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Neuroscience Research journal homepage: www.elsevier.com/locate/neures
Review article
Entorhinal cortex and consolidated memory Kaori Takehara-Nishiuchi a,b,c,∗ a
Department of Psychology, University of Toronto, Toronto, ON, Canada Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada c Neuroscience Program, University of Toronto, Toronto, ON, Canada b
a r t i c l e
i n f o
Article history: Received 19 December 2013 Received in revised form 19 February 2014 Accepted 27 February 2014 Available online xxx Keywords: Memory consolidation Hippocampus Prefrontal cortex Cingulate cortex Episodic memory Trace conditioning
a b s t r a c t The entorhinal cortex is thought to support rapid encoding of new associations by serving as an interface between the hippocampus and neocortical regions. Although the entorhinal–hippocampal interaction is undoubtedly essential for initial memory acquisition, the entorhinal cortex contributes to memory retrieval even after the hippocampus is no longer necessary. This suggests that during memory consolidation additional synaptic reinforcement may take place within the cortical network, which may change the connectivity of entorhinal cortex with cortical regions other than the hippocampus. Here, I outline behavioral and physiological findings which collectively suggest that memory consolidation involves the gradual strengthening of connection between the entorhinal cortex and the medial prefrontal/anterior cingulate cortex (mPFC/ACC), a region that may permanently store the learned association. This newly formed connection allows for close interaction between the entorhinal cortex and the mPFC/ACC, through which the mPFC/ACC gains access to neocortical regions that store the content of memory. Thus, the entorhinal cortex may serve as a gatekeeper of cortical memory network by selectively interacting either with the hippocampus or mPFC/ACC depending on the age of memory. This model provides a new framework for a modification of cortical memory network during systems consolidation, thereby adding a fresh dimension to future studies on its biological mechanism. © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impairment in consolidated memory following damage to the entorhinal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Implications from clinical populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Observations in animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relations of connectivity between the entorhinal cortex and hippocampus to systems consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relations of connections between the entorhinal cortex and cortical regions to systems consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Involvement of prefrontal and cingulate cortex in the expression of consolidated memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Connections between the entorhinal cortex and medial prefrontal/anterior cingulate cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Specific signals that the entorhinal cortex transmits across the cortical network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Impact of entorhinal input on neuron firing in the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Impact of entorhinal input on neuron firing in the sensory neocortical regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and outstanding questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Correspondence to: Department of Psychology, University of Toronto, Sidney Smith Hall Room 4007, 100 St. George Street, Toronto, ON M5S 3G3, Canada. Tel.: +1 416 978 6570. E-mail address: [email protected] http://dx.doi.org/10.1016/j.neures.2014.02.012 0168-0102/© 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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1. Introduction “People’s memories are maybe the fuel they burn to stay alive. . . . I think if I didn’t have all that fuel, if I didn’t have the memory drawers inside me, I would’ve snapped a long time ago.” – After Dark by Haruki Murakami Memory is one of the most important cognitive processes that make our lives richer and maintainable. Since the seminal work by Scoville and Milner (1957) on patient H.M., many studies have provided evidence that the medial temporal lobe, especially the hippocampus is necessary for a certain type of memory, such as memories of daily experiences (episodic memory) and personal history (autographical memory; Squire et al., 2004; Milner, 2005; Moscovitch et al., 2006). This has inspired a number of competing network models for how the brain generates and supports memories over time. One model posits that the hippocampus stores an index of cortical loci that were activated during an experiential event (Teyler and DiScenna, 1986; Teyler and Rudy, 2007). During the event, incoming sensory information is registered at various sensory and association neocortical regions. The activity of neurons in the neocortical regions then projects to the hippocampus, and synapses between neurons responding to the neocortical inputs are strengthened. Accordingly, the experience is represented simply as the set of strengthened synapses in the hippocampus that are associated with a unique set of activated neurons across the neocortex. The strengthened synapses in the hippocampus are further stabilized through the process of cellular consolidation that involves the synthesis of new proteins during a few hours after the experience (Dudai, 2004; Squire and Kandel, 2009). The stabilized synapses in the hippocampus may be capable of supporting the memory for a certain period of time; however, without any further reinforcement, it may decay eventually. The subsequent reinforcement process, what came to be called systems consolidation, is presumed to involve modifications of the synaptic connections between neurons in different brain regions (Frankland and Bontempi, 2005; Squire and Kandel, 2009). This results in gradual reorganization of brain regions supporting memory over a longer time period. Some models assume that synaptic connections between the neocortical regions are gradually strengthened (Squire and Zola-Morgan, 1991; Squire and Alvarez, 1995; McClelland et al., 1995) whereas others assume that the original neocortical activity pattern is bound to additional synaptic connections in the hippocampus and surrounding cortical regions (Nadel and Moscovitch, 1997). These two possibilities are not mutually exclusive, and in fact any synaptic connections within the network are potentially strengthened. Yet, the strengthening of specific connection may be more important than others because it has a larger impact on network operation. The entorhinal cortex is one of the cortical regions surrounding the hippocampus. It has been viewed as a hub of cortical memory network because it has reciprocal connections with the hippocampus in one hand and with the neocorotical regions on the other (Fig. 1; Burwell, 2000; Suzuki and Amaral, 2004; van Strien et al., 2009). This anatomical feature suggests that a small change in the connectivity of entorhinal cortex may have a dramatic impact on how the cortical network operates during memory retrieval. The following sections outline findings in behavioral and electrophysiological studies that addressed how long the entorhinal cortex is involved in memory retrieval and how its connectivity with the hippocampus and other cortical regions change over the course of systems consolidation. These studies collectively suggest that the entorhinal cortex plays a long-lasting role in memory retrieval by initially interacting with the hippocampus but later with the medial prefrontal/anterior cingulate cortex.
Fig. 1. Functional anatomy of the fronto-temporal cortical memory network. Based on the anatomical connectivity of entorhinal cortex with the hippocampus, medial prefrontal cortex, and neocortex, I hypothesize that highly processed sensory information in the neocortex is transferred to the hippocampus and medial prefrontal cortex through the superficial layer of entorhinal cortex (Steward and Scoville, 1976; Witter et al., 1988; Amaral and Witter, 1995; Insausti et al., 1997; Burwell and Amaral, 1998; Hoover and Vertes, 2007; Canto et al., 2008; Agster and Burwell, 2009). The output of hippocampus and medial prefrontal cortex is sent back to the neocortex through the deep layer of entorhinal cortex (Swanson and Cowan, 1977; Amaral and Witter, 1995; Apergis-Schoute et al., 2006; Jones and Witter, 2007; Canto et al., 2008). Hippocampoal output also modulates the medial prefrontal cortex via monosynaptic projections (Swanson, 1981; Jay and Witter, 1991).
2. Impairment in consolidated memory following damage to the entorhinal cortex 2.1. Implications from clinical populations Patients with damage to the medial temporal lobe are impaired with the retrieval of memory acquired before brain damage, but the degree of impairment considerably varies depending on the size of damage. In the patients with damage restricted to the hippocampus, memory impairments extend back only for a few years (Kapur and Brooks, 1999; Bayley et al., 2006; but see, Chan et al., 2002). Additional damage to adjacent regions surrounding the hippocampus impairs memory extended back for a longer period (Bright et al., 2006; Bayley et al., 2006; Noulhiane et al., 2007). A similar pattern of impairment was observed in patients with temporal lobe epilepsy (TLE). Typical pathological changes in TLE are selective neuronal loss in the hippocampus and regions connected with the hippocampus, including the entorhinal cortex (Du et al., 1993; Bonilha et al., 2003). In some cases, atrophy in the entorhinal cortex occurs without the loss of hippocampal volume (Bernasconi et al., 2001; Khalsa et al., 2006). Memory impairments in TLE patients encompass all life periods including early childhood (Manes et al., 2005; Herfurth et al., 2010). Some TLE patients also show accelerated forgetting, which indicates impairments in memory consolidation (Manes et al., 2005). Interestingly, the ability of TLE patients to perform remote autobiographical memory tests is not correlated with their ability to perform anterograde memory tasks (Herfurth et al., 2010). Given that anterograde memory deficits are correlated with the degree of hippocampal damage, this finding suggests that the impairments in remote autobiographical memory may be associated with damage outside of the hippocampus. A more direct support for this argument is found in amnesic patients with herpes simplex encephalitis. In these patients, the extent of retrograde memory impairment is correlated with the size of the parahippocampal and entorhinal cortex lesion, but not with the size of the hippocampal lesion (Yoneda et al., 1994). This agrees well with a finding that in healthy subjects the entorhinal cortex is activated during the recall of faces of people who were famous up to 20 years ago, whereas the hippocampus is only
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Fig. 2. Entorhinal cortex as a gatekeeper of cortical memory network. During learning (left) synaptic connections between neurons (red circles) in the entorhinal cortex and those in the hippocampus are rapidly strengthened to encode a new memory. Subsequent consolidation (middle) involves the reactivation of memory-bearing neurons in the hippocampus, which in turn activates the original neurons in the entorhinal cortex as well as new neurons (blue circles) in the entorhinal cortex and medial prefrontal/anterior cingulate cortex (mPFC/ACC). This process strengthens the connection between the entorhinal cortex and mPFC/ACC. During memory expression (right) the entorhinal cortex selectively activates the neurons in the hippocampus or the neurons in the mPFC/ACC depending on the age of memory.
activated during the recall of famous faces up to a few years ago (Haist et al., 2001). Together, these findings suggest that the regions surrounding the hippocampus are involved in memory retrieval for a longer period compared with the hippocampus. 2.2. Observations in animal studies Consistent with findings in patients with medial temporal lobe damage, a large lesion to the hippocampus and parahippocampal cortices in monkeys produces retrograde memory impairments that extend for a longer time window than the impairments following damage to the hippocampus alone (Suzuki et al., 1993; Thornton et al., 1997). This was replicated with a specific manipulation to a sub-region of the parahippocampal regions in rodents (Cho et al., 1993; Cho and Kesner, 1996; Burwell et al., 2004; Morrissey et al., 2012). The studies, however, do not agree on whether the degree of impairment changes with the passage of time after learning. In a spatial discrimination paradigm, the memory impairment following damage to the entorhinal cortex becomes less severe over 4–6 weeks since initial learning (Cho et al., 1993; Cho and Kesner, 1996). In contrast, in trace eyeblink conditioning, in which the hippocampus is necessary for memory expression up to two weeks following learning (Takehara et al., 2003), reversible inactivation of the lateral entorhinal cortex equally impairs the expression of memory acquired one day and one month earlier (Morrissey et al., 2012; Tanninen et al., 2013). Similarly, in contextual fear conditioning, in which the hippocampal involvement is limited to two weeks from the time of conditioning (Kim and Fanselow, 1992), damage to the perirhinal or postrhinal cortex, two parahippocampal regions closely connected with the entorhinal cortex, equally impairs retention one and one-hundred days later (Burwell et al., 2004). To summarize, the evidence describes that the entorhinal cortex is involved in memory expression for a longer time period compared with the hippocampus. The available data, however, still do not agree on the exact duration of entorhinal involvement in memory expression (i.e., permanent or temporally limited). 3. Relations of connectivity between the entorhinal cortex and hippocampus to systems consolidation Findings in clinical population and animal studies suggest that memory initially depends both on the hippocampus and entorhinal cortex, but later it becomes dependent solely on the entorhinal cortex. This predicts that the connectivity between the entorihnal
cortex and hippocampus should be involved in memory expression for a limited period of time. The connection between the entorhinal cortex and hippocampus forms a loop which originates in superficial layers of the entorhinal cortex and terminates at deep entorhinal layers (Fig. 1; Steward and Scoville, 1976; Swanson and Cowan, 1977; Amaral and Witter, 1995). Besides, the entorhinal projection to the hippocampus forms two separate pathways: the perforant path originates from layer II of the entorhinal cortex and terminates at the dentate gyrus while the temporoamonic path originates from layer III of the entorhinal cortex and projects to the CA1 region (Steward and Scoville, 1976; Witter et al., 1988; Amaral and Witter, 1995). The perforant pathway connects the entorhinal cortex to dentate gyrus and is highly plastic because of modifiable synapses (Bliss and Lomo, 1973) as well as unique structural changes associated with adult neurogenesis (Altman, 1962; Cameron et al., 1993). In the dentate gyrus, neurogenesis persists throughout adulthood, and the adult–born neurons are continuously incorporated into the existing network (Lledo et al., 2006; Ming and Song, 2011). This may induce the remodeling of local network in the dentate gyrus, which destabilizes the existing synaptic connections with the entorhinal cortex (Feng et al., 2001; Lacefield et al., 2012; Frankland et al., 2013). This active modification of dentateentorhinal connection may hinder the entorhinal inputs from activating dentate cells that were originally associated with the entorhinal inputs. Consistent with this idea, Kitamura et al. (2009) demonstrated that adult neurogenesis modulates the time window during which the hippocampus is involved in memory retrieval. When adult neurogenesis is reduced, the long-term potentiation at perforant path-dentate gyrus synapses persists for three weeks, which is longer than a normal duration of two weeks. The stable entorhinal–hippocampal synaptic connection is accompanied by a longer time window over which the expression of contextual fear memory depends on the hippocampus. Inversely, when the neurogenesis is enhanced (which is presumed to destabilize the existing entorhinal–dentate connection), contextual fear memory is dependent on the hippocampus for a shorter time periods than normal. These results suggest that the stability of dentateentorhinal connection determines the reliance of memory on the hippocampus. The temporoamonic path, on the other hand, is not involved in memory retrieval, but it plays a critical, but time-limited role in memory consolidation in a spatial memory paradigm (Remondes and Schuman, 2004). This study examined the impact of a
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specific lesion to axons of temporoamonic path on the performance in Morris water maze task. The lesion made before the training does not impair the acquisition of spatial memory or its expression one day later. In contrast, the lesion significantly impairs memory expression four weeks after learning when it is made immediately after training, but not three weeks after learning. Thus, these results suggest that ongoing entorhinal input to the CA1 region is necessary to consolidate long-term spatial memory. In summary, the two studies reviewed above showed that the perforant path is involved in the expression of memory whereas the temporoamonic path is necessary for the consolidation of memory. Importantly, the involvement of perfortnat path and temporoamonic path in the respective processes is limited only for a few weeks after learning. 4. Relations of connections between the entorhinal cortex and cortical regions to systems consolidation Compared with the connection between the entorhinal cortex and hippocampus, less is known about how the connection between the entorhinal cortex and other cortical regions changes with learning and consolidation. This question had been difficult to address because available literature had vaguely described cortical regions that are involved in the expression of a memory after it is consolidated. Evidence accumulating in the past ten years now suggests that memory consolidation involves the reorganization of network in a manner that the center of network is shifted from the hippocampus to the medial prefrontal/anterior cingulate cortex (mPFC/ACC; Frankland and Bontempi, 2005; Insel and Takehara-Nishiuchi, 2013). This raises a possibility that the mPFC/ACC may play a similar role for consolidated memories to the one that the hippocampus plays for recently formed memories (Frankland and Bontempi, 2005; Takashima et al., 2006; Insel and Takehara-Nishiuchi, 2013). Based on recent electrophysiological studies, along with a unique anatomical property of the mPFC/ACC (Fig. 1), I argue that the mPFC/ACC may gain the role by strengthening its connection with the entorhinal cortex. 4.1. Involvement of prefrontal and cingulate cortex in the expression of consolidated memory Although the expression of consolidated memory is associated with the activation of many neocortical regions (Bontempi et al., 1999; Wheeler et al., 2013), dysfunction of one of these regions, the mPFC/ACC is enough to produce a profound impairment in the expression of consolidated memory (Takehara et al., 2003; Frankland et al., 2004; Maviel et al., 2004). The mPFC/ACC appears to gain the role in memory expression as a result of local synaptic reinforcement during systems consolidation. The expression of consolidated memory is significantly impaired by a blockade of NMDA receptors in the mPFC specifically for two weeks after trace eyeblink conditioning (Takehara-Nishiuchi et al., 2006). Besides, new dendritic spines had been formed in the ACC following one month after contextual fear conditioning (Restivo et al., 2009), and suppression of the conditioning-induced dendritic spine growth in the ACC impairs the expression of consolidated memory (Vetere et al., 2011). These changes in the local network are also reflected in changes in the activity of single neurons in the mPFC. During the same time window in which the synaptic reinforcement occurs, the activity of single neurons in the mPFC becomes selective for the acquired memory associsation in trace eyeblink conditioning (Takehara-Nishiuchi and McNaughton, 2008). Besides, neurons in the ACC develop a selective activity for the remotely acquired association between a familiar object and its location (Weible et al., 2012). Together, these results sugget systems consolidation
involves synaptic reinforcement in the mPFC/ACC, which may shape the selective neuronal activity for consolidated memory in the mPFC/ACC. 4.2. Connections between the entorhinal cortex and medial prefrontal/anterior cingulate cortex All reported synaptic reinforcement in the mPFC/ACC (Takehara-Nishiuchi et al., 2006; Restivo et al., 2009) occurs postsynaptically, suggesting that the connection between the mPFC/ACC and its afferent regions may be modified during the consolidation process. Although the mPFC/ACC receives the inputs from many cortical and subcortical regions, one of the main afferent sources is the entorhinal cortex (Hoover and Vertes, 2007). The mPFC/ACC receives the projection from superficieal layers of the entorhinal cortex (Insausti et al., 1997), and sends their projections back preferentially to the deep entorhinal layers (Apergis-Schoute et al., 2006; Jones and Witter, 2007; Canto et al., 2008; Fig. 1). This pattern is similar to the connection of entorhinal cortex with the hippocampus (Steward and Scoville, 1976; Swanson and Cowan, 1977; Witter et al., 1988; Amaral and Witter, 1995); however, it sharply contrasts with its connection with other neocortical regions: the neocortical regions project to superficial layers of the entorhinal cortex while it is the deep entorhinal layers that project back to the neocortical regions (Burwell and Amaral, 1998; Burwell, 2000; Agster and Burwell, 2009; Fig. 1). Together, these anatomical properties suggest that the entorhinal cortex may serve as an interface between the mPFC/ACC and the neocortical regions as it does for the hippocampus. If the entorhinal cortex serves as the interface between the mPFC/ACC and neocortical regions, the interaction between the entorhinal cortex and mPFC/ACC should be critical for the expression of consolidated memory. Currently no studies as of yet determine whether disconnection of the entorhinal cortex from the mPFC/ACC impairs the expression of consolidated memory (but see, Tanninen et al., 2013); however, some studies reported neuronal activity patterns that suggest close coupling between these regions during memory expression. Takehara-Nishiuchi et al. (2011) simultaneously monitored local field potentials in the lateral entorhinal cortex and the prelimbic region of mPFC, as well as in the hippocampus while rats associated a neutral conditioned stimulus (CS) with mildly aversive eyelid shock presented moments later in trace eyeblink conditioning. Upon presentation of the CS, local field potentials in all three regions exhibited a clear 7 Hz (theta) rhythm. Importantly, the evoked theta oscillations were synchronized between the lateral entorhinal cortex and hippocampus during early learning, but this was reduced later in learning and following a consolidation period. Meanwhile, theta oscillations between the lateral entorhinal and prelimbic cortices were high throughout learning and during consolidation, and were also stronger on trials in which rats exhibited a conditioned response. These results suggest that with learning and subsequent consolidation, memory expression becomes increasingly relied on the functional connection between the lateral entorhinal cortex and prelimbic cortex. Paz et al. (2007) also reached a similar conclusion based on experience-dependent correlation increases between single neuron activity in the rostral cingulate cortex and entorhinal cortex in cats. By examining how cingulate neuron firings modulate the correlated neuron activity between the entorhinal cortex and perirhinal cortex, they found evidence that with learning the rostral cingulate cortex becomes more capable of driving the information transfer from the entorhinal cortex to perirhinal cortex. This observation suggests that learning enables the rostral cingulate cortex to drive the activity of downstream targets through the entorhinal cortex.
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5. Specific signals that the entorhinal cortex transmits across the cortical network Based on the studies reviewed above, I propose that the entorhinal cortex initially provides the hippocampus with access to the sensory and association neocortical regions during the retrieval of new memory. With additional network modifications during systems consolidation, it comes to play the same function for the mPFC/ACC during the retrieval of consolidated memory (Fig. 2). To further elaborate on this model, it is necessary to specify exactly what type of information is transferred among these regions. In the following section, I outline some studies which have addressed this point by examining how the incoming input from the entorhinal cortex modulates specific information represented in firing patterns of neurons in the efferent regions. 5.1. Impact of entorhinal input on neuron firing in the hippocampus Theories assume that the role of hippocampus is to bind together the features of an experience to create a unitary representation of the experience (Teyler and DiScenna, 1986; McClelland et al., 1995; Squire and Alvarez, 1995; O’Reilly and Rudy, 2001). Consistent with this argument, neurons in the hippocampus respond to the conjunction of various types of information and show a selective activity for spatial location, specific behavior, and sensory stimuli in a specific context (Wiener, 1996; Smith and Mizumori, 2006). The conjunctive activity of hippocampal neurons may be generated by convergence of the incoming inputs from many afferent regions. Several studies showed that the entorhinal cortex provides the hippocampus with the information on spatial and sensory features of experience through two parallel streams. Specifically, lesion of the medial entorhinal cortex results in the instability of spatial tuning of neurons in the CA1 region of hippocampus (Brun et al., 2008; Navawongse and Eichenbaum, 2013). In contrast, lesion of the lateral entorhinal cortex impairs firing changes of CA3 neurons in response to changes in shapes or the color of the environment while their spatial tuning remains intact (Lu et al., 2013). The apparent functional division between the inputs from the medial and lateral entorhinal cortex is consistent with the difference in the selectivity of neuron firings between these entorhinal sub-regions. Neurons in the dorsomedial portion of entorhinal cortex fire multiple locations within a place, which are aligned in a rhombus with interval angle of 60◦ and 120◦ (Fyhn et al., 2004; Doeller et al., 2010; Killian et al., 2012). In addition to these ‘grid cells’, the medial entorhinal cortex also includes neurons that are selective for the direction of head (‘head direction cell’; Sargolini et al., 2006) as well as neurons that respond to geometric boundaries of the environment (‘border cell’; Solstad et al., 2008). Importantly, grid, head direction, and border cells are active across different environment (Hafting et al., 2005; Fyhn et al., 2007; Solstad et al., 2008). This suggests that the medial entorhinal cortex may provide the hippocampus with the spatial metric of surrounding environment that can be applied universally across different environment (McNaughton et al., 2006; Moser et al., 2008; Zhang et al., 2013). It is noteworthy that entorhinal grid cells are observed only in the dorsomedial portion of entorinal cortex; neurons in the intermediate and lateral portion of entorhinal cortex rarely show spatially tuned activity in an open field (Fyhn et al., 2004; Hafting et al., 2005). Rather, these neurons are selective for non-spatial features, such as a discrete object in an environment (Deshmukh and Knierim, 2011; Tsao et al., 2013). The selective activity for an object can also be described as the selectivity for visual and tactile stimuli. In fact, many studies have reported that entorhinal neurons respond to a specific sensory stimulus during a behavioral paradigm
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without any spatial components (auditory, Segal, 1973; visual, Zhu et al., 1995; Kreiman et al., 2000; Fried et al., 2002; odor, Young et al., 1997; Xu and Wilson, 2012). Thus, the lateral entorhinal cortex may provide the hippocampus with highly specific sensory inputs irrespective of its position in the environment. 5.2. Impact of entorhinal input on neuron firing in the sensory neocortical regions Most theories assume that the interaction between the hippocampus and neocortical regions is bidirectional: the conjunctive signal in the hippocampus is projected back to the original neocortical regions that initially brought sensory information to the hippocampus (Teyler and DiScenna, 1986; Squire, 1992; McClelland et al., 1995; Eichenbaum, 2000). This predicts that disrupting the return projection from the hippocampus should specifically abolish the signals for stimulus conjunction in the sensory neocortical regions. Consistent with this prediction, in the sensory neocortical regions, some neurons show selective firings to the physical attributes of sensory stimuli, but other neurons respond to abstract features of the stimulus, such as its association with other stimuli (Sakai and Miyashita, 1991; Erickson and Desimone, 1999). Damage to the perirhinal and entorhinal cortex in monkeys abolished the signal on the association between visual stimuli in the inferotemporal cortex while leaving the signal for physical features of visual stimuli intact (Higuchi and Miyashita, 1996). Similarly, the inactivation of entorhinal cortex abolishes a cross-modal association signal in single neuron firings in the primary auditory cortex (Chen et al., 2013). Together, these results suggest that while external sensory inputs shape the selective activity for a physical stimulus attribute in the sensory region, topdown signals from the entorhinal cortex, or its associated structures like the hippocampus, provide information on stimulus relationships learned through past experiences. In summary, the studies reviewed above suggest that the entorhinal cortex has a major, but rather specific, impact on neuronal representation in the hippocampus and neocortical regions. Currently, no study examined how the input from the entorhinal cortex modulates the activity of neurons in the mPFC/ACC. 6. Conclusions and outstanding questions The entorhinal cortex is located at a pivotal position in the cortical memory network with a reciprocal connection with the hippocampus in one hand and with the neocortical regions on the other (Fig. 1). This anatomical property suggests that the entorhinal cortex may serve as a gateway of the hippocampus to stimulus information represented in widely spread regions of the neocortex (Squire, 1992; Eichenbaum, 2000). I argue that systems consolidation may involve additional modifications of the network, which may enable the entorhinal cortex to provide the mPFC/ACC with access to the neocortical regions (Fig. 2). As a result, the entorhinal cortex becomes capable of selectively interacting with the hippocampus or mPFC/ACC depending on the age of memory to be retrieved. As reviewed above, some parts of this model are supported by available empirical data; however, several critical assumptions of the model need to be tested in future studies. I will briefly highlight four points that will provide some testable predictions for future studies. First, functional connectivity between the entorhinal cortex and mPFC/ACC and its change over the consolidation process need further examinations at the level of behavior and neuron activity. This requires newly developed tools that can specifically manipulate the connection between the two regions because a traditional pharmacological approach did not work in this connection (Tanninen et al., 2013).
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Second, it is important to identify the exact mechanism on the strengthening of entorhinal–mPFC/ACC connection after learning. Theories assume that the reactivation of learned neuron activity patterns during ‘off-line’ period such as sleep drives synaptic reinforcement during consolidation processes (Schwindel and McNaughton, 2011). Although the reactivation of neuron activity patterns has been well-documented, its causality on synaptic modifications in the cortical region remains to be tested. Third, it needs to be specified what operation the entorhinal cortex performs to selectively interact with the hippocampus or mPFC/ACC depending on the age of memory. One possibility is that the difference in the strength of entorhinal cortical connectivity between the hippocampus and mPFC/ACC may define which of them will be activated by the entorhinal input. Alternatively, the entorhinal cortex (perhaps with perirhinal and postrhinal cortices) may filter the incoming sensory input depending on familiarity (Fernandez and Tendolkar, 2006). Forth, in an intact brain the entorhinal–hippocampal connection may continue to contribute to memory expression even after the entorhinal–mPFC/ACC connection is sufficiently strengthened. A recent study by Goshen et al. (2011) demonstrated that transient, optogenetic inhibition of pyramidal neurons in the CA1 region significantly impaired the expression of old contextual fear memory. This finding sharply contrasts with intact expression of old memory following prolonged pharmacological inactivation of the same region. These findings suggest that although consolidated memory can be retrieved without the hippocampus, in an intact brain the hippocampus still participates in the retrieval process, perhaps by forming a contextual representation that matches with the one for original experience (Thompson and Best, 1990; Lever et al., 2002). Acknowledgements This work was supported by NSERC Discovery Grant and CFI Leaders Opportunity Fund. The author thanks Dr. Nathan Insel for helpful comments and discussion. References Agster, K.L., Burwell, R.D., 2009. Cortical efferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. Hippocampus 19, 1159–1186. Altman, J., 1962. Are new neurons formed in the brains of adult mammals? Science 135, 1127–1128. Amaral, D., Witter, M., 1995. Hippocampal formation. In: Paxinos, G. (Ed.), The Rat Nervous System. Academic Press, San Diego, CA, pp. 443–486. Apergis-Schoute, J., Pinto, A., Pare, D., 2006. Ultrastructural organization of medial prefrontal inputs to the rhinal cortices. Eur. J. Neurosci. 24, 135–144. Bayley, P.J., Hopkins, R.O., Squire, L.R., 2006. The fate of old memories after medial temporal lobe damage. J. Neurosci. 26, 13311–13317. Bernasconi, N., Bernasconi, A., Caramanos, Z., Dubeau, F., Richardson, J., Andermann, F., Arnold, D.L., 2001. Entorhinal cortex atrophy in epilepsy patients exhibiting normal hippocampal volumes. Neurology 56, 1335–1339. Bliss, T.V., Lomo, T., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356. Bonilha, L., Kobayashi, E., Rorden, C., Cendes, F., Li, L.M., 2003. Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy. J. Neurol. Neurosurg. Psychiatry 74, 1627–1630. Bontempi, B., Laurent-Demir, C., Destrade, C., Jaffard, R., 1999. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675. Bright, P., Buckman, J., Fradera, A., Yoshimasu, H., Colchester, A.C., Kopelman, M.D., 2006. Retrograde amnesia in patients with hippocampal, medial temporal, temporal lobe, or frontal pathology. Learn. Mem. 13, 545–557. Brun, V.H., Solstad, T., Kjelstrup, K.B., Fyhn, M., Witter, M.P., Moser, E.I., Moser, M.B., 2008. Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus 18, 1200–1212. Burwell, R.D., 2000. The parahippocampal region: corticocortical connectivity. Ann. N.Y. Acad. Sci. 911, 25–42. Burwell, R.D., Amaral, D.G., 1998. Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J. Comp. Neurol. 398, 179–205. Burwell, R.D., Bucci, D.J., Sanborn, M.R., Jutras, M.J., 2004. Perirhinal and postrhinal contributions to remote memory for context. J. Neurosci. 24, 11023–11028.
Cameron, H.A., Woolley, C.S., McEwen, B.S., Gould, E., 1993. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56, 337–344. Canto, C.B., Wouterlood, F.G., Witter, M.P., 2008. What does the anatomical organization of the entorhinal cortex tell us? Neural Plast. 2008, 381243. Chan, D., Revesz, T., Rudge, P., 2002. Hippocampal, but not parahippocampal, damage in a case of dense retrograde amnesia: a pathological study. Neurosci. Lett. 329, 61–64. Chen, X., Guo, Y., Feng, J., Liao, Z., Li, X., Wang, H., Li, X., He, J., 2013. Encoding and retrieval of artificial visuoauditory memory traces in the auditory cortex requires the entorhinal cortex. J. Neurosci. 33, 9963–9974. Cho, Y.H., Beracochea, D., Jaffard, R., 1993. Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice. J. Neurosci. 3, 1759–1766. Cho, Y.H., Kesner, R.P., 1996. Involvement of entorhinal cortex or parietal cortex in long-term spatial discrimination memory in rats: retrograde amnesia. Behav. Neurosci. 110, 436–442. Deshmukh, S.S., Knierim, J.J., 2011. Representation of non-spatial and spatial information in the lateral entorhinal cortex. Front. Behav. Neurosci. 5, 69. Doeller, C.F., Barry, C., Burgess, N., 2010. Evidence for grid cells in a human memory network. Nature 463, 657–661. Du, F., Whetsell Jr., W.O., Abou-Khalil, B., Blumenkopf, B., Lothman, E.W., Schwarcz, R., 1993. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res. 16, 223–233. Dudai, Y., 2004. The neurobiology of consolidations, or, how stable is the engram? Annu. Rev. Psychol. 55, 51–86. Eichenbaum, H., 2000. A cortical–hippocampal system for declarative memory. Nat. Rev. Neurosci. 1, 41–50. Erickson, C.A., Desimone, R., 1999. Responses of macaque perirhinal neurons during and after visual stimulus association learning. J. Neurosci. 19, 10404–10416. Feng, R., Rampon, C., Tang, Y.P., Shrom, D., Jin, J., Kyin, M., Sopher, B., Miller, M.W., Ware, C.B., Martin, G.M., Kim, S.H., Langdon, R.B., Sisodia, S.S., Tsien, J.Z., 2001. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32, 911–926. Fernandez, G., Tendolkar, I., 2006. The rhinal cortex: ‘gatekeeper’ of the declarative memory system. Trends Cogn. Sci. 10, 358–362. Frankland, P.W., Bontempi, B., 2005. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130. Frankland, P.W., Bontempi, B., Talton, L.E., Kaczmarek, L., Silva, A.J., 2004. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883. Frankland, P.W., Kohler, S., Josselyn, S.A., 2013. Hippocampal neurogenesis and forgetting. Trends Neurosci. 36, 497–503. Fried, I., Cameron, K.A., Yashar, S., Fong, R., Morrow, J.W., 2002. Inhibitory and excitatory responses of single neurons in the human medial temporal lobe during recognition of faces and objects. Cereb. Cortex 12, 575–584. Fyhn, M., Hafting, T., Treves, A., Moser, M.B., Moser, E.I., 2007. Hippocampal remapping and grid realignment in entorhinal cortex. Nature 446, 190–194. Fyhn, M., Molden, S., Witter, M.P., Moser, E.I., Moser, M.B., 2004. Spatial representation in the entorhinal cortex. Science 305, 1258–1264. Goshen, I., Brodsky, M., Prakash, R., Wallace, J., Gradinaru, V., Ramakrishnan, C., Deisseroth, K., 2011. Dynamics of retrieval strategies for remote memories. Cell 147, 678–689. Hafting, T., Fyhn, M., Molden, S., Moser, M.B., Moser, E.I., 2005. Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801–806. Haist, F., Bowden Gore, J., Mao, H., 2001. Consolidation of human memory over decades revealed by functional magnetic resonance imaging. Nat. Neurosci. 4, 1139–1145. Herfurth, K., Kasper, B., Schwarz, M., Stefan, H., Pauli, E., 2010. Autobiographical memory in temporal lobe epilepsy: role of hippocampal and temporal lateral structures. Epilepsy Behav. 19, 365–371. Higuchi, S., Miyashita, Y., 1996. Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions. Proc. Natl. Acad. Sci. U.S.A. 93, 739–743. Hoover, W.B., Vertes, R.P., 2007. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct. Funct. 212, 149–179. Insausti, R., Herrero, M.T., Witter, M.P., 1997. Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus 7, 146–183. Insel, N., Takehara-Nishiuchi, K., 2013. The cortical structure of consolidated memory: a hypothesis on the role of the cingulate–entorhinal cortical connection. Neurobiol. Learn. Mem. 106, 343–350. Jay, T.M., Witter, M.P., 1991. Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J. Comp. Neurol. 313, 574–586. Jones, B.F., Witter, M.P., 2007. Cingulate cortex projections to the parahippocampal region and hippocampal formation in the rat. Hippocampus 17, 957– 976. Kapur, N., Brooks, D.J., 1999. Temporally-specific retrograde amnesia in two cases of discrete bilateral hippocampal pathology. Hippocampus 9, 247–254. Khalsa, S.S., Moore, S.A., Van Hoesen, G.W., 2006. Hughlings Jackson and the role of the entorhinal cortex in temporal lobe epilepsy: from patient A to Doctor Z. Epilepsy Behav. 9, 524–531. Killian, N.J., Jutras, M.J., Buffalo, E.A., 2012. A map of visual space in the primate entorhinal cortex. Nature 491, 761–764.
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G Model NSR-3662; No. of Pages 7
ARTICLE IN PRESS K. Takehara-Nishiuchi / Neuroscience Research xxx (2014) xxx–xxx
Kim, J.J., Fanselow, M.S., 1992. Modality-specific retrograde amnesia of fear. Science 256, 675–677. Kitamura, T., Saitoh, Y., Takashima, N., Murayama, A., Niibori, Y., Ageta, H., Sekiguchi, M., Sugiyama, H., Inokuchi, K., 2009. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139, 814–827. Kreiman, G., Koch, C., Fried, I., 2000. Category-specific visual responses of single neurons in the human medial temporal lobe. Nat. Neurosci. 3, 946–953. Lacefield, C.O., Itskov, V., Reardon, T., Hen, R., Gordon, J.A., 2012. Effects of adultgenerated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 22, 106–116. Lever, C., Wills, T., Cacucci, F., Burgess, N., O’Keefe, J., 2002. Long-term plasticity in hippocampal place-cell representation of environmental geometry. Nature 416, 90–94. Lledo, P.M., Alonso, M., Grubb, M.S., 2006. Adult neurogenesis and functional plasticity in neuronal circuits. Nat. Rev. Neurosci. 7, 179–193. Lu, L., Leutgeb, J.K., Tsao, A., Henriksen, E.J., Leutgeb, S., Barnes, C.A., Witter, M.P., Moser, M.B., Moser, E.I., 2013. Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Nat. Neurosci. 16, 1085–1093. Manes, F., Graham, K.S., Zeman, A., de Lujan Calcagno, M., Hodges, J.R., 2005. Autobiographical amnesia and accelerated forgetting in transient epileptic amnesia. J. Neurol. Neurosurg. Psychiatry 76, 1387–1391. Maviel, T., Durkin, T.P., Menzaghi, F., Bontempi, B., 2004. Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96–99. McClelland, J.L., McNaughton, B.L., O’Reilly, R.C., 1995. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457. McNaughton, B.L., Battaglia, F.P., Jensen, O., Moser, E.I., Moser, M.B., 2006. Path integration and the neural basis of the ‘cognitive map’. Nat. Rev. Neurosci. 7, 663–678. Milner, B., 2005. The medial temporal-lobe amnesic syndrome. Psychiatr. Clin. N. Am. 28, 599–611, 609. Ming, G.L., Song, H., 2011. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702. Morrissey, M.D., Maal-Bared, G., Brady, S., Takehara-Nishiuchi, K., 2012. Functional dissociation within the entorhinal cortex for memory retrieval of an association between temporally discontiguous stimuli. J. Neurosci. 32, 5356–5361. Moscovitch, M., Nadel, L., Winocur, G., Gilboa, A., Rosenbaum, R.S., 2006. The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr. Opin. Neurobiol. 16, 179–190. Moser, E.I., Kropff, E., Moser, M.B., 2008. Place cells, grid cells, and the brain’s spatial representation system. Annu. Rev. Neurosci. 31, 69–89. Nadel, L., Moscovitch, M., 1997. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227. Navawongse, R., Eichenbaum, H., 2013. Distinct pathways for rule-based retrieval and spatial mapping of memory representations in hippocampal neurons. J. Neurosci. 33, 1002–1013. Noulhiane, M., Piolino, P., Hasboun, D., Clemenceau, S., Baulac, M., Samson, S., 2007. Autobiographical memory after temporal lobe resection: neuropsychological and MRI volumetric findings. Brain 130, 3184–3199. O’Reilly, R.C., Rudy, J.W., 2001. Conjunctive representations in learning and memory: principles of cortical and hippocampal function. Psychol. Rev. 108, 311–345. Paz, R., Bauer, E.P., Pare, D., 2007. Learning-related facilitation of rhinal interactions by medial prefrontal inputs. J. Neurosci. 27, 6542–6551. Remondes, M., Schuman, E.M., 2004. Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature 431, 699–703. Restivo, L., Vetere, G., Bontempi, B., Ammassari-Teule, M., 2009. The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex. J. Neurosci. 29, 8206–8214. Sakai, K., Miyashita, Y., 1991. Neural organization for the long-term memory of paired associates. Nature 354, 152–155. Sargolini, F., Fyhn, M., Hafting, T., McNaughton, B.L., Witter, M.P., Moser, M.B., Moser, E.I., 2006. Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science 312, 758–762. Scoville, W.B., Milner, B., 1957. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21. Schwindel, C.D., McNaughton, B.L., 2011. Hippocampal–cortical interactions and the dynamics of memory trace reactivation. Prog. Brain Res. 193, 163–177. Segal, M., 1973. Dissecting a short-term memory circuit in the rat brain. I. Changes in entorhinal unit activity and responsiveness of hippocampal units in the process of classical conditioning. Brain Res. 64, 281–292. Smith, D.M., Mizumori, S.J., 2006. Hippocampal place cells, context, and episodic memory. Hippocampus 16, 716–729. Solstad, T., Boccara, C.N., Kropff, E., Moser, M.B., Moser, E.I., 2008. Representation of geometric borders in the entorhinal cortex. Science 322, 1865–1868. Squire, L.R., 1992. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231. Squire, L.R., Alvarez, P., 1995. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5, 169–177.
7
Squire, L.R., Kandel, E.R., 2009. Memory From Mind to Molecules, second ed. Roberts & Company, Colorado. Squire, L.R., Stark, C.E., Clark, R.E., 2004. The medial temporal lobe. Annu. Rev. Neurosci. 27, 279–306. Squire, L.R., Zola-Morgan, S., 1991. The medial temporal lobe memory system. Science 253, 1380–1386. Steward, O., Scoville, S.A., 1976. Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat. J. Comp. Neurol. 169, 347–370. Suzuki, W.A., Amaral, D.G., 2004. Functional neuroanatomy of the medial temporal lobe memory system. Cortex 40, 220–222. Suzuki, W.A., Zola-Morgan, S., Squire, L.R., Amaral, D.G., 1993. Lesions of the perirhinal and parahippocampal cortices in the monkey produce long-lasting memory impairment in the visual and tactual modalities. J. Neurosci. 13, 2430–2451. Swanson, L.W., 1981. A direct projection from Ammon’s horn to prefrontal cortex in the rat. Brain Res. 217, 150–154. Swanson, L.W., Cowan, W.M., 1977. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J. Comp. Neurol. 172, 49–84. Takashima, A., Petersson, K.M., Rutters, F., Tendolkar, I., Jensen, O., Zwarts, M.J., McNaughton, B.L., Fernandez, G., 2006. Declarative memory consolidation in humans: a prospective functional magnetic resonance imaging study. Proc. Natl. Acad. Sci. U.S.A. 103, 756–761. Takehara, K., Kawahara, S., Kirino, Y., 2003. Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J. Neurosci. 23, 9897–9905. Takehara-Nishiuchi, K., Maal-Bared, G., Morrissey, M.D., 2011. Increased theta synchronization parallels decreased entorhinal–prefrontal entorhinal–hippocampal theta synchronization during learning and consolidation of associative memory. Front. Behav. Neurosci. 5, 90. Takehara-Nishiuchi, K., McNaughton, B.L., 2008. Spontaneous changes of neocortical code for associative memory during consolidation. Science 322, 960–963. Takehara-Nishiuchi, K., Nakao, K., Kawahara, S., Matsuki, N., Kirino, Y., 2006. Systems consolidation requires postlearning activation of NMDA receptors in the medial prefrontal cortex in trace eyeblink conditioning. J. Neurosci. 26, 5049–5058. Tanninen, S.E., Morrissey, M.D., Takehara-Nishiuchi, K., 2013. Unilateral lateral entorhinal inactivation impairs memory expression in trace eyeblink conditioning. PLoS ONE 8, e84543. Teyler, T.J., DiScenna, P., 1986. The hippocampal memory indexing theory. Behav. Neurosci. 100, 147–154. Teyler, T.J., Rudy, J.W., 2007. The hippocampal indexing theory and episodic memory: updating the index. Hippocampus 17, 1158–1169. Thompson, L.T., Best, P.J., 1990. Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely behaving rats. Brain Res. 509, 299–308. Thornton, J.A., Rothblat, L.A., Murray, E.A., 1997. Rhinal cortex removal produces amnesia for preoperatively learned discrimination problems but fails to disrupt postoperative acquisition and retention in rhesus monkeys. J. Neurosci. 17, 8536–8549. Tsao, A., Moser, M.B., Moser, E.I., 2013. Traces of experience in the lateral entorhinal cortex. Curr. Biol. 23, 399–405. van Strien, N.M., Cappaert, N.L., Witter, M.P., 2009. The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nat. Rev. Neurosci. 10, 272–282. Vetere, G., Restivo, L., Cole, C.J., Ross, P.J., Ammassari-Teule, M., Josselyn, S.A., Frankland, P.W., 2011. Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory. Proc. Natl. Acad. Sci. U.S.A. 108, 8456–8460. Weible, A.P., Rowland, D.C., Monaghan, C.K., Wolfgang, N.T., Kentros, C.G., 2012. Neural correlates of long-term object memory in the mouse anterior cingulate cortex. J. Neurosci. 32, 5598–5608. Wheeler, A.L., Teixeira, C.M., Wang, A.H., Xiong, X., Kovacevic, N., Lerch, J.P., McIntosh, A.R., Parkinson, J., Frankland, P.W., 2013. Identification of a functional connectome for long-term fear memory in mice. PLoS Comput. Biol. 9, e1002853. Wiener, S.I., 1996. Spatial, behavioral and sensory correlates of hippocampal CA1 complex spike cell activity: implications for information processing functions. Prog. Neurobiol. 49, 335–361. Witter, M.P., Griffioen, A.W., Jorritsma-Byham, B., Krijnen, J.L., 1988. Entorhinal projections to the hippocampal CA1 region in the rat: an underestimated pathway. Neurosci. Lett. 85, 193–198. Xu, W., Wilson, D.A., 2012. Odor-evoked activity in the mouse lateral entorhinal cortex. Neuroscience 223, 12–20. Yoneda, Y., Mori, E., Yamashita, H., Yamadori, A., 1994. MRI volumetry of medial temporal lobe structures in amnesia following herpes simplex encephalitis. Eur. Neurol. 34, 243–252. Young, B.J., Otto, T., Fox, G.D., Eichenbaum, H., 1997. Memory representation within the parahippocampal region. J. Neurosci. 17, 5183–5195. Zhang, S.J., Ye, J., Miao, C., Tsao, A., Cerniauskas, I., Ledergerber, D., Moser, M.B., Moser, E.I., 2013. Optogenetic dissection of entorhinal–hippocampal functional connectivity. Science 340, 1232627. Zhu, X.O., Brown, M.W., Aggleton, J.P., 1995. Neuronal signalling of information important to visual recognition memory in rat rhinal and neighbouring cortices. Eur. J. Neurosci. 7, 753–765.
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Review article
Entorhinal cortex and consolidated memory Kaori Takehara-Nishiuchi a,b,c,∗ a
Department of Psychology, University of Toronto, Toronto, ON, Canada Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada c Neuroscience Program, University of Toronto, Toronto, ON, Canada b
a r t i c l e
i n f o
Article history: Received 19 December 2013 Received in revised form 19 February 2014 Accepted 27 February 2014 Available online xxx Keywords: Memory consolidation Hippocampus Prefrontal cortex Cingulate cortex Episodic memory Trace conditioning
a b s t r a c t The entorhinal cortex is thought to support rapid encoding of new associations by serving as an interface between the hippocampus and neocortical regions. Although the entorhinal–hippocampal interaction is undoubtedly essential for initial memory acquisition, the entorhinal cortex contributes to memory retrieval even after the hippocampus is no longer necessary. This suggests that during memory consolidation additional synaptic reinforcement may take place within the cortical network, which may change the connectivity of entorhinal cortex with cortical regions other than the hippocampus. Here, I outline behavioral and physiological findings which collectively suggest that memory consolidation involves the gradual strengthening of connection between the entorhinal cortex and the medial prefrontal/anterior cingulate cortex (mPFC/ACC), a region that may permanently store the learned association. This newly formed connection allows for close interaction between the entorhinal cortex and the mPFC/ACC, through which the mPFC/ACC gains access to neocortical regions that store the content of memory. Thus, the entorhinal cortex may serve as a gatekeeper of cortical memory network by selectively interacting either with the hippocampus or mPFC/ACC depending on the age of memory. This model provides a new framework for a modification of cortical memory network during systems consolidation, thereby adding a fresh dimension to future studies on its biological mechanism. © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impairment in consolidated memory following damage to the entorhinal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Implications from clinical populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Observations in animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relations of connectivity between the entorhinal cortex and hippocampus to systems consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relations of connections between the entorhinal cortex and cortical regions to systems consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Involvement of prefrontal and cingulate cortex in the expression of consolidated memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Connections between the entorhinal cortex and medial prefrontal/anterior cingulate cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Specific signals that the entorhinal cortex transmits across the cortical network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Impact of entorhinal input on neuron firing in the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Impact of entorhinal input on neuron firing in the sensory neocortical regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and outstanding questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Correspondence to: Department of Psychology, University of Toronto, Sidney Smith Hall Room 4007, 100 St. George Street, Toronto, ON M5S 3G3, Canada. Tel.: +1 416 978 6570. E-mail address: [email protected] http://dx.doi.org/10.1016/j.neures.2014.02.012 0168-0102/© 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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1. Introduction “People’s memories are maybe the fuel they burn to stay alive. . . . I think if I didn’t have all that fuel, if I didn’t have the memory drawers inside me, I would’ve snapped a long time ago.” – After Dark by Haruki Murakami Memory is one of the most important cognitive processes that make our lives richer and maintainable. Since the seminal work by Scoville and Milner (1957) on patient H.M., many studies have provided evidence that the medial temporal lobe, especially the hippocampus is necessary for a certain type of memory, such as memories of daily experiences (episodic memory) and personal history (autographical memory; Squire et al., 2004; Milner, 2005; Moscovitch et al., 2006). This has inspired a number of competing network models for how the brain generates and supports memories over time. One model posits that the hippocampus stores an index of cortical loci that were activated during an experiential event (Teyler and DiScenna, 1986; Teyler and Rudy, 2007). During the event, incoming sensory information is registered at various sensory and association neocortical regions. The activity of neurons in the neocortical regions then projects to the hippocampus, and synapses between neurons responding to the neocortical inputs are strengthened. Accordingly, the experience is represented simply as the set of strengthened synapses in the hippocampus that are associated with a unique set of activated neurons across the neocortex. The strengthened synapses in the hippocampus are further stabilized through the process of cellular consolidation that involves the synthesis of new proteins during a few hours after the experience (Dudai, 2004; Squire and Kandel, 2009). The stabilized synapses in the hippocampus may be capable of supporting the memory for a certain period of time; however, without any further reinforcement, it may decay eventually. The subsequent reinforcement process, what came to be called systems consolidation, is presumed to involve modifications of the synaptic connections between neurons in different brain regions (Frankland and Bontempi, 2005; Squire and Kandel, 2009). This results in gradual reorganization of brain regions supporting memory over a longer time period. Some models assume that synaptic connections between the neocortical regions are gradually strengthened (Squire and Zola-Morgan, 1991; Squire and Alvarez, 1995; McClelland et al., 1995) whereas others assume that the original neocortical activity pattern is bound to additional synaptic connections in the hippocampus and surrounding cortical regions (Nadel and Moscovitch, 1997). These two possibilities are not mutually exclusive, and in fact any synaptic connections within the network are potentially strengthened. Yet, the strengthening of specific connection may be more important than others because it has a larger impact on network operation. The entorhinal cortex is one of the cortical regions surrounding the hippocampus. It has been viewed as a hub of cortical memory network because it has reciprocal connections with the hippocampus in one hand and with the neocorotical regions on the other (Fig. 1; Burwell, 2000; Suzuki and Amaral, 2004; van Strien et al., 2009). This anatomical feature suggests that a small change in the connectivity of entorhinal cortex may have a dramatic impact on how the cortical network operates during memory retrieval. The following sections outline findings in behavioral and electrophysiological studies that addressed how long the entorhinal cortex is involved in memory retrieval and how its connectivity with the hippocampus and other cortical regions change over the course of systems consolidation. These studies collectively suggest that the entorhinal cortex plays a long-lasting role in memory retrieval by initially interacting with the hippocampus but later with the medial prefrontal/anterior cingulate cortex.
Fig. 1. Functional anatomy of the fronto-temporal cortical memory network. Based on the anatomical connectivity of entorhinal cortex with the hippocampus, medial prefrontal cortex, and neocortex, I hypothesize that highly processed sensory information in the neocortex is transferred to the hippocampus and medial prefrontal cortex through the superficial layer of entorhinal cortex (Steward and Scoville, 1976; Witter et al., 1988; Amaral and Witter, 1995; Insausti et al., 1997; Burwell and Amaral, 1998; Hoover and Vertes, 2007; Canto et al., 2008; Agster and Burwell, 2009). The output of hippocampus and medial prefrontal cortex is sent back to the neocortex through the deep layer of entorhinal cortex (Swanson and Cowan, 1977; Amaral and Witter, 1995; Apergis-Schoute et al., 2006; Jones and Witter, 2007; Canto et al., 2008). Hippocampoal output also modulates the medial prefrontal cortex via monosynaptic projections (Swanson, 1981; Jay and Witter, 1991).
2. Impairment in consolidated memory following damage to the entorhinal cortex 2.1. Implications from clinical populations Patients with damage to the medial temporal lobe are impaired with the retrieval of memory acquired before brain damage, but the degree of impairment considerably varies depending on the size of damage. In the patients with damage restricted to the hippocampus, memory impairments extend back only for a few years (Kapur and Brooks, 1999; Bayley et al., 2006; but see, Chan et al., 2002). Additional damage to adjacent regions surrounding the hippocampus impairs memory extended back for a longer period (Bright et al., 2006; Bayley et al., 2006; Noulhiane et al., 2007). A similar pattern of impairment was observed in patients with temporal lobe epilepsy (TLE). Typical pathological changes in TLE are selective neuronal loss in the hippocampus and regions connected with the hippocampus, including the entorhinal cortex (Du et al., 1993; Bonilha et al., 2003). In some cases, atrophy in the entorhinal cortex occurs without the loss of hippocampal volume (Bernasconi et al., 2001; Khalsa et al., 2006). Memory impairments in TLE patients encompass all life periods including early childhood (Manes et al., 2005; Herfurth et al., 2010). Some TLE patients also show accelerated forgetting, which indicates impairments in memory consolidation (Manes et al., 2005). Interestingly, the ability of TLE patients to perform remote autobiographical memory tests is not correlated with their ability to perform anterograde memory tasks (Herfurth et al., 2010). Given that anterograde memory deficits are correlated with the degree of hippocampal damage, this finding suggests that the impairments in remote autobiographical memory may be associated with damage outside of the hippocampus. A more direct support for this argument is found in amnesic patients with herpes simplex encephalitis. In these patients, the extent of retrograde memory impairment is correlated with the size of the parahippocampal and entorhinal cortex lesion, but not with the size of the hippocampal lesion (Yoneda et al., 1994). This agrees well with a finding that in healthy subjects the entorhinal cortex is activated during the recall of faces of people who were famous up to 20 years ago, whereas the hippocampus is only
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Fig. 2. Entorhinal cortex as a gatekeeper of cortical memory network. During learning (left) synaptic connections between neurons (red circles) in the entorhinal cortex and those in the hippocampus are rapidly strengthened to encode a new memory. Subsequent consolidation (middle) involves the reactivation of memory-bearing neurons in the hippocampus, which in turn activates the original neurons in the entorhinal cortex as well as new neurons (blue circles) in the entorhinal cortex and medial prefrontal/anterior cingulate cortex (mPFC/ACC). This process strengthens the connection between the entorhinal cortex and mPFC/ACC. During memory expression (right) the entorhinal cortex selectively activates the neurons in the hippocampus or the neurons in the mPFC/ACC depending on the age of memory.
activated during the recall of famous faces up to a few years ago (Haist et al., 2001). Together, these findings suggest that the regions surrounding the hippocampus are involved in memory retrieval for a longer period compared with the hippocampus. 2.2. Observations in animal studies Consistent with findings in patients with medial temporal lobe damage, a large lesion to the hippocampus and parahippocampal cortices in monkeys produces retrograde memory impairments that extend for a longer time window than the impairments following damage to the hippocampus alone (Suzuki et al., 1993; Thornton et al., 1997). This was replicated with a specific manipulation to a sub-region of the parahippocampal regions in rodents (Cho et al., 1993; Cho and Kesner, 1996; Burwell et al., 2004; Morrissey et al., 2012). The studies, however, do not agree on whether the degree of impairment changes with the passage of time after learning. In a spatial discrimination paradigm, the memory impairment following damage to the entorhinal cortex becomes less severe over 4–6 weeks since initial learning (Cho et al., 1993; Cho and Kesner, 1996). In contrast, in trace eyeblink conditioning, in which the hippocampus is necessary for memory expression up to two weeks following learning (Takehara et al., 2003), reversible inactivation of the lateral entorhinal cortex equally impairs the expression of memory acquired one day and one month earlier (Morrissey et al., 2012; Tanninen et al., 2013). Similarly, in contextual fear conditioning, in which the hippocampal involvement is limited to two weeks from the time of conditioning (Kim and Fanselow, 1992), damage to the perirhinal or postrhinal cortex, two parahippocampal regions closely connected with the entorhinal cortex, equally impairs retention one and one-hundred days later (Burwell et al., 2004). To summarize, the evidence describes that the entorhinal cortex is involved in memory expression for a longer time period compared with the hippocampus. The available data, however, still do not agree on the exact duration of entorhinal involvement in memory expression (i.e., permanent or temporally limited). 3. Relations of connectivity between the entorhinal cortex and hippocampus to systems consolidation Findings in clinical population and animal studies suggest that memory initially depends both on the hippocampus and entorhinal cortex, but later it becomes dependent solely on the entorhinal cortex. This predicts that the connectivity between the entorihnal
cortex and hippocampus should be involved in memory expression for a limited period of time. The connection between the entorhinal cortex and hippocampus forms a loop which originates in superficial layers of the entorhinal cortex and terminates at deep entorhinal layers (Fig. 1; Steward and Scoville, 1976; Swanson and Cowan, 1977; Amaral and Witter, 1995). Besides, the entorhinal projection to the hippocampus forms two separate pathways: the perforant path originates from layer II of the entorhinal cortex and terminates at the dentate gyrus while the temporoamonic path originates from layer III of the entorhinal cortex and projects to the CA1 region (Steward and Scoville, 1976; Witter et al., 1988; Amaral and Witter, 1995). The perforant pathway connects the entorhinal cortex to dentate gyrus and is highly plastic because of modifiable synapses (Bliss and Lomo, 1973) as well as unique structural changes associated with adult neurogenesis (Altman, 1962; Cameron et al., 1993). In the dentate gyrus, neurogenesis persists throughout adulthood, and the adult–born neurons are continuously incorporated into the existing network (Lledo et al., 2006; Ming and Song, 2011). This may induce the remodeling of local network in the dentate gyrus, which destabilizes the existing synaptic connections with the entorhinal cortex (Feng et al., 2001; Lacefield et al., 2012; Frankland et al., 2013). This active modification of dentateentorhinal connection may hinder the entorhinal inputs from activating dentate cells that were originally associated with the entorhinal inputs. Consistent with this idea, Kitamura et al. (2009) demonstrated that adult neurogenesis modulates the time window during which the hippocampus is involved in memory retrieval. When adult neurogenesis is reduced, the long-term potentiation at perforant path-dentate gyrus synapses persists for three weeks, which is longer than a normal duration of two weeks. The stable entorhinal–hippocampal synaptic connection is accompanied by a longer time window over which the expression of contextual fear memory depends on the hippocampus. Inversely, when the neurogenesis is enhanced (which is presumed to destabilize the existing entorhinal–dentate connection), contextual fear memory is dependent on the hippocampus for a shorter time periods than normal. These results suggest that the stability of dentateentorhinal connection determines the reliance of memory on the hippocampus. The temporoamonic path, on the other hand, is not involved in memory retrieval, but it plays a critical, but time-limited role in memory consolidation in a spatial memory paradigm (Remondes and Schuman, 2004). This study examined the impact of a
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specific lesion to axons of temporoamonic path on the performance in Morris water maze task. The lesion made before the training does not impair the acquisition of spatial memory or its expression one day later. In contrast, the lesion significantly impairs memory expression four weeks after learning when it is made immediately after training, but not three weeks after learning. Thus, these results suggest that ongoing entorhinal input to the CA1 region is necessary to consolidate long-term spatial memory. In summary, the two studies reviewed above showed that the perforant path is involved in the expression of memory whereas the temporoamonic path is necessary for the consolidation of memory. Importantly, the involvement of perfortnat path and temporoamonic path in the respective processes is limited only for a few weeks after learning. 4. Relations of connections between the entorhinal cortex and cortical regions to systems consolidation Compared with the connection between the entorhinal cortex and hippocampus, less is known about how the connection between the entorhinal cortex and other cortical regions changes with learning and consolidation. This question had been difficult to address because available literature had vaguely described cortical regions that are involved in the expression of a memory after it is consolidated. Evidence accumulating in the past ten years now suggests that memory consolidation involves the reorganization of network in a manner that the center of network is shifted from the hippocampus to the medial prefrontal/anterior cingulate cortex (mPFC/ACC; Frankland and Bontempi, 2005; Insel and Takehara-Nishiuchi, 2013). This raises a possibility that the mPFC/ACC may play a similar role for consolidated memories to the one that the hippocampus plays for recently formed memories (Frankland and Bontempi, 2005; Takashima et al., 2006; Insel and Takehara-Nishiuchi, 2013). Based on recent electrophysiological studies, along with a unique anatomical property of the mPFC/ACC (Fig. 1), I argue that the mPFC/ACC may gain the role by strengthening its connection with the entorhinal cortex. 4.1. Involvement of prefrontal and cingulate cortex in the expression of consolidated memory Although the expression of consolidated memory is associated with the activation of many neocortical regions (Bontempi et al., 1999; Wheeler et al., 2013), dysfunction of one of these regions, the mPFC/ACC is enough to produce a profound impairment in the expression of consolidated memory (Takehara et al., 2003; Frankland et al., 2004; Maviel et al., 2004). The mPFC/ACC appears to gain the role in memory expression as a result of local synaptic reinforcement during systems consolidation. The expression of consolidated memory is significantly impaired by a blockade of NMDA receptors in the mPFC specifically for two weeks after trace eyeblink conditioning (Takehara-Nishiuchi et al., 2006). Besides, new dendritic spines had been formed in the ACC following one month after contextual fear conditioning (Restivo et al., 2009), and suppression of the conditioning-induced dendritic spine growth in the ACC impairs the expression of consolidated memory (Vetere et al., 2011). These changes in the local network are also reflected in changes in the activity of single neurons in the mPFC. During the same time window in which the synaptic reinforcement occurs, the activity of single neurons in the mPFC becomes selective for the acquired memory associsation in trace eyeblink conditioning (Takehara-Nishiuchi and McNaughton, 2008). Besides, neurons in the ACC develop a selective activity for the remotely acquired association between a familiar object and its location (Weible et al., 2012). Together, these results sugget systems consolidation
involves synaptic reinforcement in the mPFC/ACC, which may shape the selective neuronal activity for consolidated memory in the mPFC/ACC. 4.2. Connections between the entorhinal cortex and medial prefrontal/anterior cingulate cortex All reported synaptic reinforcement in the mPFC/ACC (Takehara-Nishiuchi et al., 2006; Restivo et al., 2009) occurs postsynaptically, suggesting that the connection between the mPFC/ACC and its afferent regions may be modified during the consolidation process. Although the mPFC/ACC receives the inputs from many cortical and subcortical regions, one of the main afferent sources is the entorhinal cortex (Hoover and Vertes, 2007). The mPFC/ACC receives the projection from superficieal layers of the entorhinal cortex (Insausti et al., 1997), and sends their projections back preferentially to the deep entorhinal layers (Apergis-Schoute et al., 2006; Jones and Witter, 2007; Canto et al., 2008; Fig. 1). This pattern is similar to the connection of entorhinal cortex with the hippocampus (Steward and Scoville, 1976; Swanson and Cowan, 1977; Witter et al., 1988; Amaral and Witter, 1995); however, it sharply contrasts with its connection with other neocortical regions: the neocortical regions project to superficial layers of the entorhinal cortex while it is the deep entorhinal layers that project back to the neocortical regions (Burwell and Amaral, 1998; Burwell, 2000; Agster and Burwell, 2009; Fig. 1). Together, these anatomical properties suggest that the entorhinal cortex may serve as an interface between the mPFC/ACC and the neocortical regions as it does for the hippocampus. If the entorhinal cortex serves as the interface between the mPFC/ACC and neocortical regions, the interaction between the entorhinal cortex and mPFC/ACC should be critical for the expression of consolidated memory. Currently no studies as of yet determine whether disconnection of the entorhinal cortex from the mPFC/ACC impairs the expression of consolidated memory (but see, Tanninen et al., 2013); however, some studies reported neuronal activity patterns that suggest close coupling between these regions during memory expression. Takehara-Nishiuchi et al. (2011) simultaneously monitored local field potentials in the lateral entorhinal cortex and the prelimbic region of mPFC, as well as in the hippocampus while rats associated a neutral conditioned stimulus (CS) with mildly aversive eyelid shock presented moments later in trace eyeblink conditioning. Upon presentation of the CS, local field potentials in all three regions exhibited a clear 7 Hz (theta) rhythm. Importantly, the evoked theta oscillations were synchronized between the lateral entorhinal cortex and hippocampus during early learning, but this was reduced later in learning and following a consolidation period. Meanwhile, theta oscillations between the lateral entorhinal and prelimbic cortices were high throughout learning and during consolidation, and were also stronger on trials in which rats exhibited a conditioned response. These results suggest that with learning and subsequent consolidation, memory expression becomes increasingly relied on the functional connection between the lateral entorhinal cortex and prelimbic cortex. Paz et al. (2007) also reached a similar conclusion based on experience-dependent correlation increases between single neuron activity in the rostral cingulate cortex and entorhinal cortex in cats. By examining how cingulate neuron firings modulate the correlated neuron activity between the entorhinal cortex and perirhinal cortex, they found evidence that with learning the rostral cingulate cortex becomes more capable of driving the information transfer from the entorhinal cortex to perirhinal cortex. This observation suggests that learning enables the rostral cingulate cortex to drive the activity of downstream targets through the entorhinal cortex.
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5. Specific signals that the entorhinal cortex transmits across the cortical network Based on the studies reviewed above, I propose that the entorhinal cortex initially provides the hippocampus with access to the sensory and association neocortical regions during the retrieval of new memory. With additional network modifications during systems consolidation, it comes to play the same function for the mPFC/ACC during the retrieval of consolidated memory (Fig. 2). To further elaborate on this model, it is necessary to specify exactly what type of information is transferred among these regions. In the following section, I outline some studies which have addressed this point by examining how the incoming input from the entorhinal cortex modulates specific information represented in firing patterns of neurons in the efferent regions. 5.1. Impact of entorhinal input on neuron firing in the hippocampus Theories assume that the role of hippocampus is to bind together the features of an experience to create a unitary representation of the experience (Teyler and DiScenna, 1986; McClelland et al., 1995; Squire and Alvarez, 1995; O’Reilly and Rudy, 2001). Consistent with this argument, neurons in the hippocampus respond to the conjunction of various types of information and show a selective activity for spatial location, specific behavior, and sensory stimuli in a specific context (Wiener, 1996; Smith and Mizumori, 2006). The conjunctive activity of hippocampal neurons may be generated by convergence of the incoming inputs from many afferent regions. Several studies showed that the entorhinal cortex provides the hippocampus with the information on spatial and sensory features of experience through two parallel streams. Specifically, lesion of the medial entorhinal cortex results in the instability of spatial tuning of neurons in the CA1 region of hippocampus (Brun et al., 2008; Navawongse and Eichenbaum, 2013). In contrast, lesion of the lateral entorhinal cortex impairs firing changes of CA3 neurons in response to changes in shapes or the color of the environment while their spatial tuning remains intact (Lu et al., 2013). The apparent functional division between the inputs from the medial and lateral entorhinal cortex is consistent with the difference in the selectivity of neuron firings between these entorhinal sub-regions. Neurons in the dorsomedial portion of entorhinal cortex fire multiple locations within a place, which are aligned in a rhombus with interval angle of 60◦ and 120◦ (Fyhn et al., 2004; Doeller et al., 2010; Killian et al., 2012). In addition to these ‘grid cells’, the medial entorhinal cortex also includes neurons that are selective for the direction of head (‘head direction cell’; Sargolini et al., 2006) as well as neurons that respond to geometric boundaries of the environment (‘border cell’; Solstad et al., 2008). Importantly, grid, head direction, and border cells are active across different environment (Hafting et al., 2005; Fyhn et al., 2007; Solstad et al., 2008). This suggests that the medial entorhinal cortex may provide the hippocampus with the spatial metric of surrounding environment that can be applied universally across different environment (McNaughton et al., 2006; Moser et al., 2008; Zhang et al., 2013). It is noteworthy that entorhinal grid cells are observed only in the dorsomedial portion of entorinal cortex; neurons in the intermediate and lateral portion of entorhinal cortex rarely show spatially tuned activity in an open field (Fyhn et al., 2004; Hafting et al., 2005). Rather, these neurons are selective for non-spatial features, such as a discrete object in an environment (Deshmukh and Knierim, 2011; Tsao et al., 2013). The selective activity for an object can also be described as the selectivity for visual and tactile stimuli. In fact, many studies have reported that entorhinal neurons respond to a specific sensory stimulus during a behavioral paradigm
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without any spatial components (auditory, Segal, 1973; visual, Zhu et al., 1995; Kreiman et al., 2000; Fried et al., 2002; odor, Young et al., 1997; Xu and Wilson, 2012). Thus, the lateral entorhinal cortex may provide the hippocampus with highly specific sensory inputs irrespective of its position in the environment. 5.2. Impact of entorhinal input on neuron firing in the sensory neocortical regions Most theories assume that the interaction between the hippocampus and neocortical regions is bidirectional: the conjunctive signal in the hippocampus is projected back to the original neocortical regions that initially brought sensory information to the hippocampus (Teyler and DiScenna, 1986; Squire, 1992; McClelland et al., 1995; Eichenbaum, 2000). This predicts that disrupting the return projection from the hippocampus should specifically abolish the signals for stimulus conjunction in the sensory neocortical regions. Consistent with this prediction, in the sensory neocortical regions, some neurons show selective firings to the physical attributes of sensory stimuli, but other neurons respond to abstract features of the stimulus, such as its association with other stimuli (Sakai and Miyashita, 1991; Erickson and Desimone, 1999). Damage to the perirhinal and entorhinal cortex in monkeys abolished the signal on the association between visual stimuli in the inferotemporal cortex while leaving the signal for physical features of visual stimuli intact (Higuchi and Miyashita, 1996). Similarly, the inactivation of entorhinal cortex abolishes a cross-modal association signal in single neuron firings in the primary auditory cortex (Chen et al., 2013). Together, these results suggest that while external sensory inputs shape the selective activity for a physical stimulus attribute in the sensory region, topdown signals from the entorhinal cortex, or its associated structures like the hippocampus, provide information on stimulus relationships learned through past experiences. In summary, the studies reviewed above suggest that the entorhinal cortex has a major, but rather specific, impact on neuronal representation in the hippocampus and neocortical regions. Currently, no study examined how the input from the entorhinal cortex modulates the activity of neurons in the mPFC/ACC. 6. Conclusions and outstanding questions The entorhinal cortex is located at a pivotal position in the cortical memory network with a reciprocal connection with the hippocampus in one hand and with the neocortical regions on the other (Fig. 1). This anatomical property suggests that the entorhinal cortex may serve as a gateway of the hippocampus to stimulus information represented in widely spread regions of the neocortex (Squire, 1992; Eichenbaum, 2000). I argue that systems consolidation may involve additional modifications of the network, which may enable the entorhinal cortex to provide the mPFC/ACC with access to the neocortical regions (Fig. 2). As a result, the entorhinal cortex becomes capable of selectively interacting with the hippocampus or mPFC/ACC depending on the age of memory to be retrieved. As reviewed above, some parts of this model are supported by available empirical data; however, several critical assumptions of the model need to be tested in future studies. I will briefly highlight four points that will provide some testable predictions for future studies. First, functional connectivity between the entorhinal cortex and mPFC/ACC and its change over the consolidation process need further examinations at the level of behavior and neuron activity. This requires newly developed tools that can specifically manipulate the connection between the two regions because a traditional pharmacological approach did not work in this connection (Tanninen et al., 2013).
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Second, it is important to identify the exact mechanism on the strengthening of entorhinal–mPFC/ACC connection after learning. Theories assume that the reactivation of learned neuron activity patterns during ‘off-line’ period such as sleep drives synaptic reinforcement during consolidation processes (Schwindel and McNaughton, 2011). Although the reactivation of neuron activity patterns has been well-documented, its causality on synaptic modifications in the cortical region remains to be tested. Third, it needs to be specified what operation the entorhinal cortex performs to selectively interact with the hippocampus or mPFC/ACC depending on the age of memory. One possibility is that the difference in the strength of entorhinal cortical connectivity between the hippocampus and mPFC/ACC may define which of them will be activated by the entorhinal input. Alternatively, the entorhinal cortex (perhaps with perirhinal and postrhinal cortices) may filter the incoming sensory input depending on familiarity (Fernandez and Tendolkar, 2006). Forth, in an intact brain the entorhinal–hippocampal connection may continue to contribute to memory expression even after the entorhinal–mPFC/ACC connection is sufficiently strengthened. A recent study by Goshen et al. (2011) demonstrated that transient, optogenetic inhibition of pyramidal neurons in the CA1 region significantly impaired the expression of old contextual fear memory. This finding sharply contrasts with intact expression of old memory following prolonged pharmacological inactivation of the same region. These findings suggest that although consolidated memory can be retrieved without the hippocampus, in an intact brain the hippocampus still participates in the retrieval process, perhaps by forming a contextual representation that matches with the one for original experience (Thompson and Best, 1990; Lever et al., 2002). Acknowledgements This work was supported by NSERC Discovery Grant and CFI Leaders Opportunity Fund. The author thanks Dr. Nathan Insel for helpful comments and discussion. References Agster, K.L., Burwell, R.D., 2009. Cortical efferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. Hippocampus 19, 1159–1186. Altman, J., 1962. Are new neurons formed in the brains of adult mammals? Science 135, 1127–1128. Amaral, D., Witter, M., 1995. Hippocampal formation. In: Paxinos, G. (Ed.), The Rat Nervous System. Academic Press, San Diego, CA, pp. 443–486. Apergis-Schoute, J., Pinto, A., Pare, D., 2006. Ultrastructural organization of medial prefrontal inputs to the rhinal cortices. Eur. J. Neurosci. 24, 135–144. Bayley, P.J., Hopkins, R.O., Squire, L.R., 2006. The fate of old memories after medial temporal lobe damage. J. Neurosci. 26, 13311–13317. Bernasconi, N., Bernasconi, A., Caramanos, Z., Dubeau, F., Richardson, J., Andermann, F., Arnold, D.L., 2001. Entorhinal cortex atrophy in epilepsy patients exhibiting normal hippocampal volumes. Neurology 56, 1335–1339. Bliss, T.V., Lomo, T., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356. Bonilha, L., Kobayashi, E., Rorden, C., Cendes, F., Li, L.M., 2003. Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy. J. Neurol. Neurosurg. Psychiatry 74, 1627–1630. Bontempi, B., Laurent-Demir, C., Destrade, C., Jaffard, R., 1999. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675. Bright, P., Buckman, J., Fradera, A., Yoshimasu, H., Colchester, A.C., Kopelman, M.D., 2006. Retrograde amnesia in patients with hippocampal, medial temporal, temporal lobe, or frontal pathology. Learn. Mem. 13, 545–557. Brun, V.H., Solstad, T., Kjelstrup, K.B., Fyhn, M., Witter, M.P., Moser, E.I., Moser, M.B., 2008. Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus 18, 1200–1212. Burwell, R.D., 2000. The parahippocampal region: corticocortical connectivity. Ann. N.Y. Acad. Sci. 911, 25–42. Burwell, R.D., Amaral, D.G., 1998. Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J. Comp. Neurol. 398, 179–205. Burwell, R.D., Bucci, D.J., Sanborn, M.R., Jutras, M.J., 2004. Perirhinal and postrhinal contributions to remote memory for context. J. Neurosci. 24, 11023–11028.
Cameron, H.A., Woolley, C.S., McEwen, B.S., Gould, E., 1993. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56, 337–344. Canto, C.B., Wouterlood, F.G., Witter, M.P., 2008. What does the anatomical organization of the entorhinal cortex tell us? Neural Plast. 2008, 381243. Chan, D., Revesz, T., Rudge, P., 2002. Hippocampal, but not parahippocampal, damage in a case of dense retrograde amnesia: a pathological study. Neurosci. Lett. 329, 61–64. Chen, X., Guo, Y., Feng, J., Liao, Z., Li, X., Wang, H., Li, X., He, J., 2013. Encoding and retrieval of artificial visuoauditory memory traces in the auditory cortex requires the entorhinal cortex. J. Neurosci. 33, 9963–9974. Cho, Y.H., Beracochea, D., Jaffard, R., 1993. Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice. J. Neurosci. 3, 1759–1766. Cho, Y.H., Kesner, R.P., 1996. Involvement of entorhinal cortex or parietal cortex in long-term spatial discrimination memory in rats: retrograde amnesia. Behav. Neurosci. 110, 436–442. Deshmukh, S.S., Knierim, J.J., 2011. Representation of non-spatial and spatial information in the lateral entorhinal cortex. Front. Behav. Neurosci. 5, 69. Doeller, C.F., Barry, C., Burgess, N., 2010. Evidence for grid cells in a human memory network. Nature 463, 657–661. Du, F., Whetsell Jr., W.O., Abou-Khalil, B., Blumenkopf, B., Lothman, E.W., Schwarcz, R., 1993. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res. 16, 223–233. Dudai, Y., 2004. The neurobiology of consolidations, or, how stable is the engram? Annu. Rev. Psychol. 55, 51–86. Eichenbaum, H., 2000. A cortical–hippocampal system for declarative memory. Nat. Rev. Neurosci. 1, 41–50. Erickson, C.A., Desimone, R., 1999. Responses of macaque perirhinal neurons during and after visual stimulus association learning. J. Neurosci. 19, 10404–10416. Feng, R., Rampon, C., Tang, Y.P., Shrom, D., Jin, J., Kyin, M., Sopher, B., Miller, M.W., Ware, C.B., Martin, G.M., Kim, S.H., Langdon, R.B., Sisodia, S.S., Tsien, J.Z., 2001. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32, 911–926. Fernandez, G., Tendolkar, I., 2006. The rhinal cortex: ‘gatekeeper’ of the declarative memory system. Trends Cogn. Sci. 10, 358–362. Frankland, P.W., Bontempi, B., 2005. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130. Frankland, P.W., Bontempi, B., Talton, L.E., Kaczmarek, L., Silva, A.J., 2004. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883. Frankland, P.W., Kohler, S., Josselyn, S.A., 2013. Hippocampal neurogenesis and forgetting. Trends Neurosci. 36, 497–503. Fried, I., Cameron, K.A., Yashar, S., Fong, R., Morrow, J.W., 2002. Inhibitory and excitatory responses of single neurons in the human medial temporal lobe during recognition of faces and objects. Cereb. Cortex 12, 575–584. Fyhn, M., Hafting, T., Treves, A., Moser, M.B., Moser, E.I., 2007. Hippocampal remapping and grid realignment in entorhinal cortex. Nature 446, 190–194. Fyhn, M., Molden, S., Witter, M.P., Moser, E.I., Moser, M.B., 2004. Spatial representation in the entorhinal cortex. Science 305, 1258–1264. Goshen, I., Brodsky, M., Prakash, R., Wallace, J., Gradinaru, V., Ramakrishnan, C., Deisseroth, K., 2011. Dynamics of retrieval strategies for remote memories. Cell 147, 678–689. Hafting, T., Fyhn, M., Molden, S., Moser, M.B., Moser, E.I., 2005. Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801–806. Haist, F., Bowden Gore, J., Mao, H., 2001. Consolidation of human memory over decades revealed by functional magnetic resonance imaging. Nat. Neurosci. 4, 1139–1145. Herfurth, K., Kasper, B., Schwarz, M., Stefan, H., Pauli, E., 2010. Autobiographical memory in temporal lobe epilepsy: role of hippocampal and temporal lateral structures. Epilepsy Behav. 19, 365–371. Higuchi, S., Miyashita, Y., 1996. Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions. Proc. Natl. Acad. Sci. U.S.A. 93, 739–743. Hoover, W.B., Vertes, R.P., 2007. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct. Funct. 212, 149–179. Insausti, R., Herrero, M.T., Witter, M.P., 1997. Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus 7, 146–183. Insel, N., Takehara-Nishiuchi, K., 2013. The cortical structure of consolidated memory: a hypothesis on the role of the cingulate–entorhinal cortical connection. Neurobiol. Learn. Mem. 106, 343–350. Jay, T.M., Witter, M.P., 1991. Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J. Comp. Neurol. 313, 574–586. Jones, B.F., Witter, M.P., 2007. Cingulate cortex projections to the parahippocampal region and hippocampal formation in the rat. Hippocampus 17, 957– 976. Kapur, N., Brooks, D.J., 1999. Temporally-specific retrograde amnesia in two cases of discrete bilateral hippocampal pathology. Hippocampus 9, 247–254. Khalsa, S.S., Moore, S.A., Van Hoesen, G.W., 2006. Hughlings Jackson and the role of the entorhinal cortex in temporal lobe epilepsy: from patient A to Doctor Z. Epilepsy Behav. 9, 524–531. Killian, N.J., Jutras, M.J., Buffalo, E.A., 2012. A map of visual space in the primate entorhinal cortex. Nature 491, 761–764.
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G Model NSR-3662; No. of Pages 7
ARTICLE IN PRESS K. Takehara-Nishiuchi / Neuroscience Research xxx (2014) xxx–xxx
Kim, J.J., Fanselow, M.S., 1992. Modality-specific retrograde amnesia of fear. Science 256, 675–677. Kitamura, T., Saitoh, Y., Takashima, N., Murayama, A., Niibori, Y., Ageta, H., Sekiguchi, M., Sugiyama, H., Inokuchi, K., 2009. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139, 814–827. Kreiman, G., Koch, C., Fried, I., 2000. Category-specific visual responses of single neurons in the human medial temporal lobe. Nat. Neurosci. 3, 946–953. Lacefield, C.O., Itskov, V., Reardon, T., Hen, R., Gordon, J.A., 2012. Effects of adultgenerated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 22, 106–116. Lever, C., Wills, T., Cacucci, F., Burgess, N., O’Keefe, J., 2002. Long-term plasticity in hippocampal place-cell representation of environmental geometry. Nature 416, 90–94. Lledo, P.M., Alonso, M., Grubb, M.S., 2006. Adult neurogenesis and functional plasticity in neuronal circuits. Nat. Rev. Neurosci. 7, 179–193. Lu, L., Leutgeb, J.K., Tsao, A., Henriksen, E.J., Leutgeb, S., Barnes, C.A., Witter, M.P., Moser, M.B., Moser, E.I., 2013. Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Nat. Neurosci. 16, 1085–1093. Manes, F., Graham, K.S., Zeman, A., de Lujan Calcagno, M., Hodges, J.R., 2005. Autobiographical amnesia and accelerated forgetting in transient epileptic amnesia. J. Neurol. Neurosurg. Psychiatry 76, 1387–1391. Maviel, T., Durkin, T.P., Menzaghi, F., Bontempi, B., 2004. Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96–99. McClelland, J.L., McNaughton, B.L., O’Reilly, R.C., 1995. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457. McNaughton, B.L., Battaglia, F.P., Jensen, O., Moser, E.I., Moser, M.B., 2006. Path integration and the neural basis of the ‘cognitive map’. Nat. Rev. Neurosci. 7, 663–678. Milner, B., 2005. The medial temporal-lobe amnesic syndrome. Psychiatr. Clin. N. Am. 28, 599–611, 609. Ming, G.L., Song, H., 2011. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702. Morrissey, M.D., Maal-Bared, G., Brady, S., Takehara-Nishiuchi, K., 2012. Functional dissociation within the entorhinal cortex for memory retrieval of an association between temporally discontiguous stimuli. J. Neurosci. 32, 5356–5361. Moscovitch, M., Nadel, L., Winocur, G., Gilboa, A., Rosenbaum, R.S., 2006. The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr. Opin. Neurobiol. 16, 179–190. Moser, E.I., Kropff, E., Moser, M.B., 2008. Place cells, grid cells, and the brain’s spatial representation system. Annu. Rev. Neurosci. 31, 69–89. Nadel, L., Moscovitch, M., 1997. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227. Navawongse, R., Eichenbaum, H., 2013. Distinct pathways for rule-based retrieval and spatial mapping of memory representations in hippocampal neurons. J. Neurosci. 33, 1002–1013. Noulhiane, M., Piolino, P., Hasboun, D., Clemenceau, S., Baulac, M., Samson, S., 2007. Autobiographical memory after temporal lobe resection: neuropsychological and MRI volumetric findings. Brain 130, 3184–3199. O’Reilly, R.C., Rudy, J.W., 2001. Conjunctive representations in learning and memory: principles of cortical and hippocampal function. Psychol. Rev. 108, 311–345. Paz, R., Bauer, E.P., Pare, D., 2007. Learning-related facilitation of rhinal interactions by medial prefrontal inputs. J. Neurosci. 27, 6542–6551. Remondes, M., Schuman, E.M., 2004. Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature 431, 699–703. Restivo, L., Vetere, G., Bontempi, B., Ammassari-Teule, M., 2009. The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex. J. Neurosci. 29, 8206–8214. Sakai, K., Miyashita, Y., 1991. Neural organization for the long-term memory of paired associates. Nature 354, 152–155. Sargolini, F., Fyhn, M., Hafting, T., McNaughton, B.L., Witter, M.P., Moser, M.B., Moser, E.I., 2006. Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science 312, 758–762. Scoville, W.B., Milner, B., 1957. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21. Schwindel, C.D., McNaughton, B.L., 2011. Hippocampal–cortical interactions and the dynamics of memory trace reactivation. Prog. Brain Res. 193, 163–177. Segal, M., 1973. Dissecting a short-term memory circuit in the rat brain. I. Changes in entorhinal unit activity and responsiveness of hippocampal units in the process of classical conditioning. Brain Res. 64, 281–292. Smith, D.M., Mizumori, S.J., 2006. Hippocampal place cells, context, and episodic memory. Hippocampus 16, 716–729. Solstad, T., Boccara, C.N., Kropff, E., Moser, M.B., Moser, E.I., 2008. Representation of geometric borders in the entorhinal cortex. Science 322, 1865–1868. Squire, L.R., 1992. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231. Squire, L.R., Alvarez, P., 1995. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5, 169–177.
7
Squire, L.R., Kandel, E.R., 2009. Memory From Mind to Molecules, second ed. Roberts & Company, Colorado. Squire, L.R., Stark, C.E., Clark, R.E., 2004. The medial temporal lobe. Annu. Rev. Neurosci. 27, 279–306. Squire, L.R., Zola-Morgan, S., 1991. The medial temporal lobe memory system. Science 253, 1380–1386. Steward, O., Scoville, S.A., 1976. Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat. J. Comp. Neurol. 169, 347–370. Suzuki, W.A., Amaral, D.G., 2004. Functional neuroanatomy of the medial temporal lobe memory system. Cortex 40, 220–222. Suzuki, W.A., Zola-Morgan, S., Squire, L.R., Amaral, D.G., 1993. Lesions of the perirhinal and parahippocampal cortices in the monkey produce long-lasting memory impairment in the visual and tactual modalities. J. Neurosci. 13, 2430–2451. Swanson, L.W., 1981. A direct projection from Ammon’s horn to prefrontal cortex in the rat. Brain Res. 217, 150–154. Swanson, L.W., Cowan, W.M., 1977. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J. Comp. Neurol. 172, 49–84. Takashima, A., Petersson, K.M., Rutters, F., Tendolkar, I., Jensen, O., Zwarts, M.J., McNaughton, B.L., Fernandez, G., 2006. Declarative memory consolidation in humans: a prospective functional magnetic resonance imaging study. Proc. Natl. Acad. Sci. U.S.A. 103, 756–761. Takehara, K., Kawahara, S., Kirino, Y., 2003. Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J. Neurosci. 23, 9897–9905. Takehara-Nishiuchi, K., Maal-Bared, G., Morrissey, M.D., 2011. Increased theta synchronization parallels decreased entorhinal–prefrontal entorhinal–hippocampal theta synchronization during learning and consolidation of associative memory. Front. Behav. Neurosci. 5, 90. Takehara-Nishiuchi, K., McNaughton, B.L., 2008. Spontaneous changes of neocortical code for associative memory during consolidation. Science 322, 960–963. Takehara-Nishiuchi, K., Nakao, K., Kawahara, S., Matsuki, N., Kirino, Y., 2006. Systems consolidation requires postlearning activation of NMDA receptors in the medial prefrontal cortex in trace eyeblink conditioning. J. Neurosci. 26, 5049–5058. Tanninen, S.E., Morrissey, M.D., Takehara-Nishiuchi, K., 2013. Unilateral lateral entorhinal inactivation impairs memory expression in trace eyeblink conditioning. PLoS ONE 8, e84543. Teyler, T.J., DiScenna, P., 1986. The hippocampal memory indexing theory. Behav. Neurosci. 100, 147–154. Teyler, T.J., Rudy, J.W., 2007. The hippocampal indexing theory and episodic memory: updating the index. Hippocampus 17, 1158–1169. Thompson, L.T., Best, P.J., 1990. Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely behaving rats. Brain Res. 509, 299–308. Thornton, J.A., Rothblat, L.A., Murray, E.A., 1997. Rhinal cortex removal produces amnesia for preoperatively learned discrimination problems but fails to disrupt postoperative acquisition and retention in rhesus monkeys. J. Neurosci. 17, 8536–8549. Tsao, A., Moser, M.B., Moser, E.I., 2013. Traces of experience in the lateral entorhinal cortex. Curr. Biol. 23, 399–405. van Strien, N.M., Cappaert, N.L., Witter, M.P., 2009. The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nat. Rev. Neurosci. 10, 272–282. Vetere, G., Restivo, L., Cole, C.J., Ross, P.J., Ammassari-Teule, M., Josselyn, S.A., Frankland, P.W., 2011. Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory. Proc. Natl. Acad. Sci. U.S.A. 108, 8456–8460. Weible, A.P., Rowland, D.C., Monaghan, C.K., Wolfgang, N.T., Kentros, C.G., 2012. Neural correlates of long-term object memory in the mouse anterior cingulate cortex. J. Neurosci. 32, 5598–5608. Wheeler, A.L., Teixeira, C.M., Wang, A.H., Xiong, X., Kovacevic, N., Lerch, J.P., McIntosh, A.R., Parkinson, J., Frankland, P.W., 2013. Identification of a functional connectome for long-term fear memory in mice. PLoS Comput. Biol. 9, e1002853. Wiener, S.I., 1996. Spatial, behavioral and sensory correlates of hippocampal CA1 complex spike cell activity: implications for information processing functions. Prog. Neurobiol. 49, 335–361. Witter, M.P., Griffioen, A.W., Jorritsma-Byham, B., Krijnen, J.L., 1988. Entorhinal projections to the hippocampal CA1 region in the rat: an underestimated pathway. Neurosci. Lett. 85, 193–198. Xu, W., Wilson, D.A., 2012. Odor-evoked activity in the mouse lateral entorhinal cortex. Neuroscience 223, 12–20. Yoneda, Y., Mori, E., Yamashita, H., Yamadori, A., 1994. MRI volumetry of medial temporal lobe structures in amnesia following herpes simplex encephalitis. Eur. Neurol. 34, 243–252. Young, B.J., Otto, T., Fox, G.D., Eichenbaum, H., 1997. Memory representation within the parahippocampal region. J. Neurosci. 17, 5183–5195. Zhang, S.J., Ye, J., Miao, C., Tsao, A., Cerniauskas, I., Ledergerber, D., Moser, M.B., Moser, E.I., 2013. Optogenetic dissection of entorhinal–hippocampal functional connectivity. Science 340, 1232627. Zhu, X.O., Brown, M.W., Aggleton, J.P., 1995. Neuronal signalling of information important to visual recognition memory in rat rhinal and neighbouring cortices. Eur. J. Neurosci. 7, 753–765.
Please cite this article in press as: Takehara-Nishiuchi, K., Entorhinal cortex and consolidated memory. Neurosci. Res. (2014), http://dx.doi.org/10.1016/j.neures.2014.02.012
