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The hippocampus is critical for rapid acquisition of many forms of memory, although the circuit-level mechanisms through which the hippocampus rapidly consolidates novel information are unknown. Here, the activity of large ensembles of hippocampal neurons in adult male Long-Evans rats was monitored across a period of rapid spatial learning to assess how the network changes during the initial phases of memory formation and retrieval. In contrast to several reports, the hippocampal network did not display enhanced representation of the goal location via accumulation of place fields or elevated firing rates at the goal. Rather, population activity rates increased globally as a function of experience. These alterations in activity were mirrored in the power of the theta oscillation and in the quality of theta sequences, without preferential encoding of paths to the learned goal location. In contrast, during brief "offline" pauses in movement, representation of a novel goal location emerged rapidly in ripples, preceding other changes in network activity. These data demonstrate that the hippocampal network can facilitate active navigation without enhanced goal representation during periods of active movement, and further indicate that goal representation in hippocampal ripples before movement onset supports subsequent navigation, possibly through activation of downstream cortical networks. [ABSTRACT FROM AUTHOR]

Just as hippocampal lesions are principally responsible for “temporal lobe” amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, “diencephalic” amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology. [ABSTRACT FROM AUTHOR]

Diverse functions such as decision-making and memory consolidation may depend on communication between neurons in the hippocampus (HP) and prefrontal cortex (PFC). HP replay is a candidate mechanism to facilitate this communication, however details remain largely unknown because of the technical challenges of recording sufficient numbers of HP neurons for replay while also recording PFC neurons. Here, we implanted male rats with 40-tetrode drives, split between HP and PFC, during learning of a Y-maze spatial memory task. Surprisingly, we found that in contrast to their non-selectivity for maze arm during movement, a portion of PFC neurons were highly selective for HP replay of different arms. Moreover, PFC neurons' selectivity to HP non-local arm representation during running tended to match their replay arm selectivity and was predictive of future choice. Thus, PFC activity that is tuned to HP activity is best explained by non-local HP position representations rather than HP representation of actual position, providing a new potential mechanism of HP-PFC coordination during HP replay. [ABSTRACT FROM AUTHOR]

Several decades of research have established that different kinds of memories result from the activity of discrete neural networks. Studying how these networks process information in experiments that target specific types of mnemonic representations has provided deep insights into memory architecture and its neural underpinnings. However, in natural settings reality confronts organisms with problems that are not neatly compartmentalized. Thus, a critical problem in memory research that still needs to be addressed is how distinct types of memories are ultimately integrated. Here we demonstrate how two memory networks, the hippocampus and dorsolateral striatum, may accomplish such a goal. The hippocampus supports memory for facts and events, collectively known as declarative memory and often studied as spatial memory in rodents. The dorsolateral striatum provides the basis for habits that are assessed in stimulus-response types of tasks. Expanding previous findings, the current work revealed that in male Long-Evans rats, the hippocampus and dorsolateral striatum use time and space in distinct and largely complementary ways to integrate spatial and habitual representations. Specifically, the hippocampus supported both types of memories when they were formed in temporal juxtaposition, even if the learning took place in different environments. In contrast, the lateral striatum supported both types of memories if they were formed in the same environment, even at temporally distinct points. These results reveal for the first time that by using fundamental aspects of experience in specific ways, the hippocampus and dorsolateral striatum can transcend their attributed roles in information storage. [ABSTRACT FROM AUTHOR]

The hippocampus is a key brain area to encoding and storing memories. Hippocampal place cells encode the position of an animal in space by firing when the subject is at a specific location in the environment. Therefore, place cells are considered essential to spatial memory and navigation. It has recently been revealed that place-cell activity is not constant even in a familiar environment, but changes dynamically over time. However, the mechanism behind these changes in activity is not yet fully understood. In this study, the activity of hippocampal CA1 neurons of male mice was tracked during repeated performances of a spatial task in a virtual reality environment. By comparing place-cell ensemble representations among repeated performance of the task, the overlap rate of the active place-cell population was found to be time dependent but independent of the number of tasks within a fixed time. These findings suggest that place codes change automatically and at a constant speed. Furthermore, the dynamics of place-cell activity were found to be suppressed by an NMDA receptor antagonist. In summary, the spontaneously dynamic nature of place-cell activity is at least in part regulated by NMDA receptors, and the dynamics may encode temporal information of episodes. [ABSTRACT FROM AUTHOR]

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred. [ABSTRACT FROM AUTHOR]

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JNK-interacting protein 1 (JIP1) scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jipl gene that selectively blocks JlPl-mediated JNK activation. These male mutant mice exhibited increased NMDAR currents, increased NMDAR-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse model that suppresses JNK activity. Together, these observations establish that JIP1 -mediated JNK activation contributes to the regulation of hippocampus-dependent, NMDAR-mediated synaptic plasticity and learning. [ABSTRACT FROM AUTHOR]

The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip-mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields. [ABSTRACT FROM AUTHOR]

The hippocampal and striatal memory systems are thought to operate independently and in parallel in supporting cognitive memory and habits, respectively. Much of the evidence for this principle comes from double dissociation data, in which damage to brain structure A causes deficits in Task 1 but not Task 2, whereas damage to structure B produces the reverse pattern of effects. Typically, animals are explicitly trained in one task. Here, we investigated whether this principle continues to hold when animals concurrently learn two types of tasks. Rats were trained on a plus maze in either a spatial navigation or a cue-response task (sequential training), whereas a third set of rats acquired both (concurrent training). Subsequently, the rats underwent either sham surgery or neurotoxic lesions of the hippocampus (HPC), medial dorsal striatum (DSM), or lateral dorsal striatum (DSL), followed by retention testing. Finally, rats in the sequential training condition also acquired the novel "other" task. When rats learned one task, HPC and DSL selectively supported spatial navigation and cue response, respectively. However, when rats learned both tasks, HPC and DSL additionally supported the behavior incongruent with the processing style of the corresponding memory system. Thus, in certain conditions, the hippocampal and striatal memory systems can operate cooperatively and in synergism. DSM significantly contributed to performance regardless of task or training procedure. Experience with the cue-response task facilitated subsequent spatial learning, whereas experience with spatial navigation delayed both concurrent and subsequent response learning. These findings suggest that there are multiple operational principles that govern memory networks. [ABSTRACT FROM AUTHOR]

Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (~70 ms) high-frequency oscillatory events generated in the hippocampus and are associated with the consolidation of spatial memories. Given the connection between ripple oscillations and memory consolidation, we investigated whether the structure of ripple oscillations and ripple-triggered patterns of single-unit activity are altered in aged rats. Local field and single-unit activity surrounding sharp-wave ripple events were examined in the CA1 region of the hippocampus of old (n = 5) and young (n = 6) F344 rats during periods of rest preceding and following performance on a place-dependent eyeblink-conditioning task. Neural responses in aged rats differed from responses in young rats in several ways. First, compared with young rats, the rate of ripple occurrence (ripple density) is reduced in aged rats during postbehavior rest. Second, mean ripple frequency during prebehavior and postbehavior rest is lower in aged animals (aged: 132 Hz; young: 146 Hz). Third, single neurons in aged animals responded more consistently from ripple to ripple. Fourth, variability in interspike intervals was greater in aged rats. Finally, neurons were tuned to a narrower range of phases of the ripple oscillation relative to young animals. Together, these results suggest that the CA1 network in aged animals has a reduced "vocabulary" of available representational states. [ABSTRACT FROM AUTHOR]

During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9-/- adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9-/- mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors. [ABSTRACT FROM AUTHOR]

The perirhinal cortex (PRC) is reportedly important for object recognition memory, with supporting physiological evidence obtained largely from primate studies. Whether neurons in the rodent PRC also exhibit similar physiological correlates of object recognition, however, remains to be determined. We recorded single units from the PRC in a PRC-dependent, object-cued spatial choice task in which, when cued by an object image, the rat chose the associated spatial target from two identical discs appearing on a touchscreen monitor. The firing rates of PRC neurons were significantly modulated by critical events in the task, such as object sampling and choice response. Neuronal firing in the PRC was correlated primarily with the conjunctive relationships between an object and its associated choice response, although some neurons also responded to the choice response alone. However, we rarely observed a PRC neuron that represented a specific object exclusively regardless of spatial response in rats, although the neurons were influenced by the perceptual ambiguity of the object at the population level. Some PRC neurons fired maximally after a choice response, and this post-choice feedback signal significantly enhanced the neuronal specificity for the choice response in the subsequent trial. Our findings suggest that neurons in the rat PRC may not participate exclusively in object recognition memory but that their activity may be more dynamically modulated in conjunction with other variables, such as choice response and its outcomes. [ABSTRACT FROM AUTHOR]

Hippocampal sharp wave-ripples (SPW-Rs) and associated place-cell reactivations are crucial for spatial memory consolidation during sleep and rest. However, it remains unclear how learning and consolidation requirements influence and regulate subsequent SPW-R activity. Indeed, SPW-R activity has been observed not only following complex behavioral tasks, but also after random foraging in familiar environments, despite markedly different learning requirements. Because transient increases in SPW-R rates have been reported following training on memory tasks, we hypothesized that SPW-R activity following learning (but not routine behavior) could involve specific regulatory processes related to ongoing consolidation. Interfering with ripples would then result in a dynamic compensatory response only when initial memory traces required consolidation. Here we trained rats on a spatial memory task, and showed that subsequent sleep periods where ripple activity was perturbed by timed electrical stimulation were indeed characterized by increased SPW-R occurrence rates compared with control sleep periods where stimulations were slightly delayed in time and did not interfere with ripples. Importantly, this did not occur following random foraging in a familiar environment. We next showed that this dynamic response was abolished following injection of an NMDA receptor blocker (MK-801) before, but not after training. Our results indicate that NMDA receptor-dependent processes occurring during learning, such as network "tagging" and plastic changes, regulate subsequent ripplemediated consolidation of spatial memory during sleep. [ABSTRACT FROM AUTHOR]

Chronic pain patients commonly complain of working memory deficits, but the mechanisms and brain areas underlying this cognitive impairment remain elusive. The neuronal populations of the mPFC and dorsal CAI (dCA1) are well known to form an interconnected neural circuit that is crucial for correct performance in spatial memory-dependent tasks. In this study, we investigated whether the functional connectivity between these two areas is affected by the onset of an animal model of peripheral neuropathic pain. To address this issue, we implanted two multichannel arrays of electrodes in the mPFC and dCA 1 of rats and recorded the neuronal activity during a food-reinforced spatial working memory task in a reward-based alternate trajectory maze. Recordings were performed for 3 weeks, before and after the establishment of the spared nerve injury model of neuropathy. Our results show that the nerve lesion caused an impairment of working memory performance that is temporally associated with changes in the mPFC populational firing activity patterns when the animals navigated between decision points--when memory retention was most needed. Moreover, the activity of both recorded neuronal populations after the nerve injury increased their phase locking with respect to hippocampal theta rhythm. Finally, our data revealed that chronic pain reduces the overall amount of information flowing in the fronto-hippocampal circuit and induces the emergence of different oscillation patterns that are well correlated with the correct/incorrect performance of the animal on a trial-by-trial basis. The present results demonstrate that functional disturbances in the fronto-hippocampal connectivity are a relevant cause for pain-related working memory deficits. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channel-la (ASICla) is localized in brain regions with high synaptic density and is thought to contribute to synaptic plasticity, learning, and memory. A prominent hypothesis is that activation of postsynaptic ASICs promotes depolarization, thereby augmenting JV-methyl-D-aspartate receptor function and contributing to the induction of long-term potentiation (LTP). However, evi-dence for activation of postsynaptic ASICs during neurotransmission has not been established. Here, we re-examined the role of ASICla in LTP in the hippocampus using pharmacological and genetic approaches. Our results showed that a tarantula peptide psalmotoxin, which profoundly blocked ASIC currents in the hippocampal neurons, had no effect on LTP. Similarly, normal LTP was robustly gener-ated in ASICla-null mice. A further behavioral analysis showed that mice lacking ASICla had normal performance in hippocampus-dependent spatial memory. In summary, our results indicate that ASICla is not required for hippocampal LTP and spatial memory. We therefore propose that the role of ASICla in LTP and spatial learning should be reassessed. [ABSTRACT FROM AUTHOR]

The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups:500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks. [ABSTRACT FROM AUTHOR]

Successful spatial navigation is thought to employ a combination of at least two strategies: the following of landmark cues and path integration. Path integration requires that the brain use the speed and direction of movement in a meaningful way to continuously compute the position of the animal. Indeed, the running speed of rats modulates both the firing rate of neurons and the spectral properties of low frequency, theta oscillations seen in the local field potential (LFP) of the hippocampus, a region important for spatial memory formation. Higher frequency, gamma-band LFP oscillations are usually associated with decision-making, increased attention, and improved reaction times. Here, we show that increased running speed is accompanied by large, systematic increases in the frequency of hippocampal CA1 network oscillations spanning the entire gamma range (30 -120 Hz) and beyond. These speed-dependent changes in frequency are seen on both linear tracks and two-dimensional platforms, and are thus independent of the behavioral task. Synchrony between anatomically distant CA1 regions also shifts to higher gamma frequencies as running speed increases. The changes in frequency are strongly correlated with changes in the firing rates of individual interneurons, consistent with models of gamma generation. Our results suggest that as a rat runs faster, there are faster gamma frequency transitions between sequential place cell-assemblies. This may help to preserve the spatial specificity of place cells and spatial memories at vastly different running speeds. [ABSTRACT FROM AUTHOR]

The authors reflect on an article regarding the significant step toward addressing whether hippocampal and dorsal striatal contributions are necessary and sufficient in supporting boundary-based and landmark-based allocentric spatial memory. The relationship between memory errors and volume of the dorsal striatum thalamus and nucleus accumbens is tackled. The hippocampal dysfunction that affects scene representations and the allocentric relations between non-scene stimuli are explored.

The hippocampus provides a spatial map of the environment. Changes in the environment alter the firing patterns of hippocampal neurons, but are presumably constrained by elements of the network dynamics. We compared the neural activity in CA1 and CA3 regions of the hippocampus in rats running for water reward on a linear track, before and after the track length was shortened. A fraction of cells lost their place fields and new sets of cells with fields emerged, indicating distinct representation of the two tracks. Cells active in both environments shifted their place fields in a location-dependent manner, most notably at the beginning and the end of the track. Furthermore, peak firing rates and place-field sizes decreased, whereas place-field overlap and coactivity increased. Power in the theta-frequency band of the local field potentials also decreased in both CA1 and CA3, along with the coherence between the two structures. In contrast, the theta-scale (0 -150 ms) time lags between cell pairs, representing distances on the tracks, were conserved, and the activity of the inhibitory neuron population was maintained across environments. We interpret these observations as reflecting the freedoms and constraints of the hippocampal network dynamics. The freedoms permit the necessary flexibility for the network to distinctly represent unique patterns, whereas the dynamics constrain the speed at which activity propagates between the cell assemblies representing the patterns. [ABSTRACT FROM AUTHOR]

In humans, recognition memory declines with aging, and this impairment is characterized by a selective loss in recollection of previously studied items contrasted with relative sparing of familiarity for items in the study list. Rodent models of cognitive aging have focused on water maze learning and have demonstrated an age-associated loss in spatial, but not cued memory. The current study examined odor recognition memory in young and aged rats and compared performance in recognition with that in water maze learning. In the recognition task, young rats used both recollection and familiarity. In contrast, the aged rats showed a selective loss of recollection and relative sparing of familiarity, similar to the effects of hippocampal damage. Furthermore, performance on the recall component, but not the familiarity component, of recognition was correlated with spatial memory and recollection was poorer in aged rats that were also impaired in spatial memory. These results extend the pattern of impairment in recollection and relative sparing of familiarity observed in human cognitive aging to rats, and suggest a common age-related impairment in both spatial learning and the recollective component of nonspatial recognition memory. [ABSTRACT FROM AUTHOR]

The hippocampus and parahippocampal cortices exhibit theta oscillations during spatial navigation in animals and humans, and in the former are thought to mediate spatial memory formation. Functional specificity of human hippocampal theta, however, is unclear. Neuromagnetic activity was recorded with a whole-head 275-channel magnetoencephalographic (MEG) system as healthy participants navigated to a hidden platform in a virtual reality Morris water maze. MEG data were analyzed for underlying oscillatory sources in the 4-8 Hz band using a spatial filtering technique (i.e., synthetic aperture magnetometry). Source analyses revealed greater theta activity in the left anterior hippocampus and parahippocampal cortices during goal-directed navigation relative to aimless movements in a sensorimotor control condition. Additional analyses showed that left anterior hippocampal activity was predominantly observed during the first one-half of training, pointing to a role for this region in early learning. Moreover, posterior hippocampal theta was highly correlated with navigation performance, with the former accounting for 76% of the variance of the latter. Our findings suggest human spatial learning is dependent on hippocampal and parahippocampal theta oscillations, extending to humans a significant body of research demonstrating such a pivotal role for hippocampal theta in animal navigation. [ABSTRACT FROM AUTHOR]

Brain circuits involved in pattern completion, or retrieval of memory from fragmented cues, were investigated. Using different versions of the Morris water maze, we explored the roles of the CA3 subregion of the hippocampus and the medial prefrontal cortex (mPFC) in spatial memory retrieval under various conditions. In a hidden platform task, both CA3 and mPFC lesions disrupted memory retrieval under partial-cue, but not under full-cue, conditions. For a delayed matching-to-place task, CA3 lesions produced a deficit in both forming and recalling spatial working memory regardless of extramaze cue conditions. In contrast, damage to mPFC impaired memory retrieval only when a fraction of cues was available. To corroborate the lesion study, we examined the expression of the immediate early gene c-fos in mPFC and the hippocampus. After training of spatial reference memory in full-cue conditions for 6 d, the same training procedure in the absence of all cues except one increased the number of Fos-immunoreactive cells inmPFC and CA3. Furthermore, mPFC inactivation with muscimol, a GABA agonist, blocked memory retrieval in the degraded-cue environment. However, mPFC-lesioned animals initially trained in a single-cue environment had no difficulty in retrieving spatial memory when the number of cues was increased, demonstrating that contextual change per se did not impair the behavioral performance of the mPFC-lesioned animals. Together, these findings strongly suggest that pattern completion requires interactions between mPFC and the hippocampus, in which mPFC plays significant roles in retrieving spatial information maintained in the hippocampus for efficient navigation. [ABSTRACT FROM AUTHOR]

Studies of hippocampal long-term potentiation (LTP), a cellular model of memory storage, implicate cAMP-dependent protein kinase (PKA) in presynaptic and postsynaptic mechanisms of LTP. The anchoring of PKA to AKAPs (A kinase-anchoring proteins) creates compartmentalized pools of PKA, but the roles of presynaptically and postsynaptically anchored forms of PKA in late-phase LTP are unclear. In this study, we have created genetically modified mice that conditionally express Ht31, an inhibitor ofPKAanchoring, to probe the roles of anchored PKA in hippocampal LTP and spatial memory. Our findings show that at hippocampal Schaffer collateral CA3--CA1 synapses, theta-burst LTP requires presynaptically anchored PKA. In addition, a pool of anchored PKA in hippocampal area CA3 is required for spatial memory. These findings reveal a novel and significant role for anchored PKA signaling in cellular mechanisms underlying memory storage. [ABSTRACT FROM AUTHOR]

Young healthy participants spontaneously use different strategies in a virtual radial maze, an adaptation of a task typically used with rodents. Functional magnetic resonance imaging confirmed previously that people who used spatial memory strategies showed increased activity in the hippocampus, whereas response strategies were associated with activity in the caudate nucleus. Here, voxel based morphometry was used to identify brain regions covarying with the navigational strategies used by individuals. Results showed that spatial learners had significantly more gray matter in the hippocampus and less gray matter in the caudate nucleus compared with response learners. Furthermore, the gray matter in the hippocampus was negatively correlated to the gray matter in the caudate nucleus, suggesting a competitive interaction between these two brain areas. In a second analysis, the gray matter of regions known to be anatomically connected to the hippocampus, such as the amygdala, parahippocampal, perirhinal, entorhinal and orbitofrontal cortices were shown to covary with gray matter in the hippocampus. Because low gray matter in the hippocampus is a risk factor for Alzheimer's disease, these results have important implications for intervention programs that aim at functional recovery in these brain areas. In addition, these data suggest that spatial strategies may provide protective effects against degeneration of the hippocampus that occurs with normal aging. [ABSTRACT FROM AUTHOR]

Path integration, the ability to sense self-motion for keeping track of changes in orientation and position, constitutes a fundamental mechanism of spatial navigation and a keystone for the development of cognitive maps. Whereas animal path integration is predominantly supported by the head-direction, grid, and place cell systems, the neural foundations are not well understood in humans. Here we used functional magnetic resonance imaging and a virtual rendition of a triangle completion paradigm to test whether human path integration recruits a cortical system similar to that of rodents and nonhuman primates. Participants traveled along two legs of a triangle before pointing toward the starting location. In accordance with animal models, stronger right hippocampal activation predicted more accurate updating of the starting location on a trial-by-trial basis. Moreover, between-subjects fluctuations in response consistency were negatively correlated with bilateral hippocampal and medial prefrontal activation, and bilateral recruitment of the human motion complex (hMT+) covaried with individual path integration capability. Given that these effects were absent in a perceptual control task, the present study provides the first evidence that visual path integration is related to the dynamic interplay of self-motion processing in hMT+, higher-level spatial processes in the hippocampus, and spatial working memory in medial prefrontal cortex. [ABSTRACT FROM AUTHOR]

Place cells in hippocampal area CA1 are essential for spatial learning and memory. Here, we examine whether daily exposure to a previously unexplored environment can alter place cell properties. We demonstrate two previously unreported slowly developing plasticities in mouse place fields: both the spatial tuning and the trial-to-trial reproducibility of CA1 place fields improve over days. We asked whether these two components of improved spatial coding rely on the α-isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) autophosphorylation, an effector mechanism of NMDA receptor-dependent long-term potentiation and an essential molecular process for spatial memory formation. We show that, in mice with deficient autophosphorylation of αCaMKII, the spatial tuning of place fields is initially similar to that of wild-type mice, but completely fails to show the experience-dependent increase over days. In contrast, place field reproducibility in the mutants, although impaired, does show the experience-dependent increase over days. Consequently, the progressive improvement in spatial coding in new hippocampal place cell maps depends on the existence of two molecularly dissociable, experience-dependent processes. [ABSTRACT FROM AUTHOR]

The tuberous sclerosis complex--mammalian target of rapamycin (TSC--mTOR) cascade integrates growth factor and nutritional signals to regulate the synthesis of specific proteins. Because both growth factor signaling and glucose have been implicated in memory formation, we questioned whether mTOR activity is required for long-term spatial memory formation and whether this cascade is involved in the memory-augmenting effect of centrally applied glucose. To test our hypothesis, we directly administered rapamycin (an inhibitor of mTOR), glucose, 5-aminoimidazole-4-carboxamide-1β-4-ribonucleoside (AICAR; an activator of AMP kinase), or glucose plus rapamycin into the dorsal hippocampus after we trained rats in the Morris water maze task. The results from these studies indicate that glucose enhances, where as AICAR and rapamycin both impair, long-term spatial memory. Furthermore, the memory-impairing effect of targeted rapamycin administration could not be overcome by coadministration of glucose. Consistent with these behavioral results, biochemical analysis revealed that glucose and AICAR had opposing influences on the activation of the TSC--mTOR cascade, as indicated by the phosphorylation of ribosomal S6 kinase (S6K) and 4E binding protein 1 (4EBP1), targets of mTOR. Together, these findings suggest that memory formation requires the mTOR cascade and that the memory-enhancing effect of glucose involves its ability to activate this pathway. [ABSTRACT FROM AUTHOR]

Influential recent proposals state that the anterior thalamic (AT) nuclei constitute key components of an "extended hippocampal system." This idea is, however, based on lesion studies that used spatial memory tasks and there has been no evidence that AT lesions cause deficits in any hippocampal-dependent nonspatial tasks. The present study investigated the role of the AT nuclei in nonspatial memory for a sequence of events based on the temporal order of a list of odors, because this task has recently been shown to depend on the integrity of the hippocampal formation. After preoperative training, rats with excitotoxic lesions of the AT nuclei showed a severe and selective postoperative impairment when required to remember the order of pseudorandom sequences of six odors. The rats with AT lesions were able instead to learn two new tasks that required recognition memory and the identification of the prior occurrence of events independent of their order. These results strongly matched those described after hippocampal lesions and provide the first unequivocal evidence of a detrimental effect of an AT lesion on a nonspatial hippocampal-dependent memory task. [ABSTRACT FROM AUTHOR]

Apamin-sensitive, small-conductance, Ca2+-activated K+ channels (SK channels) modulate neuronal excitability in CA1 neurons. Blocking all SK channel subtypes with apamin facilitates the induction of hippocampal synaptic plasticity and enhances hippocampal learning. In CA1 dendrites, SK channels are activated by Ca2+ through NMDA receptors and restrict glutamate-mediated EPSPs. Studies of SK channel knock-out mice reveal that of the three apamin-sensitive SK channel subunits (SK1-SK3), only SK2 subunits are necessary for the apamin-sensitive currents in CA1 hippocampal neurons. To determine the specific influence of SK2 channels on hippocampal synaptic plasticity, learning, and memory, we used gene targeting through homologous recombination in embryonic stem cells to generate transgenic mice that overexpress SK2 subunits by 10-fold (SK2+/T). In these mice, the apamin-sensitive current inCA1neurons was increased by approximately fourfold, relative to wild-type (WT) littermates. In addition, the amplitude of synaptically evoked EPSPs recorded from SK2+/T CA1 neurons increased twice as much in response to SK channel blockade relative to EPSPs recorded from WT CA1 neurons. Consistent with this, SK2 overexpression reduced long-term potentiation after high-frequency stimulation compared with WT littermates and severely impaired learning in both hippocampus- and amygdala-dependent tasks. We conclude that SK2 channels regulate hippocampal synaptic plasticity and play a critical role in modulating mechanisms of learning and memory. [ABSTRACT FROM AUTHOR]

Aging is associated with spatial memory impairments and with deficient encoding of information by the hippocampus. In young adult rats, recent studies on the firing properties of hippocampal neurons have emphasized the importance of the CA3 subregion in the rapid encoding of new spatial information. Here, we compared the spatial firing patterns of CA1 and CA3 neurons in aged memory-impaired rats with those of young rats as they explored familiar and novel environments. We found that CA1 place cells in aged and young rats had similar firing characteristics in the familiar and novel environments. In contrast, aged CA3 place cells had higher firing rates in general and failed to change their firing rates and place fields as much as CA3 cells of young rats when the rats were introduced to a novel environment. Thus, aged CA3 cells failed to rapidly encode new spatial information compared with young CA3 cells. These data suggest an important and selective contribution of CA3 dysfunction to age-related memory impairment. [ABSTRACT FROM AUTHOR]

Monkeys with damage to the parahippocampal (TH/TF) or perirhinal (PRh) cortex were tested on two sets of the transverse patterning (TP) problem (A+/B-, B+/C-, C+/A- and D+/E-, E+/F-, F+/D-) and delayed nonmatching-to-location paradigm (DNML), with delays ranging from 10 to 600 s. Damage to either area impaired acquisition and performance of TP but not of linear discriminations (e.g., A>B>C>X). Damage to areas TH/TF impaired performance of the DNML at all delays but only affected memory for objects at the longest delay, as measured by a delayed nonmatching-to-sample task (DNMS) (Nemanic et al., 2004). Damage to the PRh impaired performance of the DNMS but not of the DNML. The results present a dissociation in object and place memory for these two cortical regions and suggest a role for each in the cortical circuitry supporting configural/relational memory. [ABSTRACT FROM AUTHOR]

Previous findings indicate that administration of a β-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that β-adrenoceptor activation in the hippocampus and the basolateral complex of the amygdala (BLA) is implicated in the impairing effects of glucocorticoids on memory retrieval. The specific glucocorticoid receptor (GR) agonist 11β,17β-dihydroxy-6,21-dimethyl-17α-pregna-4,6-trien-20yn-3-one (RU 28362) (15 ng) infused into the hippocampus of male Sprague Dawley rats 60 min before water maze retention testing, 24 hr after training, impaired probe trial retention performance, as assessed by quadrant search time and initial latency to cross the platform location. Because we found previously that RU 28362 infused into the hippocampus does not affect water maze acquisition or immediate recall, the findings suggest that the GR agonist-induced retention impairment was attributable to a selective influence on long-term memory retrieval. Likewise, systemic injections of the β1-adrenoceptor partial agonist xamoterol (3.0 or 10.0 mg/kg, s.c.) 60 min before the probe trial dose-dependently impaired retention performance. The β-adrenoceptor antagonist propranolol (2.0 mg/kg) administered subcutaneously before retention testing did not affect retention performance alone, but blocked the memory retrieval impairment induced by concurrent intrahippocampal infusions of RU 28362. Pretest infusions of the β1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 µg in 0.5 µ1) or the BLA (0.5 µg in 0.2 µl) also prevented the GR agonist-induced memory retrieval impairment. These findings suggest that glucocorticoids impair retrieval of long-term spatial memory by facilitating noradrenergic mechanisms in the hippocampus, and additionally, that norepinephrine-mediated BLA activity is critical in enabling hippocampal glucocorticoid... [ABSTRACT FROM AUTHOR]

Spatial learning impairment in aged rats is associated with changes in hippocampal connectivity and plasticity. Several studies have explored the age-related deficit in spatial information processing by recording the location-specific activity of hippocampal neurons (place cells). However, these studies have generated disparate characterizations of place cells in aged rats as unstable (Barnes et al., 1997), resistant to change (Tanila et al., 1997b; Oler and Markus, 2000; Wilson et al., 2003), or delayed in using external cues (Rosenzweig et al., 2003). To reconcile these findings, we recorded place cells from aged and young rats as they repeatedly explored both a highly familiar environment and an initially novel environment, and we repeatedly tested whether the place fields formed in the novel environment were anchored by external cues. Initially, spatial representations in aged rats were abnormally maintained between the familiar and novel environments. Then, new representations were formed but were also delayed in becoming anchored to the external landmarks. Finally, even when the new spatial representations became bound to the landmarks, they were multi-stable across repetitive exposures to the formerly novel environment. These observations help to reconcile previously divergent characterizations of spatial representation in aged rats and suggest a model of cognitive aging and hippocampal function. [ABSTRACT FROM AUTHOR]