expert observers differ from those of novices; experts have learned to ignore features that are visually salient but are not relevant to the interpretation of the image. We have studied the neural basis of this form of perceptual-motor learning using monkeys that have learned to search for a visual target among distractors. Monkeys trained to search only for, say, a red stimulus among green distractors will ignore green stimuli even if they subsequently appear as targets in a complementary search array, that is, among red distractors. We recorded from neurons in the frontal eye field (FEF), a cortical area that responds to visual stimuli and controls purposive eye movements. Normally, FEF neurons do not exhibit feature selectivity, but their activity evolves to signal the target for an incipient eye movement. In monkeys trained exclusively on targets of one colour, however, FEF neurons show selectivity for stimuli of that colour. Because this selective response occurs so soon after presentation of the stimulus array, and is independent of location within the visual field, we propose that it reflects a form of experience-dependent plasticity that mediates the learning of arbitrary stimulus-response associations.

Freedman, D. J., M. Riesenhuber, T. Poggio, and E. K. Miller. "Categorical representation of visual stimuli in the primate prefrontal cortex." Science. 291, 5502, 12 Jan. 2001, 312-6.

PubMed abstract: The ability to group stimuli into meaningful categories is a fundamental cognitive process. To explore its neural basis, we trained monkeys to categorize computer-generated stimuli as "cats" and "dogs." A morphing system was used to systematically vary stimulus shape and precisely define the category boundary. Neural activity in the lateral prefrontal cortex reflected the category of visual stimuli, even when a monkey was retrained with the stimuli assigned to new categories.

Developmental Plasticity in the Somatosensory System

Allard, T., S. A. Clark, W. M. Jenkins, and M. M. Merzenich. "Reorganization of somatosensory area 3b representations in adult owl monkeys after digital syndactyly." J Neurophysiol. 66, 3, Sep. 1991, 1048-58.

PubMed abstract: These experiments were designed to test the hypothesis that temporally correlated afferent input activity plays a lifelong role in the establishment and modification of receptive fields (RFs) and representational topographies in the primary somatosensory cortex of adult monkeys. They were based in part on the finding that adjacent digits of the hand are represented discontinuously in area 3b of the adult owl monkey. If cortical receptive fields and the details of cortical topographic representations are shaped by the weights of the temporal correlations among afferent inputs, then representational discontinuities between digits would be expected to arise because inputs from the skin surfaces of adjacent digits are largely independent in the critical time domain. 2. In the present experiments, the skin of adjacent digits 3 and 4 of the monkey hand was surgically connected to create an artificial syndactyly, or webbed-finger condition. Highly detailed microelectrode maps of the cortical representation of the syndactyl digits were obtained 3-7.5 mo later. This experimental manipulation greatly increased the amount of simultaneous or nearly simultaneous input from the normally separated, now fused, surfaces of adjacent fingers. 3. Cortical maps of the representations of finger surfaces were highly modified from the normal after a several-month-long period of digital fusion. Specifically, the normal discontinuity between the cortical representations of adjacent fingers was abolished. Within a wide cortical zone, RFs were defined that extended across the line of syndactyly onto the surgically joined skin of both fused digits. The representational topography of the fused digits was similar to any normal single digit and was characterized by a continuous progression of partially overlapping RFs. 4. Control observations revealed that these reorganizational changes cannot be accounted for by any changes in cutaneous innervation induced by the surgery. They must arise from representational changes in the central somatosensory system. 5. These findings reveal that cortical maps can be altered in detail in adult monkeys by modifying the distributed temporal structure of afferent inputs. They support the longstanding hypothesis that the temporal coincidence of inputs plays a role in the grouping of input subsets into specific cortical RFs and, consequently, in the shaping of selected effective cortical inputs and representational topographies throughout life.

Steinmetz, P. N., A. Roy, P. J. Fitzgerald, S. S. Hsiao, K. O. Johnson, and E. Niebur. "Attention modulates synchronized neuronal firing in primate somatosensory cortex." Nature. 404, 6774, 9 Mar. 2000, 187-90.

PubMed abstract: A potentially powerful information processing strategy in the brain is to take advantage of the temporal structure of neuronal spike trains. An increase in synchrony within the neural representation of an object or location increases the efficacy of that neural representation at the next synaptic stage in the brain; thus, increasing synchrony is a candidate for the neural correlate of attentional selection. We investigated the synchronous firing of pairs of neurons in the secondary somatosensory cortex (SII) of three monkeys trained to switch attention between a visual task and a tactile discrimination task. We found that most neuron pairs in SII cortex fired synchronously and, furthermore, that the degree of synchrony was affected by the monkey's attentional state. In the monkey performing the most difficult task, 35% of neuron pairs that fired synchronously changed their degree of synchrony when the monkey switched attention between the tactile and visual tasks. Synchrony increased in 80% and decreased in 20% of neuron pairs affected by attention.

Developing Plasticity in the Visual System

Frank, M. G., N. P. Issa, and M. P. Stryker. "Sleep enhances plasticity in the developing visual cortex." Neuron. 30, 1, Apr. 2001, 275-87.

PubMed abstract: During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.

Huh, G. S., L. M. Boulanger, H. Du, P. A. Riquelme, T. M. Brotz, and C. J. Shatz. "Functional requirement for class I MHC in CNS development and plasticity." Science. 290, 5499, 15 Dec. 2000, 2155-9.

PubMed abstract: Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).