Semantic memory and the human hippocampus

It has been unclear whether the hippocampus is uniquely important for episodic memory (memory for events that are specific to time and place) or whether the hippocampus is also important for learning and remembering facts (semantic memory). In two studies, we assessed the capacity for semantic memory in patients with bilateral damage thought to be restricted primarily to the hippocampal region who developed memory impairment at a known time. Since the onset of their memory impairment, the patients have acquired less factual knowledge than controls. The patients also exhibit temporally limited retrograde amnesia for factual information from the several years preceding the onset of memory impairment. Remote memory for factual knowledge (from 11-30 years before amnesia) is intact. The results show that the hippocampal region supports semantic memory as well as episodic memory and that its role in the acquisition and storage of semantic knowledge is time limited.     

The human hippocampus and spatial and episodic memory

Finding one's way around an environment and remembering the events that occur within it are crucial cognitive abilities that have been linked to the hippocampus and medial temporal lobes. Our review of neuropsychological, behavioral, and neuroimaging studies of human hippocampal involvement in spatial memory concentrates on three important concepts in this field: spatial frameworks, dimensionality, and orientation and self-motion. We also compare variation in hippocampal structure and function across and within species. We discuss how its spatial role relates to its accepted role in episodic memory. Five related studies use virtual reality to examine these two types of memory in ecologically valid situations. While processing of spatial scenes involves the parahippocampus, the right hippocampus appears particularly involved in memory for locations within an environment, with the left hippocampus more involved in context-dependent episodic or autobiographical memory.     

Prospective and retrospective memory coding in the hippocampus

The effect of memory on hippocampal neuronal activity was assessed as rats performed a spatial task that was impaired by fornix lesions. The influences of current location, recently entered places, and places about to be entered were compared. Three new findings emerged. (1) Current, retrospective, and prospective coding were common and recorded simultaneously in neural ensembles. (2) The origin of journeys influenced firing even when rats made detours, showing that recent memory could modulate neuronal activity more than spatial trajectory. (3) Diminished retrospective coding and, more markedly, reduced prospective coding in error trials suggested that the neuronal signal was important for task performance. The population of hippocampal neurons thus encoded information about the recent past, the present, and the imminent future, consistent with a neuronal mechanism for episodic memory.     

Episodic memory signals in the rat hippocampus

How does the hippocampus signal memory for episodes? In this issue of Neuron, Ferbinteanu and Shapiro show that classic place cell activity in the rat hippocampus together with robust retrospective and prospective memory signals reflects the sequence of past, present, and future events that make up an episode.     

Neuronal networks and memory: role of the hippocampus

Learning and memory are related both to cognitive processes and to neurobiological mechanisms. The human pathology focused on the role of the hippocampus and animal experiments have analyzed its implications. The most usually admitted hypothesis is that memories are underlied by distributed specific neural networks defined through the strengthening of certain synapses, under the action of the flow of information during learning. The best candidate for this strengthening of the synapses is a change in synaptic plasticity similar to the artificial phenomenon of long-term potentiation. During memory processes, the hippocampus would play a particular role in information processing (analyzing novelty and significance of the information) and would allow the specification of the neural network, mainly in the cortical territories. We report data in olfactory learning in rats comforting these hypotheses. Considering neurochemistry of memory processes, specific synaptic changes and neuromodulatory processes must be distinguished. We report data about vasopressin illustrating both kinds of mechanisms in the hippocampus.     

Human memory: The hippocampus is the key

A recent study of brain-damaged patients with various degrees of amnesia provides compelling new evidence that the hippocampus plays a vital role in the laying down of new memories. Why existing memories are also affected by hippocampal damage is particularly puzzling.     

The ecology of the avian brain: food-storing memory and the hippocampus

Some species of birds store food, often hoarding several hundreds of seeds over a period of just a few weeks. Field and laboratory studies have demonstrated that food-storing species have an impressive memory and an enlarged region of the brain, the hippocampal region. Lesion experiments have shown that the hippocampus is important in accurate retrieval of stored food. Taken together, these results have led to the hypothesis that the enlarged hippocampus is associated with the memory requirements of retrieving stored food. In this review, we discuss four areas of study: comparative studies of the brain, comparative studies of behaviour, developmental plasticity and seasonal changes in food storing and the hippocampus.     

The ecology of the avian brain: food-storing memory and the hippocampus

Some species of birds store food, often hoarding several hundreds of seeds over a period of just a few weeks. Field and laboratory studies have demonstrated that food-storing species have an impressive memory and an enlarged region of the brain, the hippocampal region. Lesion experiments have shown that the hippocampus is important in accurate retrieval of stored food. Taken together, these results have led to the hypothesis that the enlarged hippocampus is associated with the memory requirements of retrieving stored food. In this review, we discuss four areas of study: comparative studies of the brain, comparative studies of behaviour, developmental plasticity and seasonal changes in food storing and the hippocampus.     

The hippocampus and memory: insights from spatial processing

The hippocampus appears to be crucial for long-term episodic memory, yet its precise role remains elusive. Electrophysiological studies in rodents offer a useful starting point for developing models of hippocampal processing in the spatial domain. Here we review one such model that points to an essential role for the hippocampus in the construction of mental images. We explain how this neural-level mechanistic account addresses some of the current controversies in the field, such as the role of the hippocampus in imagery and short-term memory, and discuss its broader implications for the neural bases of episodic memory.     

The hippocampus and memory: a comparative and ethological perspective

During the past year, considerable progress has been made in our understanding of the wide-ranging functions of the hippocampus. Highlights include the development of new tasks with which to assess spatial/topographic memory in humans and monkeys, novel tests of relational memory in rats, and episodic-like memory tasks in birds. In addition, novel theories of hippocampal function have been developed that are notable for their applicability to both humans and animal models.     

Regulation of histone acetylation during memory formation in the hippocampus

Formation of long term memory begins with the activation of many disparate signaling pathways that ultimately impinge on the cellular mechanisms regulating gene expression. We investigated whether mechanisms regulating chromatin structure were activated during the early stages of long term memory formation in the hippocampus. Specifically, we investigated hippocampal histone acetylation during the initial stages of consolidation of long term association memories in a contextual fear conditioning paradigm. Acetylation of histone H3 in area CA1 of the hippocampus was regulated in contextual fear conditioning, an effect dependent on activation of N-methyl-D-aspartic acid (NMDA) receptors and ERK, and blocked using a behavioral latent inhibition paradigm. Activation of NMDA receptors in area CA1 in vitro increased acetylation of histone H3, and this effect was blocked by inhibition of ERK signaling. Moreover, activation of ERK in area CA1 in vitro through either the protein kinase C or protein kinase A pathways, biochemical events known to be involved in long term memory formation, also increased histone H3 acetylation. Furthermore, we observed that elevating levels of histone acetylation through the use of the histone deacetylase inhibitors trichostatin A or sodium butyrate enhanced induction of long term potentiation at Schaffer-collateral synapses in area CA1 of the hippocampus, a candidate mechanism contributing to long term memory formation in vivo. In concert with our findings in vitro, injection of animals with sodium butyrate prior to contextual fear conditioning enhanced formation of long term memory. These results indicate that histone-associated heterochromatin undergoes changes in structure during the formation of long term memory. Mimicking memory-associated changes in heterochromatin enhances a cellular process thought to underlie long term memory formation, hippocampal long term potentiation, and memory formation itself.     

Systems-level reconsolidation: reengagement of the hippocampus with memory reactivation

Certain types of memories are dependent on the hippocampus for a short period of time following training, after which they are no longer susceptible to hippocampal manipulations. Having completed this initial consolidation process, a memory may once again engage the hippocampus (undergo reconsolidation) when recalled. Two studies in the current issue of Neuron make important advances in our understanding of reconsolidation but reach different conclusions about the modifiability of old memories.     

Network properties of memory trace formation in the hippocampus.

Based on the experimental evidence from his laboratory and the relevant literature the Author outlines a formal model of memory trace formation. During exploratory (theta) behaviors the neocortical information is transmitted to the hippocampus via the fast-firing granule cells which may induce a weak and transient heterosynaptic potentiation in a subgroup of CA3 pyramidal cells. The weakly potentiated CA3 neurons will then initiate population bursts upon the termination of exploratory activity (sharp wave state). It is assumed that recurrent excitation during the population burst is strongest on those cells which initiated the population event. It is suggested that the strong excitatory drive brought about by the sharp wave-concurrent population bursts during consummatory behaviors, immobility, and slow wave sleep may be sufficient for the induction of long-term synaptic modification in the initiator neurons of the CA3 region and in their targets in CA1. In this two-stage model both exploratory (theta) and sharp wave states of the hippocampus are essential and any interference that might modify the structure of the population bursts (e.g., epileptic spikes) are detrimental to memory trace formation.     

Luteinizing hormone acts at the hippocampus to dampen spatial memory

Luteinizing hormone (LH) rises dramatically during and after menopause, and has been correlated with an increased incidence of Alzheimer's disease and decreased memory performance in humans and animal models. To test whether LH acts directly on the dorsal hippocampus to affect memory, ovariectomized female rats were infused with either the LH-homologue human chorionic gonadotropin (hCG) or the LH receptor antagonist deglycosylated-hCG (dg-hCG). Infusion of hCG into either the lateral ventricle or the dorsal hippocampus caused significant memory impairments in ovariectomized estradiol-treated females. Consistent with this, infusion of the LH antagonist dg-hCG into the dorsal hippocampus caused an amelioration of memory deficits in ovariectomized females. Furthermore, the gonadotropin-releasing hormone antagonist Antide, failed to act in the hippocampus to affect memory. These findings demonstrate a significant role for LH action in the dorsal hippocampus in spatial memory dysfunction.     

Blockade of gamma-secretase activity within the hippocampus enhances long-term memory

The gamma-secretase complex, a membrane-bound aspartyl protease, hydrolyzes the transmembrane domains of several integral membrane proteins including the key signaling molecules amyloid precursor protein (APP), Notch, deleted in colorectal cancer (DCC), and N- and E-cadherins. The proteolysis processing of these proteins is critical for generation of signaling molecules that may participate in neuronal communication and plasticity. Using a potent gamma-secretase inhibitor, L-685,458, we examined if blockade of its activity in the hippocampus can influence contextual and spatial memory in rats. Surprisingly, we observed that post-training blockade of gamma-secretase activity leads to enhanced long-term memory in two hippocampus-dependent tasks. This suggests that a signaling molecule(s) generated by gamma-secretase activity may have a negative influence on long-term memory formation.     

Breast cancer affects both the hippocampus volume and the episodic autobiographical memory retrieval

Background

Neuroimaging studies show the hippocampus is a crucial node in the neural network supporting episodic autobiographical memory retrieval. Stress-related psychiatric disorders, namely Major Depression and Post Traumatic Stress Disorder (PTSD), are related to reduced hippocampus volume. However, this is not the case for remitted breast cancer patients with co-morbid stress-related psychiatric disorders. This exception may be due to the fact that, consequently to the cancer experience as such, this population might already be characterized by a reduced hippocampus with an episodic autobiographical memory deficit.

Methodology

We scanned, with a 3T Siemens TRIO, 16 patients who had lived through a “standard experience of breast cancer” (breast cancer and a standard treatment in remission since 18 month) in the absence of any associated stress-related psychiatric or neurological disorder and 21 matched controls. We then assessed their episodic autobiographical memory retrieval ability.

Principal Findings

Remitted breast cancer patients had both a significantly smaller hippocampus and a significant deficit in episodic autobiographical memory retrieval. The hippocampus atrophy was characterized by a smaller posterior hippocampus. The posterior hippocampus volume was intimately related to the ability to retrieve negative memories and to the past experience of breast cancer or not.

Conclusions/Significance

These results provide two main findings: (1) we identify a new population with a specific reduction in posterior hippocampus volume that is independent of any psychiatric or neurological pathology; (2) we show the intimate relation of the posterior hippocampus to the ability to retrieve episodic autobiographical memories. These are significant findings as it is the first demonstration that indicates considerable long-term effects of living through the experience of breast cancer and shows very specific hippocampal atrophy with a functional deficit without any presence of psychiatric pathology.     

The hippocampus supports both the recollection and the familiarity components of recognition memory

The receiver operating characteristic (ROC) has been used to investigate the component processes of recognition memory. Some studies with this technique have been taken to indicate that the hippocampus selectively supports the process of recollection, whereas adjacent cortex in the parahippocampal gyrus supports the process of familiarity. We analyzed ROC data from young adults, memory-impaired patients with limited hippocampal lesions, and age-matched controls. The shape of the ROC changed in similar ways from asymmetric to symmetric, as a function of the strength of memory (strong to weak) in both the young adults and the patients. Moreover, once overall memory strength was similar, the shape of the patient ROC was asymmetric and matched the control ROC. These results suggest that the component processes that determine the shape of the ROC are operative in the absence of the hippocampus, and they argue against the idea that the hippocampus selectively supports the recollection process.