The role of the hippocampus in object recognition in rats: examination of the influence of task parameters and lesion size

Studies examining the effects of hippocampal lesions on object recognition memory in rats have produced conflicting results. The present study investigated how methodological differences and lesion size may have contributed to these discrepancies. In Experiment 1 we compared rats with complete, partial (septal) and sham hippocampal lesions on a spontaneous object recognition task, using a protocol previously reported to result in deficits following large hippocampal lesions . Rats with complete and partial hippocampal lesions were unimpaired, suggesting the hippocampus is not required for object recognition memory. However, rats with partial lesions showed relatively poor performance raising the possibility that floor effects masked a deficit on this group. In Experiment 2, we used a second spontaneous object recognition protocol similar to that used by the two other studies that have reported deficits following hippocampal lesions . Rats with complete hippocampal lesions were significantly impaired, whereas rats with partial lesions were unimpaired. However, the complete lesion group showed less object exploration during the sample phase. Thus, the apparent recognition memory deficit in Experiment 2 may be attributable to differential encoding. Together, these findings suggest that the hippocampus is not required for intact spontaneous object recognition memory. These findings suggest that levels of object exploration during the sample phase may be a critical issue, and raise the possibility that previous reports of object recognition deficits may be due to differences in object exploration rather than deficits in object recognition per se.     

Hippocampal damage and anterograde object-recognition in rats after long retention intervals

Although several studies in rats have found that hippocampal damage has negligible effects on anterograde object-recognition memory, the findings are not entirely conclusive, because most studies have used retention intervals lasting only a few hours. We assessed the effects of neurotoxic hippocampal lesions on anterograde object recognition, using a novel-object preference test, with retention intervals that were considerably longer than in previous studies-24 h, 1 week, and 3 weeks. To promote object recognition after such long intervals, rats were familiarized with a sample object in an open field for 5 min/day for 5 consecutive days. Recognition was assessed by comparing the amount of time spent investigating the sample versus a novel object on a preference test at one of the postlearning intervals. The rats with hippocampal lesions displayed a normal novelty preference after a 3-week interval, and their performance across the three delay conditions was not significantly different from that of control rats. The findings indicate that extensive hippocampal damage spares anterograde object recognition in rats, even after retention intervals lasting days or weeks.     

Spatial and object reversal learning in monkeys with partial temporal lobe ablations

Effects of frontal and combined medial temporal, or amygdala and hippocampal lesions separately, were compared on delayed alternation, delayed response, spatial and object reversals and non-spatial delayed alternation. Failure on spatial delayed alternation but not delayed response characterized all monkeys with temporal lobe lesions. Frontal, medial temporal and amygdala lesions resulted in varying degrees of impairment on spatial and object reversals, while hippocampal lesion produced a deficit on spatial but not object reversals. All monkeys with temporal lobe lesions achieved normal learning scores on nonspatial delayed alternation, but hippocampal monkeys were most efficient. The effects of medial temporal lesions are discussed in terms of the relative contributions of the amygdala and hippocampal ablations to the total syndrome.     

Effects of hippocampal administration of a cannabinoid receptor agonist WIN 55,212-2 on spontaneous object and place recognition in rats

Involvement of hippocampal cannabinoid receptors in short-term memory was investigated in rats using spontaneous object and place recognition memory tasks. Rats were allowed to explore the field in which two identical objects were presented. Then after a delay period, they were placed again in the same field in which one of the two objects was replaced by another object (object recognition task) or moved to another place (place recognition task), and their exploration behavior to these objects were analyzed. Activation of hippocampal cannabinoid receptors by an agonist WIN 55,212-2 (1–2 μg/side) dose-dependently decreased the exploration of object in a new place, while it did not affect the exploration of a new object. Disruptive effect of WIN 55,212-2 on place recognition was antagonized by the pretreatment with a cannabinoid receptor antagonist AM 281 (2 mg/kg, i.p.). Results suggest that hippocampal cannabinoid receptors play an important role in place recognition or spatial memory.     

Unilateral hippocampal and inferotemporal cortex lesions in opposite hemispheres impair learning of single-pair visual discriminations as well as visuovisual conditional tasks in monkeys

Monkeys with unilateral ablations of the inferotemporal (IT) cortex were not impaired on learning or retention of single-pair object discriminations or visuovisual conditional tasks. Addition of an excitotoxic hippocampal lesion to the hemisphere opposite to the IT ablation impaired retention and acquisition of single-pair object discriminations and visuovisual conditional tasks. Histology revealed no areas of bilaterally symmetrical damage. Previous experiments have shown that bilateral excitotoxic hippocampal lesions do not impair single-pair object discriminations although they do produce a substantial impairment on visuovisual conditional tasks. Bilateral IT ablations produce impairment on single-pair object discrimination tasks. It is argued that the hippocampus in the hemisphere with the IT ablation is deprived of feed-forward visual input and that this, in addition to the contralateral hippocampal lesion, accounts for the impairment on the visuovisual conditional tasks. It is also argued that feed-back projections from the hippocampus to the IT cortex influence the learning of single-pair object discriminations. This influence may be difficult to demonstrate by the addition of hippocampal lesions to IT lesions because of the substantial effect of the IT lesion alone. It may be difficult to demonstrate by bilateral hippocampal lesions alone since the effect may be below that which generates an observable impairment. Nonetheless, an effect may be seen when a hippocampal lesion is made in monkeys with some IT damage, as in this experiment, as well as by the general observation that large lesions of the temporal lobes produce larger perceptuo-mnemonic impairments than lesions confined to the hippocampus or temporal neocortex in monkeys and man.     

Hippocampal lesions that abolish spatial maze performance spare object recognition memory at delays of up to 48 hours

The hippocampus is widely considered to be a critical component of a medial temporal lobe memory system, necessary for normal performance on tests of declarative memory. Object recognition memory is thought to be a classic test of declarative memory function. However, previous tests of the effects of hippocampal lesions on object recognition memory have not always supported this view. One possible reason for this inconsistency is that previously reported effects of hippocampal lesions on object recognition memory tasks may have stemmed not from a deficit in object recognition memory per se, but as a result of spatial and contextual confounds in the task. Thus, in the present study, we used a spontaneous object recognition test in a modified apparatus designed to minimize spatial and contextual factors. A group of rats with complete excitotoxic lesions of the hippocampus and a group of control rats were tested on this modified spontaneous object recognition task with retention delays of up to 48 h. These rats were also tested on a spatial nonmatching-to-place task. Spatial memory performance was abolished following hippocampal lesions, whereas performance on the recognition memory task was intact at all delays tested.     

Acute exposure to a novel object during consolidation enhances cognition

Environmental enrichment enhances learning and memory in both rodents and man. We examined the effect of active manipulation of a novel object (toy) on cognitive performance and acetylcholine (ACh) efflux in the hippocampus of rats. Animals exposed to the toy showed a significant increase in hippocampal ACh efflux provided that they actively manipulated the object. Similarly, a single 1 h introduction of the novel object (toy) immediately after a training session in a radial arm maze significantly improved memory only if the animals actively manipulated the object. The data suggest that environmental enrichment during a critical period (consolidation) is sufficient to improve learning and memory. This effect is likely mediated through an enhancement of hippocampal cholinergic neurotransmission.     

Functional difference between rat perirhinal cortex and hippocampus in object and place discrimination tasks

The present study was designed to determine the degree of functional dissociation between the rat perirhinal cortex and hippocampus for reference memory performance on object and place discrimination tasks. In one experiment, 30 rats were trained on a two-pair concurrent object discrimination task in an elevated radial arm maze. Rats with a perirhinal cortex lesion needed significantly more days to attain the criterion in the relearning of a pre-operatively acquired object discrimination task than the control rats and rats with a hippocampal lesion. However, there were no significant differences between the three groups in the days to attain the criterion in learning post-operatively the original object discrimination task with new discriminanda and its relearning. The rats with a hippocampal lesion did not show any impairment in object discrimination. In a second experiment, 27 rats were trained on a place discrimination task in the same maze. Rats with a hippocampal lesion required more days to attain the criterion than the control rats to relearn the pre-operatively acquired place discrimination task, and they had fewer correct responses in the first three sessions with new discriminanda than the control rats. Rats with a perirhinal cortex lesion, on the other hand, showed mild relearning impairment. These results suggest that there is a functionally single dissociation between the perirhinal cortex and hippocampus for reference memory performance on object and place discrimination tasks. They also suggest the possible involvement of the perirhinal cortex in spatial reference memory performance.     

Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism

Congenital hypothyroidism is a pediatric endocrine disorder caused by insufficient endogenous thyroid hormone production. Children with congenital hypothyroidism have difficulties with episodic memory and abnormalities in hippocampal structure, suggesting deficient hippocampal functioning. To assess hippocampal activation in adolescents with congenital hypothyroidism (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years), a functional magnetic resonance imaging visuospatial memory task was used. In this task, participants had to decide if object pairings were novel or were previously studied or if object pairs were in the same location as they were at study or had switched locations. Despite no group differences in task performance, adolescents with congenital hypothyroidism showed both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life. These results suggest that perinatal deprivation of thyroid hormone has longstanding effects on hippocampal function and may account for memory problems experienced by adolescents with congenital hypothyroidism.     

Under what conditions is recognition spared relative to recall after selective hippocampal damage in humans?

The claim that recognition memory is spared relative to recall after focal hippocampal damage has been disputed in the literature. We examined this claim by investigating object and object-location recall and recognition memory in a patient, YR, who has adult-onset selective hippocampal damage. Our aim was to identify the conditions under which recognition was spared relative to recall in this patient. She showed unimpaired forced-choice object recognition but clearly impaired recall, even when her control subjects found the object recognition task to be numerically harder than the object recall task. However, on two other recognition tests, YR's performance was not relatively spared. First, she was clearly impaired at an equivalently difficult yes/no object recognition task, but only when targets and foils were very similar. Second, YR was clearly impaired at forced-choice recognition of object-location associations. This impairment was also unrelated to difficulty because this task was no more difficult than the forced-choice object recognition task for control subjects. The clear impairment of yes/no, but not of forced-choice, object recognition after focal hippocampal damage, when targets and foils are very similar, is predicted by the neural network-based Complementary Learning Systems model of recognition. This model postulates that recognition is mediated by hippocampally dependent recollection and cortically dependent familiarity; thus hippocampal damage should not impair item familiarity. The model postulates that familiarity is ineffective when very similar targets and foils are shown one at a time and subjects have to identify which items are old (yes/no recognition). In contrast, familiarity is effective in discriminating which of similar targets and foils, seen together, is old (forced-choice recognition). Independent evidence from the remember/know procedure also indicates that YR's familiarity is normal. The Complementary Learning Systems model can also accommodate the clear impairment of forced-choice object-location recognition memory if it incorporates the view that the most complete convergence of spatial and object information, represented in different cortical regions, occurs in the hippocampus.     

Organizational connectivity among the CA1, subiculum,presubiculum, and entorhinal cortex in the rabbit

The laminar and topographical organization of connections between the hippocampal formation and parahippocampal regions was investigated in the rabbit following in vivo injection of cholera toxin B subunit as a retro‐ and antero‐grade tracer and biotinylated dextran amine as an anterograde tracer. We confirmed several connectional features different from those of the rat, that is, the rabbit presubiculum received abundant afferents from CA1 and had many reciprocal connections with the entorhinal cortex. On the other hand, we identified many similarities with the rat: both the CA1 and subicular afferents that originated from the entorhinal cortex were abundant; moreover, the presubiculum received many inputs from the subiculum and sent massive projections to the entorhinal cortex. By plotting retrograde and anterograde labels in two‐dimensional unfolded maps of the entire hippocampal and parahippocampal regions, we found that each group of entorhinal cells that project to CA1, subiculum, and presubiculum, and also the termination of the presubiculo‐entorhinal projection, was distributed in band‐like zones in layers II–III, extending across the medial and lateral entorhinal cortex. Our results suggest that the rabbit has a basic connectivity that is common with that of the rat, and also has additional hippocampal–presubicular and entorhino–presubicular connections that may reflect functional evolution in learning and memory.     

Hippocampal cellular plasticity during extinction of classically conditioned nictitating membrane behavior

Hippocampal unit responses were recorded during extinction of classically conditioned nictitating membrane (NM) behavior in the rabbit. Prior studies have shown that during the acquisition phase of nictitating membrane conditioning, the frequency of hippocampal cell firing increases at a faster rate (across trials) than learned behavior. Results reported here show that, during the early phases of extinction, conditioned hippocampal unit responses decrement at a faster rate than learned NM behavior. Furthermore, only certain components of the conditioned hippocampal unit response display robust spontaneous recovery across successive days of extinction training. In all, results show that changes in the activity of hippocampal neurons predict changes in learned behavior over trials of conditioning and extinction, and demonstrate that hippocampal cellular activity is particularly sensitive to stimulus configurations or environmental contingencies that produce changes in behavior.     

Adult newborn neurons are involved in learning acquisition and long‐term memory formation: The distinct demands on temporal neurogenesis of different cognitive tasks

There is evidence that adult hippocampal neurogenesis influences hippocampal function, although the role these neurons fulfill in learning and consolidation processes remains unclear. Using a novel fast X‐ray ablation protocol to deplete neurogenic cells, we demonstrate that immature adult hippocampal neurons are required for hippocampal learning and long‐term memory formation. Moreover, we found that long‐term memory formation in the object recognition and passive avoidance tests, two paradigms that involve circuits with distinct emotional components, had different temporal demands on hippocampal neurogenesis. These results reveal new and unexpected aspects of neurogenesis in cognitive processes. © 2014 Wiley Periodicals, Inc.     

Reactivity to object and spatial novelty is normal in older Ts65Dn mice that model Down syndrome and Alzheimer's disease

Ts65Dn mice, a model for Down syndrome and Alzheimer's disease, have a spontaneous age-related reduction of cholinergic markers in medial septal neurons, hippocampal abnormalities, and an age-related learning deficit in a task that requires an intact hippocampus. Others have shown that when normal rodents explored an open field with objects, they detected the displacement of some of the familiar objects within the arena (spatial novelty) and the presence of a new object (object novelty); whereas rodents with hippocampal, fornix, or neonatal selective basal forebrain cholinergic lesions were impaired in detecting spatial, but not object, novelty. In this study, both control and Ts65Dn mice responded to both the spatial and object changes. This unexpected finding could have several explanations. One may be related to recent studies that suggest that only rats with neonatal, but not adult, basal forebrain cholinergic 192 IgG-saporin lesions are impaired in reacting to spatial novelty.     

Discrimination learning alters the distribution of protein kinase C in the hippocampus of rats

Protein kinase C (PKC), an enzyme that plays an essential role in eukaryotic cell regulation (Nishizuka, 1988; Huang et al., 1989), is critical to memory storage processes both in the marine snail Hermissenda crassicornis and in the rabbit (Alkon et al., 1988; Bank et al., 1988; Olds et al., 1989). Specifically, activation of PKC mimics neurobiological correlates of classical conditioning in both Hermissenda and the rabbit, and the distribution of the enzyme within the rabbit hippocampus changes after Pavlovian conditioning. Here, we report that the amount of PKC, as assayed by specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBU), decreased significantly within the hippocampal CA3 cell region in rats trained to solve a water maze task either by cognitive mapping or by visual discrimination strategies, but not in control rats. Furthermore, hippocampal lesions interfered with acquisition of both of these tasks. We interpret these findings to support the conclusion that distributional changes of PKC within the mammalian hippocampus play a crucial role in memory storage processes.     

Retention deficits after combined amygdalo-hippocampal and selective hippocampal resections in the monkey

In one experiment, monkeys with either combined amygdalo-hippocampal, or selective hippocampal or entorhinal resections, were impaired on a task which required both visual recognition of objects and retention of their reward-value. In a second experiment, monkeys with selective hippocampal resections were impaired on the same task in the tactual modality. In the last two experiments, monkeys with hippocampal, or entorhinal area resections, were impaired in retaining two-choice object discriminations at either 1 or 24 hr intervals. Thus, retention deficits can follow hippocampal damage in non-human primates, provided appropriate tasks are used.     

Differential development of relational memory and pattern separation

Researchers have taken a number of different approaches in their exploration of hippocampal function. One approach seeks to describe hippocampal function by probing the memory representations that the hippocampus supports. Another approach focuses on the role of the hippocampus in pattern separation and completion. Each of these approaches to understanding hippocampal function utilizes a distinct set of specialized tasks, and both of these task sets are known to be sensitive to changes in hippocampal function with age and disease status. But the question remains whether the tasks utilized in these two approaches tap into the same aspects of hippocampal function. We explored this question in the context of hippocampal development. Preadolescent children (N = 73) and young adults (N = 41) completed an identical battery of cognitive tasks consisting of a spatial reconstruction relational memory task, the mnemonic similarity task (MST)—an object‐based pattern separation task, and a novel hybrid task—the Object Discrimination and Distribution (ODD) Task—designed to integrate and simultaneously tax pattern separation and spatial relational memory. Children did not demonstrate impairments in lure discrimination relative to young adults on either the object‐based pattern separation task or for aspects of the ODD task that required pattern separation in the absence of relational memory demands but performed more poorly across aspects of tasks that required relational binding.     

Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus

Social isolation from weaning affects hippocampal structure and function in the rat. The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. Accordingly, the present paper investigated the effects of social isolation on hippocampal levels of alpha-tubulin isoforms associated with microtubule dynamics, the dendritic marker MAP-2 and alterations in locomotor activity and recognition memory. Male Lister Hooded rats (postnatal day 25-28) were housed either in groups or singly (isolated animals) for 30 days. Locomotor activity in a novel arena and novel object recognition were monitored in activity boxes. The hippocampus was dissected out 18 h after the novel object recognition task. Levels of alpha-tubulin isoforms and MAP-2 were analysed using Western blots. The experiments were conducted in duplicate, using two batches of rats obtained from different suppliers. Isolated animals were hyperactive and showed recognition memory deficits in the novel object recognition task. These behavioural alterations were accompanied by specific alterations in hippocampal alpha-tubulin isoforms and decreased MAP-2 expression. The results confirm that rearing rats in isolation produces hyperactivity and cognitive deficits. The behavioural alterations were accompanied by hippocampal cytoskeletal changes consistent with microtubule stabilization, and by decreased MAP-2 expression. These findings are indicative of an abnormal development of synaptic connections and/or reductions in neuronal cell number. The developmental structural abnormalities in the hippocampus may contribute to the cognitive impairments which result from isolation rearing in rats.     

Spatial view cells in the primate hippocampus and memory recall

Hippocampal spatial view neurons in primates provide allocentric representations of a view of space 'out there'. The responses depend on where the monkey is looking; and can be updated by idiothetic (self-motion) inputs provided by eye movements when the view is hidden. In a room-based object-place memory task, some hippocampal neurons respond to the objects shown, some to the places viewed, and some to combinations of the places viewed and the objects present in those locations. In an object-place recall task when the location in space at which an object has been seen is recalled by the presentation of the object, some primate hippocampal neurons maintain their responding to the object recall cue in a delay period without the object visible while the place is being recalled; and other neurons respond to the place being recalled. Other spatial view neurons form associations with the rewards present at particular locations in space. These findings, and computational models of the hippocampus, help to show how the primate including human hippocampus is involved in episodic memory.     

Increased glutamine synthetase immunoreactivity in experimental pneumococcal meningitis

Glutamine synthetase (GS), glial fibrillary acidic protein (GFAP) immunohistochemistry and neuronal apoptotic cell death were evaluated in a rabbit model of pneumococcal meningitis. Meningitis caused an increase of GS immunoreactivity in the cerebral cortex, but not in the hippocampal formation. GFAP immunoreactivity remained unchanged. This may represent a protective mechanism for cortical neurons. The inability of hippocampal GS to counteract the detrimental effects of glutamate may be the cause of neuronal apoptosis observed in the dentate gyrus during meningitis. Received: 23 September 1996 / Revised, accepted: 21 November 1996