Spatial Memory in Rodents and Humans

Spatial Memory

• In order to effectively navigate through the world, forage for food, avoid danger, and seek shelter,
all animals rely on the crucial brain processes that constitute spatial memory.

• Spatial memory allows us to remember routes to make our way through an ever-changing
environment as well as the locations of items within this dynamic environment.

• When spatial memory is disrupted, we aren’t able to form representations of space from
landmarks that aid in goal-directed behavior, nor are we able to orient ourselves and our passage
through space in relation to our surroundings.

• Spatial memory has representations in short term and long term memory. This system is used
for the temporary storage, maintenance, and manipulation of spatial information over short time
intervals. For rodents, this is temporary spatial information indicating, for instance, that a certain
maze arm is not baited, which will not be relevant in the next trial.

• On the other hand, spatial reference memory refers to spatial information that has been
consolidated and is maintained for long time periods. For instance, this may refer to the trial-
independent locations where food may be found in a maze.

• In rodent experiments, spatial working memories are formed within a single, specific trial which
could last from seconds to minutes, while spatial reference memories are created over a
succession of trials from the constant circumstances of the task and may last days, weeks, or even
longer.

• Spatial working memory is commonly assessed using the Corsi block tapping test in humans and
alternation tasks such as the T-maze or Y-maze in rodents. Spatial reference memory can be
assessed with water mazes such as the Morris Water Maze in rodents and using virtual reality
environments in humans. The radial arm maze can be used to evaluate both spatial working and
reference memory in rodents.

• The study of spatial memory in animals has led to important translational findings in humans due to
the straightforward spatial paradigm used between all model species.
Brain Regions Associated with Spatial Memory

• As animals navigate the world, multiple sensory inputs are combined into a seamless whole that
forms a spatial representation of the surroundings.

• The hippocampal formation is a network of key brain regions involved in forming this coherent
representation of external space.

• The hippocampal formation is located bilaterally in the medial temporal lobe, encompassing
the hippocampus, the dentate gyrus, and the subicular cortex.

1. The Hippocampus

• John O’Keefe was the first researcher to recognize that the hippocampus proper encodes a
multisensory representation of the spatial environment. Many rodent studies utilizing mazes
have later confirmed its importance in spatial navigation and processing. When the
hippocampus is lesioned, rats have an impaired ability to navigate to rewards or remember
specific locations.

• The hippocampus contains place cells, which are neurons that fire in relation to the animal’s
position in space. In this way, the brain reduces its surroundings to small, overlapping areas in
the environment called place fields. These place fields form a mosaic that is represented by the
firing of specific place cells in the hippocampus.
• The activity of hippocampal cells, specifically in the CA3 region of the hippocampus, is also
informed by environmental context, so that specific spatial cues can activate the entire neural
ensemble encoding the spatial memory.

The spatial map constructed by the coordinated firing of place cells is “learned” in a matter of
minutes once the animal has navigated a new environment. Modulatory processes like attention
further contribute to the long-term stability of these maps.

• When the hippocampus is lesioned or plasticity is inhibited, problems with spatial navigation
and goal-directed behavior result. Lesions to the dorsal hippocampus create deficits in the
retrieval and processing of short-term memory and disrupt the encoding of long-lasting spatial
representations.

Indeed, dorsal lesions lead to impairments in delayed alternation tasks in rats, while lesions to
the ventral hippocampus do not alter spatial memory but instead appear to causally influence
fear and defensive behavior.

2. Entorhinal Cortex

• The entorhinal cortex is another crucial brain structure for spatial memory and navigation. The
brain region is the main interface between the neocortex and the hippocampus.

The dorsolateral medial entorhinal cortex projects heavily to the hippocampus, relaying spatial
information important for the formation of long-lasting representations of the environment. The
entorhinal cortex contains grid cells, which constitute a hexagonal topographical map of the spatial
environment.

• The periodic firing patterns of these cells are important for the encoding of geometric and
spatial properties of the environment and path integration, which is the animal’s use of self-
motion cues to update an estimate of their current position and direction.

Lesions to the entorhinal cortex produce delay-dependent impairments in spatial navigation and
alter the processing of spatial information in exploration tasks.
3. Retrosplenial Cortex

Found at the back of the corpus callosum, the retrosplenial cortex (RSC) is another key brain region in
learning, spatial navigation, episodic memory, and imagination. It projects heavily to the
hippocampus, providing important visual and spatial information.

Like the hippocampus, it contains place cells that encode important geometric properties of the
environment. Lesions to the area induce impairments in spatial navigation abilities as measured by a
deficit in the ability to find a fixed-platform in the Morris Water Maze and impairments in the radial
arm maze in normal light conditions.

4. Parietal Cortex

While the hippocampal formation is associated with stable spatial representations of the
environment, the locations of objects relative to the animal are represented in the parietal lobe. The
posterior parietal cortex is implicated in attention, spatial processing, and planned movements.
Damage to this area can cause impairments in perception and memory of spatial relationships,
inaccurate grasping, and hemispatial neglect. Hemispatial neglect causes deficits in the awareness
and attention of one-half of the visual field.

5. Prefrontal Cortex

The PFC is canonically important for short-term memory and executive function. The PFC is
implicated in task-specific behavior involving selective attention, organization, planning, and
coordination of multiple information sources.

This area has heavy reciprocal connections with the hippocampus since contextual representations
from the ventral hippocampus are sent to the medial PFC. It is therefore thought to play a key role in
the retrieval of spatial information encoded in the hippocampus for goal-directed navigation.

This is supported by lesioning studies, where medial PFC lesions disrupt performance on a
previously trained radial arm maze task and memory retrieval under partial-cue conditions in a
hidden platform task.
Different Types of Maze

Behavioral Assays for Spatial Memory

Due to its fundamental importance across all animals, spatial memory research, including its
experimental paradigms, is highly translational across model species.

1. Alternation Tasks

• The T-maze and Y-maze take advantage of the natural tendency for rodents to explore novel
environments and locate food rewards. The maze takes into account the alternating behavior of
rats as they search for food in two arms. It is popularly used to investigate spatial working
memory, and so is sensitive to lesions in the hippocampus.

• The total amount of arm entries and the sequence of entries is used to calculate the percentage of
alternation. The percentage of alternation can be used to assess hippocampal dysfunction due to
lesions, the effects of drugs on spatial learning and memory, and cognitive deficits in transgenic
mice used to model human neurological and neuropsychiatric deficits. In a modified T-maze,
researchers can join many simple T-mazes together to create a more complex task which can
access place learning and cognitive mapping.

• Advantages of the maze are ease of setup, simplicity of learning, and minimal stress on the rat. In
some paradigms, the rat must be food-deprived, which may be a drawback. Since the trials are
usually short and spatial memories are only used by the rat from the previous trial to make the
correct choice for the food reward, the maze has limited value in assessing spatial reference
memories, that is, information that is useful on any day of testing.
2. Radial Arm Maze

• Created in the mid-1970s, the radial arm maze is a common behavioral assay for spatial
memory in rodents. Throughout the maze, the rodent must remember the location of the arms it
has already visited for the reward and which arms it has not searched. Therefore, the Radial
Arm Maze assesses the spatial memory of the rat as it navigates the maze and remembers the
correct and incorrect pathways.

• This task requires several days or weeks of training and does not use distant visual cues to aid
spatial learning, as in the Morris Water Maze. The maze allows for researchers to control several
variables, including the type of food reward hidden, the locations of the reward, the olfactory cues
that may confound results, and the retention interval, which is defined as the time between the
exposure of information (goal reward locations) and the testing of the retention of that
information.

3. Morris Water Maze

• The Morris Water Maze (MWM) is another commonly used task designed by Richard Morris in
the 1980s to assess hippocampal spatial learning and memory in rodents. Unlike the binary choice
paradigm found in the T-maze or Y-maze, the Morris Water Maze requires the animal to
continually choose its route to find the reward. Many aspects of the task are derived from the
activity of place cells in the hippocampus, cells whose activity represents specific locations in the
maze.

Across trials, which may be multiple days, the animal under normal circumstances progressively
finds quicker routes to the submerged platform in part through the use of visual and other
external cues. In the process, it forms spatial reference memories quantified as reduced escape
latency, or the time it takes to find the platform or an increased search in the correct quadrant
when the exposed platform is removed.[9]

• This maze is frequently used when assessing the effects of age-related cognitive decline,
hippocampal formation lesions, and pharmacological agents on spatial memory. The maze is
particularly sensitive to hippocampal dysfunction, as evidenced by impaired performance in
rodents with lesions to the dorsal region of this area.
• The Morris Water Maze has several advantages compared to other tasks, namely, little pre-
training required, no food restrictions, ease-of-use, quick learning times, and flexible control of
cues, including the removal of undesired olfactory cues. Additionally, the animal’s motivation is
equal across tasks, as opposed to food-motivated tasks where hunger and satiety can influence its
results. There are some concerns about confounds such as the effects of stress on performance.

4. Virtual Environments

Virtual reality has the advantage of awarding researchers great control over the test environment and
the possibility of creating environments that one wouldn’t normally find in the real world. In
humans, virtual reality tasks are often used in conjunction with imaging techniques such as
functional MRI.

This allow researchers to monitor real-time activity of regions associated with spatial memory while
the subject navigates through virtual mazes such as the virtual Morris Water Maze or virtual radial
arm maze. More complicated virtual arenas and large-scale worlds can also be created to easily
assess hippocampal function.

5. Corsi Block tapping test

• The Corsi block-tapping test is a commonly encountered spatial memory task for humans. This
test is modeled after the digit span test created by Hebb for assessing working memory, but in
this case, the numerical items are replaced by spatial test items, namely, blocks.

• In this task, the experimenter taps on blocks in a particular pattern that the subject then must
replicate. The pattern increases in complexity as the number of blocks increases. The test usually
reaches a maximum of nine blocks, and the average number of blocks an individual can reach is
five.

• Online Corsi Block Tapping Test:

https://www.memorylosstest.com/corsi-block-tapping-test/
Drugs Affecting Spatial Memory

• Spatial memory formation can be augmented by drugs that increase synaptic plasticity in the brain
regions associated with spatial memory and learning, notably the hippocampus and prefrontal
cortex.

Glutamatergic, dopaminergic, and cholinergic transmission is all critical to increase synaptic

strength and mediate long-term potentiation in the hippocampus. For instance, D1 receptor
agonists infused in the medial PFC improves performance on a delayed variant of a radial arm
maze task in rats and object recognition before memory retrieval.

• Acetylcholinesterase inhibitors such as Donepezil are commonly prescribed in early

Alzheimer’s disease and work by inhibiting the breakdown of acetylcholine in the synaptic
cleft. They have been shown to attenuate deficits in recognition memory as well as
scopolamine-induced and alcohol-induced spatial memory deficits in rodent studies with
mazes.

• Many drugs of abuse, including methamphetamine, ketamine, MDMA, alcohol, and cocaine,
affect spatial processing and memory. Frequent ketamine and opiate users show reduced
activation in hippocampal and parahippocampal regions, resulting in spatial memory deficits as
measured in a virtual reality task with concurrent fMRI analysis.
• In general, the drugs of abuse are known to recruit the hippocampus, which processes contextual
drug associations and plays a role in the acquisition of drug-related associative memories. Drug
abuse is thought to involve the disruption of hippocampal long-term potentiation caused by
certain features of drug addiction such as context-dependent withdrawal. In rodents, these drugs of
abuse, even with their markedly different mechanisms of action, induce cognitive impairments in
hippocampal-dependent spatial navigation tasks such as the T-maze, radial arm maze, and Morris
water maze.

Polyunsaturated Fatty Acids and Spatial Memory

Polyunsaturated fatty acids promote or inhibit immune and inflammatory responses. Omega-3s
show anti-inflammatory properties and promote immune functions, which can attenuate the effects
of in utero inflammation caused by maternal immune activation. Omega-3 PUFA deficiency induces
spatial memory deficits and results in altered lipid compositions in the brains of adult mice within a
lipopolysaccharide model of maternal immune activation. The deficiency is thought to enhance pro-
inflammatory cytokines which have been associated with spatial memory modulation in several
animal models. In humans, treatment with omega-3 polyunsaturated fatty acids can improve
learning-memory functions in TBI patients by reducing oxidative stress and increasing brain-derived
neuronal factor, leading to enhanced neuronal survival.

Conclusion

• Spatial memory is a critical brain process for any properly functioning animal. It is impacted by
various drugs and common neurodegenerative and neuropsychiatric conditions.

• Spatial memory may be assessed in a variety of ways, and many of the maze-based tasks in
rodents lend themselves to quick learning times in the animals as well as easy setup and great
control of task parameters.

• Virtual reality tasks are increasingly being used with great success in rodents and humans due to
its unique and flexible ability to control the task environment. Understanding the neural and
behavioral correlates of spatial memory in rodents under varying task conditions is an effective
springboard to understanding how certain diseases and drugs may affect spatial memory in
humans.