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A place cell is a kind of pyramidal neuron within the hippocampus that becomes active when an animal enters a particular place in its environment, which is known as the place field. Place cells are thought, collectively, to act as a cognitive representation of a specific location in space, known as a cognitive map.^[1] Place cells work with other types of neurons in the hippocampus and surrounding regions to perform this kind of spatial processing,^[2] but the ways in which they function within the hippocampus are still being researched.^[3]

Place cell firing patterns are often determined by external sensory information and the local environment. Place cells have proven to have the ability to suddenly change their firing pattern from one pattern to another, a phenomenon known as remapping. Though place cells do change according to the external environment, they are stabilized by attractor dynamics which "enable the system to resist small changes in sensory input but respond collectively and coherently to large ones".^[4]

Although place cells are part of a non-sensory cortical system, their firing behavior is strongly correlated to sensory input. These circuits may have important implications for memory, as they provide the spatial context for memories and past experiences.^[5] Like many other parts of the brain, place cell circuits are dynamic. They are constantly adjusting and remapping to suit the current location and experience of the brain. Place cells do not work alone to create visuospatial representation; they are a part of a complex circuit that informs place awareness and place memory.^[5]

The 2014 Nobel Prize in Physiology or Medicine was awarded to John O'Keefe for the discovery of place cells, and to Edvard and May-Britt Moser for the discovery of grid cells.^[6]^[7]

Background

Place cells were first discovered by John O'Keefe and Jonathan Dostrovsky in 1971 in the hippocampus of rats.^[8] They noticed that rats with impairments in their hippocampus performed poorly in spatial tasks, and thus hypothesised that this area must hold some kind of spatial representation of the environment. To test this hypothesis, they developed chronic electrode implants, with which they could record the activity of individual cells extracellularly in the hippocampus. They noted that some of the cells showed activity when a rat was "situated in a particular part of the testing platform facing in a particular direction".^[8] These cells would later be called place cells.

In 1976 O'Keefe performed a follow-up study, demonstrating the presence of what they called place units.^[9] These units were cells that fired in a particular place in the environment, the place field. They are described as having a low resting firing rate (<1 Hz) when a rat is not in its place field, but a particularly high firing rate, which can be over 100 Hz in some cases, within the place field.^[10] Additionally, O'Keefe described 6 special cells, which he called misplace units, which also fire only in a particular place, but only when the rat performed an additional behaviour, such as sniffing, which was often correlated with the presence of a novel stimulus, or the absence of an expected stimulus.^[9] The findings ultimately supported the cognitive map theory, the idea that the hippocampus hold a spatial representation, a cognitive map of the environment.^[11]

There has been much debate as to whether hippocampal place cells function depends on landmarks in the environment, on environmental boundaries, or on an interaction between the two.^[12] Additionally, not all place cells rely on the same external cues. One important distinction in cues is local and distal, where local cues appear in the immediate vicinity of a subject, whereas distal cues are far away, and act more like landmarks. Individual place cells have been shown to follow either or rely on both.^[13] Additionally, the cues on which the place cells rely may depend on previous experience of the subject and the saliency of the cue.^[14]

There has also been much debate as to whether hippocampal pyramidal cells truly encode non-spatial information as well as spatial information. According to the cognitive map theory, the hippocampus's primary role is to store spatial information through place cells and the hippocampus was biologically designed to provide a subject with spatial information.^[15] Recent findings, such as a study showing that place cells respond to non-spatial dimensions, such as sound frequency, disagree with the cognitive map theory.^[16] Instead, they support a new theory saying that the hippocampus has a more general function encoding continuous variables, and location just happens to be one of those variables.^[16]This fits in with the idea that the hippocampus has a predictive function.^[17] Another non-spatial explanations of hippocampal functioning suggests that the hippocampus simply performs clustering of inputs.^[18]

Place cells fire in different, often widespread, hippocampal locations at the same time, which some interpret as their having different functions in different locations. A rat's representation of its environment is constructed by the firing of groups of place cells that are widely distributed in the hippocampus, however, this does not necessarily mean that each location serves a different purpose. When recording the firing fields of certain hippocampal cells in an open field environment, firing fields prove to be similar even when the rat travels in different directions, exhibiting omnidirectionality. However, when limitations are placed in the aforementioned environment, fields prove to be directional and fire in one direction but not in another.

The same directionality occurs when rats participate in the radial arm maze. The radial arm maze consists of a central circle from which several arm-like projections radiate. These projections either contain food or do not. Some consider the firing or lack of firing of place cells depending on the arm to be a function of goal-oriented behavior. However, when moving from one arm to another when they both contain food, place cells only fire in one direction, meaning that one cannot attribute firing purely to a goal-approach. A directionality component must be added: for example, a North goal as opposed to a South goal.^[15]

When visual cues in an environment such as visibility of a line where the wall meets the floor, height of the wall, and width of the wall are available to the rat to discern distance and location of the wall, the rat internalizes this external information to register its surroundings. However, when these visual cues are unavailable, the rat registers wall location by colliding with the wall and then place cell firing rate after the collision provides information to the rat about its distance from the wall based on the direction and speed of its movements after the collision. In this situation, the firing of place cells is due to motor inputs.^[15]

The place cells that appear to operate based solely on non-spatial memory seem to have spatial components. Many lesioning experiments attempting to inflict non-spatial memory deficits in the hippocampus have been unsuccessful. In some cases, lesioning has been successful in inflicting non-spatial memory deficits, however, other structures besides the hippocampus were affected by lesioning. Therefore, the rat's non-spatial memory deficits could have been unrelated to place cells.^[15] Thus, based on information from studies thus far, the cognitive map theory seems to be most supported and non-spatial theories may fail to take spatial components into account.^[15]

Place cells are located in the hippocampus, a brain structure located in the medial temporal lobe of the brain.

Properties

Place fields

Place cells fire in a specific region of an environment, known as a place field. Place fields are roughly analogous to the receptive fields of sensory neurons, in that the firing region corresponds to a region of sensory information in the environment. However, unlike receptive fields, place cells show no topography, meaning that two neighboring cells do not necessarily have neighboring place fields.^[19] Place cells fire spikes in bursts at a high frequency inside the place field, but outside of the place field the remain relatively inactive.^[20] Place fields are allocentric, meaning that they are defined with respect to the outside world rather than the body. By orienting based on the environment rather than the individual, place fields can work effectively as neural maps of the environment.^[21] A typical place cell will have only one or a few place fields in a small laboratory environment. However, in larger environments, place cells have been shown to contain multiple place fields which are usually irregular.^[22] Place cell may also show directionality, meaning they will only fire in a certain location when travelling in a particular direction.^[9]^[23]^[24]

Remapping

Remapping is the change in the place field characteristics that occur when a subject experiences a new environment, or the same environment in a new context. This phenomenon was first reported in 1987,^[25]^[26] and is thought that remapping plays a role in the memory function of the hippocampus.^[25] There are broadly two types of remapping: global remapping and partial remapping.^[27] When global remapping occurs, most or all of the place cells remap, meaning they lose or gain a place field, or their place field changes its location. Partial remapping means that most place fields are unchanged and only a small portion of the place cells remap. Some of the changes to the environment that have been shown to induce remapping include changing the shape,^[26] the size,^[26] the color of the walls,^[28] the smell in the environment,^[28] or the relevance of a location to the task at hand.^[29]

Phase precession

The firing of place cells is timed in relation to local theta waves, a process termed phase precession.^[30] Upon entering a place field, place cells will fire in bursts at a particular point in the phase of the underlying theta waves. However, as an animal progresses through the place field, the firing will happen progressively earlier in the phase.^[30] It is thought that this phenomenon increases the accuracy of the place coding, and aid in plasticity, which is required for learning.^[30]

Sensory input

Place cells were initially believed to fire in direct relation to simple sensory inputs, but studies have suggested that this may not be the case.^[21] Place fields are usually unaffected by large sensory changes, like removing a landmark from an environment, but respond to subtle changes, like a change in color or shape of an object.^[31] This suggests that place cells respond to complex stimuli rather than simple individual sensory cues. According to a model known as the functional differentation model, sensory information is processed in various cortical structures upstream of the hippocampus before actually reaching the structure, so that the information received by place cells is a compilation of different stimuli.^[21] Mechanisms required for memory consolidation affect place cell firing less than direct sensory input does, suggesting that it is primarily recent inputs that are retrieved during place coding.^[32]

Sensory information received by place cells can be categorized as either metric or contextual information, where metric information corresponds to where place cells should fire and contextual input corresponds to whether or not a place field should fire in a certain environment.^[33] Metric sensory information is any kind of spatial input that might indicate a distance between two points. For example, the edges of an environment might signal the size of the overall place field or the distance between two points within a place field. Metric signals can be either linear or directional. Directional inputs provide information about the orientation of a place field, whereas linear inputs essentially form a representational grid. Contextual cues allow established place fields to adapt to minor changes in the environment, such as a change in object color or shape. Metric and contextual inputs are processed together in the entorhinal cortex before reaching the hippocampal place cells. Visuospatial and olfactory inputs are examples of sensory inputs that are utilized by place cells. These types of sensory cues can include both metric and contextual information.^[33]

Visuospatial cues

Spatial cues such as geometric boundaries or orienting landmarks are important examples of metric input. Place cells mainly rely on set distal cues rather than cues in the immediate proximal environment.^[33] Movement can also be an important spatial cue. The ability of place cells to incorporate new movement information is called path integration, and it is important for keeping track of self-location during movement.^[34] Path integration is largely aided by grid cells, which are a type of neuron in the entorhinal cortex that relay information to place cells in the hippocampus. Grid cells establish a grid representation of a location, so that during movement place cells can fire according to their new location while orienting according to the reference grid of their external environment.^[33] Visual sensory inputs can also supply important contextual information. A change in color of a specific object can affect whether or not a place cell fires in a particular field.^[33] Thus, visuospatial sensory information is critical to the formation and recollection of place field.

Olfactory cues

Although place cells primarily rely on visuospatial input, some studies suggest that olfactory input may also play a role in generating and recalling place fields.^[35]^[36] Relatively little is known about the interaction between place cells and non-visual sensory cues, but preliminary studies have shown that non-visual sensory input may have supplementary role in place field formation. A study by Save et al. found that olfactory information can be used to compensate for a loss of visual information. In this study, place fields in subjects exposed to an environment with no light and no olfactory signals were unstable; the position of the place field shifted abruptly and some of the constituent place cells stopped firing entirely. However, place cells in subjects exposed to a dark environment with olfactory signals remained stable despite a lack of visual cues.^[35] An additional study by Zhang et al. examined how the hippocampus uses olfactory signals to create and recall place fields. Similar to the Save et al. study, this study exposed subjects to an environment with a series of odors but no visual or auditory information. Place fields remained stable and even adapted to the rotation of the pattern of olfactory signals. Furthermore, the place fields would remap entirely when the odors were moved randomly.^[36] This suggests that place cells not only utilize olfactory information to generate place fields, but also use olfactory information to orient place fields during movement. Using virtual reality, a study by Radvansky and Dombeck showed that an environment composed of odor gradients alone was sufficient to engage place cells.^[37]

Hippocampal memory

The hippocampus plays an essential role in episodic memory.^[38] One important aspect of episodic memory is the spatial context in which the event occurred.^[39] Hippocampal place cells have been shown to exhibit stable firing patterns even when cues from a location are removed. Additionally, specific place fields begin firing when exposed to signals or a subset of signals from a previous location.^[40] This suggests that place cells provide the spatial context for a memory by recalling the neural representation of the environment in which the memory occurred. In other words, place cells prime a memory by differentiating the context for the event.^[39] By establishing spatial context, place cells can be used to complete memory patterns.^[38] Furthermore, place cells can maintain a spatial representation of one location while recalling the neural map of a separate location, effectively differentiating between present experience and past memory.^[39] Place cells are therefore considered to demonstrate both pattern completion and pattern separation qualities.^[38]

Pattern completion

Pattern completion is the ability to recall an entire memory from a partial or degraded sensory cue.^[38] Place cells are able to maintain a stable firing field even after significant signals are removed from a location, suggesting that they can recall a pattern from only some of the original input.^[31] Furthermore, pattern completion can be symmetric in that an entire memory can be retrieved from any part of it. For example, in an object-place association memory, spatial context can be used to recall an object and the object can be used to recall the spatial context.^[38]

Pattern separation

Pattern separation is the ability to differentiate one memory from other stored memories.^[31] Pattern separation begins in the dentate gyrus, a section of the hippocampus involved in memory formation and retrieval.^[38] Granule cells in the dentate gyrus process sensory information using competitive learning, and relay a preliminary representation to form place fields.^[38] Place fields are extremely specific, as they are capable of remapping and adjusting firing rates in response to subtle sensory signal changes. This specificity is critical for pattern separation, as it distinguishes memories from one another.^[31]

Reactivation, replay, and preplay

Place cells often exhibit reactivation outside their place fields. This reactivation has a much faster time scale than the actual experience, and it occurs mostly in the same order in which it was originally experienced, or, more rarely, in reverse. Replay is believed to have a functional role in memory retrieval and memory consolidation. It was also shown that the same sequence of activity may occur before the actual experience.^[41] This phenomenon, termed preplay, may have a role in prediction and learning.

Abnormalities

Effects of ethanol

The hippocampus and related structures use place cells to construct a cognitive map of their surroundings in order to guide and inform their behavior.^[11]^[42] Just as lesioning in these structures causes rats to rely on cue-based information to function, so too does chronic ethanol exposure.^[43] Place cell firing rate decreases dramatically after ethanol exposure, causing reduced spatial sensitivity.^[43]

Studies have shown ethanol to impair both spatial long-term memory and spatial working memory in various tasks.^[43]^[44]^[45] Chronic ethanol exposure causes deficits in spatial learning and memory tasks. These deficits persist even when exposed to long periods of ethanol-free time after ethanol exposure, suggesting a long-lasting change in structure and function of the hippocampus, a change in its functional connectome. Whether these changes are due to a change in place cells or a change in neurotransmission, neuroanatomy, or protein expression in the hippocampus is unknown.^[43] However, impairments in using non-spatial components such as cues are not evident in various tasks such as the radial arm maze and the Morris water navigation task.^[43]

While research has been conducted on the effects of addictive drugs on spatial memory, there has not been research that investigates whether chronic ethanol exposure would produce tolerance to these effects in addition to ethanol tolerance.^[43]

Effects of vestibular lesioning

Varying vestibular system stimulation has an effect on place cells. The vestibular system, part of the labyrinth of the inner ear, plays an important role in spatial memory by tuning into self-motion such as acceleration. Bilateral lesions of the vestibular system in patients cause abnormal firing of hippocampal place cells as evidenced, in part, by difficulties with aforementioned spatial tasks such as the radial arm maze and the Morris water navigation task.^[46] The dysfunction in spatial memory seen with damage to the vestibular system is lasting and possibly permanent, particularly if there is bilateral damage. For example, spatial memory deficits of patients with chronic vestibular loss is seen 5–10 years after a complete loss of the bilateral vestibular labyrinths.

Due to close proximity of the structures, vestibular lesioning often results in cochlear damage, which in turn results in hearing impairments. Hearing has been shown to affect place cell functioning, therefore, spatial deficits could be in part due to damage to the cochlea. However, animals with a removed eardrum (usually causing the inability to hear) and normal vestibular labyrinths perform significantly better than animals with eardrums and lesioning in the vestibular labyrinths. These findings suggest that disruption to hearing is not the primary cause of the observed spatial memory deficits.^[46]

Diseases

Problems with spatial memory and navigation are thought to be one of the early indications of Alzheimer's disease.^[47] Delpolyi and Rankin compared thirteen mild Alzheimer's patients and twenty-one mild-cognitive impairment patients, with twenty-four subjects with normal brain functioning through a series of spatially related tasks. The first task entailed route memory and the study found that the non-control group could not find their location on the map, or recall the order in which they had seen landmarks. The overall results showed that only 10% of the control group got lost on the route while 50% of the non-control group got lost.^[48] The demonstrated issues with spatial navigation among Alzheimer's and MCI patients indicates a malfunctioning with the firing of place cells and that abnormalities within the hippocampus may be an early indicatory of disease onset. O'Keefe who originally found the existence of place cells said that, "We suspect we'll begin to see signs of changes in the functions of cells before we see changes in behavioral tasks."^[48]

Aging

Place cell function changes with age. Pharmaceuticals that target pathways involved in protein synthesis increase place cell functioning in senescence.^[49] Frequency of protein translation changes as animals age. A factor that aids in transcription, known as zif268 mRNA, is shown to decrease with age, thereby affecting memory consolidation. This form of mRNA is decreased in both the CA1 and CA2 hippocampal regions, these reduced levels causing spatial learning deficits.^[49]

Senile rats' performance on the Morris water maze does not differ from young rats' performance when the trials are repeated shortly after one another. However, when time has elapsed between trials, senile rats show spatial memory deficits that young rats do not exhibit.^[49]

Place field properties are similar between young and aged rats in the CA1 hippocampal region: rate of firing and spike characteristics (such as amplitude and width) are similar. However, while the size of place fields in the hippocampal CA3 region remains the same between young and aged rats, average firing rate in this region is higher in aged rats. Young rats exhibit place field plasticity. When they are moving along a straight path, place fields are activated one after another. When young rats repeatedly traverse the same straight path, connection between place fields are strengthened due to plasticity, causing subsequent place fields to fire more quickly and causing place field expansion, possibly aiding young rats in spatial memory and learning. Recently, there has been debate as to whether there may be bidirectionality to place cell firing. However, this observed place field expansion and plasticity is decreased in aged rat subjects, possibly reducing their capacity for spatial learning and memory.

Studies have been conducted in an attempt to restore place field firing plasticity in aged subjects. NMDA receptors, which are glutamate receptors, exhibit decreased activity in aged subjects. Memantine, an antagonist that blocks the NMDA receptors, is known to improve spatial memory and was therefore used in an attempt to restore place field plasticity in aged subjects. Memantine succeeded in increasing place field plasticity in aged rat subjects.^[49] Although memantine aids in the encoding process of spatial information in aged rat subjects, it does not help with the retrieval of this information later in time. Thus, these place fields in aged mice do not appear to endure like those of young mice. When introduced to the same environment several times, different place fields fire in the CA1 hippocampal region of aged rats, suggesting that they are "remapping" their environment each time they are exposed to it. In the CA1 region, there is an increased reliance on self-motion inputs as opposed to visual inputs compared to the CA1 region of young rats, which relies more on visual cues. The CA3 hippocampal region is affected differently by decreased plasticity than the CA1 region just discussed. Decreased plasticity in aged subjects causes the same place fields in the CA3 region to activate in similar environments, whereas different place fields in young rats would fire in similar environments because they would pick up on subtle differences in these environments.^[49] It is evident that pharmaceuticals such as Memantine can have a significant effect in mediating the age-related decline in place field plasticity.^[49]

Increased adult hippocampal place cell neurogenesis does not necessarily lead to better performance on spatial memory tasks. Just as too little neurogenesis leads to spatial memory deficits, so too does too much neurogenesis. Drugs dealing with improving place cell functioning and increasing the rate of hippocampal neurogenesis should take this balance into account.^[50]

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^ ^a ^b Zhang, Sijie; Denise Manahan-Vaughn (5 September 2013). "Spatial Olfactory Learning Contributes to Place Field Formation in the Hippocampus". Cerebral Cortex. 25 (2): 423–432. doi:10.1093/cercor/bht239. PMC 4380081. PMID 24008582.
^ ^a ^b Save, Etienne; Ludek Nerad; Bruno Poucet (23 February 2000). "Contribution of multiple sensory information to place field stability in hippocampal place cells". Hippocampus. 10 (1): 64–76. doi:10.1002/(SICI)1098-1063(2000)10:1<64::AID-HIPO7>3.0.CO;2-Y. PMID 10706218.
^ Radvansky, Brad; Daniel Dombeck (26 February 2018). "An olfactory virtual reality system for mice". Nature Communications. 9 (1): 839. doi:10.1038/s41467-018-03262-4. PMC 5827522. PMID 29483530.
^ ^a ^b ^c ^d ^e ^f ^g Rolls, Edmund T. (2013). "The mechanisms for pattern completion and pattern separation in the hippocampus". Frontiers in Systems Neuroscience. 7: 74. doi:10.3389/fnsys.2013.00074. PMC 3812781. PMID 24198767.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c Smith, David; Sheri Mizumori (10 June 2006). "Hippocampal Place Cells, Context, and Episodic Memory". Hippocampus. 16 (9): 716–729. CiteSeerX 10.1.1.141.1450. doi:10.1002/hipo.20208. PMID 16897724.
^ Nakazawa, Kazu; Thomas McHugh; Matthew Wilson; Susumu Tonegawa (May 2004). "NMDA Receptors, Place Cells and Hippocampal Spatial Memory". Nature Reviews Neuroscience. 5 (5): 368–369. doi:10.1038/nrn1385. PMID 15100719.
^ Diba, Kamran; Buzsáki, György (2007-10). "Forward and reverse hippocampal place-cell sequences during ripples". Nature neuroscience. 10 (10): 1241–1242. doi:10.1038/nn1961. ISSN 1097-6256. PMC 2039924. PMID 17828259. {{cite journal}}: Check date values in: |date= (help)
^ Nadel, Lynn (3 July 1991). "The Hippocampus and Space Revisited". Hippocampus. 1 (3): 221–229. CiteSeerX 10.1.1.622.87. doi:10.1002/hipo.450010302. PMID 1669368.
^ ^a ^b ^c ^d ^e ^f Matthews, Douglas B.; Morrow, Leslie A. (23 February 2000). "Effects of acute and chronic ethanol exposure on spatial cognitive processing and hippocampal function in the rat". Hippocampus. 10 (1): 122–130. doi:10.1002/(SICI)1098-1063(2000)10:1<122::AID-HIPO13>3.0.CO;2-V.
^ Givens, Bennet (1 June 1995). "Low doses of ethanol impair spatial working memory and reduce hippocampal theta activity". Alcoholism: Clinical and Experimental Research. 19 (3): 763–767. doi:10.1111/j.1530-0277.1995.tb01580.x. ProQuest 618978482.
^ White, Aaron, M.; Simson, P. E.; Best, Phillip J. (1 October 1997). "Comparison between the effects of ethanol and diazepam on spatial working memory in the rat". Psychopharmacology. 133 (3): 256–261. doi:10.1007/s002130050399. PMID 9361331. ProQuest 619216070.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Smith, Paul F.; Darlington, Cynthia L.; Zheng, Yiwen (29 April 2009). "Move it or lose it—Is stimulation of the vestibular system necessary for normal spatial memory?". Hippocampus. 20 (1): 36–43. doi:10.1002/hipo.20588. PMID 19405142.
^ Delpolyi, AR; Rankin, K; Mucke, L; Miller, BL; Gorno-Tempini, ML (4 September 2007). "Spatial cognition and the human navigation network in AD and MCI". Neurology. 69 (10): 1986–1997. doi:10.1212/01.wnl.0000271376.19515.c6. PMID 17785667.
^ ^a ^b Moser, Edvard I; Kropff, Emilo; Moser, May-Britt (19 February 2008). "Place Cells, Grid Cells, and the Brain's Spatial Representation System". Annual Review of Neuroscience. 31: 69–89. doi:10.1146/annurev.neuro.31.061307.090723. PMID 18284371.
^ ^a ^b ^c ^d ^e ^f Schimanski, Lesley, A.; Barnes, Carol A. (6 August 2010). "Neural protein synthesis during aging: effects on plasticity and memory". Frontiers in Aging Neuroscience. 2: 1. doi:10.3389/fnagi.2010.00026. PMC 2928699. PMID 20802800.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Pawluski, Jodi L.; Brummelte, Susanne; Barha, Cindy K.; Crozier, Tamara M.; Galea, Liisa A.M. (3 August 2009). "Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging". Frontiers in Neuroendocrinology. 30 (3): 343–357. doi:10.1016/j.yfrne.2009.03.007. PMID 19361542.

External links

Media related to Place cells at Wikimedia Commons

[1] O'Keefe, John (1978). The Hippocampus as a Cognitive Map. ISBN 978-0198572060.

[2] Muir, Gary; David K. Bilkey (1 June 2001). "Instability in the Place Field Location of Hippocampal Place Cells after Lesions Centered on the Perirhinal Cortex" (PDF). The Journal of Neuroscience. 21 (11): 4016–4025. doi:10.1523/JNEUROSCI.21-11-04016.2001. PMC 6762702. PMID 11356888.

[Redei_2008_1501-3] Redei, George (2008). Encyclopedia of Genetics, Genomics, Proteomics, and Informatics. p. 1501. ISBN 978-1-4020-6753-2..

[Jeffery_775–785-4] Jeffery, Kathryn (2007). "Integration of Sensory Inputs to Place Cells: what, where, why, and how?". Hippocampus. 17 (9): 775–785. doi:10.1002/hipo.20322. PMID 17615579. ProQuest 621877128.

[Smith-5] Smith, David; Sheri Mizumori (June 2006). "Hippocampal Place Cells, Context, and Episodic Memory". Hippocampus. 16 (9): 716–729. CiteSeerX 10.1.1.141.1450. doi:10.1002/hipo.20208. PMID 16897724.

[6] "The Nobel Prize in Physiology or Medicine 2014". Nobelprize.org. Retrieved 2014-10-06.

[7] Kiehn, Ole; Forssberg, Hans (2014). "Scientific Background: The Brain's Navigational Place and Grid Cell System" (PDF). Karolinska Institute. Retrieved September 7, 2018.

[:0-8] O'Keefe, J.; Dostrovsky, J. (November 1971). "The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat". Brain Research. 34 (1): 171–175. doi:10.1016/0006-8993(71)90358-1. ISSN 0006-8993. PMID 5124915.

[:1-9] O'Keefe, John (1976-01-01). "Place units in the hippocampus of the freely moving rat". Experimental Neurology. 51 (1): 78–109. doi:10.1016/0014-4886(76)90055-8. ISSN 0014-4886.

[10] Eichenbaum, Howard; Dudchenko, Paul; Wood, Emma; Shapiro, Matthew; Tanila, Heikki (1999-06-01). "The Hippocampus, Memory, and Place Cells: Is It Spatial Memory or a Memory Space?". Neuron. 23 (2): 209–226. doi:10.1016/S0896-6273(00)80773-4. ISSN 0896-6273. PMID 10399928.

[:2-11] O'Keefe, John; Nadel, Lynn (1 December 1979). "The Hippocampus as a Cognitive Map". Behavioral and Brain Sciences. 2 (4): 487–533. doi:10.1017/s0140525x00063949. ProQuest 616519952.

[12] Lew, Adena R. (7 February 2011). "Looking beyond the boundaries: Time to put landmarks back on the cognitive map?". Psychological Bulletin. 137 (3): 484–507. doi:10.1037/a0022315. PMID 21299273.

[13] Knierim, James J. (2002-07-15). "Dynamic Interactions between Local Surface Cues, Distal Landmarks, and Intrinsic Circuitry in Hippocampal Place Cells". Journal of Neuroscience. 22 (14): 6254–6264. doi:10.1523/JNEUROSCI.22-14-06254.2002. ISSN 0270-6474. PMID 12122084.

[14] Scaplen, Kristin M.; Gulati, Arune A.; Heimer-McGinn, Victoria L.; Burwell, Rebecca D. (2014-11). "When do objects become landmarks? Hippocampal place cells respond differently to manipulations of visual cues depending on size, perspective, and experience". Hippocampus. 24 (11): 1287–1299. doi:10.1002/hipo.22331. ISSN 1050-9631. PMC 5615844. PMID 25045010. {{cite journal}}: Check date values in: |date= (help)

[okeefe1999-15] O'Keefe, John (3 September 1999). "Do hippocampal pyramidal cells signal non-spatial as well as spatial information?". Hippocampus. 9 (4): 352–364. doi:10.1002/(SICI)1098-1063(1999)9:4<352::AID-HIPO3>3.0.CO;2-1.

[:6-16] Aronov, Dmitriy; Nevers, Rhino; Tank, David W. (2017-03-29). "Mapping of a non-spatial dimension by the hippocampal/entorhinal circuit". Nature. 543 (7647): 719–722. doi:10.1038/nature21692. ISSN 0028-0836. PMC 5492514. PMID 28358077.

[17] Stachenfeld, Kimberly L.; Botvinick, Matthew M.; Gershman, Samuel J. (2017). "The hippocampus as a predictive map". Nature Neuroscience. 20 (11): 1643–1653. doi:10.1038/nn.4650. ISSN 1546-1726.

[18] Mok, Robert M.; Love, Bradley C. (2019-12-12). "A non-spatial account of place and grid cells based on clustering models of concept learning". Nature Communications. 10 (1): 1–9. doi:10.1038/s41467-019-13760-8. ISSN 2041-1723.

[19] O'Keefe, J; Burgess, N; Donnett, J. G.; Jeffery, K. J.; Maguire, E. A. (1998). "Place cells, navigational accuracy, and the human hippocampus". Philosophical Transactions of the Royal Society B: Biological Sciences. 353 (1373): 1333–40. doi:10.1098/rstb.1998.0287. PMC 1692339. PMID 9770226.

[20] Bures J, Fenton AA, Kaminsky Y, Zinyuk L (7 January 1997). "Place cells and place navigation". Proceedings of the National Academy of Sciences. 94 (1): 343–350. doi:10.1073/pnas.94.1.343. PMC 19339. PMID 8990211.

[Jeffery_2003_201–218-21] Jeffery, Kathryn; Michael Anderson; Robin Hayman; Subhojit Chakraborty (27 October 2003). "A proposed architecture for the neural representation of spatial context". Neuroscience & Biobehavioral Reviews. 28 (2): 201–218. doi:10.1016/j.neubiorev.2003.12.002. PMID 15172764.

[22] Fenton, A. A.; Kao, H. Y.; Neymotin, S. A.; Olypher, A; Vayntrub, Y; Lytton, W. W.; Ludvig, N (2008). "Unmasking the CA1 ensemble place code by exposures to small and large environments: More place cells and multiple, irregularly arranged, and expanded place fields in the larger space". Journal of Neuroscience. 28 (44): 11250–62. doi:10.1523/JNEUROSCI.2862-08.2008. PMC 2695947. PMID 18971467.

[23] O'Keefe, John (1979-01-01). "A review of the hippocampal place cells". Progress in Neurobiology. 13 (4): 419–439. doi:10.1016/0301-0082(79)90005-4. ISSN 0301-0082.

[24] McNaughton, B. L.; Barnes, C. A.; O'Keefe, J. (1983-09-01). "The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats". Experimental Brain Research. 52 (1): 41–49. doi:10.1007/BF00237147. ISSN 1432-1106.

[:4-25] Colgin, Laura Lee; Moser, Edvard I.; Moser, May-Britt (2008-09-01). "Understanding memory through hippocampal remapping". Trends in Neurosciences. 31 (9): 469–477. doi:10.1016/j.tins.2008.06.008. ISSN 0166-2236. PMID 18687478.

[:3-26] Muller, R. U.; Kubie, J. L. (1987). "The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells". The Journal of Neuroscience. 7 (7): 1951–68. doi:10.1523/JNEUROSCI.07-07-01951.1987. PMC 6568940. PMID 3612226.

[27] Latuske, Patrick; Kornienko, Olga; Kohler, Laura; Allen, Kevin (2018-01-04). "Hippocampal Remapping and Its Entorhinal Origin". Frontiers in Behavioral Neuroscience. 11. doi:10.3389/fnbeh.2017.00253. ISSN 1662-5153. PMC 5758554. PMID 29354038.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[:5-28] Anderson, Michael I.; Jeffery, Kathryn J. (2003-10-01). "Heterogeneous Modulation of Place Cell Firing by Changes in Context". Journal of Neuroscience. 23 (26): 8827–8835. doi:10.1523/JNEUROSCI.23-26-08827.2003. ISSN 0270-6474. PMID 14523083.

[29] Deadwyler, Sam A.; Breese, Charles R.; Hampson, Robert E. (1989-09-01). "Control of place-cell activity in an open field". Psychobiology. 17 (3): 221–227. doi:10.1007/BF03337772. ISSN 0889-6313.

[OKeefe1993-30] O'Keefe, J; Recce, M. L. (1993). "Phase relationship between hippocampal place units and the EEG theta rhythm". Hippocampus. 3 (3): 317–30. doi:10.1002/hipo.450030307. PMID 8353611.

[Moser_69–77-31] Moser, Edvard; Kropff, Emilio; Moser, May-Britt (2008-02-19). "Place Cells, Grid Cells, and the Brain's Spatial Representation System". Annual Review of Neuroscience. 31: 69–77. doi:10.1146/annurev.neuro.31.061307.090723. PMID 18284371.

[pmid27760158-32] Kovacs KA, O'Neill J, Schoenenberger P, Penttonen M, Ranguel Guerrero DK, Csicsvari J (19 Nov 2016). "Optogenetically Blocking Sharp Wave Ripple Events in Sleep Does Not Interfere with the Formation of Stable Spatial Representation in the CA1 Area of the Hippocampus". PLOS ONE. 11 (10): e0164675. doi:10.1371/journal.pone.0164675. PMC 5070819. PMID 27760158.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Jeffery_2007_775–785-33] Jeffery, Kathryn (5 July 2007). "Integration of the Sensory Inputs to Place Cells: What, Where, Why, and How?". Hippocampus. 17 (9): 775–785. doi:10.1002/hipo.20322. PMID 17615579.

[34] Moser, Edvard; Kropff, Emilio; Moser, May-Britt (2008-02-19). "Place Cells, Grid Cells, and the Brain's Spatial Representation System". Annual Review of Neuroscience. 31: 69–89. doi:10.1146/annurev.neuro.31.061307.090723. PMID 18284371.

[Zhang_2013-35] Zhang, Sijie; Denise Manahan-Vaughn (5 September 2013). "Spatial Olfactory Learning Contributes to Place Field Formation in the Hippocampus". Cerebral Cortex. 25 (2): 423–432. doi:10.1093/cercor/bht239. PMC 4380081. PMID 24008582.

[Save2000-36] Save, Etienne; Ludek Nerad; Bruno Poucet (23 February 2000). "Contribution of multiple sensory information to place field stability in hippocampal place cells". Hippocampus. 10 (1): 64–76. doi:10.1002/(SICI)1098-1063(2000)10:1<64::AID-HIPO7>3.0.CO;2-Y. PMID 10706218.

[Radvansky_2018-37] Radvansky, Brad; Daniel Dombeck (26 February 2018). "An olfactory virtual reality system for mice". Nature Communications. 9 (1): 839. doi:10.1038/s41467-018-03262-4. PMC 5827522. PMID 29483530.

[Rolls_2013_74-38] ^ ^a ^b ^c ^d ^e ^f ^g Rolls, Edmund T. (2013). "The mechanisms for pattern completion and pattern separation in the hippocampus". Frontiers in Systems Neuroscience. 7: 74. doi:10.3389/fnsys.2013.00074. PMC 3812781. PMID 24198767.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Smith_2006_716–729-39] Smith, David; Sheri Mizumori (10 June 2006). "Hippocampal Place Cells, Context, and Episodic Memory". Hippocampus. 16 (9): 716–729. CiteSeerX 10.1.1.141.1450. doi:10.1002/hipo.20208. PMID 16897724.

[40] Nakazawa, Kazu; Thomas McHugh; Matthew Wilson; Susumu Tonegawa (May 2004). "NMDA Receptors, Place Cells and Hippocampal Spatial Memory". Nature Reviews Neuroscience. 5 (5): 368–369. doi:10.1038/nrn1385. PMID 15100719.

[41] Diba, Kamran; Buzsáki, György (2007-10). "Forward and reverse hippocampal place-cell sequences during ripples". Nature neuroscience. 10 (10): 1241–1242. doi:10.1038/nn1961. ISSN 1097-6256. PMC 2039924. PMID 17828259. {{cite journal}}: Check date values in: |date= (help)

[42] Nadel, Lynn (3 July 1991). "The Hippocampus and Space Revisited". Hippocampus. 1 (3): 221–229. CiteSeerX 10.1.1.622.87. doi:10.1002/hipo.450010302. PMID 1669368.

[Matthews2000-43] ^ ^a ^b ^c ^d ^e ^f Matthews, Douglas B.; Morrow, Leslie A. (23 February 2000). "Effects of acute and chronic ethanol exposure on spatial cognitive processing and hippocampal function in the rat". Hippocampus. 10 (1): 122–130. doi:10.1002/(SICI)1098-1063(2000)10:1<122::AID-HIPO13>3.0.CO;2-V.

[44] Givens, Bennet (1 June 1995). "Low doses of ethanol impair spatial working memory and reduce hippocampal theta activity". Alcoholism: Clinical and Experimental Research. 19 (3): 763–767. doi:10.1111/j.1530-0277.1995.tb01580.x. ProQuest 618978482.

[45] White, Aaron, M.; Simson, P. E.; Best, Phillip J. (1 October 1997). "Comparison between the effects of ethanol and diazepam on spatial working memory in the rat". Psychopharmacology. 133 (3): 256–261. doi:10.1007/s002130050399. PMID 9361331. ProQuest 619216070.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Smith-Darlington2009-46] Smith, Paul F.; Darlington, Cynthia L.; Zheng, Yiwen (29 April 2009). "Move it or lose it—Is stimulation of the vestibular system necessary for normal spatial memory?". Hippocampus. 20 (1): 36–43. doi:10.1002/hipo.20588. PMID 19405142.

[47] Delpolyi, AR; Rankin, K; Mucke, L; Miller, BL; Gorno-Tempini, ML (4 September 2007). "Spatial cognition and the human navigation network in AD and MCI". Neurology. 69 (10): 1986–1997. doi:10.1212/01.wnl.0000271376.19515.c6. PMID 17785667.

[Moser_2008_69–89-48] Moser, Edvard I; Kropff, Emilo; Moser, May-Britt (19 February 2008). "Place Cells, Grid Cells, and the Brain's Spatial Representation System". Annual Review of Neuroscience. 31: 69–89. doi:10.1146/annurev.neuro.31.061307.090723. PMID 18284371.

[Schimanski2010-49] ^ ^a ^b ^c ^d ^e ^f Schimanski, Lesley, A.; Barnes, Carol A. (6 August 2010). "Neural protein synthesis during aging: effects on plasticity and memory". Frontiers in Aging Neuroscience. 2: 1. doi:10.3389/fnagi.2010.00026. PMC 2928699. PMID 20802800.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

[50] Pawluski, Jodi L.; Brummelte, Susanne; Barha, Cindy K.; Crozier, Tamara M.; Galea, Liisa A.M. (3 August 2009). "Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging". Frontiers in Neuroendocrinology. 30 (3): 343–357. doi:10.1016/j.yfrne.2009.03.007. PMID 19361542.

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@@ Line 17: / Line 17: @@
 There has been much debate as to whether hippocampal place cells function depends on [[landmark]]s in the environment, on environmental boundaries, or on an interaction between the two.<ref>{{cite journal|last=Lew|first=Adena R.|title=Looking beyond the boundaries: Time to put landmarks back on the cognitive map?|journal=Psychological Bulletin|date=7 February 2011|volume=137|issue=3|pages=484–507|doi=10.1037/a0022315|pmid=21299273}}</ref> Additionally, not all place cells rely on the same external cues. One important distinction in cues is local and distal, where local cues appear in the immediate vicinity of a subject, whereas distal cues are far away, and act more like landmarks. Individual place cells have been shown to follow either or rely on both.<ref>{{Cite journal|last=Knierim|first=James J.|date=2002-07-15|title=Dynamic Interactions between Local Surface Cues, Distal Landmarks, and Intrinsic Circuitry in Hippocampal Place Cells|url=https://www.jneurosci.org/content/22/14/6254|journal=Journal of Neuroscience|language=en|volume=22|issue=14|pages=6254–6264|doi=10.1523/JNEUROSCI.22-14-06254.2002|issn=0270-6474|pmid=12122084}}</ref> Additionally, the cues on which the place cells rely may depend on previous experience of the subject and the saliency of the cue.<ref>{{Cite journal|last=Scaplen|first=Kristin M.|last2=Gulati|first2=Arune A.|last3=Heimer-McGinn|first3=Victoria L.|last4=Burwell|first4=Rebecca D.|date=2014-11|title=When do objects become landmarks? Hippocampal place cells respond differently to manipulations of visual cues depending on size, perspective, and experience|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615844/|journal=Hippocampus|volume=24|issue=11|pages=1287–1299|doi=10.1002/hipo.22331|issn=1050-9631|pmc=5615844|pmid=25045010}}</ref>
-There has also been much debate as to whether hippocampal pyramidal cells truly encode non-spatial information as well as spatial information. According to the cognitive map theory, the hippocampus's primary role is to store spatial information through place cells and the hippocampus was biologically designed to provide a subject with spatial information.<ref name="okeefe1999">{{cite journal|last=O'Keefe|first=John|title=Do hippocampal pyramidal cells signal non-spatial as well as spatial information?|journal=Hippocampus|date=3 September 1999|volume=9|issue=4|pages=352–364|doi=10.1002/(SICI)1098-1063(1999)9:4<352::AID-HIPO3>3.0.CO;2-1}}</ref> Recent findings, such as a study showing that place cells respond to non-spatial dimensions, such as sound frequency, disagree with the cognitive map theory.<ref name=":6">{{Cite journal|last=Aronov|first=Dmitriy|last2=Nevers|first2=Rhino|last3=Tank|first3=David W.|date=2017-03-29|title=Mapping of a non-spatial dimension by the hippocampal/entorhinal circuit|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492514/|journal=Nature|volume=543|issue=7647|pages=719–722|doi=10.1038/nature21692|issn=0028-0836|pmc=5492514|pmid=28358077|via=}}</ref> Instead, they support a new theory saying that the hippocampus has a more general function encoding continuous variables, and location just happens to be one of those variables.<ref name=":6" /> Another non-spatial explanations of hippocampal functioning suggests that the hippocampus simply performs clustering of inputs.<ref>{{Cite journal|last=Mok|first=Robert M.|last2=Love|first2=Bradley C.|date=2019-12-12|title=A non-spatial account of place and grid cells based on clustering models of concept learning|url=https://www.nature.com/articles/s41467-019-13760-8|journal=Nature Communications|language=en|volume=10|issue=1|pages=1–9|doi=10.1038/s41467-019-13760-8|issn=2041-1723}}</ref>
+There has also been much debate as to whether hippocampal pyramidal cells truly encode non-spatial information as well as spatial information. According to the cognitive map theory, the hippocampus's primary role is to store spatial information through place cells and the hippocampus was biologically designed to provide a subject with spatial information.<ref name="okeefe1999">{{cite journal|last=O'Keefe|first=John|title=Do hippocampal pyramidal cells signal non-spatial as well as spatial information?|journal=Hippocampus|date=3 September 1999|volume=9|issue=4|pages=352–364|doi=10.1002/(SICI)1098-1063(1999)9:4<352::AID-HIPO3>3.0.CO;2-1}}</ref> Recent findings, such as a study showing that place cells respond to non-spatial dimensions, such as sound frequency, disagree with the cognitive map theory.<ref name=":6">{{Cite journal|last=Aronov|first=Dmitriy|last2=Nevers|first2=Rhino|last3=Tank|first3=David W.|date=2017-03-29|title=Mapping of a non-spatial dimension by the hippocampal/entorhinal circuit|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492514/|journal=Nature|volume=543|issue=7647|pages=719–722|doi=10.1038/nature21692|issn=0028-0836|pmc=5492514|pmid=28358077|via=}}</ref> Instead, they support a new theory saying that the hippocampus has a more general function encoding continuous variables, and location just happens to be one of those variables.<ref name=":6" />This fits in with the idea that the hippocampus has a predictive function.<ref>{{Cite journal|last=Stachenfeld|first=Kimberly L.|last2=Botvinick|first2=Matthew M.|last3=Gershman|first3=Samuel J.|date=2017|title=The hippocampus as a predictive map|url=https://www.nature.com/articles/nn.4650|journal=Nature Neuroscience|language=en|volume=20|issue=11|pages=1643–1653|doi=10.1038/nn.4650|issn=1546-1726|via=}}</ref> Another non-spatial explanations of hippocampal functioning suggests that the hippocampus simply performs clustering of inputs.<ref>{{Cite journal|last=Mok|first=Robert M.|last2=Love|first2=Bradley C.|date=2019-12-12|title=A non-spatial account of place and grid cells based on clustering models of concept learning|url=https://www.nature.com/articles/s41467-019-13760-8|journal=Nature Communications|language=en|volume=10|issue=1|pages=1–9|doi=10.1038/s41467-019-13760-8|issn=2041-1723}}</ref>
 Place cells fire in different, often widespread, hippocampal locations at the same time, which some interpret as their having different functions in different locations. A rat's representation of its environment is constructed by the firing of groups of place cells that are widely distributed in the hippocampus, however, this does not necessarily mean that each location serves a different purpose. When recording the firing fields of certain hippocampal cells in an open field environment, firing fields prove to be similar even when the rat travels in different directions, exhibiting [[wikt:omnidirectional|omnidirectional]]ity. However, when limitations are placed in the aforementioned environment, fields prove to be directional and fire in one direction but not in another.