Hippocampal Activity Patterns Research Articles

Differential involvement of hippocampal calcineurin during learning and reversal learning in a Y-maze task

The regulation and function of the calcium-dependent phosphatase calcineurin (CaN, protein phosphatase 2B) in learning and memory remain unclear, although recent work indicates that CaN may play a differential role in training and reversal training. To gain more insight into the involvement of CaN in these two types of learning, hippocampal CaN activity, protein levels, and expression patterns were studied in mice subjected to a reference memory version of the Y-maze task. We show that (1) training but not habituation induces a decrease in cytosolic CaN activity, (2) the recovery of cytosolic CaN activity is reversal training specific and does not reflect normal restoration of basal levels unrelated to subsequent learning, (3) cytosolic protein levels for the catalytic subunit of CaN (CaNA) are decreased at the early phase of training, but not at the early phase of reversal training, (4) CaNA immunoreactivity in the dorsal hippocampus is enhanced in the CA1 and CA3 area (but not in the dentate gyrus [DG] or subiculum [SUB]) only during reversal training. These findings indicate that memory formation is accompanied by reduced CaN activity, whereas adapting to changes in a familiar environment is accompanied by restored CaN activity. Moreover, reversal training selectively affects hippocampal CA3 and CA1 regions, suggesting a specific function of these hippocampal subregions in reversal learning.

Hippocampal and cerebellar single-unit activity during delay and trace eyeblink conditioning in the rat

In delay eyeblink conditioning, the CS overlaps with the US and only a brainstem–cerebellar circuit is necessary for learning. In trace eyeblink conditioning, the CS ends before the US is delivered and several forebrain structures, including the hippocampus, are required for learning, in addition to a brainstem–cerebellar circuit. The interstimulus interval (ISI) between CS onset and US onset is perhaps the most important factor in classical conditioning, but studies comparing delay and trace conditioning have typically not matched these procedures in this crucial factor, so it is often difficult to determine whether results are due to differences between delay and trace or to differences in ISI. In the current study, we employed a 580-ms CS–US interval for both delay and trace conditioning and compared hippocampal CA1 activity and cerebellar interpositus nucleus activity in order to determine whether a unique signature of trace conditioning exists in patterns of single-unit activity in either structure. Long–Evans rats were chronically implanted in either CA1 or interpositus with microwire electrodes and underwent either delay eyeblink conditioning, or trace eyeblink conditioning with a 300-ms trace period between CS offset and US onset. On trials with a CR in delay conditioning, CA1 pyramidal cells showed increases in activation (relative to a pre-CS baseline) during the CS–US period in sessions 1–4 that was attenuated by sessions 5–6. In contrast, on trials with a CR in trace conditioning, CA1 pyramidal cells did not show increases in activation during the CS–US period until sessions 5–6. In sessions 5–6, increases in activation were present only to the CS and not during the trace period. For rats with interpositus electrodes, activation of interpositus neurons on CR trials was present in all sessions in both delay and trace conditioning. However, activation was greater in trace compared to delay conditioning in the first half of the CS–US interval (during the trace CS) during early sessions of conditioning and, in later sessions of conditioning, activation was greater in the second half of the CS–US interval (during the trace interval). These results suggest that the pattern of hippocampal activation that differentiates trace from delay eyeblink conditioning is a slow buildup of activation to the CS, possibly representing encoding of CS duration or discrimination of the CS from the background context. Interpositus nucleus neurons show strong modeling of the eyeblink CR regardless of paradigm but show a changing pattern across conditioning that may be due to the necessary contributions of forebrain processing to trace conditioning.

An fMRI Analysis of the Human Hippocampus: Inference, Context, and Task Awareness

The hippocampus is critical for encoding and retrieving semantic and episodic memories. Animal studies indicate that the hippocampus is also required for relational learning tasks. A prototypical relational learning task, and the one investigated in this experiment, using event-related functional magnetic resonance imaging, is the transitive inference (TI) task. In the TI task, participants were to choose between A and B (A?B) and learned by trial and error to choose A (A > B). There were four such premise pairs during a training (A > B, B > C, C > D, D > E). These can be acquired distinctly or can be organized into a superordinate hierarchy (A > B > C > D > E), which would efficiently represent all the learned relations and allow inferences (e.g., B > D). At test there was no reinforcement: In addition to premise pairs, untrained pairings were introduced (e.g., A?E, B?D). Correctly inferring that B > D is taken as evidence for the formation of a superordinate hierarchy; several alternatives to the superordinate hierarchy hypothesis are considered. Awareness of the formation of this hierarchy was measured by a postscan questionnaire. Four main findings are reported: (1) Inferential performance and task awareness dissociated behaviorally and at the level of hemodynamic response; (2) As expected, performance on the inferred relation, B > D, corresponded to the ability to simultaneously acquire B > C and C > D premise pairs during training; (3) Interestingly, acquiring these "inner pairs" corresponded to greater hippocampal activation than the "outer pairs" (A > B, D > E) for all participants. However, a distinct pattern of hippocampal activity for these inner pairs differentiated those able to perform the inferential discrimination, B > D, at test. Because these inner premise pairs require contextual discrimination (e.g., C is incorrect in the context of B but correct in the context of D), we argue that the TI task is hippocampal-dependent because the premise pair acquisition necessary for inference is hippocampal-dependent; (4) We found B > D related hippocampal activity at test that is anatomically consistent with preconsolidation recall effects shown in other studies.

The Dynamics of Hippocampal Activation during Encoding of Overlapping Sequences

Sequence disambiguation, the process by which overlapping sequences are kept separate, has been proposed to underlie a wide range of memory capacities supported by the hippocampus, including episodic memory and spatial navigation. We used functional magnetic resonance imaging (fMRI) to explore the dynamic pattern of hippocampal activation during the encoding of sequences of faces. Activation in right posterior hippocampus, only during the encoding of overlapping sequences but not nonoverlapping sequences, was found to correlate robustly with a subject-specific behavioral index of sequence learning. Moreover, our data indicate that hippocampal activation in response to elements common to both sequences in the overlapping sequence pair, may be particularly important for accurate sequence encoding and retrieval. Together, these findings support the conclusion that the human hippocampus is involved in the earliest stage of sequence disambiguation, when memory representations are in the process of being created, and provide empirical support for contemporary computational models of hippocampal function.

Evidence That Autobiographic Memory Retrieval Does Not Become Independent of the Hippocampus: An fMRI Study Contrasting Very Recent with Remote Events

Traditional consolidation theory, which seeks to explain how new memories are incorporated into the preexisting neural architecture, stipulates that the hippocampus plays a time-limited role in this process. However, although there is abundant research showing that the hippocampus is necessary for the initial (encoding) phase, there is very little experimental evidence with human subjects proving that the structure ceases to play a role in the retrieval of episodic items from memory stores. To test this hypothesis, we investigated recall activation associated with recent memories (2.5 days) versus remote memories (mean of 8 years) using functional magnetic resonance imaging. In accordance with the multiple memory trace theory, recall of consolidated autobiographic information, represented by the remote condition, was not independent of the hippocampus. Both types of memory retrieval produced significant activation in parahippocampal, prefrontal, and midtemporal gyri, the parietal-temporal junction, and a medial region of cortex spanning the posterior cingulate and precuneus gyri. However, where recent events activated bilateral regions of the caudate nucleus, remote events yielded significantly greater activation within the hippocampus proper. The results challenge traditional consolidation theory, which would predict greater hippocampal activity for recent events. Furthermore, they highlight the interplay between multiple memory systems in the brain. We argue that our particular question format, which encouraged depth of recall and did not require a prescan interview, as well as our delineation of the recent and remote time periods, were the determining factors for the observed pattern of hippocampal activation.

A Comparison of Two fMRI Protocols for Eliciting Hippocampal Activation

Previous research suggests that the hippocampus is modulated both by stimulus novelty and by the extent to which relational processing (formation of associations) occurs during episodic encoding. The aim of this study was to compare hippocampal activation patterns measured by functional magnetic resonance imaging (fMRI) during encoding protocols emphasizing either novelty or relational processing. fMRI was performed on 32 healthy volunteers while they encoded complex visual scenes or unrecognizable scrambled versions of the same scenes. In the Novelty contrast, encoding of novel scenes was compared with encoding of a repeated pair of scenes. In the Relational Processing contrast, semantic encoding of novel scenes was compared with structural encoding of scrambled scenes. Both protocols elicited bilateral hippocampal activation. Overall mean activation values were similar for the two protocols, but the Relational Processing protocol resulted in a larger volume of hippocampal activation. The pattern of activation along the longitudinal hippocampal axis differed for the two protocols. The Novelty contrast produced stronger activation in the posterior hippocampus, whereas the Relational Processing contrast produced stronger activation in the anterior hippocampus. Hippocampal activation is determined by both stimulus novelty and degree of relational processing during encoding. Given the importance of anterior hippocampal pathology in temporal lobe epilepsy, an approach emphasizing modulation of relational processing may be preferable for clinical fMRI of the medial temporal lobes.

Sequential-Context-Dependent Hippocampal Activity Is Not Necessary to Learn Sequences with Repeated Elements

Learning sequences of events (e.g., a-b-c) is conceptually a simple problem that can be solved using asymmetrically linked cell assemblies [e.g., "phase sequences" (Hebb, 1949)], provided that the elements of the sequence are unique. When elements repeat within the sequence, however (e.g., a-b-c-d-b-e), the same element belongs to two separate "contexts," and a more complex sequence encoding mechanism is required to differentiate between the two contexts. Some neural structure must form sequential-context-dependent, or "differential," representations of the two contexts (i.e., b as an element of "a-b-c" as opposed to "d-b-e") to allow the correct choice to be made after the repeated element. To investigate the possible role of hippocampus in complex sequence encoding, rats were trained to remember repeated-location sequences under three conditions: (1) reward was given at each location; (2) during training, moveable barriers were placed at the entry and exit of the repeated segment to direct the rat and were removed once the sequence was learned; and (3) reward was withheld at the entry and exit of the repeated segment. In the first condition, hippocampal ensemble activity did not differentiate the sequential context of the repeated segment, indicating that complex sequences with repeated segments can be learned without differential encoding within the hippocampus. Differential hippocampal encoding was observed, however, under the latter two conditions, suggesting that long-term memory for discriminative cues present only during training, working memory of the most recently visited reinforcement sites, or anticipation of the subsequent reinforcement site can separate hippocampal activity patterns at the same location.

The effects of amygdala lesions on hippocampal activity and classical eyeblink conditioning in rats

The hippocampus and the amygdala have long been associated with memory, emotion, and motivated behaviors. Although the role of these two brain areas in learning a simple, discrete motor response has been well studied, a definitive theory concerning their functions remains elusive. The present experiment involved selective lesions of the central nucleus (CE) or the basolateral nucleus (BA) of the amygdala in rats followed by single-unit analyses of hippocampal CA1 subfield activity during classical eye blink conditioning. Removal of CE or BA adversely affected the development of conditioned responding. Differences between groups in the patterns of hippocampal activity were observed. Similar to previous rabbit studies, hippocampal activity recorded from sham rats showed that CA1 cells became active during the CS–US period as conditioning progressed with activity especially prevalent just prior to US onset. Increased activity over training was seen during the CS–US interval in CE-lesioned rats, but the pattern differed from control rats—uniform excitation was seen across the entire CS–US period. BA-lesioned rats initially showed uniform CS–US period activation in early phases of training, but then showed patterns of hippocampal activity that resembled control rats in later stages of conditioning. The data suggest that the amygdala may play a modulatory role in the acquisition of conditioned eye blink responses and also in the formation of learning-related activity in the hippocampus.

Parallel processing across neural systems: Implications for a multiple memory system hypothesis

A common conceptualization of the organization of memory systems in brain is that different types of memory are mediated by distinct neural systems. Strong support for this view comes from studies that show double (or triple) dissociations between spatial, response, and emotional memories following selective lesions of hippocampus, striatum, and the amygdala. Here, we examine the extent to which hippocampal and striatal neural activity patterns support the multiple memory systems view. A comparison is made between hippocampal and striatal neural correlates with behavior during asymptotic performance of spatial and response maze tasks. Location- (or place), movement, and reward-specific firing patterns were found in both structures regardless of the task demands. Many, but not all, place fields of hippocampal and striatal neurons were similarly affected by changes in the visual and reward context regardless of the cognitive demands. Also, many, but not all, hippocampal and striatal movement-sensitive neurons showed significant changes in their behavioral correlates after a change in visual context, irrespective of cognitive strategy. Similar partial reorganization was observed following manipulations of the reward condition for cells recorded from both structures, again regardless of task. Assuming that representations that persist across context changes reflect learned information, we make the following conclusions. First, the consistent pattern of partial reorganization supports a view that the analysis of spatial, response, and reinforcement information is accomplished via an error-driven, or match–mismatch, algorithm across neural systems. Second, task-relevant processing occurs continuously within hippocampus and striatum regardless of the cognitive demands of the task. Third, given the high degree of parallel processing across allegedly different memory systems, we propose that different neural systems may effectively compete for control of a behavioral expression system. The strength of the influence of any one neural system on behavioral output is likely modulated by factors such as motivation, experience, or hormone status.

O1-04-01 Transgenic mouse models of TAU pathology in astrocytes leading to nervous system degeneration

Mental experiences can become long-term memories if the hippocampal activity patterns that encode them are broadcast during network oscillations. The activity of inhibitory neurons is essential for generating these neural oscillations, but molecular control of this dynamic process during learning remains unknown. Here, we show that hippocampal oscillatory strength positively correlates with excitatory monosynaptic drive onto inhibitory neurons (E→I) in freely behaving mice. To establish a causal relationship between them, we identified γCaMKII as the long-sought mediator of long-term potentiation for E→I synapses (LTPE→I), which enabled the genetic manipulation of experience-dependent E→I synaptic input/plasticity. Deleting γCaMKII in parvalbumin interneurons selectively eliminated LTPE→I and disrupted experience-driven strengthening in theta and gamma rhythmicity. Behaviorally, this manipulation impaired long-term memory, for which the kinase activity of γCaMKII was required. Taken together, our data suggest that E→I synaptic plasticity, exemplified by LTPE→I, plays a gatekeeping role in tuning experience-dependent brain rhythms and mnemonic function.

Transition from Interictal to Ictal Activity in Limbic NetworksIn Vitro

The transition from brief bursts of synchronous population activity characteristic of interictal epileptiform discharges (IEDs) to more prolonged epochs of population activity characteristic of seizures (ictal-like activity) was recorded in juvenile rat hippocampal-entorhinal cortex slices and hippocampal slices using multiple-site extracellular electrodes. Epileptiform activity was elicited by either increased extracellular potassium or 4-AP. IEDs originated in the CA3 a-b region and spread bidirectionally into CA1 and CA3c dentate gyrus. The transition from IEDs to ictal-like sustained epileptiform activity was reliably preceded by (1) increase in IED propagation velocity, (2) increase in IED secondary afterdischarges and their reverberation between CA3a and CA3c, and (3) shift in the IED initiation area from CA3 a-b to CA3c. Ictal-like sustained network oscillations (10-20 Hz) originated in CA3c and spread to CA1. The pattern of hippocampal ictal-like activity was unaffected by removal of the entorhinal cortex. These findings indicate that interictal and ictal activity can originate in the same neural network, and that the transition from interictal to ictal-like-sustained activity is preceded by predictable alterations in the origin and spread of IEDs. These findings elucidate new targets for investigating the proximate causes, prediction, and treatment of seizures.

Distinct patterns of hippocampal formation activity associated with different spatial tasks: a Fos imaging study in rats.

Fos levels were measured in rats trained in one of two qualitatively different spatial memory tasks in a water maze. In one task, ( landmark condition) rats found a submerged platform that was always 25 cm south of a visible landmark, the absolute position of the platform and landmark changing after every trial. In the other task ( place condition), rats swam to a platform that remained in the same absolute position on every session, but changed session to session, with this task relying on the memory of allocentric cues. Despite matched swim times, the landmark condition resulted in higher levels of Fos in a wide range of cortical and subcortical sites, including the hippocampus and its connections. Structural equation modelling revealed two different patterns of hippocampal function. In the allocentric place task there was a significant association between Fos activity in the entorhinal cortices and the hippocampus proper, while in the non-allocentric landmark task this relationship was not present, but was replaced by a connection from the entorhinal cortices to the subiculum. Thus, the two different tasks engage two different modes of hippocampal activity as demonstrated by Fos expression.

Developmental patterns and plasticities: the hippocampal model

Because developmental activity-dependent synaptic plasticity has been hypothesized to participate in network refinement, leading to the precise mapping of synaptic contacts constituting a functional brain, it is important to investigate the spatio-temporal structure of immature network activities. This article is briefly reviewing 15 years of studies on the immature rat hippocampus which, together with recent results obtained from awake rat pups, represent an important step toward the understanding of spontaneous patterns of activity and their potential implication in network maturation. Due to synergistic excitatory actions of GABA and glutamate receptor mediated signals during early postnatal life, spontaneous patterns of hippocampal activity that have been characterized both in vitro and in vivo are likely to provide hebbian modulation of developing glutamatergic and GABAergic synapses. Together with studies on trophic actions of these transmitters, study of the immature hippocampal network patterns and plasticities allows for multiple technical and conceptual approaches and represents an interesting experimental model for development studies.

Mitogen-Activated Protein Kinase Regulates Early Phosphorylation and Delayed Expression of Ca2+/Calmodulin-Dependent Protein Kinase II in Long-Term Potentiation

Activation of mitogen-activated protein kinase (MAPK) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) are required for numerous forms of neuronal plasticity, including long-term potentiation (LTP). We induced LTP in rat hippocampal area CA1 using theta-pulse stimulation (TPS) paired with beta-adrenergic receptor activation [isoproterenol (ISO)], a protocol that may be particularly relevant to normal patterns of hippocampal activity during learning. This stimulation resulted in a transient phosphorylation of p42 MAPK, and the resulting LTP was MAPK dependent. In addition, CaMKII was regulated in two, temporally distinct ways after TPS-ISO: a transient rise in the fraction of phosphorylated CaMKII and a subsequent persistent increase in CaMKII expression. The increases in MAPK and CaMKII phosphorylation were strongly colocalized in the dendrites and cell bodies of CA1 pyramidal cells, and both the transient phosphorylation and delayed expression of CaMKII were prevented by inhibiting p42/p44 MAPK. These results establish a novel bimodal regulation of CaMKII by MAPK, which may contribute to both post-translational modification and increased gene expression.

Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation.

Circuits within the hippocampal formation are active during memory processing. Here we used functional magnetic resonance imaging (fMRI) to examine multiple sites across the long axis of the hippocampal formation while subjects performed different phases of an associative memory task, learning to associate faces with names. Viewing faces and hearing names in isolation resulted in separate hippocampal activation patterns. Pairing faces with names resulted a spatially redistributed activation pattern, rather than a simple summation of the activation patterns resulting from viewing faces and hearing names in isolation. Recalling names when cued with faces reactivated a pattern similar to that found during paired training. Finally, the activation patterns representing faces and names were found to be experience dependent, emerging with repeated exposure. Interpreted in the context of hippocampal anatomy and physiology, these findings reveal hippocampal circuit mechanisms that underlie memory encoding and retrieval.

Reactivation of hippocampal ensemble activity patterns in the aging rat.

In young rats, the pattern of neuronal ensemble activity correlations expressed among hippocampal pyramidal cells during behavior persists during subsequent quiet wakefulness and slow-wave sleep, a process that may facilitate the consolidation of episodic memories. The present study explored the hypothesis that age-related changes in this process might contribute to memory impairments observed during normal aging. Neuronal activity was recorded from CA1 pyramidal cells, and in both young and old rats, there was a strong similarity between the resting epoch activity patterns and those from the preceding behavior epoch. This similarity was strongest during sharp-wave events. There were no detectable differences in the reactivation process or the decay rate between the young and old age groups. Thus, age differences in spatial memory do not appear to be explainable by differences in the spontaneous reactivation of familiar patterns within the hippocampus during the immediate postbehavior period.

Reactivation of hippocampal ensemble activity patterns in the aging rat.

Reactivation of hippocampal ensemble activity patterns in the aging rat.

Total Number and Ratio of Excitatory and Inhibitory Synapses Converging onto Single Interneurons of Different Types in the CA1 Area of the Rat Hippocampus

The least known aspect of the functional architecture of hippocampal microcircuits is the quantitative distribution of synaptic inputs of identified cell classes. The complete dendritic trees of functionally distinct interneuron types containing parvalbumin (PV), calbindin D(28k) (CB), or calretinin (CR) were reconstructed at the light microscopic level to describe their geometry, total length, and laminar distribution. Serial electron microscopic reconstruction and postembedding GABA immunostaining was then used to determine the density of GABA-negative asymmetrical (excitatory) and GABA-positive symmetrical (inhibitory) synaptic inputs on their dendrites, somata, and axon initial segments. The total convergence and the distribution of excitatory and inhibitory inputs were then calculated using the light and electron microscopic data sets. The three populations showed characteristic differences in dendritic morphology and in the density and distribution of afferent synapses. PV cells possessed the most extensive dendritic tree (4300 microm) and the thickest dendrites. CR cells had the smallest dendritic tree (2500 microm) and the thinnest shafts. The density of inputs as well as the total number of excitatory plus inhibitory synapses was several times higher on PV cells (on average, 16,294) than on CB (3839) or CR (2186) cells. The ratio of GABAergic inputs was significantly higher on CB (29.4%) and CR (20.71%) cells than on PV cells (6.4%). The density of inhibitory terminals was higher in the perisomatic region than on the distal dendrites. These anatomical data are essential to understand the distinct behavior and role of these interneuron types during hippocampal activity patterns and represent fundamental information for modeling studies.

Relationships between Hippocampal Activity and Breathing Patterns

HARPER, R. M., G. R. POE, D. M. RECTOR, M. P. KRISTENSEN. Relationships between hippocampal activity and breathing patterns. NEUROSCI BIOBEHAV REV 22(2) 233–236, 1998.—Single cell discharge, EEG activity, and optical changes accompanying alterations in breathing patterns, as well as the knowledge that respiratory musculature is heavily involved in movement and other behavioral acts, implicate hippocampal regions in some aspects of breathing control. The control is unlikely to reside in oscillatory breathing movements, because such patterns emerge in preparations retaining only the medulla (and perhaps only the spinal cord). However, momentary changes in breathing patterns induced by affect, startle, whole-body movement changes, or compensatory ventilatory changes mediated by rostral brain regions likely depend on hippocampal action in aspects of control. Hippocampal activity was enhanced prior to sighs, and this enhancement was accompanied by increased slow theta activity. Theta frequency increased during apnea, prior to return of breathing. Consideration of hippocampal contributions to breathing control should be viewed in the context that significant interactions exist between blood pressure changes and ventilation, and that modest breathing challenges, such as exposure to hypercapnia or to increased resistive loads, bring into action a vast array of brain regions involving nearly every level of the neuraxis.

Spontaneous Ca2+ transients in developing hippocampal pyramidal cells.

To determine the spatiotemporal pattern of hippocampal pyramidal cell activity during development, we examined cytosolic Ca2+ dynamics in tissue slices derived from early postnatal rats. After a brief (12-60 h) culture period, slices were stained with a calcium-sensitive dye, Fluo-3. Fluorescence imaging of the Fluo-3-stained slices with a scanning laser confocal microscope afforded simultaneous observation of many cells at high spatial resolution. Time-lapse imaging revealed spontaneous Ca2+ transients in the somata dendrites of many pyramidal cells in areas CA1 and CA3. For the most part, Ca2+ activity in neighboring pyramidal cells appeared to be uncorrelated, although we occasionally observed synchronous Ca2+ transients in adjacent cells. The transients were blocked by both tetrodotoxin (1 microM) and a mixture of the glutamate receptor antagonists, APV (50 microM) + CNQX (10 microM). Thus, spontaneous Ca2+ transients appear to be a consequence of activity-dependent release of glutamate acting postsynaptically through ionotropic glutamate receptors. Although gamma-aminobutyric acid (GABA) is thought to be an excitatory neurotransmitter during hippocampal development (Cherubini et al., 1991, Trends Neurosci. 14 (12):515-519), the spontaneous Ca2+ transients were not blocked by the GABAA receptor antagonist picrotoxin (100 microM). Furthermore, application of GABA (50 microM) abolished the spontaneous Ca2+ events, possibly via GABAB receptor-mediated inhibition of postsynaptic cells. The present results join other recent observations suggesting that isolated neural tissues support spontaneous activity, although the patterns and mechanisms of the activity reported here appear to differ from those of previous studies. Differences in the patterns of spontaneous activity during development may contribute to variations in the functional organization of different regions of CNS tissue.