User:KerzNeuroscience/sandbox

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 and 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 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.

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. 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. 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.

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.

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, 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 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.

Effects of Vesitbular Lesioning on Place Cell Function

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. 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 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.

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 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. 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.