Associative recognition and the hippocampus: Differential effects of hippocampal lesions on object‐place,object‐context and object‐place‐context memory

The hippocampus is thought to be required for the associative recognition of objects together with the spatial or temporal contexts in which they occur. However, recent data showing that rats with fornix lesions perform as well as controls in an object‐place task, while being impaired on an object‐place‐context task (Eacott and Norman ( 2004 ) J Neurosci 24:1948–1953), suggest that not all forms of context‐dependent associative recognition depend on the integrity of the hippocampus. To examine the role of the hippocampus in context‐dependent recognition directly, the present study tested the effects of large, selective, bilateral hippocampus lesions in rats on performance of a series of spontaneous recognition memory tasks: object recognition, object‐place recognition, object‐context recognition and object‐place‐context recognition. Consistent with the effects of fornix lesions, animals with hippocampus lesions were impaired only on the object‐place‐context task. These data confirm that not all forms of context‐dependent associative recognition are mediated by the hippocampus. Subsequent experiments suggested that the object‐place task does not require an allocentric representation of space, which could account for the lack of impairment following hippocampus lesions. Importantly, as the object‐place‐context task has similar spatial requirements, the selective deficit in object‐place‐context recognition suggests that this task requires hippocampus‐dependent neural processes distinct from those required for allocentric spatial memory, or for object memory, object‐place memory or object‐context memory. Two possibilities are that object, place, and context information converge only in the hippocampus, or that recognition of integrated object‐place‐context information requires a hippocampus‐dependent mode of retrieval, such as recollection. © 2009 Wiley‐Liss, Inc.     

CA1‐specific deletion of NMDA receptors induces abnormal renewal of a learned fear response

CA1 hippocampal N‐methyl‐d ‐aspartate‐receptors (NMDARs) are necessary for contextually related learning and memory processes. Extinction, a form of learning, has been shown to require intact hippocampal NMDAR signalling. Renewal of fear expression can occur after fear extinction training, when the extinguished fear stimulus is presented in an environmental context different from the training context and thus, renewal is dependent on contextual memory. In this study, we show that a Grin1 knock‐out (loss of the essential NR1 subunit for the NMDAR) restricted to the bilateral CA1 subfield of the dorsal hippocampus does not affect acquisition of learned fear, but does attenuate extinction of a cued fear response even when presented in the extinction‐training context. We propose that failure to remember the (safe) extinction context is responsible for the abnormal fear response and suggest it is a dysfunctional renewal. The results highlight the difference in outcome of extinguished fear memory resulting from a partial rather than complete loss of function of the hippocampus and suggest a potential mechanism for abnormally increased fear expression in PTSD. © 2015 Wiley Periodicals, Inc.     

Hippocampus NMDA receptors selectively mediate latent extinction of place learning

Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical “response extinction,” animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In “latent extinction,” animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)‐dependent response learning and hippocampus‐dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long‐Evans rats were trained in a response learning task in a water plus‐maze, in which animals were reinforced to make a consistent body‐turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra‐hippocampal infusions of the NMDA receptor antagonist 2‐amino‐5‐phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were effective at extinguishing memory in the place learning task. In addition, intra‐hippocampal AP5 (7.5 µg) impaired latent extinction, but not response extinction, suggesting that hippocampal NMDA receptors are selectively involved in latent extinction. © 2016 Wiley Periodicals, Inc.     

N‐methyl‐d‐aspartate receptors,learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d‐AP5 interacts directly with the neural mechanisms of spatial learning

Three experiments were conducted to contrast the hypothesis that hippocampal N‐methyl‐d ‐aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus‐dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug‐induced neuropathological and/or sensorimotor disturbances. In Experiment 1, rats given a chronic i.c.v. infusion of d ‐AP5 (30 mm ) at 0.5 μL/h were selectively impaired, relative to aCSF‐infused animals, in place but not cued navigation learning when they were trained during the 14‐day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d ‐AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d ‐AP5‐treated rats whether killed during or after chronic drug infusion. In Experiment 2, a deficit in spatial learning was also apparent in d ‐AP5‐treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d ‐AP5 in selected brain areas. In Experiment 3, rats treated with d ‐AP5 showed a delay‐dependent deficit in spatial memory in the delayed matching‐to‐place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.     

Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents

Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. Postnatal day 14 (P14) rats and mice, as well as adult (P60) rats, were anesthetized with isoflurane for 35 mins daily for four successive days. Object recognition, place learning and reversal learning as well as cell death and cytogenesis were evaluated. Object recognition and reversal learning were significantly impaired in isoflurane-treated young rats and mice, whereas adult animals were unaffected, and these deficits became more pronounced as the animals grew older. The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.     

The metabotropic glutamate receptor,mGlu5, is required for extinction learning that occurs in the absence of a context change

The metabotropic glutamate (mGlu) receptors and, in particular, mGlu5 are crucially involved in multiple forms of synaptic plasticity that are believed to underlie explicit memory. MGlu5 is also required for information transfer through neuronal oscillations and for spatial memory. Furthermore, mGlu5 is involved in extinction of implicit forms of learning. This places this receptor in a unique position with regard to information encoding. Here, we explored the role of this receptor in context‐dependent extinction learning under constant, or changed, contextual conditions. Animals were trained over 3 days to take a left turn under 25% reward probability in a T‐maze with a distinct floor pattern (Context A). On Day 4, they experienced either a floor pattern change (Context B) or the same floor pattern (Context A) in the absence of reward. After acquisition of the task, the animals were returned to the maze once more on Day 5 (Context A, no reward). Treatment with the mGlu5 antagonist, 2‐methyl‐6‐(phenylethynyl) pyridine, before maze exposure on Day 4 completely inhibited extinction learning in the AAA paradigm but had no effect in the ABA paradigm. A subsequent return to the original context (A, on Day 5) revealed successful extinction in the AAA paradigm, but impairment of extinction in the ABA paradigm. These data support that although extinction learning in a new context is unaffected by mGlu5 antagonism, extinction of the consolidated context is impaired. This suggests that mGlu5 is intrinsically involved in enabling learning that once‐relevant information is no longer valid. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Alteration of synaptic transmission in the hippocampal‐mPFC pathway during extinction trials of context‐dependent fear memory in juvenile rat stress models

The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal‐mPFC pathway is related to extinction of context‐dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear‐related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal‐mPFC pathway is associated with the extinction processes of context‐dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W‐FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W‐FS group were prevented by pretreatment with the serotonin_1A receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context‐dependent fear memory. The deficits in extinction observed in the 3W‐FS group might be attributable to dysfunction of hippocampal‐mPFC neural circuits involving 5‐HT_1A receptor mechanisms. Synapse 63:805–813, 2009. © 2009 Wiley‐Liss, Inc.     

The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

A behavioral analysis of the impact of voluntary physical activity on hippocampus‐dependent contextual conditioning

Voluntary physical activity induces molecular changes in the hippocampus consistent with improved hippocampal function, but few studies have explored the effects of wheel running on specific hippocampal‐dependent learning and memory processes. The current studies investigated the impact of voluntary wheel running on learning and memory for context and extinction using contextual fear conditioning which is known to be dependent on the hippocampus. When conditioning occurred prior to the start of 6 weeks of wheel running, wheel running had no effect on memory for context or extinction (assessed with freezing). In contrast, when wheel running occurred for 6 weeks prior to conditioning, physical activity improved contextual memory during a retention test 24 h later, but did not affect extinction learning or memory. Wheel running had no effect on freezing immediately after foot shock presentation during conditioning, suggesting that physical activity does not affect the acquisition of the context—shock association or alter the expression of freezing, per se. Instead, it is argued that physical activity improves the consolidation of contextual memories in the hippocampus. Consistent with improved hippocampus‐dependent context learning and memory, 6 weeks of wheel running also improved context discrimination and reduced the context pre‐exposure time required to form a strong contextual memory. The effect of wheel running on brain‐derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in hippocampal and amygdala subregions was also investigated. Wheel running increased BDNF mRNA in the dentate gyrus, CA1, and the basolateral amygdala. Results are consistent with improved hippocampal function following physical activity. © 2008 Wiley‐Liss, Inc.     

Retroactive interference of object‐in‐context long‐term memory: Role of dorsal hippocampus and medial prefrontal cortex

Retroactive interference (RI) is a type of amnesia in which a new learning experience can impair the expression of a previous one. It has been studied in several types of memories for over a century. Here, we aimed to study in the long‐term memory (LTM) formation of an object‐in‐context task, defined as the recognition of a familiar object in a context different to that in which it was previously encountered. We trained rats with two sample trials, each taking place in a different context in association with different objects. Test sessions were performed 24 h later, to evaluate LTM for both object‐context pairs using separate groups of trained rats. Furthermore, given the involvement of hippocampus (Hp) and medial prefrontal cortex (mPFC) in several recognition memories, we also analyzed the participation of these structures in the LTM formation of this task by the local infusion of muscimol. Our results show that object‐in‐context LTM formation is sensitive to RI by a different either familiar or novel object‐context pair trial, experienced 1 h later. This interference occurs in a restricted temporal window and works on the LTM consolidation phase, leaving intact short‐term memory expression. The second sample trial did not affect the object recognition part of the memory. Besides, muscimol treatment before the second sample trial blocks its object‐in‐context LTM and restores the first sample trial memory. We hypothesized that LTM‐RI amnesia is probably caused by resources or cellular machinery competition in these brain regions when they are engaged in memory formation of the traces. In sum, when two different object‐in‐context memory traces are being processed, the second trace interferes with the consolidation of the first one requiring mPFC and CA1 dorsal Hp activation. © 2014 Wiley Periodicals, Inc.     

Age‐associated changes in waking hippocampal sharp‐wave ripples

Hippocampal sharp‐wave ripples are brief high‐frequency (120–250 Hz) oscillatory events that support mnemonic processes during sleep and awake behavior. Although ripples occurring during sleep are believed to facilitate memory consolidation, waking ripples may also be involved in planning and memory retrieval. Recent work from our group determined that normal aging results in a significant reduction in the peak oscillatory frequency and rate‐of‐occurrence of ripples during sleep that may contribute to age‐associated memory decline. It is unknown, however, how aging alters waking ripples. We investigated whether characteristics of waking ripples undergo age‐dependent changes. Sharp‐wave ripple events were recorded from the CA1 region of the hippocampus in old (n = 5) and young (n = 6) F344 male rats as they performed a place‐dependent eyeblink conditioning task. Several novel observations emerged from this analysis. First, although aged rats expressed more waking ripples than young rats during track running and reward consumption, this effect was eliminated, and, in the case of track‐running, reversed when time spent in each location was accounted for. Thus, aged rats emit more ripples, but young rats express a higher ripple rate. This likely results from reduced locomotor activity in aged animals. Furthermore, although ripple rates increased as young rats approached rewards, rates did not increase in aged rats, and rates in aged and young animals were not affected by eyeblink conditioning. Finally, although the oscillatory frequency of ripples was lower in aged animals during rest, frequencies in aged rats increased during behavior to levels indistinguishable from young rats. Given the involvement of waking ripples in memory retrieval, a possible consequence of slower movement speeds of aged animals is to provide more opportunity to replay task‐relevant information and compensate for age‐related declines in ripple rate during task performance.     

Exercise enhances hippocampal‐dependent learning in the rat: Evidence for a BDNF‐related mechanism

Short periods of forced exercise have been reported to selectively induce enhancements in hippocampal‐dependent cognitive function, possibly via brain‐derived neurotrophic factor (BDNF)‐mediated mechanisms. In this study, we report that 1 week of treadmill running significantly enhanced both object displacement (spatial) and object substitution (nonspatial) learning. These behavioral changes were accompanied by increased expression of BDNF protein in the dentate gyrus, hippocampus, and perirhinal cortex. The effects of exercise on object substitution were mimicked by intracerebroventricular injection of BDNF protein. These data are consistent with the hypothesis that exercise has the potential to enhance cognitive function in young healthy rats, possibly via a mechanism involving increased BDNF expression in specific brain regions. © 2009 Wiley‐Liss, Inc.     

PKMζ maintains 1‐day‐ and 6‐day‐old long‐term object location but not object identity memory in dorsal hippocampus

Continuous activity of the atypical protein kinase C isoform M zeta (PKMζ) is necessary for maintaining long‐term memory acquired in aversively or appetitively motivated associative learning tasks, such as active avoidance, aversive taste conditioning, auditory and contextual fear conditioning, radial arm maze, and watermaze. Whether unreinforced, nonassociative memory will also require PKMζ for long‐term maintenance is not known. Using recognition memory for object location and object identity, we found that inactivating PKMζ in dorsal hippocampus abolishes 1‐day and 6‐day‐old long‐term recognition memory for object location, while recognition memory for object identity was not affected by this treatment. Memory for object location persisted for no more than 35 days after training. These results suggest that the dorsal hippocampus mediates long‐term memory for where, but not what things have been encountered, and that PKMζ maintains this type of spatial knowledge as long as the memory exists. © 2009 Wiley‐Liss, Inc.     

Time‐dependent enhancement of hippocampus‐dependent memory after treatment with memantine: Implications for enhanced hippocampal adult neurogenesis

Adult hippocampal neurogenesis has been suggested to play modulatory roles in learning and memory. Importantly, previous studies have shown that newborn neurons in the adult hippocampus are integrated into the dentate gyrus circuit and are recruited more efficiently into the hippocampal memory trace of mice when they become 3 weeks old. Interestingly, a single high‐dose treatment with the N‐methyl‐d ‐aspartate receptor antagonist memantine (MEM) has been shown to increase hippocampal neurogenesis dramatically by promoting cell proliferation. In the present study, to understand the impact of increased adult neurogenesis on memory performance, we examined the effects of a single treatment of MEM on hippocampus‐dependent memory in mice. Interestingly, mice treated with MEM showed an improvement of hippocampus‐dependent spatial and social recognition memories when they were trained and tested at 3–6 weeks, but not at 3 days or 4 months, after treatment with MEM. Importantly, we observed a significant positive correlation between the scores for spatial memory (probe trial in the Morris water maze task) and the number of young mature neurons (3 weeks old) in MEM‐treated mice, but not saline‐treated mice. We also observed that the young mature neurons generated by treatment with MEM were recruited into the trace of spatial memory similarly to those generated through endogenous neurogenesis. Taken together, our observations suggest that treatment with MEM temporally improves hippocampus‐dependent memory formation and that the newborn neurons increased by treatment with MEM contribute to this improvement when they become 3 weeks old. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

The role of medial prefrontal cortex in extinction and reinstatement of alcohol‐seeking in rats

The prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug‐seeking behaviour. Specifically, the PL promotes drug‐seeking whereas the IL is necessary for the inhibition of drug‐seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context‐induced reinstatement, reacquisition and extinction of alcoholic beer‐seeking. In context‐induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer‐seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug‐seeking. Rather, they support the view that PL is important for retrieval of drug‐seeking contingency information and that the use of contextual information is enhanced with IL manipulation.     

Sex‐dependent modulation of age‐related cognitive decline by the L‐type calcium channel gene Cacna1c (Cav1.2)

Increased calcium influx through L‐type voltage‐gated calcium channels has been implicated in the neuronal dysfunction underlying age‐related memory declines. The present study aimed to test the specific role of Cacna1c (which encodes Ca_v1.2) in modulating age‐related memory dysfunction. Short‐term, spatial and contextual/emotional memory was evaluated in young and aged, wild‐type as well as mice with one functional copy of Cacna1c (haploinsufficient), using the novel object recognition, Y‐maze and passive avoidance tasks, respectively. Hippocampal expression of Cacna1c mRNA was measured by quantitative polymerase chain reaction. Ageing was associated with object recognition and contextual/emotional memory deficits, and a significant increase in hippocampal Cacna1c mRNA expression. Cacna1c haploinsufficiency was associated with decreased Cacna1c mRNA expression in both young and old animals. However, haploinsufficient mice did not manifest an age‐related increase in expression of this gene. Behaviourally, Cacna1c haploinsufficiency prevented object recognition deficits during ageing in both male and female mice. A significant correlation between higher Cacna1c levels and decreased object recognition performance was observed in both sexes. Also, a sex‐dependent protective role of decreased Cacna1c levels in contextual/emotional memory loss has been observed, specifically in male mice. These data provide evidence for an association between increased hippocampal Cacna1c expression and age‐related cognitive decline. Additionally, they indicate an interaction between the Cacna1c gene and sex in the modulation of age‐related contextual memory declines.     

Lack of experience‐dependent intrinsic plasticity in the adolescent infralimbic medial prefrontal cortex

Fear extinction, an inhibitory learning that suppresses a previously learned fear memory, is diminished during adolescence. Earlier studies have shown that this suppressed fear extinction during adolescence involves an altered glutamatergic plasticity in infralimbic medial prefrontal cortical (IL‐mPFC) pyramidal neurons. However, it is unclear whether the excitability of IL‐mPFC pyramidal neurons plays a role in this development‐dependent suppression of fear extinction. Therefore, we examined whether fear conditioning and extinction affect the active and passive membrane properties of IL‐mPFC layer 5 pyramidal neurons in preadolescent, adolescent and adult mice. Both preadolescent and adult mice exhibited a bidirectional modulation of the excitability of IL‐mPFC layer 5 pyramidal neurons following fear conditioning and extinction, i.e., fear conditioning reduced membrane excitability, whereas fear extinction reversed this effect. However, the fear conditioning‐induced suppression of excitability was not reversed in adolescent mice following fear extinction training. Neither fear conditioning nor extinction affected GABAergic transmission in IL‐mPFC layer 5 pyramidal neurons, suggesting that GABAergic transmission did not play a role in experience‐dependent modulation of neuronal excitability. Our results suggest that the extinction‐specific modulation of excitability is impaired during adolescence.     

A single early-life seizure impairs short-term memory but does not alter spatial learning,recognition memory,or anxiety

The impact of a single seizure on cognition remains controversial. We hypothesized that a single early-life seizure (sELS) on rat Postnatal Day (P) 7 would alter only hippocampus-dependent learning and memory in mature (P60) rats. The Morris water maze, the novel object and novel place recognition tasks, and contextual fear conditioning were used to assess learning and memory associated with hippocampus/prefrontal cortex, perirhinal/hippocampal cortex, and amygdala function, respectively. The elevated plus maze and open-field test were used to assess anxiety associated with the septum. We report that sELS impaired hippocampus-dependent short-term memory, but not spatial learning or recall. sELS did not disrupt performance in the novel object and novel place recognition tasks. Contextual fear conditioning performance suggested intact amydgala function. sELS did not change anxiety levels as measured by the elevated plus maze or open-field test. Our data suggest that the long-term cognitive impact of sELS is limited largely to the hippocampus/prefrontal cortex.     

A single early-life seizure impairs short-term memory but does not alter spatial learning, recognition memory, or anxiety

The impact of a single seizure on cognition remains controversial. We hypothesized that a single early-life seizure (sELS) on rat Postnatal Day (P) 7 would alter only hippocampus-dependent learning and memory in mature (P60) rats. The Morris water maze, the novel object and novel place recognition tasks, and contextual fear conditioning were used to assess learning and memory associated with hippocampus/prefrontal cortex, perirhinal/hippocampal cortex, and amygdala function, respectively. The elevated plus maze and open-field test were used to assess anxiety associated with the septum. We report that sELS impaired hippocampus-dependent short-term memory, but not spatial learning or recall. sELS did not disrupt performance in the novel object and novel place recognition tasks. Contextual fear conditioning performance suggested intact amydgala function. sELS did not change anxiety levels as measured by the elevated plus maze or open-field test. Our data suggest that the long-term cognitive impact of sELS is limited largely to the hippocampus/prefrontal cortex.     

Lateral entorhinal cortex is critical for novel object‐context recognition

Episodic memory incorporates information about specific events or occasions including spatial locations and the contextual features of the environment in which the event took place. It has been modeled in rats using spontaneous exploration of novel configurations of objects, their locations, and the contexts in which they are presented. While we have a detailed understanding of how spatial location is processed in the brain relatively little is known about where the nonspatial contextual components of episodic memory are processed. Initial experiments measured c‐fos expression during an object‐context recognition (OCR) task to examine which networks within the brain process contextual features of an event. Increased c‐fos expression was found in the lateral entorhinal cortex (LEC; a major hippocampal afferent) during OCR relative to control conditions. In a subsequent experiment it was demonstrated that rats with lesions of LEC were unable to recognize object‐context associations yet showed normal object recognition and normal context recognition. These data suggest that contextual features of the environment are integrated with object identity in LEC and demonstrate that recognition of such object‐context associations requires the LEC. This is consistent with the suggestion that contextual features of an event are processed in LEC and that this information is combined with spatial information from medial entorhinal cortex to form episodic memory in the hippocampus. © 2013 Wiley Periodicals, Inc.