Past, present, and future in hippocampal formation and memory research
Mónica Muñoz-López Human Neuroanatomy Laboratory, School of Medicine and Regional Centre forBiomedical Research (CRIB), University of Castilla-La Mancha, Ave. Almansa, 14, 02006 Albacete, Spain. Phone: +34 967 599 200 ext. 2962, [email protected] Abstract
Over 100 years of research on the hippocampal formation has led us understand the consequences of lesions in humans, the functional networks, anatomical pathways, neuronal types and their local circuitry, receptors, molecules, intracellular cascades, and some of the physiological mechanisms underlying long-term spatial and episodic memory. In addition, complex computational models allow us to formulate sophisticated hypotheses; many of them testable with techniques recently developed unthinkable in the past. However, although today the neurobiology of the cognitive map is starting to be revealed, we still face a future with many unresolved questions. The aim of this commentary is twofold. First is to point out some of the critical findings in hippocampal formation research and new challenges. Second, to briefly summarize what the anatomy of memory can tell us about how highly processed sensory information from distant cortical areas communicate with different subareas of the entorhinal cortex, dentate gyrus and hippocampal subfields to integrate and consolidate unique episodic memory traces.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/hipo.22452 This article is protected by copyright. All rights reserved.
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Great revolutions in hippocampus research
The discovery of place cells and of grid cells were two revolutionary findings deserving of the Nobel Laureate of Medicine and Physiology 2014. These discoveries form part of the history of neuroscience, and especially of the hippocampal formation research. Table 1 is an attempt to summarize some of the main revolutions and their implications for hippocampus and memory research as seen from a systems neuroscience perspective.
In Washington, DC in 2005, Edvard Moser presented the discovery of the entorhinal grid cells at the Society for Neuroscience presidential lecture. It was one of those “wow moments”. The event became an episodic long-lasting memory to me and for the friend who was sitting next to me, Dr. Ricardo Insausti. I asked him “is what we have just heard what I think it is?” He responded with certainty “Yes, it is”. The
hippocampal-entorhinal-cortical
interactions
follow
a
complex
topographical organization in the rodent that gets even further complicated in the primate brain as the temporal lobe, in particular the human hippocampus develops, implicating a change of axes. A lateral view of the rodent brain reveals a C-shaped hippocampus with the top part of the C, namely dorsal or septal, critical for spatial processing, and a bottom part, ventral or temporal, critical for object processing. In the primate brain, this C-shaped hippocampus unfolds in the longitudinal plane to take an elongated shape, whereby the dorsal rodent hippocampus corresponds to the caudal hippocampus in the primate and the ventral rodent hippocampus corresponds to the rostral or uncal part in the primate brain. Despite of the different anatomical disposition of the hippocampus and medial temporal cortex, rodent and primates appear to share many of the anatomical and functional properties of the hippocampal-entorhinal-cortical, and conversely, cortical-entorhinal-hippocampal interactions through this axis. The following
paragraphs
analyze
some
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them.
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Table 1. Some of the major discoveries in hippocampal formation research Author, date/ Discovery and main implications Ramón y Cajal, 1893, 1911. Anatomical description of different neuronal types and intrinsic circuitry of the hippocampal formation in rodents and other species. A critical implication is in the understanding that there is a synaptic flow of information within the hippocampal formation. Nobel Laureate for Medicine or Physiology, 1906. Lorente de Nó, 1934, Nomenclature and subdivisions of the hippocampus used today Hebb, 1949. Main essay on neuroscience of memory. The strengthening of synaptic connections through reverberation of neuronal assemblies is put forward as the mechanism for long-term consolidation of memory. This theory has and still generates physiological and anatomical hypotheses (i.e. hebbian synapses and plasticity).
Scoville & Milner, 1957. Global Amnesia after medial temporal removal in the patient HM. The medial temporal lobe, including the hippocampus, is critical for episodic memory. O'Keefe & Dostrovsky, 1971. Cells that code the spatial position of the freely moving animal are found in the rodent hippocampus. Nobel laureate for Medicine or Physiology, 2014. Marr, 1971. Major computational model of the hippocampal formation. A theoretical and quantitative analysis of the principal neurons that form the hippocampal formation to account for memory and recall. Bliss & Lömo, 1973. Discovery of Long-Term Potentiation (LTP) in rabbits. One possible physiological mechanism underlying memory formation by means of hebbian plasticity. Mishkin, 1978. Combined lesions of amygdala and hippocampus impair memory in primates. First primate model of amnesia grounded in patient´s HM lesion and the human global amnesic syndrome. Beginning of the experimental search for the areas critical for memory in the medial temporal lobe. Van Hoesen, 1982. Highly processed information enters the parahippocampal region in the monkey. Flow of information to the hippocampus is funneled via the parahippocampal region. This study stimulated many primate and rodent studies of hippocampal-entorhinal-cortical anatomical connections. Morris et al., 1982. Spatial memory is impaired after hippocampal lesions in rodents. One of the most robust and reliable behavioral tasks invented to date to assess spatial navigation, learning, and memory. Ranck, 1984. Discovery of head direction cells in the rodent presubiculum. Not only spatial information is coded in hippocampal fields, but also information coming from our own head direction.
Morris et al., 1986. Selective impairment of spatial learning by blockade of LTP by means of NMDA antagonist. Understanding of role of synaptic plasticity in spatial navigation at behavioral, physiological, and receptor levels of analysis.
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Squire, 1987. Major review of memory research based on human neuropsychology, primate lesion studies (including his own), anatomical studies, rodent and invertebrate studies on learning and memory. Creation of a diagram of memory types, likely the most used in memory research. Concept of temporal gradient of retrograde amnesia related with extent of lesion in the hippocampal formation and adjacent temporal cortex. Insausti, Amaral and Cowan, 1987. Cortical afferents to the entorhinal cortex originate in polysensory areas of the monkey brain.
Bliss & Collingridge, 1993. Main review article about NMDA receptors and their relevance in hebbian synaptic plasticity through LTP in the hippocampus. One of the most widely cited articles in Neuroscience. Rempel-Clower et al., 1996. 10años antes Zola-Morgan et al muestran lesion en CA1 capaz de provocar amnesia duradera en el hombreDamage restricted to CA1/Subiculum is enough to cause enduring amnesia. Unique study that included neuropsychological memory assessments with lesion extent analysis in ex-vivo histological tissue from three cases of amnesic patients with restricted lesions to the hippocampal formation. Xian & Brown, 1998. Neuronal encoding of novelty, familiarity, and recency in the anterior temporal lobe in primates. This work stimulated research in neuronal recordings in perirhinal and inferotemporal cortex in awake, behaving primates during the performance of memory tasks. Eriksson et al., 1998. Neurogenesis in the adult human hippocampus. This study was followed and still is by anatomical, physiological, behavioral, environmental studies on the function of neurogenesis in different species at different stages of development, adulthood, and in aging. Fynn et al., 2004 & Hafting et al., 2005. Grid cells are discovered in the medial entorhinal cortex of rodents. Edvard and May-Britt Moser´s group discover single neurons in the medial entorhinal cortex that represent space in a hexagonal coordinate system. This important discovery stimulates the search for grid cells in other species, such as bats, primates, humans. Nobel Laureates for Medicine or Physiology, 2014. Lever et al., 2009. Boundary cells in the subiculum of rodents. Neil Burgess group discovers cells in the subiculum sensitive to boundaries in space. MacDonald et al., 2011. Time cells in the hippocampus. Howard Eichenbaum´s group reports neurons in the hippocampus that respond not only to place but also to sequence of behaviorally relevant events. Buzsaki G, 2011. A major compendium on mechanisms and functions of neuronal synchronization. The author addresses issues related to the genesis of brain rhythms and their contribution to the "invisible operations of the brain." Logothetis et al., 2012. Neural-event-triggered functional magnetic resonance or NET-fMRI tool’s development. It offers, as high temporal and high spatial resolution to correlate hippocampal neural events with BOLD response in wide areas of the cortex and subcortical structures. Couey et al., 2013. Menno Witter’s group discovers that inhibitory cells interconnecting the stellate cells of layer II of the entorhinal cortex are critical to generate grid cell-firing pattern in layer II of the entorhinal cortex. Deisseroth et al., 2006; Chung et al., 2013. Optogenetics and CLARITY. Two techniques that have and will exponentially increase the number of hypotheses that can be tested in neuroscience research, including work on memory.
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Dual streams in sensory processing and in memory
In humans, lesions restricted to CA1/subiculum or bilateral hippocampal volume reductions of over 30% are enough to cause severe amnesia including both episodic and spatial memory impairment (Rempel-Clower, 1996; Vargha-Khadem et al., 2007). Human neuropsychology thus suggests that the same structure underlies both functions, but where and how both types of information get integrated within the hippocampal formation is still a puzzle.
Recently, grid cells have been reported in the primate entorhinal cortex (Killian et al., 2013). This is an area where highly processed information converges from multiple sensory modalities and that hence codes simultaneously sensory and spatial information. In rodents, the medial division of
entorhinal cortex
contains high-resolution grid cells and seems to form part of a spatial pathway, comparable to the spatial-caudal entorhinal-posterior hippocampus pathway important for spatial information processing and consolidation (Maviel et al., 2004; Czajkowski et al., 2014).
Primate anatomical studies have shown that highly processed sensory information, although convergent in the entorhinal cortex, courses via especially organized channels, just like the dorsal and ventral streams in the visual system (Mishkin et al., 1983). In one hand, retrosplenial cortex projects to the posterior parahippocampal cortex (Suzuki and Amaral, 1994a, Kobayashi and Amaral, 2007) and to the caudal entorhinal cortex (Insausti et al., 1987). Layer II of the caudal entorhinal cortex sends this highly processed information to the dentate gyrus and layer III to area CA1 of the posterior (dorsal or septal in rodents) hippocampus (Witter and Amaral, 1991, see review in Mohedano-Moriano et al., 2007). Caudal entorhinal cortex layers V and VI then receive projections from CA1/Subiculum and return this information directly back to retrosplenial cortex (Kobayashi and Amaral, 2003; Munoz and Insausti, 2005) or indirectly via the posterior parahippocampal cortex ((Lavenex et al, 2002). Additional components of this spatial network comprise inferior parietal cortex area 7 (Suzuki and Amaral, 1994b, Munoz and Insausti, 2005, Insausti and Amaral, 2008), presubiculum, and
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parasubiculum as all have connections with the caudal (medial in rodents) entorhinal cortex (Canto et al., 2012).
In parallel, visual information from the inferotemporal cortex (area TE) reaches the perirhinal cortex (Suzuki and Amaral, 1994b), and from there, information is directed to the rostral (lateral in rodents) two thirds of the entorhinal cortex layers II-III (Suzuki and Amaral, 1994a) and then to the anterior (ventral or temporal in rodents) hippocampus (see review in Mohedano-Moriano et al., 2007). From there, information goes back directly to the neocortex (Insausti and Muñoz, 2001), to entorhinal cortex layers V-VI to visual processing areas directly (Munoz and Insausti, 2005) or via the perirhinal cortex (Lavenex et al., 2002). The perirhinal cortex is critical for in object memory, again on the basis of lesion data in primates (Meunier et al., 1993, Malkova and Mishkin, 2013). There are additional important nodes for this second object-memory pathway, such as orbitofrontal and medial frontal cortices, agranular insula, temporal pole, the polysensory area of the upper bank of superior temporal sulcus, and the amygdala. This second pathway has been also suggested to be involved in anxiety-related behaviors (see Strange et al., 2014 for review).
These two types information, spatial vs. object memory processing, seem to to stay segregated in the way they terminate in the dentate gyrus layers (at least in the rodent; less so in the primate, while it keeps unknown in humans). It is likely that this segregation continues further downstream in the synaptic relays within the hippocampal fields CA3-CA1, where, nevertheless, complex associations between them occur. The massive intrinsic and collateral connections of area CA3 of the hippocampus have been suggested by many as a possible area where information from multiple sources could be integrated through physiological mechanisms as neuronal ensemble oscillations (Buzsaki, 2001).
It is puzzling, however, that once the projections leave CA3 via CA1/Subiculum and entorhinal cortex, information of different kinds, spatial or object, still stay in segregated channels of information to reach their cortical targets located anatomically distant from each other; i.e. spatial information via
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posterior hippocampus-caudal entorhinal-posterior parahippocapmal cortex returns to inferior parietal and retrosplenial cortices, while anterior hippocampusrostral entorhinal-perirhinal projections are directed to area TE, (Insausti and Munoz, 2001; Munoz and Insausti 2005). In rodents, the lateral division of the entorhinal cortex receives sensory-specific, limbic, and amygadala projections, and is comparable to the ventral visual-perirhinal-rostral entorhinal-anterior hippocampus pathway important for object memory in primates. Despite that, this and many other small roads of the cognitive spatial and object map, are starting to be revealed, although we still don´t know what are the mechanisms by which an episodic memory trace builds up from the different space and object representations. That and many other questions are yet to be resolved (Table 2).
Table 2. Some unresolved questions in hippocampus research How does object information reach the medial temporal cortex and get stored in long-term memory? Limbic circuit of memory: hippocampus, medial temporal cortices, diencephalon, medial frontal cortex, and higher order processing areas in the cortex. What function(s) are carried out by each one of the parts?
How hippocampal-thalamic interactions contribute to memory consolidation? What are the mechanisms for hippocampal-cortical interactions and memory consolidation? What are the anatomical pathways for memory retrieval: hippocampal-prefrontal cortex interactions? Hippocampus and neuromodulation: what neurotransmitters and pathways modulate memory processing to influence the consolidation of declarative episodic memory?
Is the hippocampus always necessary for retrieval of remote memories or do they become independent in the cerebral cortex?
What are the mechanisms and hippocampal-cortical and subcortical anatomical pathways of intentional memory (rehearsal of semantic memory) versus incidental memory (non rehearsed single episodes)?
Is offline hippocampal sharp wave ripple activity a mechanism for consolidation of declarative episodic memory?
How is both spatial and object information coded within one declarative episodic memory trace?
Hippocampal formation, thalamus, frontal lobe, and memory
Neurobiology and behavioral, electrophysiological, and neuroanatomical data suggest that the same areas that underlie visual recognition of objects, faces, etc., or space perception, are the likely the repository of long-term memories via hippocampal-cortical interactions. All those cortical areas fall into the category of higher order processing areas, also named association cortex. The frontal cortex,
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also included within the category of association cortex, is, however, a particular case, as it seems to be involved in multiple executive functions as well as in emotion, and in organizing patterns for motor action. Therefore, the frontal cortex appears to function as an executive hub for controlling the interaction of diverse cortical and subcortical areas for cognitive and emotional computations and motor behavior rather than to be one of the final repositories of long-term memories.
One of the important questions that call for further research is the anatomical and functional organization of the hippocampal formation-thalamicfrontal interactions (Aggleton and Brown, 1999). Within the whole frontal cortex, the medial frontal areas, especially infralimbic area 25, prelimbic area 32, and anterior cingulate cortex area 24, seem the candidates to form part of the limbicthalamic circuit critical for declarative episodic memory across different species (Nieuwenhuis and Takashima, 2010). In primates, lesions of the ventromedial prefrontal cortex impair visual recognition performance in primates (Bachevalier and Mishkin, 1986). Medial prefrontal cortex areas have direct access to medial temporal cortex, including the perirhinal cortex, anterior entorhinal and hippocampus (Insausti et al., 1987; Suzuki and Amaral, 1994; Barbas and Blatt, 1995, Insausti and Munoz, 2001). Medial prefrontal areas could also be influenced by the medial temporal cortex via (at least) two thalamic relays: one through the magnocelular division of the dorsomedial thalamic nucleus and a second one via the fornix-mamilary bodies-anterior thalamic nuclei (Aggleton and Brown, 1999). Electrophysiological recordings in medial frontal areas of awake behaving primates reveal memory related responses, although with longer latencies compared with the temporal lobe, suggesting a flow of information from temporal lobe to frontal (Xiang and Brown, 2007).
This temporo-thalamic-medial frontal network for objects might differ from that for spatial processing. Presubiculum, retrosplenial, and inferior parietal cortex, all part of the spatial memory pathway, seem to have connections with dorsolateral prefrontal areas (Morris et al., 1999; Kobayashi and Amaral, 2003, 2007). The retrosplenial cortex has connections with the lateral dorsal thalamic nucleus (Aggleton et al., 2014), but the thalamic connections that may be
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intermediating the dialogue between spatial memory related areas and dorsolateral prefrontal cortex are still barely known. Functional studies point to lateral prefrontal cortex as important for working memory with different functions for the dorsolateral versus ventrolateral prefrontal areas (Blumenfeld and Ranganath, 2007), while medial frontal cortex is related with memory consolidation (Van Kesteren et al., 2013), but still the function of the many different areas comprising the frontal cortex remain as big questions to address with future research.
In sum, spatial and object processing streams in the earlier visual and auditory cortices stay segregated in later stages across different higher order processing areas in the cortex. These later areas funnel this information to the hippocampal formation and they form associations with each other possibly involving oscillatory activity in field CA3 of the hippocampus. An episodic trace is finally sent to those cortical areas by the reciprocal medial temporal-cortical connections, where long-term spatial or object traces are consolidated. The frontal cortex directly or via thalamic nuclei, amongst other subcortical nuclei, modulates the formation of episodic and spatial memory traces and serves as an intermediary between memory and action.
Acknowledgements Supported by Universidad de Castilla-La Mancha Erasmus Grant (2015) and the Spanish Government Institute Carlos III (FIS Pl11/02860). Special thanks to Ricardo Insausti for being a teacher and a friend, and to Richard Morris and Mar Ubero for their comments on this manuscript.
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Xiang JZ, Brown MW. 2007. Comparison of differential neuronal responsiveness for different regions of the prefrontal cortex in a conditional visual discrimination task. Eur J Neurosci 25:2916-26.
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Mónica Muñoz-López Human Neuroanatomy Laboratory, School of Medicine and Regional Centre forBiomedical Research (CRIB), University of Castilla-La Mancha, Ave. Almansa, 14, 02006 Albacete, Spain. Phone: +34 967 599 200 ext. 2962, [email protected] Abstract
Over 100 years of research on the hippocampal formation has led us understand the consequences of lesions in humans, the functional networks, anatomical pathways, neuronal types and their local circuitry, receptors, molecules, intracellular cascades, and some of the physiological mechanisms underlying long-term spatial and episodic memory. In addition, complex computational models allow us to formulate sophisticated hypotheses; many of them testable with techniques recently developed unthinkable in the past. However, although today the neurobiology of the cognitive map is starting to be revealed, we still face a future with many unresolved questions. The aim of this commentary is twofold. First is to point out some of the critical findings in hippocampal formation research and new challenges. Second, to briefly summarize what the anatomy of memory can tell us about how highly processed sensory information from distant cortical areas communicate with different subareas of the entorhinal cortex, dentate gyrus and hippocampal subfields to integrate and consolidate unique episodic memory traces.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/hipo.22452 This article is protected by copyright. All rights reserved.
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Great revolutions in hippocampus research
The discovery of place cells and of grid cells were two revolutionary findings deserving of the Nobel Laureate of Medicine and Physiology 2014. These discoveries form part of the history of neuroscience, and especially of the hippocampal formation research. Table 1 is an attempt to summarize some of the main revolutions and their implications for hippocampus and memory research as seen from a systems neuroscience perspective.
In Washington, DC in 2005, Edvard Moser presented the discovery of the entorhinal grid cells at the Society for Neuroscience presidential lecture. It was one of those “wow moments”. The event became an episodic long-lasting memory to me and for the friend who was sitting next to me, Dr. Ricardo Insausti. I asked him “is what we have just heard what I think it is?” He responded with certainty “Yes, it is”. The
hippocampal-entorhinal-cortical
interactions
follow
a
complex
topographical organization in the rodent that gets even further complicated in the primate brain as the temporal lobe, in particular the human hippocampus develops, implicating a change of axes. A lateral view of the rodent brain reveals a C-shaped hippocampus with the top part of the C, namely dorsal or septal, critical for spatial processing, and a bottom part, ventral or temporal, critical for object processing. In the primate brain, this C-shaped hippocampus unfolds in the longitudinal plane to take an elongated shape, whereby the dorsal rodent hippocampus corresponds to the caudal hippocampus in the primate and the ventral rodent hippocampus corresponds to the rostral or uncal part in the primate brain. Despite of the different anatomical disposition of the hippocampus and medial temporal cortex, rodent and primates appear to share many of the anatomical and functional properties of the hippocampal-entorhinal-cortical, and conversely, cortical-entorhinal-hippocampal interactions through this axis. The following
paragraphs
analyze
some
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of
them.
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Table 1. Some of the major discoveries in hippocampal formation research Author, date/ Discovery and main implications Ramón y Cajal, 1893, 1911. Anatomical description of different neuronal types and intrinsic circuitry of the hippocampal formation in rodents and other species. A critical implication is in the understanding that there is a synaptic flow of information within the hippocampal formation. Nobel Laureate for Medicine or Physiology, 1906. Lorente de Nó, 1934, Nomenclature and subdivisions of the hippocampus used today Hebb, 1949. Main essay on neuroscience of memory. The strengthening of synaptic connections through reverberation of neuronal assemblies is put forward as the mechanism for long-term consolidation of memory. This theory has and still generates physiological and anatomical hypotheses (i.e. hebbian synapses and plasticity).
Scoville & Milner, 1957. Global Amnesia after medial temporal removal in the patient HM. The medial temporal lobe, including the hippocampus, is critical for episodic memory. O'Keefe & Dostrovsky, 1971. Cells that code the spatial position of the freely moving animal are found in the rodent hippocampus. Nobel laureate for Medicine or Physiology, 2014. Marr, 1971. Major computational model of the hippocampal formation. A theoretical and quantitative analysis of the principal neurons that form the hippocampal formation to account for memory and recall. Bliss & Lömo, 1973. Discovery of Long-Term Potentiation (LTP) in rabbits. One possible physiological mechanism underlying memory formation by means of hebbian plasticity. Mishkin, 1978. Combined lesions of amygdala and hippocampus impair memory in primates. First primate model of amnesia grounded in patient´s HM lesion and the human global amnesic syndrome. Beginning of the experimental search for the areas critical for memory in the medial temporal lobe. Van Hoesen, 1982. Highly processed information enters the parahippocampal region in the monkey. Flow of information to the hippocampus is funneled via the parahippocampal region. This study stimulated many primate and rodent studies of hippocampal-entorhinal-cortical anatomical connections. Morris et al., 1982. Spatial memory is impaired after hippocampal lesions in rodents. One of the most robust and reliable behavioral tasks invented to date to assess spatial navigation, learning, and memory. Ranck, 1984. Discovery of head direction cells in the rodent presubiculum. Not only spatial information is coded in hippocampal fields, but also information coming from our own head direction.
Morris et al., 1986. Selective impairment of spatial learning by blockade of LTP by means of NMDA antagonist. Understanding of role of synaptic plasticity in spatial navigation at behavioral, physiological, and receptor levels of analysis.
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Squire, 1987. Major review of memory research based on human neuropsychology, primate lesion studies (including his own), anatomical studies, rodent and invertebrate studies on learning and memory. Creation of a diagram of memory types, likely the most used in memory research. Concept of temporal gradient of retrograde amnesia related with extent of lesion in the hippocampal formation and adjacent temporal cortex. Insausti, Amaral and Cowan, 1987. Cortical afferents to the entorhinal cortex originate in polysensory areas of the monkey brain.
Bliss & Collingridge, 1993. Main review article about NMDA receptors and their relevance in hebbian synaptic plasticity through LTP in the hippocampus. One of the most widely cited articles in Neuroscience. Rempel-Clower et al., 1996. 10años antes Zola-Morgan et al muestran lesion en CA1 capaz de provocar amnesia duradera en el hombreDamage restricted to CA1/Subiculum is enough to cause enduring amnesia. Unique study that included neuropsychological memory assessments with lesion extent analysis in ex-vivo histological tissue from three cases of amnesic patients with restricted lesions to the hippocampal formation. Xian & Brown, 1998. Neuronal encoding of novelty, familiarity, and recency in the anterior temporal lobe in primates. This work stimulated research in neuronal recordings in perirhinal and inferotemporal cortex in awake, behaving primates during the performance of memory tasks. Eriksson et al., 1998. Neurogenesis in the adult human hippocampus. This study was followed and still is by anatomical, physiological, behavioral, environmental studies on the function of neurogenesis in different species at different stages of development, adulthood, and in aging. Fynn et al., 2004 & Hafting et al., 2005. Grid cells are discovered in the medial entorhinal cortex of rodents. Edvard and May-Britt Moser´s group discover single neurons in the medial entorhinal cortex that represent space in a hexagonal coordinate system. This important discovery stimulates the search for grid cells in other species, such as bats, primates, humans. Nobel Laureates for Medicine or Physiology, 2014. Lever et al., 2009. Boundary cells in the subiculum of rodents. Neil Burgess group discovers cells in the subiculum sensitive to boundaries in space. MacDonald et al., 2011. Time cells in the hippocampus. Howard Eichenbaum´s group reports neurons in the hippocampus that respond not only to place but also to sequence of behaviorally relevant events. Buzsaki G, 2011. A major compendium on mechanisms and functions of neuronal synchronization. The author addresses issues related to the genesis of brain rhythms and their contribution to the "invisible operations of the brain." Logothetis et al., 2012. Neural-event-triggered functional magnetic resonance or NET-fMRI tool’s development. It offers, as high temporal and high spatial resolution to correlate hippocampal neural events with BOLD response in wide areas of the cortex and subcortical structures. Couey et al., 2013. Menno Witter’s group discovers that inhibitory cells interconnecting the stellate cells of layer II of the entorhinal cortex are critical to generate grid cell-firing pattern in layer II of the entorhinal cortex. Deisseroth et al., 2006; Chung et al., 2013. Optogenetics and CLARITY. Two techniques that have and will exponentially increase the number of hypotheses that can be tested in neuroscience research, including work on memory.
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Dual streams in sensory processing and in memory
In humans, lesions restricted to CA1/subiculum or bilateral hippocampal volume reductions of over 30% are enough to cause severe amnesia including both episodic and spatial memory impairment (Rempel-Clower, 1996; Vargha-Khadem et al., 2007). Human neuropsychology thus suggests that the same structure underlies both functions, but where and how both types of information get integrated within the hippocampal formation is still a puzzle.
Recently, grid cells have been reported in the primate entorhinal cortex (Killian et al., 2013). This is an area where highly processed information converges from multiple sensory modalities and that hence codes simultaneously sensory and spatial information. In rodents, the medial division of
entorhinal cortex
contains high-resolution grid cells and seems to form part of a spatial pathway, comparable to the spatial-caudal entorhinal-posterior hippocampus pathway important for spatial information processing and consolidation (Maviel et al., 2004; Czajkowski et al., 2014).
Primate anatomical studies have shown that highly processed sensory information, although convergent in the entorhinal cortex, courses via especially organized channels, just like the dorsal and ventral streams in the visual system (Mishkin et al., 1983). In one hand, retrosplenial cortex projects to the posterior parahippocampal cortex (Suzuki and Amaral, 1994a, Kobayashi and Amaral, 2007) and to the caudal entorhinal cortex (Insausti et al., 1987). Layer II of the caudal entorhinal cortex sends this highly processed information to the dentate gyrus and layer III to area CA1 of the posterior (dorsal or septal in rodents) hippocampus (Witter and Amaral, 1991, see review in Mohedano-Moriano et al., 2007). Caudal entorhinal cortex layers V and VI then receive projections from CA1/Subiculum and return this information directly back to retrosplenial cortex (Kobayashi and Amaral, 2003; Munoz and Insausti, 2005) or indirectly via the posterior parahippocampal cortex ((Lavenex et al, 2002). Additional components of this spatial network comprise inferior parietal cortex area 7 (Suzuki and Amaral, 1994b, Munoz and Insausti, 2005, Insausti and Amaral, 2008), presubiculum, and
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parasubiculum as all have connections with the caudal (medial in rodents) entorhinal cortex (Canto et al., 2012).
In parallel, visual information from the inferotemporal cortex (area TE) reaches the perirhinal cortex (Suzuki and Amaral, 1994b), and from there, information is directed to the rostral (lateral in rodents) two thirds of the entorhinal cortex layers II-III (Suzuki and Amaral, 1994a) and then to the anterior (ventral or temporal in rodents) hippocampus (see review in Mohedano-Moriano et al., 2007). From there, information goes back directly to the neocortex (Insausti and Muñoz, 2001), to entorhinal cortex layers V-VI to visual processing areas directly (Munoz and Insausti, 2005) or via the perirhinal cortex (Lavenex et al., 2002). The perirhinal cortex is critical for in object memory, again on the basis of lesion data in primates (Meunier et al., 1993, Malkova and Mishkin, 2013). There are additional important nodes for this second object-memory pathway, such as orbitofrontal and medial frontal cortices, agranular insula, temporal pole, the polysensory area of the upper bank of superior temporal sulcus, and the amygdala. This second pathway has been also suggested to be involved in anxiety-related behaviors (see Strange et al., 2014 for review).
These two types information, spatial vs. object memory processing, seem to to stay segregated in the way they terminate in the dentate gyrus layers (at least in the rodent; less so in the primate, while it keeps unknown in humans). It is likely that this segregation continues further downstream in the synaptic relays within the hippocampal fields CA3-CA1, where, nevertheless, complex associations between them occur. The massive intrinsic and collateral connections of area CA3 of the hippocampus have been suggested by many as a possible area where information from multiple sources could be integrated through physiological mechanisms as neuronal ensemble oscillations (Buzsaki, 2001).
It is puzzling, however, that once the projections leave CA3 via CA1/Subiculum and entorhinal cortex, information of different kinds, spatial or object, still stay in segregated channels of information to reach their cortical targets located anatomically distant from each other; i.e. spatial information via
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posterior hippocampus-caudal entorhinal-posterior parahippocapmal cortex returns to inferior parietal and retrosplenial cortices, while anterior hippocampusrostral entorhinal-perirhinal projections are directed to area TE, (Insausti and Munoz, 2001; Munoz and Insausti 2005). In rodents, the lateral division of the entorhinal cortex receives sensory-specific, limbic, and amygadala projections, and is comparable to the ventral visual-perirhinal-rostral entorhinal-anterior hippocampus pathway important for object memory in primates. Despite that, this and many other small roads of the cognitive spatial and object map, are starting to be revealed, although we still don´t know what are the mechanisms by which an episodic memory trace builds up from the different space and object representations. That and many other questions are yet to be resolved (Table 2).
Table 2. Some unresolved questions in hippocampus research How does object information reach the medial temporal cortex and get stored in long-term memory? Limbic circuit of memory: hippocampus, medial temporal cortices, diencephalon, medial frontal cortex, and higher order processing areas in the cortex. What function(s) are carried out by each one of the parts?
How hippocampal-thalamic interactions contribute to memory consolidation? What are the mechanisms for hippocampal-cortical interactions and memory consolidation? What are the anatomical pathways for memory retrieval: hippocampal-prefrontal cortex interactions? Hippocampus and neuromodulation: what neurotransmitters and pathways modulate memory processing to influence the consolidation of declarative episodic memory?
Is the hippocampus always necessary for retrieval of remote memories or do they become independent in the cerebral cortex?
What are the mechanisms and hippocampal-cortical and subcortical anatomical pathways of intentional memory (rehearsal of semantic memory) versus incidental memory (non rehearsed single episodes)?
Is offline hippocampal sharp wave ripple activity a mechanism for consolidation of declarative episodic memory?
How is both spatial and object information coded within one declarative episodic memory trace?
Hippocampal formation, thalamus, frontal lobe, and memory
Neurobiology and behavioral, electrophysiological, and neuroanatomical data suggest that the same areas that underlie visual recognition of objects, faces, etc., or space perception, are the likely the repository of long-term memories via hippocampal-cortical interactions. All those cortical areas fall into the category of higher order processing areas, also named association cortex. The frontal cortex,
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also included within the category of association cortex, is, however, a particular case, as it seems to be involved in multiple executive functions as well as in emotion, and in organizing patterns for motor action. Therefore, the frontal cortex appears to function as an executive hub for controlling the interaction of diverse cortical and subcortical areas for cognitive and emotional computations and motor behavior rather than to be one of the final repositories of long-term memories.
One of the important questions that call for further research is the anatomical and functional organization of the hippocampal formation-thalamicfrontal interactions (Aggleton and Brown, 1999). Within the whole frontal cortex, the medial frontal areas, especially infralimbic area 25, prelimbic area 32, and anterior cingulate cortex area 24, seem the candidates to form part of the limbicthalamic circuit critical for declarative episodic memory across different species (Nieuwenhuis and Takashima, 2010). In primates, lesions of the ventromedial prefrontal cortex impair visual recognition performance in primates (Bachevalier and Mishkin, 1986). Medial prefrontal cortex areas have direct access to medial temporal cortex, including the perirhinal cortex, anterior entorhinal and hippocampus (Insausti et al., 1987; Suzuki and Amaral, 1994; Barbas and Blatt, 1995, Insausti and Munoz, 2001). Medial prefrontal areas could also be influenced by the medial temporal cortex via (at least) two thalamic relays: one through the magnocelular division of the dorsomedial thalamic nucleus and a second one via the fornix-mamilary bodies-anterior thalamic nuclei (Aggleton and Brown, 1999). Electrophysiological recordings in medial frontal areas of awake behaving primates reveal memory related responses, although with longer latencies compared with the temporal lobe, suggesting a flow of information from temporal lobe to frontal (Xiang and Brown, 2007).
This temporo-thalamic-medial frontal network for objects might differ from that for spatial processing. Presubiculum, retrosplenial, and inferior parietal cortex, all part of the spatial memory pathway, seem to have connections with dorsolateral prefrontal areas (Morris et al., 1999; Kobayashi and Amaral, 2003, 2007). The retrosplenial cortex has connections with the lateral dorsal thalamic nucleus (Aggleton et al., 2014), but the thalamic connections that may be
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intermediating the dialogue between spatial memory related areas and dorsolateral prefrontal cortex are still barely known. Functional studies point to lateral prefrontal cortex as important for working memory with different functions for the dorsolateral versus ventrolateral prefrontal areas (Blumenfeld and Ranganath, 2007), while medial frontal cortex is related with memory consolidation (Van Kesteren et al., 2013), but still the function of the many different areas comprising the frontal cortex remain as big questions to address with future research.
In sum, spatial and object processing streams in the earlier visual and auditory cortices stay segregated in later stages across different higher order processing areas in the cortex. These later areas funnel this information to the hippocampal formation and they form associations with each other possibly involving oscillatory activity in field CA3 of the hippocampus. An episodic trace is finally sent to those cortical areas by the reciprocal medial temporal-cortical connections, where long-term spatial or object traces are consolidated. The frontal cortex directly or via thalamic nuclei, amongst other subcortical nuclei, modulates the formation of episodic and spatial memory traces and serves as an intermediary between memory and action.
Acknowledgements Supported by Universidad de Castilla-La Mancha Erasmus Grant (2015) and the Spanish Government Institute Carlos III (FIS Pl11/02860). Special thanks to Ricardo Insausti for being a teacher and a friend, and to Richard Morris and Mar Ubero for their comments on this manuscript.
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