No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Memory for objects and their locations: The role of the hippocampus in retention of object-place associations
Abstract
Computational models of hippocampal function have suggested that the hippocampus is involved in the formation and storage of arbitrary associations. Previous studies have shown that rats with hippocampal lesions are impaired in object-place associative learning. However, few studies have examined the role of the hippocampus in the retention of previously learned arbitrary associations. In the present study, male Long-Evans rats with either cortical control or hippocampal lesions were tested on a task measuring the retention of previously learned arbitrary associations using an object-place paired-associate task. To assess retention, each animal was trained on the paired-associate task for 360 trials, then received a lesion, and was retested to examine retention of the previously learned associations. The results indicate that all rats learned the task prior to surgery. Following surgery, rats with cortical control lesions were not impaired in the retention of object-place associations. In contrast, hippocampal lesions resulted in an initial deficit in retention of the paired-associate task followed by recovery. Therefore, the hippocampus may play a role in the retrieval of previously learned arbitrary association.
... Since that time a range of studies offer broad support for the view that distinct, but interacting (McIntosh and Schenk 2009), neural pathways are involved in remembering object and position information (e.g. Moscovitch et al. 1995;O'Keefe and Nadel 1978) and that hippocampal structures play a critical role in the binding of objects to locations (Bachevalier and Nemanic 2008;Crane and Milner 2005;Finke et al. 2008;Gilbert and Kesner 2004;Hannula and Ranganath 2008;Mumby et al. 2002;Nunn et al. 1999;Olson et al. 2006;Pertzov et al. 2013;Piekema et al. 2006;Postma et al. 2008;Watson et al. 2013). These conclusions are not surprising given the fundamental role of hippocampal structures to relational memory (e.g. ...
... Many researchers have noted that the binding objects to locations requires communication between the ventral (what) and dorsal (where) anatomical processing streams (Bentley and Salinas 2009;Eichenbaum et al. 2012) and on the basis of previous research on object-location memory (e.g. Crane and Milner 2005; Gilbert and Kesner 2004;Hannula and Ranganath 2008;Olson et al. 2006;Piekema et al. 2006;Postma et al. 2008), the preferential impact of glucose on binding memory is consistent with a hippocampal influence. Indeed, as the hippocampal system receives converging information from several association cortices (Shastri 2002), it is well suited to the fundamental process of binding diverse aspects of an experience into a unified episodic representation. ...
Rationale
There is evidence that glucose temporarily enhances cognition and that processes dependent on the hippocampus may be particularly sensitive. As the hippocampus plays a key role in binding processes, we examined the influence of glucose on memory for object-location bindings.
Objective
This study aims to study how glucose modifies performance on an object-location memory task, a task that draws heavily on hippocampal function.
Methods
Thirty-one participants received 30 g glucose or placebo in a single 1-h session. After seeing between 3 and 10 objects (words or shapes) at different locations in a 9 × 9 matrix, participants attempted to immediately reproduce the display on a blank 9 × 9 matrix. Blood glucose was measured before drink ingestion, mid-way through the session, and at the end of the session.
Results
Glucose significantly improves object-location binding (d = 1.08) and location memory (d = 0.83), but not object memory (d = 0.51). Increasing working memory load impairs object memory and object-location binding, and word-location binding is more successful than shape-location binding, but the glucose improvement is robust across all difficulty manipulations. Within the glucose group, higher levels of circulating glucose are correlated with better binding memory and remembering the locations of successfully recalled objects.
Conclusions
The glucose improvements identified are consistent with a facilitative impact on hippocampal function. The findings are discussed in the context of the relationship between cognitive processes, hippocampal function, and the implications for glucose’s mode of action.
... Rat hippocampus is also necessary for the recognition of positions of objects (Long and Kesner, 1996;Gilbert et al., 1998;Mumby et al., 2002;Gilbert and Kesner, 2004;McTighe et al., 2009;Talpos et al., 2009Talpos et al., , 2010Barker and Warburton, 2011). To our knowledge, the behavioral tasks that intended to study the recognition of object's position in rodents have been designed, so that the subject could make contact with the object. ...
... To our knowledge, this work shows for the first time that hippocampus is important for recognizing position of objects located outside the accessible environment. It extents previously published experiments demonstrating that hippocampus is necessary for recognizing positions of objects located within the accessible part of the environment (Long and Kesner, 1996;Gilbert et al., 1998;Mumby et al., 2002;Gilbert and Kesner, 2004;McTighe et al., 2009;Talpos et al., 2009, Barker and Warburton, 2011. In these experiments, rats made contacts with the objects at least during the learning phase. ...
Rat hippocampus plays a crucial role in many spatial tasks, including recognition of position of objects, which can be approached and explored. Whether hippocampus is also necessary for recognizing positions of objects located in an inaccessible part of the environment remains unclear. To address this question, we conditioned rats to press a lever when an object displayed on a distant computer screen was in a particular position ("reward position") and not to press the lever when the object was in other positions ("nonreward positions"). After the rats had reached an asymptotic performance, the role of the dorsal hippocampus was assessed by blocking its activity with muscimol. The rats without functional dorsal hippocampus did not discriminate the reward position from the nonreward positions. Then the same rats were trained to discriminate light and dark conditions. The hippocampal inactivation did not disrupt the ability to discriminate these two conditions. It indicated that the inactivation itself had no major effect on the operant behavior and its control by visual stimuli. We conclude that rats use dorsal hippocampus for recognizing positions of objects located in an inaccessible part of the environment. © 2012 Wiley Periodicals, Inc.
... Spatial prediction of dynamic interactions in rats approaching and contacting other objects to discriminate their positions [6,7]. Therefore, in most experimental paradigms, items of interest are placed within accessible parts of a familiar environment so that animals can associate previously visited positions with objects' locations [8]. ...
Animals and humans receive the most critical information from parts of the environment that are immediately inaccessible and highly dynamic. The brain must effectively process potential interactions between elements in such an environment to make appropriate decisions in critical situations. We trained male Long-Evans rats to discriminate static and dynamic spatial stimuli and to generalize novel dynamic spatial stimuli displayed on an inaccessible computer screen. We provide behavioral evidence indicating that rats encode dynamic visuospatial situations by constructing internal static representations that capture meaningful future interactions between objects. These observations support previous findings in humans that such internal static representations can encapsulate relevant spatiotemporal information of dynamic environments. This mechanism would allow animals and humans to process complex time-changing situations neatly.
... Psychological abilities attributed to associative memory in humans and non-human animals are typically said to be any form of long-term memorisation which involves 'pairing' or 'associating' distinct stimuli such that when presented with one stimuli, the subject can recall the other stimuli. Classical examples of this type of associative memory include pairings: name-face pairs (Sperling et al., 2003), object-sound pairs (Preziosi & Coane, 2017), and object-place pairs (Gilbert & Kesner, 2004). These types of associative memories are part of explicit or declarative memory (Ullman, 2004), i.e., long-term memory that can be explicitly or voluntarily stated or declared. ...
Hopfield networks are artificial neural networks which store memory patterns on the states of their neurons by choosing recurrent connection weights and update rules such that the energy landscape of the network forms attractors around the memories. How many stable, sufficiently-attracting memory patterns can we store in such a network using N neurons? The answer depends on the choice of weights and update rule. Inspired by setwise connectivity in biology, we extend Hopfield networks by adding setwise connections and embedding these connections in a simplicial complex. Simplicial complexes are higher dimensional analogues of graphs which naturally represent collections of pairwise and setwise relationships. We show that our simplicial Hopfield networks increase memory storage capacity. Surprisingly, even when connections are limited to a small random subset of equivalent size to an all-pairwise network, our networks still outperform their pairwise counterparts. Such scenarios include non-trivial simplicial topology. We also test analogous modern continuous Hopfield networks, offering a potentially promising avenue for improving the attention mechanism in Transformer models.
... Overall, our data released in our present study, prove singularly congruent with several studies showing that hippocampal lesions resulted in an initial retention deficit of an object-spatial location association (the equivalent of D1 in our study) and spared performance for a more recent one (the equivalent of D2 in the present study) (Jackson et al., 1998;Gilbert and Kesner, 2004). Our present data are also in agreement with studies showing that the dHPC and the mPFC play significant roles in memory for the serial order of spatial and non-spatial information (Fortin et al., 2002;Kesner et al., 2002;Hannesson et al., 2004;Lisman et al., 2005;Kesner and Hopkins, 2006). ...
... The sham-controlled study was based on the rationale 1) that task-induced engagement of target brain area during stimulation is important for modulating behavior [49,50], and 2) that stimulating key nodes of a given network would suffice to active this network [51]. Given the central role of hippocampus [52] and the right temporoparietal cortex [25,53] in OLM, atDCS was applied over right temporoparietal cortex during a 3-day OLM training aiming to stimulate one node of a broader network that is highly interconnected to the hippocampus [54]. The impact of joint intervention on training success in MCI was directly compared to the impact of stimulation in HE (data of HE was reported previously [21]; in brief, no difference between stimulation conditions was found). ...
Background
Associative object-location memory (OLM) is known to decline even in normal aging, and this process is accelerated in patients with mild cognitive impairment (MCI). Given the lack of curative treatment for Alzheimer’s disease, activating cognitive resources during its preclinical phase might prevent progression to dementia.
Objective
To evaluate the effects of anodal transcranial direct current stimulation (atDCS) combined with an associative episodic memory training on OLM in MCI patients and in healthy elderly (HE).
Methods
In a single-blind cross-over design, 16 MCI patients and 32 HE underwent a 3-day visuospatial OLM training paired with either 20 min or 30 s (sham) atDCS (1 mA, right temporoparietal cortex). Effects on immediate (training success) and long-term memory (1-month) were investigated by conducting Mixed Model analyses. In addition, the impact of combined intervention on within-session (online) and on between-session (offline) performance were explored.
Results
OLM training+atDCS enhanced training success only in MCI patients, but not HE (difference n.s.). Relative performance gain was similar in MCI patients compared to HE under atDCS. No beneficial effect was found after 1-month. Exploratory analyses suggested a positive impact on online, but a negative effect on offline performance in MCI patients. In both groups, exploratory post-hoc analyses indicated an association between initially low-performers and greater benefit from atDCS.
Conclusion
Cognitive training in MCI may be enhanced by atDCS, but further delineation of the impact of current brain state, as well as temporal characteristics of multi-session atDCS-training application, may be needed to induce longer-lasting effects.
... Hyperactivity can be difficult to control for, but DPP6-KO mice showed normal swim speed in the water maze test and normal latency in both forced and choice run of the T-maze test, like WT controls, suggesting that novelty induced hyperactivity did not strongly influence the results seen in these studies. Object location memory is hippocampal dependent, and dependent on CA1 specifically (Gilbert and Kesner, 2004;Hunsaker et al., 2007), consistent with DPP6-KO impairment in CA1-dependent spatial memory. Memory for objects themselves (novel object recognition) is often described as not requiring the hippocampus, but a long delay, like that used in the current study, disruption of CA1 does impair object recognition (Hammond et al., 2004), suggesting that effects of DPP6-KO in this test is consistent with CA1 specific synaptic impairment as well. ...
DPP6 is well known as an auxiliary subunit of Kv4-containing, A-type K+ channels which regulate dendritic excitability in hippocampal CA1 pyramidal neurons. We have recently reported, however, a novel role for DPP6 in regulating dendritic filopodia formation and stability, affecting synaptic development and function. These results are notable considering recent clinical findings associating DPP6 with neurodevelopmental and intellectual disorders. Here we assessed the behavioral consequences of DPP6 loss. We found that DPP6 knockout (DPP6-KO) mice are impaired in hippocampus-dependent learning and memory. Results from the Morris water maze and T-maze tasks showed that DPP6-KO mice exhibit slower learning and reduced memory performance. DPP6 mouse brain weight is reduced throughout development compared with WT, and in vitro imaging results indicated that DPP6 loss affects synaptic structure and motility. Taken together, these results show impaired synaptic development along with spatial learning and memory deficiencies in DPP6-KO mice.
... The hippocampus plays important roles in forming new memories, emotional responses, spatial navigation and modulation of short-term memory to long-term memory [1,2]. It shows an impressive capacity for structural reorganization throughout life. ...
Hippocampus is highly susceptible to endocrine disrupting chemicals exposure particularly during the critical phase of brain development. In the present study, mice offspring were exposed to endocrine disruptors mancozeb (MCZ) and imidacloprid (IMI) individually (40 mg MCZ and 0.65 mg IMI/kg/day) as well as to their equimixture (40 mg MCZ + 0.65 mg IMI/kg/day) through the diet of lactating mothers from post-natal day (PND) 1 to PND 28. Half of the randomly selected male offspring were killed at PND 29 and the rest half were left unexposed and killed at PND 63. Brain weight, histology, plasma hormone profile and working memory performance were the various endpoints studied. Brain weight was significantly decreased in the mixture-exposed group at PND 29, which persisted to PND 63. Total thickness of pyramidal cell layers decreased significantly along with misalignment, shrinkage and degeneration of pyramidal neurons in CA1 and CA3 regions of the IMI and mixture-exposed groups. The length and branch points of dendrites of pyramidal neurons were decreased significantly in mixture-exposed group at both PND 29 and PND 63. Dendritic spine density was also reduced in mixture-exposed group offspring. Testosterone level was significantly decreased only at PND 29 but corticosterone level was increased at both PND 29 and PND 63 in mixture-exposed offspring. T-maze task performance revealed significantly increased time duration and reduced path efficiency in mixture-exposed group offspring. The results thus indicate that pesticide mixture exposure could lead to changes in learning behaviour even at doses that individually did not induce any adverse effect on hippocampal organization. This article is protected by copyright. All rights reserved.
... ORM is based on the natural tendency of rodents to explore novel objects [48] and is widely used as a measure of memory in rodents [40,41,[49][50][51]. ORM was evaluated in a 40 X 40 cm open field surrounded by 35-cm-high walls made of Plexiglas (Stoelting, Wood Dale, IL) [24]. ...
The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5-Azacytidine (5-AzaC), a DNA methyltransferase inhibitor, on neurobehavioral abnormalities in mice. Our findings suggest that the 5-AzaC treatment significantly inhibited DNA methylation, impaired extracellular signal-regulated kinase (ERK1/2) activation and reduced expression of the activity-regulated cytoskeleton-associated protein (Arc). These events lead to the activation of caspase-3 (a marker for neurodegeneration) in several brain regions, including the hippocampus and cortex, two brain areas that are essential for memory formation and memory storage, respectively. 5-AzaC treatment of P7 mice induced significant deficits in spatial memory, social recognition, and object memory in adult mice and deficits in long-term potentiation (LTP) in adult hippocampal slices. Together, these data demonstrate that the inhibition of DNA methylation by 5-AzaC treatment in P7 mice causes neurodegeneration and impairs ERK1/2 activation and Arc protein expression in neonatal mice and induces behavioral abnormalities in adult mice. DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function.
... After lesion of the hippocampus, remembering previously learned "object-place" associations is impaired [2]. It is also known that the processes of memory and learning, which involve the hippocampus, such as spatial learning and context processing, are critically influenced by dopamine. ...
A hypothetical mechanism for the influence of dopamine on the formation of neuronal representations
of “object–place” associations in the hippocampus is proposed for spatial learning. According to this
mechanism, dopamine that is released in a new situation or during expectation of reinforcement improves
conditions for the development of homosynaptic long-term potentiation (LTP) of the input to the dentate
gyrus granule cells from the medial entorhinal cortex, which transmits information about spatial location of
objects and characteristics of objects. The effect occurs due to the activation of D1/D5 receptors on granule
cells and D2 receptors on inhibitory interneurons. Heterosynaptic depression is simultaneously developed in
inputs that were not activated. As a result, a contrasting representation of the learned “object–place” association
is formed on neurons of the dentate gyrus. From these neurons, information about the association via
the CA3 field is transmitted to the radial layer of the CA1 field by Schaffer collaterals, whereas the stratum
lacunosum-moleculare receives signals directly from the entorhinal cortex and thalamic nucleus reuniens,
which connects the hippocampus with the prefrontal cortex. The sign of the modulatory influence of dopamine
on the efficacy of excitatory inputs to pyramid neurons of the CA1 field depends on the relationship
between excitation and inhibition of these neurons, as well as the dopamine concentration. By acting on
D1/D5 receptors on the pyramidal neurons of the CA1 field, dopamine can promote LTP induction in Schaffer
collaterals simultaneously with LTP induction in the relatively strong perforant input, whereas relatively
weak perforant input, as well as the input from the nucleus reuniens, become depressed. This depression is
promoted by the activation of D1/D5 receptors on the inhibitory interneurons of the CA1 field, induction of
LTP in these neurons, and the following enhancement of afferent inhibition of pyramidal cells. As a consequence,
neuronal representation of the learned “object–place” association in the CA1 field is distorted more
weakly by non-relevant information that comes from the entorhinal cortex and thalamus. As a result, the error
probability during the performance of spatial task decreases. Because activation of D1/D5 receptors on pyramidal
neurons of the prefrontal cortex promotes LTP induction in the input from the CA1 field, dopamine
must improve the goal-directed performance of spatial tasks. The proposed mechanism explains the results
of some experimental studies that seemed to be contradictory or incomprehensible.
... We do not. Much of the large body of research on navigation has explored maze learning, object location learning, or goal switching (e.g., Morris et al., 1982;Packard and McGaugh, 1996;Gilbert and Kesner, 2004;Tse et al., 2007). Only one study, to our knowledge, has examined the impact of hippocampal lesions on a detour task (Winocur et al., 2010), see Figure 2A. ...
Adapting behavior to accommodate changes in the environment is an important function of the nervous system. A universal problem for motile animals is the discovery that a learned route is blocked and a detour is required. Given the substantial neuroscience research on spatial navigation and decision-making it is surprising that so little is known about how the brain solves the detour problem. Here we review the limited number of relevant functional neuroimaging, single unit recording and lesion studies. We find that while the prefrontal cortex (PFC) consistently responds to detours, the hippocampus does not. Recent evidence suggests the hippocampus tracks information about the future path distance to the goal. Based on this evidence we postulate a conceptual model in which: Lateral PFC provides a prediction error signal about the change in the path, frontopolar and superior PFC support the re-formulation of the route plan as a novel subgoal and the hippocampus simulates the new path. More data will be required to validate this model and understand (1) how the system processes the different options; and (2) deals with situations where a new path becomes available (i.e., shortcuts).
... The first possibility is that the HPC is not crucial for intact mice to learn the task during the extensive daily training of 40 sessions, but may be involved in some processes underlying remote memory consolidation of critical information needed to perform the task after a long retention delay. Interestingly, transient deficits in retrieval performance were observed 1-2 weeks after post-training HPC lesions in rats previously trained in an object paired-associate task and in a delayed matching-to-place task in lever-press operant chambers (Gilbert & Kesner, 2004;Sloan, Good, & Dunnett, 2006). Here, the mice were unable to relearn the task in 5 sessions. ...
... Although we did not directly test the involvement of certain brain regions it appears that, based on the observed results, memory processes which require a high amount of hippocampal activation are highly susceptible during the normalization phase to acute stress. Spatial reference memory as tested in the water maze and object-place associations as tested in the episodic-like memory task have been extensively linked to the hippocampus [26][27][28][29][30]. Temporal order memory and working memory appear to depend mainly on an intact prefrontal cortex [31,32]. ...
Adaptively responding to acute stress has been of great importance for human and animal survival. However, for our species, stress-related disorders are putting an ever-increasing burden on healthcare systems. It is thus crucial to understand the basic processes and cognitive changes associated with acute stress. Here, we examined the effects of repeated acute stress exposure on spatial (watermaze) and memory (delayed match to sample and episodic-memory-like tasks) performance within the same group of freely-behaving rats. We found striking performance deficits in stressed animals navigating in the water maze. We also found, in an episodic-like memory task, striking object-location deficits, but not in temporal-object association learning in stressed animals. Finally, no differences were apparent for any delay periods (up to 30sec.) in a delayed match to sample task. Taken together, these results show a strong differential effect of repeated acute stress on differing memory processes.
... Overall, our data released in our present study, prove singularly congruent with several studies showing that hippocampal lesions resulted in an initial retention deficit of an object-spatial location association (the equivalent of D1 in our study) and spared performance for a more recent one (the equivalent of D2 in the present study) (Jackson et al., 1998;Gilbert and Kesner, 2004). Our present data are also in agreement with studies showing that the dHPC and the mPFC play significant roles in memory for the serial order of spatial and non-spatial information (Fortin et al., 2002;Kesner et al., 2002;Hannesson et al., 2004;Lisman et al., 2005;Kesner and Hopkins, 2006). ...
Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hippocampo-prefrontal cortex interplay. The role of the stress-induced regional corticosterone increase in such dysfunction remains however unclear, since there is no published study as yet dedicated to measuring corticosterone concentrations simultaneously in both the prefrontal cortex (mPFC) and the hippocampus (dHPC) in relation with memory impairments. To that aim, we first showed in Experiment 1 that an acute stress (3 electric footschocks; 0.9 mA each) delivered before memory testing reversed the memory retrieval pattern (MRP) in a serial discrimination task in which mice learned two successive discriminations. More precisely, whereas non-stressed animals remembered accurately the first learned discrimination and not the second one, stressed mice remembered more accurately the second discrimination but not the first one. We demonstrated that local inactivation of dHPC or mPFC with the anesthetic lidocaine recruited the dHPC activity in non-stress conditions whereas the stress-induced MRP inversion recruited the mPFC activity. In a second experiment, we showed that acute stress induced a very similar time-course evolution of corticosterone rises within both the mPFC and dHPC. In a 3rd experiment, we found however that in situ injections of corticosterone either within the mPFC or the dHPC before memory testing favored the emergence of the mPFC-dependent MRP but blocked the emergence of the dHPC-dependent one. Overall, our study evidences that the simultaneous increase of corticosterone after stress in both areas induces a shift from dHPC (non-stress condition) to mPFC-dependent MRP and that corticosterone is critically involved in mediating the deleterious effects of stress on cognitive functions involving the mPFC-HPC interplay.
... The rats have to recognize position of the object located in an inaccessible part of the environment in this task. Our recent study showed that rats use hippocampus in the task (Levcik et al. 2013) similarly as in the tasks with approachable objects that can be explored by the animals (Mumby et al. 2002, Gilbert and Kesner 2004). Therefore, this is the first study, in which the effect of prazosin on spatial cognition has been studied in a hippocampal-dependent operant task. ...
Prazosin, an alpha(1)-adrenoceptor antagonist, is well known for its depressant effect on motivation and motor activity, while it has no effect on retention of spatial behavior in several tasks, e.g. in the Morris water maze and radial arm maze. The role of alpha(1)-adrenoceptors in operant tasks with stimulus-controlled behavior has not yet been tested. The present study investigated the effect of prazosin on the modulation of overall motor activity and on cognitive performance in a spatial operant task called object-position recognition task, where operant behavior (lever pressing) was controlled by spatial stimuli displayed on a computer screen. This task has been previously showed to be hippocampal-dependent. Pre-test injection of prazosin at the dose of 3 mg/kg decreased the responding rate, while it did not affect the recognition of object's position. In conclusion, we validated the new cognitive test with a drug with known pharmacological effects on behavior and confirmed the depressant effect of prazosin on motor activity and no effect on retrieval of spatial memory in the hippocampal-dependent operant task.
... A large body of literature suggests that the hippocampus is important for remembering objects and their associated locations (Parkinson et al., 1988;Cahusac et al., 1989;Save et al., 1992;Gilbert and Kesner, 2004;Lee and Solivan, 2008;Manns and Eichenbaum, 2009;Kim et al., 2011;Yoon et al., 2012), which presumably subserves episodic memory (Tulving and Markowitsch, 1998). It is hypothesized that the hippocampus receives critical information from the cortical areas in the medial temporal lobe such as PER, postrhinal cortex (POR), lateral entorhinal cortex (LEC), and medial entorhinal cortex (MEC; Witter and Amaral, 2004). ...
Objects and their locations can associatively define an event and a conjoint representation of object-place can form an event memory. Remembering how to respond to a certain object in a spatial context is dependent on both hippocampus and perirhinal cortex (PER). However, the relative functional contributions of the two regions are largely unknown in object-place associative memory. We investigated the PER influence on hippocampal firing in a goal-directed object-place memory task by comparing the firing patterns of CA1 and CA3 of the dorsal hippocampus between conditions of PER muscimol inactivation and vehicle control infusions. Rats were required to choose one of the two objects in a specific spatial context (regardless of the object positions in the context), which was shown to be dependent on both hippocampus and PER. Inactivation of PER with muscimol (MUS) severely disrupted performance of well-trained rats, resulting in response bias (i.e., choosing any object on a particular side). MUS did not significantly alter the baseline firing rates of hippocampal neurons. We measured the similarity in firing patterns between two trial conditions in which the same target objects were chosen on opposite sides within the same arm [object-in-place (O-P) strategy] and compared the results with the similarity in firing between two trial conditions in which the rat chose any object encountered on a particular side [response-in-place (R-P) strategy]. We found that the similarity in firing patterns for O-P trials was significantly reduced with MUS compared to control conditions (CTs). Importantly, this was largely because MUS injections affected the O-P firing patterns in CA1 neurons, but not in CA3. The results suggest that PER is critical for goal-directed organization of object-place associative memory in the hippocampus presumably by influencing how object information is associated with spatial information in CA1 according to task demand.
... A large body of literature suggests that the hippocampus is important for remembering objects and their associated locations (Parkinson et al., 1988; Cahusac et al., 1989; Save et al., 1992; Gilbert and Kesner, 2004; Lee and Solivan, 2008; Manns and Eichenbaum, 2009; Kim et al., 2011; Yoon et al., 2012 ), which presumably subserves episodic memory (Tulving and Markowitsch, 1998). It is hypothesized that the hippocampus receives critical information from the cortical areas in the medial temporal lobe such as PER, postrhinal cortex (POR), lateral entorhinal cortex (LEC), and medial entorhinal cortex (MEC; Witter and Amaral, 2004). ...
... This task thus required contextual item–response selection. Normal rats learned to approach the rewarding object and to inhibit such responses to the unrewarded object, whereas electrolytic lesions in the hippocampus completely abolished such learning capability (Gilbert and Kesner, 2002 ) as well as performance when lesions were produced after learning (Gilbert and Kesner, 2004). The same results were reported when different odors must be discriminated contextually (but not when object-odor associations were required). ...
Animals including humans engage in goal-directed behavior flexibly in response to items and their background, which is called contextual behavior in this review. Although the concept of context has long been studied, there are differences among researchers in defining and experimenting with the concept. The current review aims to provide a categorical framework within which not only the neural mechanisms of contextual information processing but also the contextual behavior can be studied in more concrete ways. For this purpose, we categorize contextual behavior into three subcategories as follows by considering the types of interactions among context, item, and response: contextual response selection, contextual item selection, and contextual item-response selection. Contextual response selection refers to the animal emitting different types of responses to the same item depending on the context in the background. Contextual item selection occurs when there are multiple items that need to be chosen in a contextual manner. Finally, when multiple items and multiple contexts are involved, contextual item-response selection takes place whereby the animal either chooses an item or inhibits such a response depending on item-context paired association. The literature suggests that the rhinal cortical regions and the hippocampal formation play key roles in mnemonically categorizing and recognizing contextual representations and the associated items. In addition, it appears that the fronto-striatal cortical loops in connection with the contextual information-processing areas critically control the flexible deployment of adaptive action sets and motor responses for maximizing goals. We suggest that contextual information processing should be investigated in experimental settings where contextual stimuli and resulting behaviors are clearly defined and measurable, considering the dynamic top-down and bottom-up interactions among the neural systems for contextual behavior.
... This is in contrast to simple left/right position differences between stimuli as seen in delayed nonmatch or match to sample tasks. In rodents, a common approach is to use paired-associates paradigms in which animals must remember specific odoreplace (Day et al., 2003, Rajji et al., 2006) or objecteplace associations (Gilbert and Kesner, 2003, 2004). Similar item-in-place paradigms have been developed using computer screens in nonhuman primates (Baxter et al., 2007; Gaffan, 1994), and have proved successful in detecting early symptoms of cognitive decline associated with AD dementia (Taffe et al., 2004). ...
... In this task, as the start box door was opened, the rat saw an object against a certain visual background in the room because the open field was not walled off from the environment. Normal rats learned to approach the rewarding object but to inhibit such responses to the unrewarded object, whereas electrolytic lesions in the hippocampus completely abolished such learning capability ( Gilbert and Kesner, 2002 ) as well as performance when lesions were produced after learning ( Gilbert and Kesner, 2004 ). The same results were reported when different odors must be discriminated contextually (but not when object-odor associations were required). ...
Abstract Animals including humans experience objects in a certain environment, that is, a context. Same objects may have to be treated differently, or different objects may need to be treated similarly depending on contexts. Flexible behavioral choice in such ambiguous situations involves dynamic interactions among brain regions, but underlying neural mechanisms are poorly understood. In this article, prior studies that have examined (mostly in rodents) some of the brain regions involved in contextual processing of object information using goal-directed tasks are selectively reviewed. The current review identifies the hippocampus, prefrontal cortex (PFC) and perirhinal cortex (PER) as key regions for associating the same objects with different reward values and responses depending on the background visual context. The hippocampus is particularly important for contextual choice behavior when the context must be used as a conditional cue that can disambiguate reward-related 'meanings' of objects. The PER appears to play significant roles in such tasks during initial learning (but not so much for retrieval) because perturbations in the PER produce severe deficits in the acquisition of the contextual object memory task. Perturbations in the PFC also affect performance when flexible contextual responses should be made toward otherwise ambiguous objects.
... 51,52 These findings led the authors to conclude that the dentate gyrus and CA3 of the hippocampus are critical to the formation of object location memory based on relationships of distance and angle. 53 In the present study, LFP resulted in a significant decrease in the number of CA2/3 neurons in the dorsal hippocampus ipsilateral to injury. Consistent with previous lesion studies of the CA3 in the dorsal hippocampus, LFP-injured animals with a loss of CA2/3 neurons failed to re-explore two objects when there was a change in the distance between the objects. ...
Impairments in learning and memory occur in as many as 50% of patients following traumatic brain injury (TBI). Similar impairments occur in rodent models of TBI, and the development of new memory testing procedures provide an opportunity to examine how TBI affects memory processing in specific neural memory systems. Specifically, metric, topological and temporal ordering tasks are object-based tests for memory of spatial orientation and temporal sequencing working memory developed for use in rodents. Previous studies demonstrated that specific lesions of the dentate gyrus/CA3 of the hippocampus and the parietal cortex result in deficits in the metric and topological spatial orientation tasks respectively. Lesions of the CA1 impaired a rat's ability to recall the temporal order of odors. The purpose of the following study was to determine whether moderate lateral fluid percussion TBI would generate deficits in these working memory tasks and whether observed deficits were associated with cell loss in the CA2/3 and/or CA1 of the hippocampus. Two weeks following a moderate lateral fluid percussion TBI, adult rats demonstrated significant deficits in both the metric and temporal ordering tasks (p < 0.05) but not in the topological task. Stereological analysis identified a significant reduction in neurons in the CA2/3 (p < 0.05) but not the CA1 of the hippocampus. These data demonstrate the utility of three object-based tasks to expand our understanding of how different neural memory systems are affected by TBI.
... Deletions of the NR1 gene in the CA3 subregion of dorsal hippocampus were shown to disrupt learning of the odor-context associations but did not affect expression of previously learned associations (Rajji et al., 2006). A previously published study by Gilbert and Kesner (2004) also showed that hippocampal lesions, including the CA3 subregion, do not completely abolish retrieval of previously learned object-place associations but rather result in a 8 transient deficit. Therefore, the CA3 subregion of the hippocampus may be necessary for the formation of novel arbitrary associations but may play only a limited role in the retrieval of previously learned associations. ...
Computational models, behavioral data, and electrophysiological data suggest that the CA3 subregion of the hippocampus may support multiple mnemonic processes critical to the formation and subsequent retrieval of spatial memories. Multiple researchers have proposed that the CA3 subregion contains an autoassociative network in which synaptic connections between CA3 neurons that represent different components of a memory are strengthened via recurrent collateral connections. As a result, it has been suggested that the CA3 autoassociative network may support multiple processes including the formation of spatial arbitrary associations, temporary maintenance of spatial working memory, and spatial pattern completion. In addition, the CA3 subregion has been suggested to be involved in spatial pattern separation. The separation of patterns is hypothesized to be accomplished based on the low probability that any two CA3 neurons will receive mossy-fiber input synapses from a similar subset of dentate gyrus cells. The separation of patterns also may be enhanced by competitive inhibition within CA3 and dentate gyrus. This review will focus on the mnemonic processes supported by CA3 neurons and how these processes may facilitate the encoding and retrieval of spatial information. Although there is growing evidence indicating that the hippocampus plays a role in the processing of nonspatial information as well, the scope of the present review will focus on the role of the CA3 subregion in spatial memory.
... For example, the OLT has a spatial component which is lacking in ORT. In addition, the hippocampus has been demonstrated to be critical for the object-place associations in OLT [57][58][59]. However, its roles in ORT have yielded inconsistent results. ...
Studies on how acute stress and the stress-related hormones affect learning and memory have yielded inconsistent findings, which might be due to some variables such as the properties of stressors, the nature of memory, the protocols for behavioral tasks and the characteristics of the subjects. However, the impacts of acute stress on different memory components have not been clearly demonstrated within one single experiment. The aim of present study was to evaluate the effects of 1-h restraint stress and the stress-induced plasma corticosterone elevation on memory acquisition, consolidation, and retrieval in mice, using object-recognition task (ORT) and object-location task (OLT) with a 4-h or 24-h intertrial interval (ITI). The results showed that, regardless of ITI, the recognition memory retrieval was significantly disrupted by acute restraint stress exposure, which started 75 min before the test session of both ORT and OLT. Acute restraint stress performed immediately after memory acquisition interrupted the consolidation of short-term recognition memories (4-h ITI) into long-term ones (24-h ITI). Moreover, the disrupted memory retrieval or consolidation was strongly related to the stress-induced plasma corticosterone elevation in a negative manner. These preliminary results clarified that acute restraint stress differently impacts three memory components, and the enhanced plasma corticosterone level under stressful situation plays critical roles in the information processing of memory under the stressful situation.
... The leading hypothesis suggests that object-place pairedassociative memory is likely to require unique contributions of multiple brain areas: The PoR-MEC pathway may process spatial information ( Brun et al., 2002;Hargreaves et al., 2005), the PR-LEC may represent object information ( Bussey et al., 2003;Albasser et al., 2010), and the spatial information may be further elaborated and associated with object information finally in the hippocampus ( Gilbert and Kesner, 2004;Bachevalier and Nemanic, 2008;Lee and Solivan, 2008). Although additional experimental studies are needed in the future to verify such hypothesis and to measure detailed amounts of spatial-nonspatial interactions at different levels, the current study emphasizes that the functional interaction between the hippocampus and PR (directly and/or indirectly via the EC) is necessary when ambiguity in object identity needs to be cleared using spatial information. ...
The hippocampus and the perirhinal cortex (PR) are reciprocally connected both directly and indirectly via the entorhinal cortex. Although it has been hypothesized that the two regions should have intimate functional interactions with each other on the basis of the anatomical connectivity, many lesion studies have demonstrated functional dissociations instead between the hippocampus and PR. To show a tight functional relationship between the two regions, we used reversible inactivation techniques targeting both the hippocampus and PR within subjects, combined with a biconditional memory task in which the rat must consider information about objects and their locations. Specifically, rats were implanted with two sets of bilateral cannulas into the hippocampus and PR, and were tested in an object-place paired-associate task in a radial maze. While alternating between two arms, the rats were required to choose one of the objects exclusively associated with a given arm for food. Bilateral muscimol (MUS) injections into either the hippocampus or PR equally produced chance level performance. When a functional disconnection procedure was used to disrupt the interaction between the hippocampus and PR, contralateral MUS injections into the hippocampus and PR resulted in severe impairment in performance. However, inactivating the hippocampus and PR ipsilaterally did not affect the performance. In a simple object discrimination task, the same functional disconnection protocol with MUS did not affect the performance. The results powerfully demonstrate that the hippocampus, the PR, and their functional interactions are all indispensable when objects and their spatial locations must be processed at the same time.
... As our aim was to focus on the associative memory between the objects and their location, we targeted hippocampus which seems to be more specifically involved in object-location memory [13,14]. Hippocampus is known to be important for object-location memory14151617 ; although other regions such as mPFC and perirhinal cortex are also implicated in such tasks, they are probably more involved in novelty processing. Especially, it was recently reported that PKMzeta inhibitor destructed object location memory, but not object identity memory, when it was locally applied in hippocampus [18]. ...
Although some reports indicate that protein synthesis dependent process may be induced by updating information, the role of protein synthesis and degradation in changing the content of pre-existing memory is yet unclear. In this study, we utilized an object rearrangement task, in which partial information related to a pre-existing memory is changed, promoting memory modification. Inhibitors of both protein synthesis and protein degradation impaired adequate incorporation of the altered information, each in a distinctive way. These results indicate that protein synthesis and degradation play key roles in memory modification.
... For example, associative memory is important for remembering where things are located in the world around us (object-place associations). In humans, nonhuman primates, and rodents, hippocampal damage impairs acquisition of object-place associations (Kessels et al. 2001;Gilbert and Kesner 2004;Crane and Milner 2005;Rolls et al. 2005;Gilbert et al. 2008). Further, studies in humans find that an intact hippocampus is required for face-house (Stark et al. 2002), word-word (Davachi and Wagner 2002;Meltzer and Constable 2005), object-context (Goh et al. 2004), and face-name (Chua et al. 2007) associative memory. ...
Hippocampal lesions in rodents impair both object-place and odor-place associative memory. Subjects with hippocampal damage have impaired associative memory such as object-place memory. Whereas studies have investigated some types of associative memory, no investigation has specifically examined odor-place associative memory in subjects with well-defined amnesia. It is unknown whether amnesic subjects with hippocampal damage would be impaired on an odor-place associative task. We investigated the effect of hippocampal damage in amnesic subjects with hippocampal atrophy on odor-place associative memory and recognition memory tasks. Amnesic and healthy comparison subjects matched for age and education were tested on an odor-place associative task, an odor recognition task, and a place recognition task. The odor-place associative task required subjects to associate 6 odors with 6 spatial locations on a board. The recognition tasks required subjects to identify the 6 odors and the 6 locations that were presented during the associative task. Amnesic subjects were impaired for odor-place memory and place recognition, but not odor recognition compared with comparison subjects. These results suggest that the human hippocampus is necessary for odor-place associative memory and spatial recognition memory. These data provide support for the idea that odor-place associative memory is mediated by the hippocampus in both humans and rodents, suggesting an evolutionary continuity in cognitive function assigned to the hippocampus.
... The PFC, in turn, organizes and provides multiple motor plans to drive goaldirected behavior (Floresco et al. 1997;Kolb 1984;Izaki et al. 2000;Ruit and Neafsey 1988;Vertes 2002;Verwer et al. 1997;Broadbent et al. 2004). Previous studies have also demonstrated that the HIP is critical for object-place associations (Gilberta and Kesner 2004;Mumby et al. 2002;Lee et al. 2005;Murai et al. 2007;De Rosa et al. 2005). The increased expression of caspase-3 in the HIP suggests that spatial memory and its information transfer were damaged. ...
Chronic exposure to d-galactose (D-Gal), which causes acceleration in aging and simulated symptoms of natural senescence, has been used as a reliable animal model of aging. However, the different influences of D-Gal on spatial and nonspatial cognition are as yet unclear.
In the present study, the object recognition test (ORT), object location test (OLT) and Y-maze test were carried out to assess the cognitive performance of mice after 8 weeks of chronic D-Gal exposure. The expression of oxidative-stress biomarkers in the prefrontal cortex (PFC) and caspase-3 in the hippocampus (HIP) were also determined.
The results of the behavioral tests indicated that after chronic D-Gal exposure, the spatial memory of mice was seriously impaired, whereas nonspatial cognition remained intact. D-Gal exposure also induced more significant changes in malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities in the HIP than in the PFC. Furthermore, chronic D-Gal exposure triggered more substantial caspase-3 overexpression in the HIP than in the PFC.
Together, these findings suggest the impairment of spatial, but not nonspatial, cognitive ability after chronic D-Gal exposure. The differential nature of this impairment might be due to the more substantial reduction of antioxidant enzyme activities and more severe neuronal apoptosis mediated by caspase-3 in the HIP. The present results also indicate that the HIP and HIP-dependent spatial cognition might be more susceptible to oxidative stress during senescence or other pathological processes.
... For example, no impairment was seen in odour and object pairing tasks, while pairings of object and location or odour and location were both impaired by lesions of the hippocampus (Gilbert and Kesner 2002). If one of the associates is within the spatial domain, then lesions of the hippocampus cause impairments during task acquisition, but not always in retention (Gilbert and Kesner 2004;Tse et al. 2006Tse et al. , 2007. Such tasks can be rapidly learned and the data highly informative; however, the touchscreen version of PAL will be a particularly attractive alternative for those researchers interested in mimicking as closely as possible the test setting of the human version of the task. ...
Paired-associate learning (PAL), as part of the Cambridge Neuropsychological Test Automated Battery, is able to predict who from an at-risk population will develop Alzheimer's disease. Schizophrenic patients are also impaired on this same task. An automated rodent model of PAL would be extremely beneficial in further research into Alzheimer's disease and schizophrenia.
The objective of this study was to develop a PAL task using touchscreen-equipped operant boxes and test its sensitivity to manipulations of the hippocampus, a brain region of interest in both Alzheimer's disease and schizophrenia.
Previous work has shown that spatial and non-spatial memory can be tested in touchscreen-equipped operant boxes. Using this same apparatus, rats were trained on two variants of a PAL task differing only in the nature of the S- (the unrewarded stimuli, a combination of image and location upon the screen). Rats underwent cannulation of the dorsal hippocampus, and after recovery were tested under the influence of intra-hippocampally administered glutamatergic and cholinergic antagonists while performing the PAL task.
Impairments were seen after the administration of glutamatergic antagonists, but not cholinergic antagonists, in one of the two versions of PAL.
De-activation of the hippocampus caused impairments in a PAL task. The selective nature of this effect (only one of the two tasks was impaired), suggests the effect is specific to cognition and cannot be attributed to gross impairments (changes in visual learning). The pattern of results suggests that rodent PAL may be suitable as a translational model of PAL in humans.
... Spatio-tactile novel stimulation was produced by transiently introducing four different objects in the corners of the recording box for 20 minutes, as previously described . Exposure to novel objects elicits robust IEG transcriptional upregulation in the hippocampus and primary sensory cortices during WK (Wallace et al., 1995), and REM sleep (Ribeiro et al., 1999), but the recall of novel object memories becomes hippocampal-independent over time (Forwood et al., 2005;Gilbert and Kesner, 2004). All recordings were performed under infrared illumination. ...
Episodic and spatial memories engage the hippocampus during acquisition but migrate to the cerebral cortex over time. We have recently proposed that the interplay between slow-wave (SWS) and rapid eye movement (REM) sleep propagates recent synaptic changes from the hippocampus to the cortex. To test this theory, we jointly assessed extracellular neuronal activity, local field potentials (LFP), and expression levels of plasticity-related immediate-early genes (IEG) arc and zif-268 in rats exposed to novel spatio-tactile experience. Post-experience firing rate increases were strongest in SWS and lasted much longer in the cortex (hours) than in the hippocampus (minutes). During REM sleep, firing rates showed strong temporal dependence across brain areas: cortical activation during experience predicted hippocampal activity in the first post-experience hour, while hippocampal activation during experience predicted cortical activity in the third post-experience hour. Four hours after experience, IEG expression was specifically upregulated during REM sleep in the cortex, but not in the hippocampus. Arc gene expression in the cortex was proportional to LFP amplitude in the spindle-range (10–14 Hz) but not to firing rates, as expected from signals more related to dendritic input than to somatic output. The results indicate that hippocampo-cortical activation during waking is followed by multiple waves of cortical plasticity as full sleep cycles recur. The absence of equivalent changes in the hippocampus may explain its mnemonic disengagement over time.
... This remapping allows the hippocampus to create context-specific representations of different environments (or even the same environment), which can be used to disambiguate the behavioral contingencies of similar stimuli that can occur in different spatial or behavioral contexts (Nadel et al., 1985); (2) the hippocampus may create configural object þ place representations by combining the object-related information from the LEC and the spatial information from MEC. Thus, each context-specific, hippocampal map can become associated with the individual items that occupy locations in the map and events that occur in that environment (O'Keefe and Nadel, 1978; Nadel et al., 1985; Gilbert and Kesner, 2004; Janzen and van Turennout, 2004; Rivard et al., 2004). This binding may also allow the hippocampus to activate the same representation each time the rat enters a familiar environment (Touretzky and Redish, 1996; Redish and Touretzky, 1997; Kentros et al., 1998 ). ...
The hippocampus is thought to be involved in episodic memory in humans. Place cells of the rat hippocampus offer a potentially important model system to understand episodic memory. However, the difficulties in determining whether rats have episodic memory are profound. Progress can be made by considering the hippocampus as a computational device that presumably performs similar transformations on its inputs in both rats and in humans. Understanding the input/output transformations of rat place cells can thus inform research on the computational basis of human episodic memory. Two examples of different transformations in the CA3 and CA1 regions are presented. In one example, CA3 place fields are shown to maintain a greater degree of population coherence than CA1 place fields after a rearrangement of the salient landmarks in an environment, in agreement with computational models of CA3 as an autoassociative network. In the second example, CA3 place field appears to store information about the spatiotemporal sequences of place fields, starting with the first exposure to a cue-altered environment, whereas CA1 place fields store this information only on a temporary basis. Finally, recordings of hippocampal afferents from the lateral and medial entorhinal cortex (EC) suggest that these two regions convey fundamentally different representations to the hippocampus, with spatial information conveyed by the medial EC and nonspatial information conveyed by the lateral EC. The dentate gyrus and CA3 regions may create configural object+place (or item+context) representations that provide the spatiotemporal context of an episodic memory.
... It is possible, however, that damage to barrel cortex altered the rat's ability to feel its way during the dark probe trial; however, given that the PC-lesioned rats made few errors on the egocentric version, this is not likely. The fact that lesions of the hippocampus produced a mild impairment during maze retention for both maze versions was not altogether predicted; however, these data support findings by Gilbert and Kesner (2004), who found that lesions of the hippocampus initially impair the retention of object–place associations followed by recovery. The retention data in this study indicate similar results. ...
The present experiments used 2 versions of a modified Hebb-Williams maze to test the role of the dorsal hippocampus (dHip) and parietal cortex (PC) in processing allocentric and egocentric space during acquisition and retention. Bilateral lesions were made to either the dHip or PC before maze testing (acquisition) or after maze testing (retention). The results indicate that lesions of the dHip impair allocentric maze acquisition, whereas lesions of the PC impair egocentric maze acquisition. During retention, lesions of the PC produced a significant impairment on both maze versions, whereas lesions of the dHip produced short-lived, transient impairments on both maze versions. These results suggest that during acquisition, the hippocampus and PC process spatial information in parallel; however, long-term retention of spatial information requires the PC with the dHIP as necessary for retrieval and/or access but not necessarily storage.
Nelumbo nucifera Gaertn. (N. nucifera) tea is used as food and folk medicine to reduce toxicity in Southeast Asia. Mancozeb (Mz) is used for controlling fungi in agriculture and contains heavy metals. This study aimed to examine the effect of white N. nucifera petal tea on cognitive behavior, hippocampus histology, oxidative stress, and amino acid metabolism in rats poisoned with mancozeb. Seventy-two male Wistar rats were divided into nine groups (n = 8 in each). Y-maze spontaneous alternation test was used to assess cognitive behavior, and amino acid metabolism was investigated by nuclear magnetic resonance spectroscopy (¹H-NMR) from blood. There was a significant increase in relative brain weight in the Mz co-administered with the highest dose (2.20 mg/kg bw) of white N. nucifera group. The levels of tryptophan, kynurenine, picolinic acid, and serotonin in blood showed a significant decrease in the Mz group and a significant increase in the Mz co-administered with low dose (0.55 mg/kg bw) of white N. nucifera group. However, there was no significant difference in cognitive behavior, hippocampus histology, oxidative stress, and corticosterone. This study demonstrated that a low dose of white N. nucifera petal tea has a neuroprotective effect against mancozeb.
Leucine-rich repeat (LRR) transmembrane proteins have been directly linked to neurodevelopmental and cognitive disorders. We have previously shown that the LRR transmembrane protein Lrig1 is a physiological regulator of dendrite complexity of hippocampal pyramidal neurons and social behavior. In this study, we performed a battery of behavioral tests to evaluate spatial memory and cognitive capabilities in Lrig1 mutant mice. Cognitive assessment demonstrated deficits in recognition and spatial memory, evaluated by novel object recognition and novel object location tests. Moreover, we found that Lrig1-deficient mice present specific impairments in the processing of similar, but not dissimilar locations in a spatial pattern separation task, wich correlated with an enhanced denditic growth and branching of Doublecortin (DCX)-positive immature granule cells (GCs) of the dentate gyrus (DG). Altogether, these findings indicate that Lrig1 plays an essential role controlling morphological and functional plasticity in the hippocampus.
This article is protected by copyright. All rights reserved
Traumatic brain injury (TBI) is a major public health concern worldwide, and is the leading cause of disability and death in children and young adults. One of the most common consequences of TBI is cognitive impairment, including deficits in memory and executive function. Although some recovery of function is typical after injury, many individuals are left with lifelong memory problems. Therefore, it is important to understand how the brain’s memory systems are affected by various types of TBI. Such knowledge will improve our ability to understand what memory functions are most vulnerable to injury and then to use this information to develop more effective treatments and rehabilitation strategies to improve cognitive outcome. This chapter reviews studies of memory loss following TBI, with a focus on studies in animal models of brain injury and how results from these studies have shaped our understanding of the mechanisms and consequences of TBI on the brain’s memory systems. The chapter also considers how understanding the organization of multiple memory systems is shaping current research in the field, and describes recent studies based on the Kesner attribute model that provide new insights into how TBI affects memory and cognition.
Extensive research indicates that the hippocampus is crucial for the formation and use of memory in humans. Memory is extremely complex in terms of the kind of information that is represented in the brain, the processes associated with it, and its distribution across a variety of neural systems. While most investigators agree that the hippocampus is an essential neural structure involved in memory, debate remains regarding the exact information the hippocampus processes such as temporal, spatial, sensory (e.g., odors, objects, sounds, etc.), response, reward, linguistic, and relational information. In the context of the Attribute Model of Memory, this chapter will discuss the effects of hippocampal damage on memory in humans based on findings from behavioral and neuroimaging studies.
The recollection of attended events in terms of their content, place, and temporal context is known as episodic memory. It has long been held that episodic memory is unique to humans, because it was accepted that animals lack autonoetic awareness/conciousness, and the ability to subjectively sense time. These assumptions are currently being challenged. Evidence has accumulated which indicates that various animal species, indeed, show behavioral manifestations of phenomenological and objective features of episodic memory, such as, e.g., metacognition, conscious recollection, mental time travel, temporal order memory, as well as the simultaneous remembering of the what, where, and when elements of unique events. With this chapter we summarize the progress made in modeling different prerequisites and features of human episodic memory in animals and try to identify possible neural substrates of episodic memory. Animal research has led to the definition of objective behavioral criteria by which different features of episodic memory can be operationalized experimentally and assessed in both animals and humans. An operational definition of episodic memory is proposed and open questions on the nature of episodic memory, e.g., the necessary conditions and mechanisms for encoding episodes and/or events are discussed.
Remembering the location of objects, an integral part of everyday life, is known to decline with advancing age and early in the course of neurodegenerative dementia. Here, we aimed to test if object-location learning and its retention could be modified by noninvasive brain stimulation. In a group of 20 elderly (mean age 62.1 years) right-handed individuals, we applied transcranial direct current stimulation (tDCS; 20 minutes, 1 mA) over the right temporoparietal cortex, while subjects acquired the correct position of buildings on a street map using an associative learning paradigm. Each subject participated in a randomized and balanced order in 1 session of anodal tDCS and 1 session of sham stimulation, in a double-blind design with 2 parallel versions of the task. Outcome measures were learning success at the end of each session, and immediate as well as delayed (1 week) free recall. We found that subjects performed comparably in the learning task in the 2 conditions, but showed improved recall 1 week after learning with anodal tDCS compared with learning with sham stimulation. In conclusion, retention of object-location learning in the elderly may be modulated by noninvasive brain stimulation, a finding of potential relevance not only for normal aging but also for memory deficits in pathological aging.
Ca(V)2.1 is highly expressed in the nervous system and plays an essential role in the presynaptic modulation of neurotransmitter release machinery. Recently, the antiepileptic drug levetiracetam was reported to inhibit presynaptic Ca(V)2.1 functions, reducing glutamate release in the hippocampus, although the precise physiological role of Ca(V)2.1-regulated synaptic functions in cognitive performance at the system level remains unknown. This study examined whether Ca(V)2.1 mediates hippocampus-dependent spatial short-term memory using the object location and Y-maze tests, and perirhinal cortex-dependent nonspatial short-term memory using the object recognition test, via a combined pharmacological and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation had normal spatial and nonspatial short-term memory. A 100mg/kg dose of levetiracetam, which is ineffective in wild-type controls, blocked spatial short-term memory in rol/+ mice. At 5mg/kg, the N-methyl-D-aspartate (NMDA) receptor blocker (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which is ineffective in wild-type controls, also blocked the spatial short-term memory in rol/+ mice. Furthermore, a combination of subthreshold doses of levetiracetam (25 mg/kg) and CPP (2.5mg/kg) triggered a spatial short-term memory deficit in rol/+ mice, but not in wild-type controls. Similar patterns of nonspatial short-term memory were observed in wild-type and rol/+ mice when injected with levetiracetam (0-300 mg/kg). These results indicate that Ca(V)2.1-mediated NMDA receptor signaling is critical in hippocampus-dependent spatial short-term memory and differs in various regions. The combination subthreshold pharmacological and genetic approach presented here is easily performed and can be used to study functional signaling pathways in neuronal circuits.
Heterozygous rolling Nagoya (rol/+) mice carrying Ca(V)2.1 alpha(1) mutation demonstrated normal behavior in Y maze test. Similar spontaneous alternation patterns were noted in wild-type and rol/+ mice injected with N-methyl-D-aspartate (NMDA; 0-50mg/kg, sc). Systemic injection of NMDA receptor blocker (MK-801; 0.05 mg/kg, ip) or intrahippocampal injection of MK-801 (0.5 microg/side), which had no effect in wild-type controls, decreased spatial cognition in rol/+ mice. These results indicate that Ca(V)2.1 alpha(1) mutation probably through decrease in Ca(2+) influx lowers the threshold for learning impairment. The combination subthreshold pharmacological and genetic approach is useful to study functional pathways in neuronal circuits.
Remembering events frequently involves associating objects and their associated locations in space, and it has been implicated that the areas associated with the hippocampus are important in this function. The current study examined the role of the perirhinal cortex in retrieving familiar object-place paired associates, as well as in acquiring novel ones. Rats were required to visit one of two locations of a radial-arm maze and choose one of the objects (from a pair of different toy objects) exclusively associated with a given arm. Excitotoxic lesions of the perirhinal cortex initially impaired the normal retrieval of object-place paired-associative memories that had been learned presurgically, but the animals relearned gradually to the level of controls. In contrast, when required to associate a novel pair of objects with the same locations of the maze, the same lesioned rats were severely impaired with minimal learning, if any, taking place throughout an extensive testing period. However, the lesioned rats were normal in discriminating two different objects presented in a fixed arm in the maze. The results suggest that the perirhinal cortex is indispensable to forming discrete representations for object-place paired associates. Its role, however, may be compensated for by other structures when familiar object-place paired associative memories need to be retrieved.
Associative learning is critical to normal cognitive development in children. However, young adults typically outperform children on paired-associate tasks involving visual, verbal and spatial location stimuli. The present experiment investigated cross-modal odour-place associative memory in children (7-10 years) and young adults (18-24 years). During the study phase, six odours were individually presented and paired with one of 12 spatial locations on a board. During the test phase, participants were presented with the six stimuli individually and were asked to place each stimulus on the correct spatial location. Children committed significantly more errors on the odour-place task than did young adults. However, item recognition memory for the odours or spatial locations involved in the odour-place associative memory task was similar between children and young adults. Therefore, poor odour-place associative memory in children did not result from impaired memory for the individual odours or spatial locations involved in the associations. The results suggest that cross-modal associative memory is not fully developed in children.
Object location task (OLT) has been used as a model of hippocampal-dependent memory. Despite this application, there is neither a consistent pharmacological validation of NMDA receptor modulation nor an evaluation of hippocampal participation in mice. In the OLT, mice were placed in the open field with two identical objects for 3 min and, after a delay of 30, 90, 180 or 360 min, one object was moved to a new location and the time spent exploring the objects in new, (novel) and old (familiar) locations was recorded. Our results showed that the mice were able to discriminate object location when tested either 90 or 180 min after training. Intraperitoneal administration of MK801 (NMDA receptors antagonist) or scopolamine (mACh antagonist) induced amnesic effects. On the other hand, D-cycloserine (NMDA agonist) or tacrine (cholinesterase inhibitor) were able to improve memory in the mice tested. In addition, lidocaine infusion in the hippocampal CA1 region 10 min before training blocked object location memory. In short, this work indicates that OLT is susceptible to modulation of NMDA receptors, cholinergic neurotransmission and it is the first to characterize the participation of the hippocampal CA1 region, in this task.
We previously showed that 24h after learning, mice significantly remembered the first (D1) but not the second (D2) discrimination in a serial spatial task and that an acute stress delivered 5min before the test phase reversed this memory retrieval pattern. A first experiment evaluated the effects of dorsal hippocampus (HPC) or prefrontal cortex (PFC) lesions, these two brain areas being well-known for their involvement in serial and spatial memory processes. For this purpose, six independent groups of mice were used: non-lesioned (controls), PFC or HPC-lesioned animals, submitted or not to an acute stress (electric footshocks; 0.9mA). Results show that (i) non-stressed controls as well as PFC-lesioned mice (stressed or not) remembered D1 but not D2; (ii) stressed controls and HPC-lesioned mice (stressed or not) remembered D2 but not D1; (iii) stress significantly increased plasma corticosterone in controls and PFC-lesioned mice, but not in HPC-lesioned mice which already showed a significant plasma corticosterone increase in non-stressed condition. Since data from this first experiment showed that stress inhibited the hippocampal-dependent D1 memory retrieval, a second experiment evaluated the behavioral effect of intrahippocampal corticosterone injection in non-stressed mice. Results show that intrahippocampal corticosterone injection induced a reversal of serial memory retrieval pattern similar to that induced by acute stress. Overall, our study shows that (i) in non-stress condition, the emergence of D1 is HPC-dependent; (ii) in stress condition, the emergence of D2 requires the PFC integrity; moreover, intrahippocampal corticosterone injection mimicked the effects of stress in the CSD task.
Odor-place and object-place associative memory were compared in healthy older (over the age of 65) and young (18 to 25 years of age) adults. Twelve spatial locations were defined on a tabletop board. Either six odors or six objects were presented one at a time and each was paired with a location on the board. The participant then was presented with each stimulus individually and asked to place it in its paired location. Older adults showed impaired odor-place associative memory but unimpaired object-place memory compared to young adults. Item recognition memory for the individual stimuli or locations used on the associative memory task was similar in both groups. The results suggest that odor-place associative memory is particularly affected by age-related brain changes.
Place cells are hippocampal neurons whose discharge is strongly related to a rat's location in the environment. The existence of such cells, combined with the reliable impairments seen in spatial tasks after hippocampal damage, has led to the proposal that place cells form part of an integrated neural system dedicated to spatial navigation. This hypothesis is supported by the strong relationships between place cell activity and spatial problem solving, which indicate that the place cell representation must be both functional and in register with the surroundings for the animal to perform correctly in spatial tasks. The place cell system nevertheless requires other essential elements to be competent, such as a component that specifies the overall goal of the animal and computes the path required to take the rat from its current location to the goal. Here, we propose a model of the neural network responsible for spatial navigation that includes goal coding and path selection. In this model, the hippocampal formation allows for place recognition, and stores the set of places that can be accessed from each position in the environment. The prefrontal cortex is responsible for encoding goal location and for route planning. The nucleus accumbens translates paths in neural space into appropriate locomotor activity that moves the animal towards the goal in real space. The complete model assumes that the hippocampal output to nucleus accumbens and prefrontal cortex provides information for generating solutions to spatial problems. In support of this model, we finally present preliminary evidence that the goal representation necessary for path planning might be encoded in the prelimbic/infralimbic region of the medial prefrontal cortex.
Human episodic memory refers to the recollection of an unique past experience in terms of what happened, and where and when it happened. Factoring out the issue of conscious recollection, episodic memory, even at the behavioral level, has been difficult to demonstrate in non-human mammals. Although, it was previously shown that rodents can associate what and when or what and where information given on unique trials, it proved to be difficult to demonstrate memory for what, where, and when simultaneously in mammals, without using extensive training procedures, which might induce semantic rather than episodic memory recall. Towards the goal of an animal model of human episodic memory we designed an three-trial object exploration task in which different versions of the novelty-preference paradigm were combined to subsume (a) object recognition memory, (b) the memory for locations in which objects were explored, and (c) the temporal order memory for object presented at distinct time points. We found that mice spent more time exploring two "old familiar" objects relative to two "recent familiar" objects, reflecting memory for what and when and concomitantly directed more exploration at a spatially displaced "old familiar" object relative to a stationary "old familiar" object, reflecting memory for what and where. These results suggest that during a single test trial the mice were able to (a) recognize previously explored objects, (b) remember the location in which particular objects were previously encountered, and (c) to discriminate the relative recency in which different objects were presented. According to the currently discussed behavioral criteria for episodic-like memory in animals, our results suggest that mice are capable to form such higher order memories.
Episodic memory refers to the conscious recollection of a unique past experience in terms of "what" happened and "where" and "when" it happened. Since deficits in episodic memory are found in a number of neuropsychiatric diseases, such as Alzheimer's disease, for which several pharmacological, lesion and genetic animal models are available, there is a need for animal models of episodic-like memory, which can be used to devise appropriate treatments. However, even when the problem of conscious recollection in animals is factored out, episodic memory has been difficult to demonstrate in nonhuman mammals because it has not yet been possible to demonstrate an integrated memory for "what",-"where"-and-"when". We designed a three-trial "what",-"where"-and-"when" object exploration task in which different versions of the novelty preference paradigm were combined to subsume (a) object recognition memory, (b) the memory for locations in which objects were explored and (c) the temporal order memory for objects presented at distinct time points. Our results suggest that mice are able to (a) recognize previously explored objects, (b) remember the location in which particular objects were previously encountered and (c) discriminate the relative recency in which different objects were presented. We suggest that our protocol providing the simultaneous assessment of object memory for "what",-"where"-and-"when" in mice might be useful in the search for the neural substrates of episodic memory, the screening for promnestic drugs and the behavioral phenotyping of genetic models of neuropsychiatric diseases affecting episodic memory.
The present study examined the effects of a human APPswe mutation on object recognition memory in adult Tg2576 mice. The results showed that 14-month old Tg2576 mice were able to detect object novelty as well as control mice, even with delays of up to 24 hr. In addition, transgenic mice showed a normal recency effect and explored the most recently encountered object significantly less than an object encountered earlier in a trial. However, adult Tg2576 mice showed impairments in detecting a change in the relative positions of an array of familiar objects. The results suggest that the formation of representations involving a combination of object identity and spatial information are particularly sensitive to amyloid pathology in adult APPswe mutant mice.
Human episodic memory refers to the recollection of an unique past experience in terms of its details, its locale, and temporal occurrence. Episodic memory, even in principle, has been difficult to demonstrate in non-verbal mammals. Previously, we provided evidence that mice are able to form an integrated memory for "what," "where," and "when" aspects of single experiences by combining different versions of the novelty-preference paradigm, i.e., object recognition memory, the memory for locations in which objects were explored, and the temporal order memory for objects presented at distinct time points. In the present series of experiments we evaluated whether this paradigm, with minor modifications, also works with rats. We found that rats spent more time exploring an "old familiar" object relative to a "recent familiar" object, suggesting that they recognized objects previously explored during separate trials and remembered their order of presentation. Concurrently, the rats responded differentially to spatial object displacement dependent on whether an "old familiar" or "recent familiar" object was shifted to a location, where it was not encountered previously. These results provide strong evidence that the rats established an integrated memory for "what," "where," and "when." We also found that acute stress impaired the animal's performance in the episodic-like memory task, which, however, could be partially reversed by the N-Methyl-D-aspartate-receptors agonist D-cycloserine.
The conscious recollection of unique personal experiences in terms of their details (what), their locale (where) and temporal occurrence (when) is known as episodic memory and is thought to require a 'self-concept', autonoetic awareness/conciousness, and the ability to subjectively sense time. It has long been held that episodic memory is unique to humans, because it was accepted that animals lack a 'self-concept', 'autonoetic awareness', and the ability to 'subjectively sense time'. These assumptions are now being questioned by behavioral evidence showing that various animal species indeed show behavioral manifestations of different features of episodic memory such as, e.g. 'metacognition', 'conscious recollection' of past events, 'temporal order memory', 'mental time travel' and have the capacity to remember personal experiences in terms of what happened, where and when. The aim of this review is to provide a comprehensive overview on the current progress in attempts to model different prerequisites and features of human episodic memory in animals and to identify possible neural substrates of animal episodic memory. The literature covered includes behavioral and physiological studies performed with different animal species, such as non-human primates, rodents, dolphins and birds. The search for episodic memory in animals has forced researchers to define objective behavioral criteria by which different features of episodic memory can be operationalized experimentally and assessed in both animals and humans. This is especially important because the current definition of episodic memory in terms of mentalistic constructs such as 'self', 'autonoetic awareness/consciousness', and 'subjectively sensed time', not only hinders animal research on the neurobiology of episodic memory but also research with healthy human subjects as well as neuropsychiatric patients with impaired language or in children with less-developed verbal abilities.
Rhesus monkeys learned 10 visual stimulus-stimulus association, or paired associates. They then received bilateral removals of either the amygdaloid complex and underlying cortex, the hippocampal formation and underlying cortex, or both combined, or they were retained as unoperated controls. After surgery or rest, the monkeys were tested for their retention of the preoperatively learned set of paired associates, as well as for their ability to learn new associations of the same type. Both unoperated controls and hippocampectomized monkeys relearned the preoperatively trained set of paired associates almost immediately. By contrast, monkeys with amygdala removals were moderately retarded in relearning, and monkeys with combined amygdala and hippocampal ablations were severely retarded. When confronted with new sets of visual stimuli, monkeys with amygdala removals or hippocampal removals learned new sets of paired associates at the same rate as the controls, whereas monkeys with the combined ablation were again profoundly retarded. Only one monkey with the combined lesion was able to learn new stimulus-stimulus associations to criterion, and then only after extensive training, despite the ability of all three animals in this group to perform delayed matching-to-sample with the same stimuli and the same intraatrial delays as those used in the paired associate task. At the end of the main experiment, two of the unoperated controls received bilateral ablations of the rhinal cortex. These monkeys showed the same level of difficulty in learning new paired associates as the animals in the main experiment that had received the combined amygdala plus hippocampal ablations. The results implicate the medial temporal lobe, and particularly the rhinal cortex, in the formation of stimulus-stimulus associative memories.
Rats with complete cytotoxic hippocampal lesions exhibited spatial memory impairments in both the water maze and elevated T maze. They were hyperactive in photocell cages; swam faster in the water maze; and were less efficient on a nonspatial, differential reinforcement of low rates (DRL) task. Performance on both spatial tasks was also impaired by selective dorsal but not ventral lesions; swim speed was increased by ventral but not dorsal lesions. Both partial lesions caused a comparable reduction in DRL efficiency, although these effects were smaller than those of complete lesions. Neither partial lesion induced hyperactivity when rats were tested in photocell cages, although both complete and ventral lesion groups showed increased activity after footshock in other studies (Richmond et al., 1999). These results demonstrate possible functional dissociations along the septotemporal axis of the hippocampus.
The present experiment was conducted in order to test the hypotheses (1) that the posterior parietal cortex (PPC) serves as a neural system that is critical for binding spatial location and object information in long-term memory and (2) that even restricted lesions of the PPC would result in similar deficits. Long-Evans rats were given either a large or a small PPC lesion or a control surgery under Nembutal anesthesia. After a 1-week recovery period, the rats were tested on either an object or a spatial location go/no-go successive discrimination task. After reaching criterion (a minimum of a 5 sec difference between reward and nonreward trials), they were trained on the other discrimination. After reaching criterion on the second discrimination, all of the rats were trained on a successive discrimination go/no-go task in which they had to remember which object/spatial location pairs had been associated with reward. As compared with controls, neither the small nor the large PPC lesion impaired object or spatial location discrimination. In the paired-associate object/spatial location task, both large and small PPC lesioned rats were impaired, relative to controls. These data suggest that the rodent PPC is not involved in object or spatial location discrimination but rather is involved in discrimination and long- term memory for the combination of object and spatial location information.
Abstract A series of five experiments investigated the relationship between object memory and scene memory in normal and fornix-transected monkeys. An algorithm created formally defined background and objects on a large visual display; the disposition of some particular objects in particular places in a particular background constitutes a formally defined scene. The animals learned four types of discrimination problem: (1) object-in-place discrimination learning, in which the correct (rewarded) response was to a particular object that always occupied the same place in a particular unique background, (2) place discrimination learning, in which the correct response was to a particular place in a unique background, with no distinctive object at that place, (3) object discrimination learning in unique backgrounds, in which the correct response was to a particular object that could occupy one or the other of two possible places in a unique background, and (4) object discrimination learning in varying backgrounds, in which the correct response was to a particular object that could appear at any place in any background. The severest impairment produced by fornix transection was in object-in-place learning. Fornix transection did not impair object discrimination learning in varying backgrounds. The results from the other two types of learning task showed intermediate severity of impairment in the fornix-transected animals. The idea that fornix transection in the monkey impairs spatial memory but leaves object memory intact is thus shown to be an oversimplification. The impairments of object memory in the present experiments are analogous to the impairments of episodic memory seen in human amnesic patients.
show that the empirical physiological characteristics of plasticity (synaptic learning) in the hippocampus are generally consistent with the kinds of Hebbian autoassociative models frequently studied in connectionist theory / point out . . . the important role of the temporal interactions among diverse circuit elements, especially inhibitory interneurons, which are often ignored in more abstract formal models (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Tested 33 male rats for their ability to learn a list of 4 paired associates (foods paired with spatial locations). Ss increased levels of correct orienting responses (CORs) as a function of serial position of the paired associate within the list (temporal order function [TOF]) when short intertrial intervals were used between paired associates. Ss were more likely to use intramaze rather than extramaze cues. Rats may use a temporal strategy to remember a list of paired associates. After training, 22 new rats received medial prefrontal cortex (PFC), hippocampus, parietal cortex, or cortical control lesions and were retested. Ss with cortical control lesions continued to display a TOF, whereas Ss with medial PFC lesions showed a reduction in the number of CORs and failed to demonstrate the TOF, suggesting that the medial PFC might mediate the selection of temporal strategies. Ss with hippocampal lesions also showed a marked reduction in level of CORs, but they continue to display a TOF. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Three groups of neurosurgical patients with temporal lobe excisions, frontal lobe excisions or unilateral amygdalo-hippocampectomy were assessed on a computerized battery of tasks designed to investigate visuo-spatial short-term recognition memory and learning. A double dissociation is reported between deficits of pattern recognition memory and spatial recognition memory which were observed in the two posterior groups and frontal lobe patients, respectively. In addition, both the temporal lobe and amygdalo-hippocampectomy patients were also impaired on a delayed matching-to-sample paradigm whilst frontal lobe patients performed at an equivalent level to controls. Finally, whilst the impaired performance of the three groups was indistinguishable on a test of paired-associate learning, quite different patterns of deficit were observed on a test of spatial working memory. These results are discussed with reference to recent suggestions that visual recognition memory is mediated by a neural system which includes, as major components, the inferotemporal cortex, the medial temporal lobe structures and particular sectors of the frontal lobe, and are compared to previous findings from patients with idiopathic Parkinson's disease and dementia of the Alzheimer type.
Rats with lesions of the fornix, the dorsal hippocampus, or a control operation were trained on a spatial-visual conditional associative learning task in which they had to learn to associate particular locations with specific visual stimuli. Animals with damage of the fornix were able to learn the task at a rate comparable to that of the control animals, but the performance of the hippocampal rats was significantly impaired in comparison with that of both the control and the fornix groups. In a second experiment, lesions to the fornix or the dorsal hippocampus significantly impaired performance on a spatial working memory task, the eight-arm radial maze. These findings suggest that the interaction between the hippocampus and subcortical structures via the fornix may be critical only for certain types of spatial learning and memory.
In each of three experiments with Cynomolgus monkeys (Macaca fascicularis), there was a group of normal control animals, a group with bilateral cortical ablations in the principal sulcus, and a group with fornix transection. In Expt. 1, half of each group learned problems in which the position of a pair of visual stimuli, to the monkey's left or right, indicated which of the visual stimuli was the correct (rewarded) one. The other animals learned problems in which visual stimuli indicated, irrespective of their own spatial position, whether reward was to be found on the monkey's left or on the right. The animals with fornix transection were impaired in both tasks. The animals with sulcus principalis ablation were also impaired in both tasks. The impairment caused by fornix transection was more severe than that caused by sulcus principalis ablation. Within each of the two operated groups, the degree of impairment in the two tasks was equal, when assessed in proportion to the difficulty of each task for control animals. Expt. 2 showed that neither of the operated groups was impaired in visual discrimination learning with spatial position irrelevant. Expt. 3 tested spatial discrimination learning (acquisition and reversal of a left-right discrimination) with irrelevant visual cues. Here the fornix-transected group was impaired but the group with sulcus principalis ablations was normal. It is suggested, on the basis of these findings and previous results, that fornix transection produces a general deficit in remembering the spatial arrangement of whole scenes, while sulcus principalis ablation produces a deficit in high-order integration involving spatial information.
Monkeys were trained preoperatively on a one-trial learning task in which they were required to associate in memory a novel object and the place in which it had just appeared. After learning the task to a level of 80% correct responses, they received bilateral ablations of either the hippocampal formation or the amygdaloid complex. The monkeys with amygdalectomy showed a small drop in performance initially but then regained their preoperative level. By contrast, the monkeys with hippocampectomy dropped to near-chance levels of performance and remained there throughout postoperative testing. Both groups performed at better than 90% correct responses on a test of recognition memory. These results, taken together with earlier work, suggest that although the hippocampus and amygdala appear to participate equally in object recognition, only the hippocampus is critical for the rapid formation of object-place associations.
A theory which holds that information is normally stored within a specialized memory rather than the system immediately responsible for the performance of behavior is advanced. The transfer of information from storage to the system immediately responsible for performance, according to the theory, can occur independently of the occurrence of external stimuli. Usually such information transfer would be prompted by motivational cues and always result in anticipation of stimuli.
The hippocampus is regarded as part of a system responsible for determining which information is to be transferred from storage to the performance system. The effects of hippocampal ablation are explained in terms of the elimination of such transfer. A subsidiary system relying upon habit formation is held to be responsible for the learning of which hippocampally ablated animals are capable.
The hippocampus and related structures are thought to be capable of 1) representing cortical activity in a way that minimizes overlap of the representations assigned to different cortical patterns (pattern separation); and 2) modifying synaptic connections so that these representations can later be reinstated from partial or noisy versions of the cortical activity pattern that was present at the time of storage (pattern completion). We point out that there is a trade-off between pattern separation and completion and propose that the unique anatomical and physiological properties of the hippocampus might serve to minimize this trade-off. We use analytical methods to determine quantitative estimates of both separation and completion for specified parameterized models of the hippocampus. These estimates are then used to evaluate the role of various properties and of the hippocampus, such as the activity levels seen in different hippocampal regions, synaptic potentiation and depression, the multi-layer connectivity of the system, and the relatively focused and strong mossy fiber projections. This analysis is focused on the feedforward pathways from the entorhinal cortex (EC) to the dentate gyrus (DG) and region CA3. Among our results are the following: 1) Hebbian synaptic modification (LTP) facilitates completion but reduces separation, unless the strengths of synapses from inactive presynaptic units to active postsynaptic units are reduced (LTD). 2) Multiple layers, as in EC to DG to CA3, allow the compounding of pattern separation, but not pattern completion. 3) The variance of the input signal carried by the mossy fibers is important for separation, not the raw strength, which may explain why the mossy fiber inputs are few and relatively strong, rather than many and relatively weak like the other hippocampal pathways. 4) The EC projects to CA3 both directly and indirectly via the DG, which suggests that the two-stage pathway may dominate during pattern separation and the one-stage pathway may dominate during completion; methods the hippocampus may use to enhance this effect are discussed.
Damage to either the fimbria-fornix or to the hippocampus can produce a deficit in spatial behavior and change in locomotor activity but the extent to which the two kinds of damage are comparable is not known. Here we contrasted the effects of cathodal sections of the fimbria-fornix with ibotenic acid lesions of the cells of the hippocampus (Ammon's horn and the dentate gyrus) on place learning in a swimming pool and on circadian activity. Rats in both ablation groups were impaired relative to control rats in learning a single place response but they did acquire the response as measured by swim latencies, errors, and by enhanced searching on probe trials. They were also more active than the control group on the test of activity. Nevertheless, the fimbria-fornix group was initially more impaired on learning and was more active than the hippocampal group. Analysis of the strategies used in learning indicated that the lesion groups were very similar to each other but different from the control group especially in that at asymptotic performance, rats in both lesion groups made rather tight loops as they swam toward the platform. This strategy likely contributed to the greater proportion of time they spent swimming in the correct quadrant on the subsequent probe trial. These findings confirm that rats with fimbria-fornix or hippocampal damage display impairments in place learning and are hyperactive but also show that there are lesion differences. The results are discussed with respect to the relative effectiveness of the lesions and the possibility that fibers in the fimbria-fornix may mediate some functions that are not attributable to the hippocampus.
Normal rats rapidly acquire and remember associations between nonspatial stimuli as expressed in the social transmission of food preferences. In the present study, rats with selective neurotoxic lesions including all subdivisions of the hippocampal region (hippocampus proper, dentate gyrus, and subiculum) normally acquired and briefly retained the food odor association as demonstrated by intact memory immediately after social training. However, long-term memory in these animals was severely impaired in contrast to strong 24-h retention by intact rats. More selective lesions to the hippocampus proper plus dentate gyrus alone, or the subiculum alone had no effect on memory at either test interval. These findings indicate that the hippocampal region is required for long-term retention of a nonspatial form of natural memory.
First, what is computed by the hippocampus is considered. Based on the effects of damage to the hippocampus and neuronal activity recorded in the primate hippocampus, it is suggested that it is involved in associating together information usually originating from different cortical regions, for example, about objects and their place in a spatial environment. The rapid formation of such context-dependent memories is prototypical of memories of particular events or episodes. Second, a computational theory of how it performs this function, based on neuroanatomical and neurophysiological information about the different neuronal systems contained within the hippocampus, is described. Key hypotheses are that the CA3 pyramidal cells operate as a single autoassociation network to store new episodic information as it arrives via a number of specialized preprocessing stages from many different association areas of the cerebral cortex, and that the dentate granule cell/mossy fiber system is important particularly during learning to help to produce a new pattern of firing in the CA3 cells for each episode. The computational analysis shows how many memories could be stored in the hippocampus, and how quickly the CA3 autoassociation system would operate during recall. The analysis is then extended to show how the CA3 system could be used to recall the whole of an episodic memory when only a fragment of it is presented. It is shown how this retrieval within the hippocampus could lead to recall of neuronal activity in association areas of the cerebral neocortex similar to that present during the original episode, via modified synapses in backprojection pathways from the hippocampus to the cerebral neocortex. The recalled information in the cerebral neocortex could then by used by the neocortex in the formation of long-term memories and/or in the selection of appropriate actions.
Macaque monkeys can learn arbitrary mappings between stimuli and spatially directed actions (often termed conditional motor learning), and, after the development of a strong learning set, can do so in just a few trials. Ablation studies have shown that the hippocampus plus subjacent cortex is necessary for this rapid and highly flexible type of learning. We consider evidence that the arbitrary mapping function of the hippocampal system may be more general and fundamental than currently accepted and what limitations there may be, if any, on the information that it can map. Removal of the hippocampal system yields a pattern of deficits and preserved abilities that correlates remarkably closely with that found in human global amnesics, such as patient H.M., on a variety of declarative memory tasks. Thus, the rapid acquisition of arbitrary visuomotor mappings may represent an example of declarative memory in nonhuman primates.
In recent years, a number of computational neural networks have been proposed aimed at describing memory functions associated with different subregions of the hippocampus, namely dentate gyrus, CA3 and CA1. Recent evidence suggests that indeed specific subregions of the hippocampus may subserve different computational functions, such as spatial and temporal pattern separation, short-term or working memory, pattern association, and temporal pattern completion.
The neurobiology of the attribute model of memory suggests that that there are potential interactions between the hippocampus and parietal cortex (PC) during learning, consolidation, and retrieval of spatial but not nonspatial information. In addition, the model suggests that there are double dissociations between the hippocampus and PC with respect to the intrinsic processes of spatial perceptual memory and spatial short-term or working memory. Data are presented that support both suggestions. There is a good possibility that spatial information is initially processed in parallel in the hippocampus and PC, followed by transfer of spatial information from the hippocampus to the PC for subsequent long-term storage.
The ability of rats with control or hippocampal lesions to learn an object-place, odor-place, or object-odor paired-associate task was assessed in a cheeseboard maze apparatus. The data indicate that rats with hippocampal lesions were significantly impaired, compared with controls, in learning both the object-place and the odor-place paired-associate tasks. However, rats with hippocampal lesions learned the object-odor paired-associate task as readily as did controls. The data suggest that the rodent hippocampus is involved in paired-associate learning when a stimulus must be associated with a spatial location. However, the hippocampus is not involved in paired-associate learning when the association does not involve a spatial component.
Hippocampal function and interference Conditional associa-tive learning and the hippocampal system
- M L Shapiro
- D S Olton
- V Sziklas
- S Lebel
- M Petrides
Shapiro, M. L., & Olton, D. S. (1994). Hippocampal function and interference. In D. L. Schacter, & E. Tulving (Eds.), Memory systems (pp. 141–146). London: MIT Press. Sziklas, V., Lebel, S., & Petrides, M. (1998). Conditional associa-tive learning and the hippocampal system. Hippocampus, 8, 131– 137.
The hippocampal system and declarative memory in humans and animals: Experimental analysis and historical origins
- H Eichenbaum
Eichenbaum, H. (1994). The hippocampal system and declarative memory in humans and animals: Experimental analysis and historical origins. In D. L. Schacter, & E. Tulving (Eds.), Memory systems (pp. 147–201). London: MIT Press.