Place cell

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.

Place cells are a type of neuron located in the hippocampus that play a role in spatial representation and self-location. Although place cells are part of a non-sensory cortical system, their firing behavior is strongly correlated to sensory input. Place cells fire in circuits known as place fields, which act as internal spatial representations of an environment. These circuits may have important implications for memory, as they provide the spatial context for memories and past experiences. 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 .

Table of Contents

Background

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. 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. The rat hippocampus was biologically designed to provide the rat with spatial information.

However, there have been investigations as to whether the hippocampus may store other non-spatial information as well. 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. 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. It must then choose that same visual representation during a choice phase. But it must go further than that: in order to obtain a reward, it must choose the representation that is different from what was presented. Its completion of this task requires flexibility. However, during this task, hippocampal activity does not sufficiently increase and lesioning in the hippocampus does not does not change the rat's performance on this task.

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.

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.

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. Lesioning experiments attempting to inflict non-spatial memory deficits in the hippocampus have either failed to induce a deficit or induce a deficit using lesioning methods that affect more than just the hippocampus. 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 into account spatial components.

Place Fields

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. 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.

Sensory Input

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. 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. This suggests that place cells respond to complex stimuli rather than simple individual sensory cues. According to a model known as the functional differentiation 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 .

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 . 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 .

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.. 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. 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. 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. 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 . 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. 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. 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

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

Pattern Completion

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

Pattern Separation

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

Abnormalities in Place Cell Function

Effects of Ethanol on Place Cell Function

The hippocampus and related structures use place cells to construct a cognitive map of their surroundings in order to guide and inform their behavior. Just as lesioning in these structures causes rats to rely on cue-based information to function, so too does chronic ethanol exposure. Place cell firing rate decreases dramatically after ethanol exposure, causing reduced spatial sensitivity. Interestingly, studies have shown that repeated exposure to ethanol leads to a similar shift in the rat's needing to rely on non-spatial information to assess its surroundings. The behavior following repeated ethanol exposure can be explained, in part, by changes at a cellular level.

Ethanol greatly alters the firing of hippocampal place cells. Studies have proven ethanol to impair both spatial long-term memory and spatial working memory in various tasks. 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 and before testing on tasks, 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. 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.

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 properties.

Effects of Vesitbular Lesioning on Place Cell Function

Varying vestibular system stimulation has an effect on place cells. The vestibular system of the 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. 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.

Place Cells and Aging

Place cell function changes with age. Pharmaceuticals that target pathways involved in protein synthesis increase place cell functioning in senescence. Frequency of protein translation changes as animals age. A factor that aids in transctiption, 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.

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.

Place field properties are similar between young and aged rats in the CA1 hippocampal region: rate of firing and spike characteristics (such as amplitutde 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. 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. (9) It is evident that pharmaceuticals such as Memantine can have a significant effect in mediating the age-related decline in place field plasticity.

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.

References

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