Zinc transporter ZnT3 is involved in memory dependent on the hippocampus and perirhinal cortex

Since zinc transporter ZnT3 is localized to the hippocampus and perirhinal cortex, we used ZnT3 knockout mice (KO) to analyze the role of ZnT3 in memory and behavior dependent on these brain regions. ZnT3KO mice were normal in initial learning in the standard water maze but had difficulty finding a second platform location. The mutants showed increased social interaction but were deficient in social and object recognition memory. These data suggest that ZnT3 is involved in certain types of spatial memory and behavior dependent on the hippocampus and perirhinal cortex.     

Distinct roles of hippocampus and medial prefrontal cortex in spatial and nonspatial memory

In earlier work, patients with hippocampal damage successfully path integrated, apparently by maintaining spatial information in working memory. In contrast, rats with hippocampal damage were unable to path integrate, even when the paths were simple and working memory might have been expected to support performance. We considered possible ways to understand these findings. We tested rats with either hippocampal lesions or lesions of medial prefrontal cortex (mPFC) on three tasks of spatial or nonspatial memory: path integration, spatial alternation, and a nonspatial alternation task. Rats with mPFC lesions were impaired on both spatial and nonspatial alternation but performed normally on path integration. By contrast, rats with hippocampal lesions were impaired on path integration and spatial alternation but performed normally on nonspatial alternation. We propose that rodent neocortex is limited in its ability to construct a coherent spatial working memory of complex environments. Accordingly, in tasks such as path integration and spatial alternation, working memory cannot depend on neocortex alone. Rats may accomplish many spatial memory tasks by relying on long‐term memory. Alternatively, they may accomplish these tasks within working memory through sustained coordination between hippocampus and other cortical brain regions such as mPFC, in the case of spatial alternation, or parietal cortex in the case of path integration. © 2016 Wiley Periodicals, Inc.     

Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus

The medial prefrontal cortex and the hippocampus serve well recognized roles in memory processing. The hippocampus projects densely to, and exerts strong excitatory actions on, the medial prefrontal cortex. Interestingly, the medial prefrontal cortex, in rats and other species, has no direct return projections to the hippocampus, and few projections to parahippocampal structures including the entorhinal cortex. It is well established that the nucleus reuniens of the midline thalamus is the major source of thalamic afferents to the hippocampus. Since the medial prefrontal cortex also distributes to nucleus reuniens, we examined medial prefrontal connections with populations of nucleus reuniens neurons projecting to hippocampus. We used a combined anterograde and retrograde tracing procedure at the light and electron microscopic levels. Specifically, we made Phaseolus vulgaris-leuccoagglutinin (PHA-L) injections into the medial prefrontal cortex and Fluorogold injections into the hippocampus (CA1/subiculum) and examined termination patterns of anterogradely PHA-L labeled fibers on retrogradely FG labeled cells of nucleus reuniens. At the light microscopic level, we showed that fibers from the medial prefrontal cortex form multiple putative synaptic contacts with dendrites of hippocampally projecting neurons throughout the extent of nucleus reuniens. At ultrastructural level, we showed that medial prefrontal cortical fibers form asymmetric contacts predominantly with dendritic shafts of hippocampally projecting reuniens cells. These findings indicate that nucleus reuniens represents a critical link between the medial prefrontal cortex and the hippocampus. We discuss the possibility that nucleus reuniens gates the flow of information between the medial prefrontal cortex and hippocampus dependent upon attentive/arousal states of the organism.     

Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus

Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesized to be necessary and sufficient for the maintenance of long‐term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluA2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluA2‐dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluA2‐independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation. © 2014 Wiley Periodicals, Inc.     

The case for episodic memory in animals

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.     

The medial prefrontal cortex—lateral entorhinal cortex circuit is essential for episodic‐like memory and associative object‐recognition

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item‐associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic‐like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic‐like (what‐where‐when) and object‐recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic‐like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic‐like and associative object‐recognition memory. © 2015 Wiley Periodicals, Inc.     

Differential BDNF signaling in dentate gyrus and perirhinal cortex during consolidation of recognition memory in the rat

Consolidation of long‐term memory is dependent on synthesis of new proteins in the hippocampus and associated cortical regions. The neurotrophin brain‐derived neurotrophic factor (BDNF) is tightly regulated by activity‐dependent cellular processes and is strongly linked with mechanisms underlying learning and memory. BDNF activation of tyrosine receptor kinase (TrkB) stimulates intracellular signaling cascades implicated in plasticity, including the extracellular‐signal related kinase (ERK)/mitogen‐activated protein kinase (MAPK) pathway and the phosphatidylinositide‐3‐kinase (PI3K)/Akt pathway. Here, we investigate the role of BDNF, ERK/MAPK, and PI3K/AKT signaling cascade in recognition memory in the rat. We report that recognition memory was associated with increased release of BDNF in the dentate gyrus and perirhinal cortex. This was associated with significant increases in p44ERK activation and c‐fos expression in the dentate gyrus and PI3K activation and c‐fos expression in the perirhinal cortex. Furthermore, both recognition memory and the associated cell signaling events in dentate gyrus and perirhinal cortex were blocked by intraperitoneal injection of the Trk receptor inhibitor tyrphostin AG879. These data are consistent with the hypothesis that BDNF‐stimulated intracellular signaling plays a role in consolidation of recognition memory in the rat. © 2012 Wiley Periodicals, Inc.     

Exercise improves recognition memory and synaptic plasticity in the prefrontal cortex for rats modelling vascular dementia

Objectives: Functional electrical stimulation (FES) may induce involuntary exercise and make beneficial effects on vascular dementia (VD) by strengthening the BDNF-pCREB-mediated pathway and hippocampal plasticity. Whether FES improves recognition memory and synaptic plasticity in the prefrontal cortex (PFC) was investigated by establishing a VD model.

Methods: The VD rats were administered with two weeks of voluntary exercise, forced exercise, or involuntary exercise induced with FES. Sham-operated and control groups were also included. The behavioral changes were assessed with the novel object recognition test and novel object location test. The expression levels of key proteins related to synaptic plasticity in the PFC were also detected.

Results: All types of exercise improved the rats’ novel object recognition index, but only voluntary exercise and involuntary exercise induced with FES improved the novel object location index. Any sort of exercise enhanced the expression of key proteins in the PFC.

Conclusion: Involuntary exercise induced with FES can improve recognition memory in VD better than forced exercise. The mechanism is associated with increased synaptic plasticity in the PFC. FES may be a useful alternative tool for cognitive rehabilitation.     

A 5-month period of epilepsy impairs spatial memory, decreases anxiety, but spares object recognition in the lithium-pilocarpine model in adult rats

PURPOSE: In temporal lobe epilepsy (TLE), interictal behavioral disorders affect patients' quality of life. Therefore we studied long-term behavioral impairments in the lithium-pilocarpine (li-pilo) model of TLE. METHODS: Eleven li-pilo adult rats exhibiting spontaneous recurrent seizures (SRSs) during 5 months were compared with 11 li-saline rats. Spatial working memory was tested in a radial arm maze (RAM), anxiety in an elevated plus-maze (EPM), and nonspatial working memory in an object-recognition paradigm. Neuronal loss was assessed on thionine brain sections after behavioral testing. RESULTS: In the RAM, the time to complete each session and the number of errors per session decreased over a 5-day period in li-saline rats but remained constant and significantly higher in li-pilo rats. In the EPM, the number of entries in and time spent on open arms were significantly higher in li-pilo than li-saline rats. In the object-recognition task, the two groups exhibited a comparable novelty preference for the new object. Neuronal loss reached 47-90% in hilus, CA1, amygdala, and piriform and entorhinal cortex. CONCLUSIONS: In li-pilo rats having experienced SRS for 5 months, performance in the object-recognition task is spared, which suggests that object discrimination remains relatively intact despite extensive damage. Neuronal loss in regions mediating memory and anxiety, such as hippocampus, entorhinal cortex, and amygdala, may relate to impaired spatial orientation and decreased anxiety.     

Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys

Two recent meta-analyses, drawing on data from many of the same studies with monkeys, reached different conclusions about the relationship between hippocampal damage and recognition memory performance. Both studies found evidence of recognition memory impairment following hippocampal damage. However, Zola et al. (J Neurosci 2000;20:451-463) found no significant correlation between extent of hippocampal damage and recognition memory performance, whereas Baxter and Murray (Hippocampus 2001;11:61-71) concluded that the extent of hippocampal damage in monkeys was inversely correlated with impaired performance. Here, we first consider the requirements for carrying out a valid meta-analysis, and point out that the analysis carried out by Baxter and Murray (Hippocampus 2001;11:61-71) is invalid on simple statistical grounds. We then adopt the appropriate statistical procedures (multiple regression analyses rather than simple correlational analysis) to assess the relationship between extent of hippocampal damage and recognition performance across different studies. None of these analyses, including a reanalysis of the data of Baxter and Murray (Hippocampus 2001;11:61-71), revealed a significant inverse relationship between lesion size and behavioral impairment. Most of the variance was explained by differences between the studies that contributed to the meta-analysis, not by lesion size itself. Indeed, analysis of covariance indicated that there were differences among the studies beyond lesion size that significantly affected performance. Finally, we consider what relationship might hold between lesion size and memory performance in the monkey.     

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.     

Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats

In clinical studies, interictal EEG spikes (IS) have been associated with numerous neuropsychological abnormalities, ranging from transitory cognitive impairment to epileptic encephalopathies. Understanding the pathophysiological mechanisms of IS has been hampered by the lack of validated animal models. To mimic IS, a stimulating microelectrode was implanted in the ventral hippocampal commissure and a recording microelectrode in the CA1 region of the hippocampus of normal male rats. Spike patterns were induced using a series of electrical pulses 10-30 ms in duration with a frequency of 0.5-2Hz and a current of 0.2mA. The commissural stimulation-evoked population discharges in the hippocampus resembled naturally occurring IS in epileptic rats and, in no cases, resulted in behavioral seizures. For behavioral testing, the Morris water maze, radial arm maze, and object recognition tasks were used. Spikes were induced during sleep between the two sets of water maze trials; during the trials in the radial arm maze task; and prior to the sample phase and during the delay periods in the object recognition task. We demonstrated that rats that received spikes took longer to reach the escape platform in the second set of water maze trials; had significantly more reference errors and required more trials to complete the radial arm maze task; and had lower investigation ratios in the object recognition task. The results indicate that induction of spikes in the hippocampus results in impairment of spatial reference and nonspatial object recognition memory.     

The hippocampus,medial prefrontal cortex,and selective memory retrieval: Evidence from a rodent model of the retrieval‐induced forgetting effect

Inhibition is an important component of many cognitive functions, including memory. For example, the retrieval‐induced forgetting (RIF) effect occurs when extra practice with some items from a study list inhibits the retrieval of the nonpracticed items relative to a baseline condition that does not involve extra practice. Although counterintuitive, the RIF phenomenon may be important for resolving interference by inhibiting potentially competing retrieval targets. Neuroimaging studies suggest that the hippocampus and prefrontal cortex are involved in the RIF effect, but controlled lesion studies have not yet been performed. We developed a rodent model of the RIF training procedure and trained control rats and rats with temporary inactivation of the hippocampus or medial prefrontal cortex (mPFC). Rats were trained on a list of odor cues, presented in cups of digging medium with a buried reward, followed by additional practice trials with a subset of the cues. We then tested the rats' memories for the cues and their association with reward by presenting them with unbaited cups containing the test odorants and measuring how long they persisted in digging. Control rats exhibited a robust RIF effect in which memory for the nonpracticed odors was significantly inhibited. Thus, extra practice with some odor cues inhibited memory for the others, relative to a baseline condition that involved an identical amount of training. Inactivation of either the hippocampus or the mPFC blocked the RIF effect. We also constructed a computational model of a representational learning circuit to simulate the RIF effect. We show in this model that “sideband suppression” of similar memory representations can reproduce the RIF effect and that alteration of the suppression parameters and learning rate can reproduce the lesion effects seen in our rats. Our results suggest that the RIF effect is widespread and that inhibitory processes are an important feature of memory function. © 2014 Wiley Periodicals, Inc.     

D1 dopamine and NMDA receptors interactions in the medial prefrontal cortex: Modulation of spatial working memory in rats

Dopamine (DA) and N-methyl-d-aspartate (NMDA) receptors seem to be critically involved in working memory processing in the medial prefrontal cortex (mPFC). Effects of NMDA receptors blockade on dopamine D₁ receptors activation in the mPFC on spatial working memory was investigated. Adult male Wistar rats, well trained in an eight-arm radial maze and bilaterally cannulated in the mPFC, received intracortical administrations of saline (SAL) or SKF-38393 (DA D₁ receptor agonist) followed, 10 min later, by MK-801 (non-competitive NMDA receptor antagonist). They were tested in 1 h delayed tasks after 5 min of the second administration. SKF-38393 (0.56 and 1.8 μg) was disruptive to working memory, increasing significantly the number of errors in the 1 h post-delay performance when administered into the mPFC. MK-801, at doses with no significant effects alone (0.32 or 1.0 μg), reduced significantly the disruptive effect of 0.56 μg SKF-38393. These results showed that the disruptive effect of DA D₁ receptors activation in the mPFC on working memory was significantly reduced by an open-channel NMDA receptor blockade, suggesting that the processing of working memory in the mPFC involving DA D₁ receptors depend, at least in part, of NMDA receptors activity in this cortical area.     

Relational memory for object identity and spatial location in rats with lesions of perirhinal cortex, amygdala and hippocampus

Previous studies dissociate medial temporal lobe regions using non-relational object versus relational spatial tasks. We compared a relational object identity task to the commonly used, relational spatial Morris water task. Lesions of perirhinal cortex, amygdala and hippocampus led to impaired performance on only the relational object preference task. Rats with perirhinal cortex and amygdala lesions performed normally on the Morris water task, but showed reduced perseveration in the correct quadrant on the probe trial. Rats with hippocampal damage were impaired on all measures of the Morris water task. Our findings demonstrate that perirhinal and amygdala damage creates impairments for relational tasks that rely on information processed by these structures (object identity and stimulus valence, respectively). In addition, these structures contribute non-essentially to performance of relational spatial tasks. The hippocampus is critical for all tasks that require the use of relational representations, regardless of whether the disambiguating information is provided by object identity or spatial arrangements. The current pattern of results suggests that the previous object-spatial dissociations among medial temporal lobe regions may be due to the relational nature of the spatial tasks versus the non-relational nature of the object tasks. Further, they illustrate that discrete dissociations among different types of processing may be an oversimplification.     

The role of the medial prefrontal cortex of rats in short-term memory functioning: further support for involvement of cholinergic, rather than dopaminergic mechanisms

The putative involvement of the dopaminergic innervation of the medial part of the prefrontal cortex (PFC) in short-term memory functioning was investigated by evaluating the effects of local infusions of dopaminergic drugs into the ventral part of the medial PFC of rats in an operant delayed-matching-to-position (DMTP) task. Two separate groups of rats were tested after bilateral microinfusion of several doses of either the dopamine receptor agonist apomorphine (APO) or the dopamine receptor antagonist cis-flupenthixol (FLU) into the ventromedial PFC. In addition, all animals were tested after infusion of several doses of the muscarinic receptor antagonist scopolamine (SCO) and the dopamine D1 receptor antagonist SCH-23390 (SCH). The drugs tested affected DMTP performance differentially. APO had no effect on response accuracy, although it dose-dependently affected nose poke activity and response latencies. FLU and SCH both induced a dose-dependent, but delay-independent deterioration of response accuracy that was paralleled by increased in response latencies and decreases in nose poke frequencies, causing some animals to stop responding after infusion of the highest doses of both drugs. In contrast, SCO infusions into the ventromedial PFC induced a dose- and delay-dependent deterioration of response accuracy, that was accompanied by an increase in response latencies only. Taken together, these results provide additional support for the involvement of cholinergic, rather than dopaminergic mechanisms in short-term memory processes supported by the medial PFC of the rat, and they are not in favor of a functional dissociation between the dorsomedial PFC and the ventromedial PFC in this role.     

A critical role for the anterior hippocampus in relational memory: evidence from an fMRI study comparing associative and item recognition

Neuroscientific research has established that the hippocampal formation, a structure within the medial temporal lobe (MTL), plays a critical role in memory for facts and events (declarative memory) (Milner et al., 1998). However, its precise role remains unclear. According to one view, the hippocampus has a special role in relating or binding together previously unrelated pieces of information, while another view proposes that the hippocampus is equally involved in all forms of declarative memory, regardless of their demands on relational processing. Using functional magnetic resonance imaging (fMRI), we show that hippocampal activation is modulated by the extent to which a retrieval task depends on relational processing.     

Memory for spatial location and object-place associations are differently processed by the hippocampal formation, parahippocampal areas TH/TF and perirhinal cortex

To clarify the specific contribution of the medial temporal lobe structures in spatial memory, we tested monkeys (Macaca mulatta) with sham operations and with lesions of either the hippocampal formation, areas TH/TF or perirhinal cortex on two versions of the visual-paired comparison task, measuring Spatial Location, and Object-in-Place associations. In the Spatial Location version, the comparison was between two identical objects presented simultaneously in a familiar and a novel location. In the Object-in-Place version, the comparison was between an image consisting of five objects and another image showing the same five objects, but with the position of 2, 3, or 4 of the objects rearranged. Finally, a VPC-Control task was given to animals with hippocampal and perirhinal lesions, in which the comparison was between an image consisting of five objects and another image showing four of the five familiar objects and a new one. Perirhinal lesions yielded no deficit in the Spatial Location task and a deficit in the Object-in-Place task associated with a deficit in the VPC-control task, suggesting that this cortical area does not participate in spatial memory unless the stimuli have overlapping features. Areas TH/TF lesions produced a deficit in both Spatial Location and Object-in-Place tasks, whereas the hippocampal lesions resulted in a deficit of Object-in-Place associations only. The data showed that the hippocampal formation, areas TH/TF, and perirhinal cortex appear to contribute interactively to object and spatial memory processes.