Place cell, Head direction cell, Grid cell, Border cells

9:53 AM | BY ZeroDivide EDIT
Spatial firing patterns of 8 place cells recorded from the CA1 layer of a rat. The rat ran back and forth along an elevated track, stopping at each end to eat a small food reward. Dots indicate positions where action potentials were recorded, with color indicating which neuron emitted that action potential.
A place cell is a type of pyramidal neuron within the hippocampus that becomes active when the animal enters a particular place in the environment; this place is known as the place field. A given place cell will have only one, or a few, place fields in a typical small laboratory environment, but more in a larger region.[1] There is no apparent topography to the pattern of place fields, unlike other brain areas such as visual cortex - neighboring place cells are as likely to have distant fields as neighboring ones.[2] In a different environment, typically about half the place cells will still have place fields, but these will be in new places unrelated to their former locations.[3]
The place cells are thought, collectively, to act as a cognitive representation of a specific location in space, known as a cognitive map.[4] Place cells work with other types of neurons in the hippocampus and surrounding regions to perform this kind of spatial processing.[5] but the ways in which they function within the hippocampus are still being researched.[6]
Studies with rats have shown that place cells tend to fire quickly when a rat enters a new, open environment, however outside of a firing field, place cells tend to be relatively inactive.[7] Together place cells are thought to form a "cognitive map" in which they have localized firing patterns called place fields.[8]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 “re-mapping” and 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."[8]
Although place cells are part of a non-sensory cortical system, their firing behavior is strongly correlated to sensory input. Place cells fire when an animal is located in parts of the environment known as place fields.[9] These circuits may have important implications for memory, as they provide the spatial context for memories and past experiences.[9] 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.[9]
The 2014 Nobel Prize in Physiology or Medicine was awarded in part to John O'Keefe for the discovery of place cells.[10]

Background[edit]

These cells were first discovered in the brain, and specifically in the hippocampus, by O’Keefe and Dostrovsky (1971).[11] Though the hippocampus plays a role in learning and memory, the existence of place cells within the hippocampus demonstrates the role it plays with spatial adaptation and awareness. There have been recorded increases in firing patterns of rats in open environments and recorded spatial learning and awareness impairments after damage to the hippocampus and the place cells within.[11] Studies with rats have shown that place cells are very responsive to spatial surroundings. For example a study by John O'Keefe and Lynn Nadel found that space cells would fire more rapidly when rats ran past places in the environment. when a new item was added to the environment, or when an item that is usually there is not present.[12]
After O'Keefe and Dostrovsky first found the existence of place cells within the hippocampus in 1971, they conduced a study five years later with rats that demonstrated these place cells would fire whenever the rat was within a certain place in the environment.[13] This was one of the first indicators that place cells were related to spatial orientation. They also discovered that space cells fired in different areas of the hippocampus depending on where the rat went, and this whole firing network made up the rat’s environment (O’Keefe 1976, Wilson & McNaughton 1993). As environments changed, the same place cells would fire, but the relationship and dynamic between firing fields would change (O’Keefe & Conway 1978). Therefore place cells are thought to give humans and animals a guide to the environment it is navigating and its position in that environment. Place cells are generally observed through recorded action potentials. As humans or animals navigate large environments and then arrive at a particular location, there is a notable increase in the place cell firing rate once that specific location has been reached (Eichenbaum, Dudchencko Wood, Shaprio and Tanila, 1999). For more information on studies with rats, "Place Cells and Aging".
There has been much debate as to whether hippocampal place cells function based upon landmarks in the environment or on environmental boundaries or an interaction between the two.[14] There has also been much study as to whether hippocampal pyramidal cells (mostly in rats) signal non-spatial information as well as spatial information. According to the cognitive map theory, the hippocampus's primary role in the rat is to store spatial information through place cells and the rat hippocampus was biologically designed to provide the rat with spatial information.[15]
However, there have been investigations as to whether the hippocampus may store other non-spatial information as well.[15] These other explanations in favor of non-spatial components of the hippocampus argue that the hippocampus has "flexible" functions in that it can apply memory in circumstances different from those under which these relationships were learned. There are also views that claim that the hippocampus has functions altogether removed from time and space.[15] However, other explanations of data that prematurely support the existence of non-spatial functions in the hippocampus must be considered. Evidence against this flexibility theory comes in the form of using the delayed non-match-to sample task. This task uses flexibility in that the rat is first presented with a visual representation such as a block. After a delay, when presented with the block and a novel object, the rat must choose the novel object in order to obtain a reward. Its completion of this task requires flexibility. However, during this task, hippocampal activity does not sufficiently increase and lesioning (induced trauma) in the hippocampus does not change the rat's performance on this task.[15]
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]
There are both simple place cells with purely locational correlates and also complex place cells that increase their firing rate when the rat encounters a particular object or experience. Others fire when a rat's expectations in a particular location are not met or when they encounter novelty along their path: the cells that fire in these situations are known as misplace cells.
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.

Function[edit]

Place fields[edit]

Place cells fire in a specific region 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. A good depiction of place fields can be seen here[16] This animation shows place fields firing in succession as a rat moves along a linear track. Place fields are thus considered to be allocentric rather than egocentric, 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.[17]

Sensory input[edit]

Place cells were initially believed to fire in direct relation to simple sensory inputs, but recent studies suggest that this may not be the case.[17] 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.[18]This suggests that place cells respond to complex stimuli rather than simple individual sensory cues. According to a model known as the functional differentiationmodel, 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.[17]
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.[19] 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.[19]

Visuospatial cues[edit]

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.[19] 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.[20] 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.[19] Visual sensory inputs can also supply important contextual information. A change in color of a specific object can affect whether or not a place field fires in a particular environment.[19] Thus, visuospatial sensory information is critical to the formation and recollection of place field.

Olfactory cues[edit]

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.[21][22] 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.[21] 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.[22] 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.

Hippocampal memory[edit]

The hippocampus plays an essential role in episodic memory.[23] One important aspect of episodic memory is the spatial context in which the event occurred.[24] 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.[25] 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.[24] By establishing spatial context, place cells can be used to complete memory patterns.[23] 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.[24] Place cells are therefore considered to demonstrate both pattern completion and pattern separation qualities.[23]

Pattern completion[edit]

Pattern completion is the ability to recall an entire memory from a partial or degraded sensory cue.[23] 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.[18] 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.[23]

Pattern separation[edit]

Pattern separation is the ability to differentiate one memory from other stored memories.[18] Pattern separation begins in the dentate gyrus, a section of the hippocampus involved in memory formation and retrieval.[23] Granule cells in the dentate gyrus process sensory information using competitive learning, and relay a preliminary representation to form place fields.[23] 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.[18]

Reactivation, replay, and preplay[edit]

Main article: Hippocampal Replay
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. This phenomenon, termed preplay, may have a role in prediction and learning.

Abnormalities[edit]

Effects of ethanol[edit]

The hippocampus and related structures use place cells to construct a cognitive map of their surroundings in order to guide and inform their behavior.[26][27] Just as lesioning in these structures causes rats to rely on cue-based information to function, so too does chronic ethanol exposure.[28] Place cell firing rate decreases dramatically after ethanol exposure, causing reduced spatial sensitivity.[28]
Studies have shown ethanol to impair both spatial long-term memory and spatial working memory in various tasks.[28][29][30] 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/protein expression in the hippocampus is unknown.[28] 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.[28]
Future research should investigate whether chronic ethanol exposure produces a functional tolerance to ethanol’s effects and whether there is specificity of place cell firing during the formation of this tolerance. Research should also be done on whether chronic ethanol exposure produces a tolerance to other abused drugs with similar addictive properties. 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 drugs in addition to ethanol tolerance.[28]

Effects of vestibular lesioning[edit]

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 asacceleration. 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.[31] 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.[31]

Diseases[edit]

Problems with spatial memory and navigation are thought to be one of the early indications of Alzheimer’s Disease.[32] 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.[13] 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."[13]

Aging[edit]

Place cell function changes with age. Pharmaceuticals that target pathways involved in protein synthesis increase place cell functioning in senescence.[33] 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 CA2hippocampal regions, these reduced levels causing spatial learning deficits.[33]
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.[33]
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.[33] 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, wheraes different place fields in young rats would fire in similar environments because they would pick up on subtle differences in these environments.[33] It is evident that pharmaceuticals such as Memantine can have a significant effect in mediating the age-related decline in place field plasticity.[33]
Interestingly, 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.[34]

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  34. Jump up^ 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. Retrieved 10 November 2013.
 Grid cell topology.
Trajectory of a rat through a square environment is shown in black. Red dots indicate locations at which a particular entorhinal grid cell fired.
A grid cell is a type of neuron in the brains of many species that allows them to understand their position in space.[1][2][3][4][5][6]
Grid cells derive their name from the fact that connecting the centers of their firing fields gives a triangular grid.
Triangular grids of synchronized neurons were predicted by William H. Calvin in his 1996 monograph The Cerebral Code on the basis of recurrent collateral branches in neocortical pyramidal neurons that had synaptic clusters at a standard spacing.[7] Grid cells were discovered in 2005 by Edvard Moser, May-Britt Moser and their students Torkel Hafting, Marianne Fyhn and Sturla Molden at the Centre for the Biology of Memory (CBM) in Norway. They were awarded the 2014 Nobel Prize in Physiology or Medicine together with John O'Keefe for their discoveries of cells that constitute a positioning system in the brain. The arrangement of spatial firing fields all at equal distances from their neighbors led to a hypothesis that these cells encode a cognitive representation of Euclidean space.[1] The discovery also suggested a mechanism for dynamic computation of self-position based on continuously updated information about position and direction.
In a typical experimental study, an electrode capable of recording the activity of an individual neuron is implanted in the cerebral cortex of a rat, in a section called the dorsomedial entorhinal cortex, and recordings are made as the rat moves around freely in an open arena. For a grid cell, if a dot is placed at the location of the rat's head every time the neuron emits an action potential, then as illustrated in the adjoining figure, these dots build up over time to form a set of small clusters, and the clusters form the vertices of a grid of equilateral triangles. This regular triangle-pattern is what distinguishes grid cells from other types of cells that show spatial firing. By contrast, if a place cell from the rat hippocampus is examined in the same way (i.e., by placing a dot at the location of the rat's head whenever the cell emits an action potential), then the dots build up to form small clusters, but frequently there is only one cluster (one "place field") in a given environment, and even when multiple clusters are seen, there is no perceptible regularity in their arrangement.

Background[edit]

In 1971, John O'Keefe and Jonathon Dostrovsky reported the discovery of place cells in the rat hippocampus — cells that fire action potentials when an animal passes through a specific small region of space, which is called the place field of the cell.[8] This discovery, although controversial at first, led to a series of investigations that culminated in the 1978 publication of a book by O'Keefe and his colleague Lynn Nadel called The Hippocampus as a Cognitive Map[9] — the book argued that the hippocampal neural network instantiates cognitive maps as hypothesized by the psychologist Edward C. Tolman. This theory aroused a great deal of interest, and motivated hundreds of experimental studies aimed at clarifying the role of the hippocampus in spatial memory and spatial navigation.
Because the entorhinal cortex provides by far the largest input to the hippocampus, it was clearly important to understand the spatial firing properties of entorhinal neurons. The earliest studies, such as Quirk et al. (1992), described neurons in the entorhinal cortex as having relatively large and fuzzy place fields.[10] The Mosers, however, thought it was possible that a different result would be obtained if recordings were made from a different part of the entorhinal cortex. The entorhinal cortex is a strip of tissue running along the back edge of the rat brain from the ventral to the dorsal sides. Anatomical studies had shown that different sectors of the entorhinal cortex project to different levels of the hippocampus: the dorsal end of the EC projects to the dorsal hippocampus, the ventral end to the ventral hippocampus.[11] This was relevant because several studies had shown that place cells in the dorsal hippocampus have considerably sharper place fields than cells from more ventral levels.[12] Every study of entorhinal spatial activity prior to 2004, however, had made use of electrodes implanted near the ventral end of the EC. Accordingly, together with Marianne Fyhn, Sturla Molden and Menno Witter, the Mosers set out to examine spatial firing from the different dorsal-to-ventral levels of the entorhinal cortex. They found that in the dorsal part of medial entorhinal cortex (MEC), cells had sharply defined place fields like in the hippocampus but the cells fired at multiple locations.[13] The arrangement of the firing fields showed hints of regularity, but the size of the environment was too small for spatial periodicity to be visible in this study.
The next set of experiments, reported in 2005, made use of a larger environment, which led to the recognition that the cells were actually firing in a hexagonal grid pattern.[1] The study showed that cells at similar dorsal-to-ventral MEC levels had similar grid spacing and grid orientation but the phase of the grid (the offset of the grid vertices relative to the x and y axes) appeared to be randomly distributed between cells. The periodic firing pattern was expressed independently of the configuration of landmarks, in darkness as well as in the presence of visible landmarks and independently of changes in the animal’s speed and direction, leading the authors to suggest that grid cells expressed a path-integration dependent dynamic computation of the animal’s location.
In 2014 John O'Keefe, May-Britt Moser, and Edvard Moser were awarded the Nobel Prize in Physiology or Medicine for their discoveries of grid cells.

Properties[edit]

Spatial autocorrelogram of the neuronal activity of the grid cell from the first figure.
Grid cells are neurons that fire when a freely moving animal traverses a set of small regions (firing fields) which are roughly equal in size and arranged in a periodic triangular array that covers the entire available environment.[1] Cells with this firing pattern have been found in all layers of the dorsocaudal medial entorhinal cortex (dMEC), but cells in different layers tend to differ in other respects. Layer II contains the largest density of pure grid cells, in the sense that they fire equally regardless of the direction in which an animal traverses a grid location. Grid cells from deeper layers are intermingled with conjunctive cells[14] and head direction cells (i.e. in layers III, V and VI there are cells with a grid-like pattern that fire only when the animal is facing a particular direction).[15]
Grid cells that lie next to one another (i.e., cells recorded from the same electrode) usually show the same grid spacing and orientation, but their grid vertices are displaced from one another by apparently random offsets. Cells recorded from separate electrodes at a distance from one another, however, frequently show different grid spacings. Cells that are located more ventrally (that is, farther from the dorsal border of the MEC) generally have larger firing fields at each grid vertex, and correspondingly greater spacing between the grid vertices.[1] The total range of grid spacings is not well established: the initial report described a roughly twofold range of grid spacings (from 39 cm to 73 cm) across the dorsalmost part (upper 25%) of the MEC,[1] but there are indications of considerably larger grid scales in more ventral zones. Brun et al. (2008) recorded grid cells from multiple levels in rats running along an 18 meter track, and found that the grid spacing expanded from about 25 cm in their dorsalmost sites to about 3 m at the ventralmost sites.[16] These recordings only extended 3/4 of the way to the ventral tip, so it is possible that even larger grids exist.
Grid cell activity does not require visual input, since grid patterns remain unchanged when all the lights in an environment are turned off.[1] When visual cues are present, however, they exert strong control over the alignment of the grids: Rotating a cue card on the wall of a cylinder causes grid patterns to rotate by the same amount.[1] Grid patterns appear on the first entrance of an animal into a novel environment, and usually remain stable thereafter.[1] When an animal is moved into a completely different environment, grid cells maintain their grid spacing, and the grids of neighboring cells maintain their relative offsets.[1]

Interactions with hippocampal place cells[edit]

When a rat is moved to a different environment, the spatial activity patterns of hippocampal place cells usually show "complete remapping" — that is, the pattern of place fields reorganizes in a way that bears no detectable resemblance to the pattern in the original environment (Muller and Kubie, 1987).[17] If the features of an environment are altered less radically, however, the place field pattern may show a lesser degree of change, referred to as "rate remapping", in which many cells alter their firing rates but the majority of cells retain place fields in the same locations as before. Fyhn et al. (2007) examined this phenomenon using simultaneous recordings of hippocampal and entorhinal cells, and found that in situations where the hippocampus shows rate remapping, grid cells show unaltered firing patterns, whereas when the hippocampus shows complete remapping, grid cell firing patterns show unpredictable shifts and rotations.[18]

Theta rhythmicity[edit]

Neural activity in nearly every part of the hippocampal system is modulated by the limbic theta rhythm, which has a frequency range of about 6–9 Hz in rats. The entorhinal cortex is no exception: like the hippocampus, it receives cholinergic and GABAergic input from the medial septal area, the central controller of theta. Grid cells, like hippocampal place cells, show strong theta modulation.[1] Grid cells from layer II of the MEC also resemble hippocampal place cells in that they show phase precession—that is, their spike activity advances from late to early phases of the theta cycle as an animal passes through a grid vertex. Most grid cells from layer III do not precess, but their spike activity is largely confined to half of the theta cycle. The grid cell phase precession is not derived from the hippocampus, because it continues to appear in animals whose hippocampus has been inactivated by an agonist of GABA.[19]

Possible functions[edit]

Many species of mammals can keep track of spatial location even in the absence of visual, auditory, olfactory, or tactile cues, by integrating their movements—the ability to do this is referred to in the literature as path integration. A number of theoretical models have explored mechanisms by which path integration could be performed by neural networks. In most models, such as those of Samsonovich and McNaughton (1997)[20] or Burak and Fiete (2009),[21] the principal ingredients are (1) an internal representation of position, (2) internal representations of the speed and direction of movement, and (3) a mechanism for shifting the encoded position by the right amount when the animal moves. Because cells in the MEC encode information about position (grid cells[1]) and movement (head direction cells and conjunctive position-by-direction cells[15]), this area is currently viewed as the most promising candidate for the place in the brain where path integration occurs. However, the question remains unresolved, as in humans the entorhinal cortex does not appear to be required for path integration.[22] Burak and Fiete (2009) showed that a computational simulation of the grid cell system was capable of performing path integration to a high level of accuracy.[21] However, more recent theoretical work has suggested that grid cells might perform a more general denoising process not necessarily related to spatial processing.[23]
Hafting et al. (2005) suggested that a place code is computed in the entorhinal cortex and fed into the hippocampus, which may make the associations between place and events that are needed for the formation of memories.
In contrast to a hippocampal place cell, a grid cell has multiple firing fields, with regular spacing, which tessellate the environment in a hexagonal pattern. The unique properties of grid cells are as follows:
A hexagonal lattice.
  1. Grid cells have firing fields dispersed over the entire environment (in contrast to place fields which are restricted to certain specific regions of the environment)
  2. The firing fields are organized into a hexagonal lattice
  3. Firing fields are generally equally spaced apart, such that the distance from one firing field to all six adjacent firing fields is approximately the same (though when an environment is resized, the field spacing may shrink or expand differently in different directions; Barry et al. 2007)
  4. Firing fields are equally positioned, such that the six neighboring fields are located at approximately 60 degree increments
The grid cells are anchored to external landmarks, but persist in darkness, suggesting that grid cells may be part of a self-motion based map of the spatial environment.
Boundary cells (also known as border cells or boundary vector cells) are neurons found in the hippocampal formation that respond to the presence of an environmental boundary at a particular distance and direction from an animal. The existence of cells with these firing characteristics were first predicted on the basis of properties of place cells. Boundary cells were subsequently discovered in several regions of the hippocampal formation: the subiculum, presubiculum and entorhinal cortex.
Firing of a boundary cell recorded in rat subiculum in 1 x 1 metre square-walled box with 50 cm-high walls. A 50 cm-long barrier inserted into box elicits second field along north side of barrier in addition to original field along south wall. Left: Firing rate map, one of 5 colours in locational bin indicates spatially-smoothed firing rate in that bin (autoscaled to firing rate peak, dark blue: 0-20%; light blue: 20-40%; green: 40-60%; yellow: 60-80%; red: 80-100%. The maximum firing rate is 14.2 Hz). Right: path taken by rat is shown in black, locations where spikes were recorded indicated by green squares.
O'Keefe and Burgess[1] had noted that the firing fields of place cells, which characteristically respond only in a circumscribed area of an animal's environment, tended to fire in 'corresponding' locations when the shape and size of the environment was altered. For example, a place cell that fired in the northeastern corner of a rectangular environment might continue to fire in the northeastern corner when the size of the environment was doubled. To explain these observations, the Burgess and O'Keefe groups developed a computational model[2][3] (Boundary Vector Cell - or BVC - model) of place cells that relied on inputs sensitive to the geometry of the environment to determine where a given place cell would fire in environments of different shapes and sizes. The hypothetical input cells (BVCs) responded to environmental boundaries at particular distances and allocentric directions from the rat.
Separate studies emerging from different research groups identified cells with these characteristics in the subiculum,[4][5] entorhinal cortex[6][7] and pre- and para-subiculum[8] where they were described variously as "BVCs", "boundary cells" and "border cells". These terms are somewhat interchangeable; the critical defining functional characteristics of associated with the different labelling schemes are rather arbitrary and any functional differences in cells found in different anatomical regions are not yet fully clear. For example, neurons classified as "border cells" may include some that fire at short range to any environmental boundary (regardless of direction). Additionally, the BVC model predicted the existence of a small proportion of cells with longer range tunings (i.e., firing parallel to, but at some distance from boundaries) and few such cells have been described to date. In general, although the general predictions of the BVC model regarding the existence of geometric boundary sensitive inputs were confirmed by the empirical observations it prompted, the more detailed characteristics such as the distribution of distance and direction tunings remain to be determined.
In medial entorhinal cortex border/boundary cells comprise about 10% of local population, being intermingled with grid cells and head direction cells. During development MEC border cells (and HD cells but not grid cells) show adult-like firing fields as soon as rats are able to freely explore their environment at around 16-18 days old. This suggests HD and border cells, rather than grid cells, provide the first critical spatial input to hippocampal place cells.[9]

See also[edit]

See also[edit]

Head direction (HD) cells are neurons present in the brains of many mammals, which increase their firing rates above baseline levels only when the animal's head points in a specific direction. When stimulated, these neurons fire at a steady rate (i.e.—they do not show adaptation), but decrease back to their baseline rates as the animal's head turns away from the preferred direction (usually about 45° away from this direction).[1]
These cells are found in many brain areas, including the post-subiculum, retrosplenial cortex, the thalamus (the anterior and the lateral dorsal thalamic nuclei), lateral mammillary nucleus, dorsal tegmental nucleus, striatum and entorhinal cortex (Sargolini et al., Science, 2006).
The system is related to the place cell system, which is mostly orientation-invariant and location-specific, while HD cells are mostly orientation-specific and location-invariant. However, HD cells do not require a functional hippocampus, where strong place cells are found, to show their head direction specificity. Head direction cells are not sensitive to geomagnetic fields (i.e. they are not "magnetic compass" cells), and are neither purely driven by nor are independent of sensory input. They strongly depend on the vestibular system, and the firing is independent of the position of the animal's body relative to its head.
Some HD cells exhibit anticipatory behaviour: the best match between HD activity and the animal's actual head direction has been found to be up to 95 ms in future. That is, activity of head direction cells predicts, 95 ms in advance, what the animal's head direction will be.

Vestibular influences[edit]

The HD compass is inertial: it continues to operate even in the absence of light. Experiments have shown that the inertial properties are dependent on the vestibular system, especially thesemicircular canals of the inner ear, which respond to rotations of the head. The HD system integrates the vestibular output to maintain a signal of cumulative rotation. The integration is less than perfect, though, especially for slow head rotations. If an animal is placed on an isolated platform and slowly rotated in the dark, the alignment of the HD system usually shifts a little bit for each rotation. If an animal explores a dark environment with no directional cues, the HD alignment tends to drift slowly and randomly over time.

Visual influences[edit]

One of the most interesting aspects of head direction cells is that their firing is not fully determined by sensory features of the environment. When an animal comes into a novel environment for the first time, the alignment of the head direction system is arbitrary. Over the first few minutes of exploration, the animal learns to associate the landmarks in the environment with directions. When the animal comes back into the same environment at a later time, if the head direction system is misaligned, the learned associations serve to realign it.
It is possible to temporarily disrupt the alignment of the HD system, for example by turning out the lights for a few minutes. Even in the dark, the HD system continues to operate, but its alignment to the environment may gradually drift. When the lights are turned back on and the animal can once more see landmarks, the HD system usually comes rapidly back into the normal alignment. Occasionally the realignment is delayed: the HD cells may maintain an abnormal alignment for as long as a few minutes, but then abruptly snap back.
If these sorts of misalignment experiments are done too often, the system may break down. If an animal is repeatedly disoriented, and then placed into an environment for a few minutes each time, the landmarks gradually lose their ability to control the HD system, and eventually, the system goes into a state where it shows a different, and random, alignment on each trial.
There is evidence that the visual control of HD cells is mediated by the postsubiculum. Lesions of the postsubiculum do not eliminate thalamic HD cells, but they often cause the directionality to drift over time, even when there are plenty of visual cues. Thus, HD cells in postsub-lesioned animals behave like HD cells in intact animals in the absence of light. Also, only a minority of cells recorded in the postsubiculum are HD cells, and many of the others show visual responses. In familiar environments, HD cells show consistent preferred directions across time as long as there is a polarizing cue of some sort that allows directions to be identified (in a cylinder with unmarked walls and no cues in the distance, preferred directions may drift over time).

History[edit]

Head direction cells were discovered by James B. Ranck, Jr., in the rat dorsal presubiculum, a structure that lies near the hippocampus on the dorsocaudal brain surface. Ranck reported his discovery in a Society for Neuroscience abstract in 1984. Jeffrey Taube, a postdoctoral fellow working in Ranck's laboratory, made these cells the subject of his research. Taube, Ranck and Bob Muller summarized their findings in a pair of papers in the Journal of Neuroscience in 1990.[2][3] These seminal papers served as the foundation for all of the work that has been done subsequently. Taube, after taking a position at Dartmouth College, has devoted his career to the study of head direction cells, and been responsible for a number of the most important discoveries, as well as writing several key review papers.
The postsubiculum has numerous anatomical connections. Tracing these connections led to the discovery of head direction cells in other parts of the brain. In 1993, Mizumori and Williams reported finding HD cells in a small region of the rat thalamus called the lateral dorsal nucleus.[4] Two years later, Taube found HD cells in the nearby anterior thalamic nuclei.[5] Chen et al. found limited numbers of HD cells in posterior parts of the neocortex.[6] The observation in 1998 of HD cells in the lateral mammillary area of the hypothalamus completed an interesting pattern: the parahippocampus, mammillary nuclei, anterior thalamus, and retrosplenial cortex are all elements in a neural loop called the Papez circuit, proposed by Walter Papez in 1939 as the neural substrate of emotion. Limited numbers of robust HD cells have also been observed in the hippocampus and dorsal striatum. Recently, substantial numbers of HD cells have been found in the medial entorhinal cortex, intermingled with spatially tuned grid cells.
The remarkable properties of HD cells, most particularly their conceptual simplicity and their ability to maintain firing when visual cues were removed or perturbed, led to considerable interest from theoretical neuroscientists. Several mathematical models were developed, which differed on details but had in common a dependence on mutually excitatory feedback to sustain activity patterns: a type of working memory, as it were.[7]

References[edit]

  1. Jump up^ Taube, JS (2007). "The head direction signal: Origins and sensory-motor integration.". Ann. Rev. Neurosci. 30: 181–207. doi:10.1146/annurev.neuro.29.051605.112854. PMID 17341158.
  2. Jump up^ Taube, JS; Muller RU, Ranck JB Jr. (1 February 1990). "Head-direction cells recorded from the postsubiculum in freely moving rats. I. Description and quantitative analysis.". J. Neurosci. 10 (2): 420–435. PMID 2303851.
  3. Jump up^ Taube, JS; Muller, RU; Ranck, JB (February 1990). "Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulations.". J. Neurosci. 10 (2): 436–447. PMID 2303852.
  4. Jump up^ Mizumori, SJ; Williams JD (September 1, 1993). "Directionally selective mnemonic properties of neurons in the lateral dorsal nucleus of the thalamus of rats.". J. Neurosci. 13 (9): 4015–4028.PMID 8366357.
  5. Jump up^ Taube, JS (January 1, 1995). "Head direction cells recorded in the anterior thalamic nuclei of freely moving rats.". J. Neurosci. 15 (1): 70–86. PMID 7823153.
  6. Jump up^ Chen, LL; Lin LH; Green EJ; Barnes CA; McNaughton BL (1994). "Head-direction cells in the rat posterior cortex. I. Anatomical distribution and behavioral modulation.". Exp. Brain Res. 101 (1): 8–23.doi:10.1007/BF00243212. PMID 7843305.
  7. Jump up^ Zhang, K (March 15, 1996). "Representation of spatial orientation by the intrinsic dynamics of the head-direction cell ensemble: a theory.". J. Neurosci. 16 (6): 2112–2126. PMID 8604055.

Additional Reading[edit]

  • Blair, HT; Cho J; Sharp PE (1998). "Role of the lateral mammillary nucleus in the rat head direction circuit: a combined single unit recording and lesion study.". Neuron 21 (6): 1387–1397.doi:10.1016/S0896-6273(00)80657-1. PMID 9883731.
  • For a review on the HD system and place field system, see Muller (1996): “A quarter of a Century of Place Cells”, Sharp et al. (2001): “The anatomical and computational basis of rat HD signal.”

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