Stable, long-term, spatial memory in young and aged rats achieved with a one day Morris water maze training protocol.

Here, we present data demonstrating that a 1 d Morris water maze training protocol is effective at producing stable, long-term spatial memory in both young (3 mo old) and aged (24 mo old) F344xBN rats. Four trials in each of four sessions separated by a 2.5 h ISI produced robust selective search for the platform 1 and 4 d after training, in both age groups. A 1 h ISI protocol did not produce good retention. Also, compressing the trials into just two sessions separated by a 2.5 h ISI produced limited retention in only young rats.

Variation in the persistence of memory: An interplay between actin dynamics and AMPA receptors.

William James noted that memories could persist from minutes to weeks. This essay attempts to explain this variation by situating the explanation in the biochemistry of dendritic spines. Two outcomes are critical to generate the synaptic basis of memory: (1) the actin cytoskeleton in the spine must be degraded to permit (2) additional AMPA receptors (GluA1s) to enter new "hot spots" in the postsynaptic density. These initial outcomes can support short-lasting memories. The threshold for these events is low but the underlying synaptic changes cannot resist the endocytic processes that remove the added AMPA receptors. For the memory to persist the degraded actin cytoskeleton must be rebuilt and the vacated "hot spots" refilled with GluA2 receptors. A primary claim is that it is the stabilization of an enlarged actin cytoskeleton that is the target outcome that consolidates the synaptic basis of memory (see Lynch et al., 2007). The stabilized actin cytoskeleton has properties that enable it to garner the synaptic proteins it needs to self sustain the potentiated state and to benefit from activation of memory modulation systems. This article is part of a Special Issue entitled Brain and Memory.

Actin dynamics and the evolution of the memory trace.

The goal of this essay is to link the regulation of actin dynamics to the idea that the synaptic changes that support long-term potentiation and memory evolve in temporally overlapping stages-generation, stabilization, and consolidation. Different cellular/molecular processes operate at each stage to change the spine cytoarchitecture and, in doing so, alter its function. Calcium-dependent processes that degrade the actin cytoskeleton network promote a rapid insertion of AMPA receptors into the post synaptic density, which increases a spine's capacity to express a potentiated response to glutamate. Other post-translation events then begin to stabilize and expand the actin cytoskeleton by increasing the filament actin content of the spine and reorganizing it to be resistant to depolymerizing events. Disrupting actin polymerization during this stabilization period is a terminal event-the actin cytoskeleton shrinks and potentiated synapses de-potentiate and memories are lost. Late-arriving, new proteins may consolidate changes in the actin cytoskeleton. However, to do so requires a stabilized actin cytoskeleton. The now enlarged spine has properties that enable it to capture other newly transcribed mRNAs or their protein products and thus enable the synaptic changes that support LTP and memory to be consolidated and maintained. This article is part of a Special Issue entitled SI: Brain and Memory.

Inhibiting PKMζ reveals dorsal lateral and dorsal medial striatum store the different memories needed to support adaptive behavior.

Evidence suggests that two regions of the striatum contribute differential support to instrumental response selection. The dorsomedial striatum (DMS) is thought to support expectancy-mediated actions, and the dorsolateral striatum (DLS) is thought to support habits. Currently it is unclear whether these regions store task-relevant information or just coordinate the learning and retention of these solutions by other brain regions. To address this issue, we developed a two-lever concurrent variable-interval reinforcement operant conditioning task and used it to assess the trained rat's sensitivity to contingency shifts. Consistent with the view that these two regions make different contributions to actions and habits, injecting the NMDA antagonist DL-AP5 into the DMS just prior to the shift impaired the rat's performance but enhanced performance when injected into the DLS. To determine if these regions support memory content, we first trained rats on a biased concurrent schedule (Lever 1: VI 40" and Lever 2: VI 10"). With the intent of "erasing" the memory content stored in striatum, after this training we inhibited the putative memory-maintenance protein kinase C isozyme protein kinase Mζ (PKMζ). Infusing zeta inhibitory peptide (ZIP) into the DLS enhanced the rat's ability to adapt to the contingency shift 2 d later, whereas injecting it into the DMS had the opposite effect. Infusing GluR2(3Y) into the DMS 1 h before ZIP infusions prevented ZIP from impairing the rat's sensitivity to the contingency shift. These results support the hypothesis that the DMS stores information needed to support actions and the DLS stores information needed to support habits.

Acute neuroimmune modulation attenuates the development of anxiety-like freezing behavior in an animal model of traumatic brain injury.

Chronic anxiety is a common and debilitating result of traumatic brain injury (TBI) in humans. While little is known about the neural mechanisms of this disorder, inflammation resulting from activation of the brain's immune response to insult has been implicated in both human post-traumatic anxiety and in recently developed animal models. In this study, we used a lateral fluid percussion injury (LFPI) model of TBI in the rat and examined freezing behavior as a measure of post-traumatic anxiety. We found that LFPI produced anxiety-like freezing behavior accompanied by increased reactive gliosis (reflecting neuroimmune inflammatory responses) in key brain structures associated with anxiety: the amygdala, insula, and hippocampus. Acute peri-injury administration of ibudilast (MN166), a glial cell activation inhibitor, suppressed both reactive gliosis and freezing behavior, and continued neuroprotective effects were apparent several months post-injury. These results support the conclusion that inflammation produced by neuroimmune responses to TBI play a role in post-traumatic anxiety, and that acute suppression of injury-induced glial cell activation may have promise for the prevention of post-traumatic anxiety in humans.

Post-conditioning experience with acute or chronic inflammatory pain reduces contextual fear conditioning in the rat.

There is evidence that pain can impact cognitive function in people. The present study evaluated whether Pavlovian fear conditioning in rats would be reduced if conditioning were followed by persistent inflammatory pain induced by a subcutaneous injection of dilute formalin or complete Freund's adjuvant (CFA) on the dorsal lumbar surface of the back. Formalin-induced pain specifically impaired contextual fear conditioning but not auditory cue conditioning (Experiment 1A). Moreover, formalin pain only impaired contextual fear conditioning if it was initiated within 1h of conditioning and did not have a significant effect if initiated 2, 8 or 32 h after (Experiments 1A and 1B). Experiment 2 showed that formalin pain initiated after a session of context pre-exposure reduced the ability of that pre-exposure to facilitate contextual fear when the rat was limited to a brief exposure to the context during conditioning. Similar impairments in context- but not CS-fear conditioning were also observed if the rats received an immediate post-conditioning injection with CFA (Experiment 3). Finally, we confirmed that formalin and CFA injected s.c. on the back induced pain-indicative behaviours, hyperalgesia and allodynia with a similar timecourse to intraplantar injections (Experiment 4). These results suggest that persistent pain impairs learning in a hippocampus-dependent task, and may disrupt processes that encode experiences into long-term memory.

Activation of the infralimbic cortex in a fear context enhances extinction learning.

Activation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) reduces conditioned fear in a variety of situations, and the IL is thought to play an important role in the extinction of conditioned fear. Here we report a series of experiments using contextual fear conditioning in which the IL is activated with the GABAa antagonist picrotoxin (Ptx) during a single extinction session in the fear context. We investigate the impact of this manipulation on subsequent extinction sessions in which Ptx is no longer present. First, we demonstrate that a single treatment with intra-IL Ptx administered in a conditioned fear context greatly accelerates the rate of extinction on the following days. Importantly, IL-Ptx also enhances extinction to a different fear context than the one in which IL-Ptx was administered. Thus, IL-Ptx primes extinction learning regardless of the fear context in which the IL was initially activated. Second, activation of the IL must occur in conjunction with a fear context in order to enhance extinction; the extinction enhancing effect is not observable if IL-Ptx is administered in a neutral context. Finally, this extinction enhancing effect is specific to the IL for it does not occur if Ptx is injected into the prelimbic region (PL) of the mPFC. The results indicate a novel persisting control of fear induced by activation of the IL and suggest that IL activation induces changes in extinction-related circuitry that prime extinction learning.

Context representations, context functions, and the parahippocampal-hippocampal system.

Psychologists and neurobiologists have a long-standing interest in understanding how the context surrounding the events of our lives is represented and how it influences our behavior. The hippocampal formation emerged very early as a major contributor to how context is represented and functions. There is a large literature examining its contribution that on the surface reveals an array of conflicting outcomes and controversy. This review reveals that these conflicts can be resolved by building Nadel and Willner's dual-process theory of context representations. Two general conclusions emerge: (1) There are two neural systems that can support context representations and functions-a neocortical system composed primarily of perirhinal and postrhinal cortices and a hippocampal system that includes perirhinal, postrhinal, entorhinal cortices, and the hippocampal formation. (2) These two systems are not equivalent-some context representations and functions are uniquely supported by the hippocampal system. These conclusions are discussed in the context of canonical ideas about the special properties of the hippocampal system that enable it to make unique contributions to memory.

DHPG activation of group 1 mGluRs in BLA enhances fear conditioning.

Group 1 metabotropic glutamate receptors are known to play an important role in both synaptic plasticity and memory. We show that activating these receptors prior to fear conditioning by infusing the group 1 mGluR agonist, (R.S.)-3,5-dihydroxyphenylglycine (DHPG), into the basolateral region of the amygdala (BLA) of adult Sprague-Dawley rats enhances freezing normally supported by a weak footshock. This effect of DHPG was blocked when it was co-infused with either the general group 1 mGluR1 antagonist, (R,S)-1-aminoindan-1,5 dicarboxylic acid (AIDA), or with the selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). These results support previous findings by Rodrigues and colleagues that mGluR5s in the lateral region of the amygdala make an import contribution to fear conditioning. More importantly, they support the general ideas embedded in the concept of metaplasticity, as per Abraham, and the synaptic-tagging hypothesis per Frey and Morris-that the processes that specify the content of experience can be experimentally separated from those needed to acquire the memory.

Characterization of the sickness response in young and aging rats following E. coli infection.

To more fully characterize the sickness response in young (3 mo) and older (24 mo) rats, we measured core body temperature (CBT), activity level, and body weight changes for 7 days following a peripheral immune challenge with Escherichia coli. CBT increases were delayed and blunted during the 12h following infection in older rats. Indeed, in aging subjects the initial response was hypothermia, but this was followed by a significant and prolonged elevation in CBT lasting 3 days. Young rats, in contrast, generated a rapid and robust CBT elevation lasting just over a day. Activity level was significantly reduced only on the day of E. coli administration in both young and older rats. Body weight loss was equivalent in both age groups one day after E. coli administration, although there was a trend for older rats to continue losing more weight across the next 6 days than in young rats. This is the first study to examine CBTs in young and older rats for a protracted amount of time, thereby revealing that aging rats do have an exaggerated, albeit delayed, fever which is in keeping with other exaggerated sickness behavioral responses observed in aging rodents.

Hippocampal and extrahippocampal systems compete for control of contextual fear: role of ventral subiculum and amygdala.

Two neural systems, a hippocampal system and an extrahippocampal system compete for control over contextual fear, and the hippocampal system normally dominates. Our experiments reveal that output provided by the ventral subiculum is critical for the hippocampal system to win this competition. Bilateral electrolytic lesions of the ventral subiculum after conditioning, but not before conditioning, impaired contextual fear conditioning. Reversibly inactivating this region by bilateral injections of muscimol produced the same results-no impairment when the injection occurred prior to conditioning but a significant impairment when this region was inactivated after conditioning. Thus, the extrahippocampal system can support contextual fear conditioning if the ventral subiculum is disabled before conditioning but not if it is disabled after conditioning. Our experiments also reveal that the basolateral region of the amygdala (BLA) is where the two systems compete for associative control of the fear system. To test this hypothesis we reasoned that the extrahippocampal system would also acquire associative control over the fear system, even if the hippocampal system were functional, if the basal level of plasticity potential in the BLA could be increased. We did this by injecting the D1 dopamine agonist, SKF82958, into the BLA just prior to conditioning. This treatment resulted in a significant increase in freezing when the ventral subiculum was disabled prior to the test. These results are discussed in relationship to the idea that D1 agonists increase plasticity potential by increasing the pool of available extrasynaptic GluR1 receptors in the population of neurons supporting acquired fear.

Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection.

We previously reported that aging F344XBN rats are more vulnerable to disruptions of memory consolidation processes following an injection of Escherichia coli than are young rats. Furthermore, this disruption was specific to hippocampal-dependent memory. In the present study we examined the time course of the proinflammatory cytokine IL-1 beta in young and old rats following a peripheral injection of E. coli. Compared to young rats, aging rats treated with E. coli showed an exaggerated and prolonged up-regulation of IL-1 beta protein in the hippocampus, but not in hypothalamus, parietal cortex, prefrontal cortex, serum or spleen. Aging rats showed greater hippocampal IL-1 beta protein levels than their young counterparts 4h after E. coli, and these levels remained significantly elevated for 8 but not 14 days after E. coli. In a second experiment, aging rats exhibited anterograde memory consolidation impairments 4 and 8 days after an E. coli injection, but not after 14 days. A third experiment revealed that following an E. coli injection, bacterial clearance from the spleen and peritoneum was not impaired in aged rats, suggesting that elevations in hippocampal IL-1 beta were not mediated by impaired clearance in the periphery in aging rats. These data suggest that the exaggerated and prolonged elevation of IL-1 beta, specifically in the hippocampus, may be responsible for hippocampal-dependent memory impairments observed in aging rats following a bacterial infection.

PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMzeta), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMzeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMzeta activity. We then examined, using ZIP, the effect of PKMzeta inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMzeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMzeta activity. Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMzeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMzeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMzeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.

The role of the dorsal striatum and dorsal hippocampus in probabilistic and deterministic odor discrimination tasks.

Three experiments explored the contribution of the cortico-striatal system and the hippocampus system to the acquisition of solutions to simultaneous instrumental odor discriminations. Inactivation of the dorsal striatum after rats had reached criterion on a three problem probabilistic set of discriminations--A (80%) vs. B (20%), C (67%) vs. D (33%), E(67%) vs. F(33%)--impaired test performance and disrupted performance when the rats were tested with novel cue combinations (C vs. F and E vs. D), where control animals chose C and F. In contrast, inactivating the dorsal hippocampus enhanced performance on this task and on a deterministic discrimination A (100%) vs. B (0%). These results are consistent with the complementary learning systems view, which assumes that the cortico-striatal and hippocampal system capture information in parallel. How this information combines to influence task performance depends on the compatibility of the content captured by each system. These results suggest that the trial-specific information captured by the hippocampal system can be incompatible with the across-trial integration of trial outcomes captured by the cortico-striatal system.

Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood.

Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments following a peripheral immune challenge in adulthood. Here, we determined whether neonatal infection plus an immune challenge in adult rats is associated with impaired induction of brain-derived neurotrophic factor (BDNF) within the hippocampus (CA1, CA3, and dentate gyrus) following fear conditioning. BDNF is well characterized for its critical role in learning and memory. Rats injected on postnatal day 4 with PBS (vehicle) or Escherichia coli received as adults either no conditioning or a single 2min trial of fear conditioning. Half of the rats in the conditioned group then received a peripheral injection of 25mug/kg lipopolysaccharide (LPS) and all were sacrificed 1 or 4h later. Basal (unconditioned) BDNF mRNA did not differ between groups. However, following conditioning, neonatal infection with E. coli led to decreased BDNF mRNA induction in all regions compared to PBS-treated rats. This decrease in E. coli-treated rats was accompanied by a large increase in IL-1beta mRNA in CA1. Taken together, these data indicate that early infection strongly influences the induction of IL-1beta and BDNF within distinct regions of the hippocampus, which likely contribute to observed memory impairments in adulthood.

Is there a baby in the bathwater? Maybe: some methodological issues for the de novo protein synthesis hypothesis.

The de novo protein synthesis hypothesis has a long history and will no doubt continue to influence research. Yet, the primary behavioral evidence for this claim continues to come from studies in which amnesia is produced by broad scale protein synthesis inhibitors such as anisomycin. What is remarkable is the uncritical acceptance of the idea that because anisomycin is a protein synthesis inhibitor then it must have produced amnesia because it prevented translation. Several viable alternative interpretations of such experiments are discussed here and it is concluded that there is nothing to be gained by the continued use of broad-scaled antibiotics to address this hypothesis. Moreover, this approach cannot answer two critical and related questions - why must new proteins be synthesized and what are they? A focus on specific proteins such as those synthesized locally and upregulate the translation of other proteins may be a promising approach to answering these questions.

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear.

The hippocampal indexing theory and episodic memory: updating the index.

A little over 20 years ago, (Teyler and DiScenna,1986; Behav Neurosci 100:147-152) proposed the hippocampal memory index theory. It offered an account of episodic memory based on the intrinsic organization of the hippocampus, its synaptic physiology and its anatomical relationship to other regions of the brain. The essence of their idea was that the hippocampus was functionally designed and anatomically situated to capture information about neocortical activity generated by the individual features of behavioral episode. Moreover, because the hippocampus projects back to these neocortical regions the information it stored could serve as an index to the pattern of neocortical activity produced by the episode. Consequently, a partial cue that activated the index could activate the neocortical patterns and thus retrieve the memory of the episode. In this article we revisit and update indexing theory. Our conclusion is that it has aged very well. Its core ideas can be seen in many contemporary theories and there is a wealth of data that support this conceptual framework.