Memory and emotion are two of the faculties central to human psychology and human life and are closely intertwined. From this interaction, we can derive a concept of emotional memory, a concept relevant to both a neuroscientific and a medical context which can also be assessed through behavioral testing.
The use of mouse models for the study of behavioral neuroscience and the investigation of disease pathology is ubiquitous in science. Paradigms have been developed that allow scientists to assess the effects of drugs and diseases on the emotional memory of mouse models. The results of these studies have been foundational for research on a number of important human diseases.
In this article, we will begin by looking at what emotional memory is and what parts of the brain have been linked with it in humans and mice. We will then go on to discuss which diseases affect emotional memory, and then, what experimental designs have been created to examine variability in emotional memory, before finally looking at how different drugs can affect the performance of model animals in these tests.
What is Emotional Memory?
While memory and emotion may seem like very different phenomena, recent neuroscientific research continues to uncover tight links between them. Our memories are emotionally laden, and attaching affective content to our experiences helps us to behave more efficiently, allowing us to quickly evaluate different scenarios and make helpful decisions. This synergy between emotion, memory, and behavior may be the basis of what is commonly called “intuition”.
An emotion is a psychological phenomenon, something subjective that is experienced and felt by one particular individual e.g. a person may feel happy or sad. Since these emotions are mental phenomena, they must involve neural processes. Emotions also have somatic correlates known as “affects” e.g. fear may cause an increase in heart rate or increased sweating. Since emotions are impossible to objectively measure and characterize (i.e. we can never know if a mouse is really feeling something), affects and neural correlates, as well as the behaviors they impact, have become the variables of interest in the study of emotion.
Memory is a broad, multifaceted phenomenon. At root, it is simply the ability of a system to retain information from some prior state, and then use that information in determining some later state. Memory in humans is normally divided between declarative memory (memory of facts), episodic memory (memory of experiences) and procedural memory (memory of how to do things). The concept of emotional memory overlaps primarily with episodic memory (evaluation of experiences) and also to some extent declarative memory.
Emotional Memory & the Brain
There is no single part of the brain that is dedicated to emotions, although a network of brain regions known as the limbic system is most commonly implicated in them. The limbic system includes the amygdala, hypothalamus, hippocampus, the fornix, and the cingulate gyrus. Other brain structures implicated in emotion include the striatum, insula, cerebellum, and parts of the frontal cortex. In other words, almost the entire brain has been in some way implicated in emotion.
A lot of interest has centered on the role of the amygdala. This brain region, situated in the temporal lobe, is most commonly associated with the processing of fear (the “fight or flight” response), although its functions are more complicated than commonly assumed. The amygdala integrates episodic memories with the sensory experiences associated with those memories. This allows the subject to learn which actions lead to experiencing aversive stimuli, and so adjust their behavior accordingly.
Most knowledge of functional modularity in the brain comes from case studies of patients with brain damage. Since the amygdala is a small region deep in the brain, it is rare for a patient to have damage localized solely to this region, and so the amount of data on this subject is small. Patients with specific amygdala lesions do still exhibit some emotional memory, and their emotional responses seem normal, but they have issues integrating their emotional responses with their memories and in particular, find it difficult to filter out key information concerning emotion-laden events. Mice with amygdala lesions perform badly in fear conditioning tests.
The hippocampus has also been implicated in emotional memory. Traditionally, the hippocampus is seen as the site in the brain where short-term episodic memories “mature” into long-term memories which are then stored in the frontal cortex. However, recent research has extended knowledge of the role of the hippocampus to more emotion-focussed situations, situating it as part of a system where it works in tandem with the amygdala.
In humans, work by Antonio Damasio and others has revealed how a region of the frontal lobe known as the orbitofrontal cortex (OFC) appears to use emotional memories to make decisions. Patients with OFC lesions have intact practical reasoning capabilities but are impulsive and unable to make good, intuitive decisions on the basis of reasoning and evidence. A region analogous to the OFC is thought to exist in the brains of mice, although this is disputed.
Diseases Affecting Emotional Memory
The most prominent condition affecting emotional memory in humans is Alzheimer’s disease (AD). AD is a neurodegenerative disorder in which the accumulation of protein plaques in neurons is associated with mass neuronal death and loss of cognitive functions, especially loss of short-term episodic memory in the early stages. One of the main regions affected by AD is the amygdala, leading to rapid impairment in the formation and retrieval of emotional memories.
Emotional memory is also negatively impacted in patients with bipolar disorder, a psychological condition causing sudden and intense mood changes. A 2008 study showed that the memory-enhancing effect normally seen with emotionally laden information in healthy participants was not seen with bipolar individuals. Further, unlike controls, when asked to recall and describe how an emotionally laden narrative had affected them, bipolar individuals did not highlight the emotional aspect of it.
Another condition that can impair emotional memory is schizophrenia. A review published by Herbener in 2008 looked at a large number of studies comparing emotional memory in schizophrenics and healthy subjects and found that schizophrenics’ had a significantly weaker memory for emotional experiences. This deficit appeared to worsen the further in the past the experience was. The author suggests that this diminished emotional memory may contribute to schizophrenics’ reduced motivation and capacity for setting goals.
Ageing, while typically not considered a medical condition as such, is associated with a number of pathological symptoms, among them, memory loss. Stereotypically, elderly humans show a reduction in short-term episodic memory and working memory, as well as difficulties in forming new declarative and procedural memories. Two studies show that the elderly have a better memory for positive than negative events, and suggest this may be due to a shift in activity over time from the amygdala and hippocampus to the frontal cortex.
Major Tests for Emotional Memory in Mice
The use of fear as an instrument in learning and memory experiments has a very long precedent. Neuroscientist Eric Kandel famously used fear conditioning with the sea-slug Aplysia in the 1960s, designing an electric-shock based paradigm to study synaptic plasticity. The incorporation of similar techniques into behavioral experiments with mice and rats has now become very popular, and standardized experimental setups have emerged to administer and assess them.
All fear conditioning paradigms involve attempting to teach the experimental animal to associate a conditioned stimulus with an unconditioned stimulus. The terms conditioned stimulus and unconditioned stimulus come from classical Pavlovian conditioning. The unconditioned stimulus is some aversive stimulus which naturally evokes fear from the mouse, most commonly a mild electric shock. The animal exhibits a behavioral response (freezing on the spot) which allows experimenters to infer that it is experiencing fear.
By pairing an ordinarily neutral stimulus (one that would typically not evoke fear on its own) in time with the unconditioned stimulus, researchers can give the mouse a memory in which the neutral stimulus becomes a conditioned stimulus, i.e. predictor of the unconditioned stimulus. The mouse will then react to the conditioned stimulus as if it were the unconditioned stimulus. Forming this kind of associative emotional memory depends on both the amygdala and the hippocampus. Once formed, the memory lasts a long time, allowing it to be used in multiple experiments with the same animals.
Fear conditioning can be divided into two kinds: trace conditioning, where the conditioned stimulus either occurs at exactly the same time as the unconditioned stimulus or immediately after it, and delay conditioning where an extra time interval is left in between the two stimuli. The interval can be anywhere from a few seconds to an entire minute. Trace conditioning is more cognitively demanding, recruiting additional brain areas, since it is more difficult for the animal to associate stimuli further away in time.
Fear conditioning can also be separated into contextual fear conditioning and cued fear conditioning. With contextual conditioning, the mouse learns to associate a certain environment with receiving an aversive stimulus, and so will display a freezing behavior when returned to that environment. In contrast, with cued fear conditioning, the animal is allowed to acclimatize to the environment before the conditioned stimulus is presented, and so learns to associate the unconditioned stimulus more with the conditioned stimulus and less with the environment. Check out our articles on Cued Fear Conditioning and Contextual Fear Conditioning to learn more
Many studies have used fear conditioning to assess emotional memory. For example, a 2016 paper from a French research team examined the effects of radio frequency electromagnetic fields on the brains of rats. They found that the application of RF-EMF was associated with astrogliosis in the rats, and this, in turn, was associated with a worse performance than controls in contextual fear conditioning.
Passive Avoidance Task
The Passive Avoidance Task is a paradigm that is similar to fear conditioning, used with research on CNS disorders. Like with contextual fear conditioning, the mouse comes to form a memory associating a certain environment with receiving an aversive stimulus. The apparatus used in the passive avoidance task also borrows design elements from the light-dark box test.
A chamber is used that has two compartments: a light compartment and a dark compartment, with a strict dividing line between the two. First, the mouse is simply placed in the chamber and left to move freely between two compartments, allowing it to acclimatize to the apparatus. After this, the mouse receives an aversive stimulus, generally a foot-shock, causing it to experience fear and associate that fear with either the light or the dark compartment.
Finally, after this association has been formed, the mouse is placed back into the compartment where it did not receive the aversive stimulus. The key variable measured here is the latency for the mouse to move into the compartment where it did receive the aversive stimulus. Since we expect the mouse to fear that compartment and desire to keep away from it, a shorter latency indicates a weaker emotional memory.
One example of a study employing this paradigm is a paper from 2014 examining the effects of phosphodiesterase inhibitors on emotional memory in mice. They found that the drug rolipram, increased the latency to move to the aversive compartment, suggesting that it increased the strength of emotional memory. This corroborated previous speculation that rolipram could be used to improve memory in human Alzheimer’s disease patients.
Drugs Affecting Performance in Emotional Memory Tests
Researchers have investigated the effects of many drugs on mouse performance in fear conditioning tests. For example, several studies have shown that antagonists of the receptor NMDAR, long known to be involved with the formation of long-term episodic memories, reduce the performance of mice compared to controls in contextual fear conditioning. Further research has shown that this effect is not due to state dependency (where performance in memory tests depends on the current state of consciousness of the subject). This has implications for the treatment of anxiety disorders in humans.
A complex effect was seen in one study when mice were administered with the recreational drug, cocaine. At low doses, the drug enhanced memory in contextual fear conditioning. However, above a certain dosage threshold, increasing dosage caused fear conditioning performance to gradually worsen. This led the researchers to question cocaine’s status as a performance-enhancing drug, suggesting that at higher doses it has a disruptive effect on cognitive function.
Ketamine, a drug used both recreationally and now for therapeutic purposes, has been shown to negatively affect the performance of mice in the passive avoidance task. More specifically, researchers argue that ketamine prevents the acquisition of emotional memory in the test and that it does this by interfering with dopaminergic signaling. The administration of dopaminergic antagonists was observed to alleviate the effects of the ketamine.
Besides dopaminergic pathways, cholinergic pathways have also been implicated in emotional memory via the effects of drugs. One study reports that four different cholinergic antagonists were all able to reduce the performance of mice in the passive avoidance task. This reduction only occurred if the drugs were administered before training but not afterward, suggesting again that the drugs interfered with the acquisition of the salient emotional memory.
A suitable degree of emotional memory is vital for a functioning human life. Emotional memory is impacted by aging, drugs, and a range of important diseases. Experimental protocols have been developed to investigate this. It is hoped that the information provided in this article will assist researchers in further elucidating the workings of emotional memory in mouse models and in the human brain.
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