Emotional Learning & Memory: Why Study It?
Emotions play a significant role in our daily lives. For years, the brain's emotion system was largely ignored by scientists, in part because it was believed that emotions did not lend themselves to empirical investigation. Within the last 20 years, however, emotion research has enjoyed a resurgence in both Psychology and the Neurosciences, fueled in part by the rapid and impressive progress made in understanding one very important emotion: fear. Like other emotions, fears can be both innate (or unlearned) or acquired through experience. For example, we learn to fear a hot stove, the dentist’s drill, or flying around in airplanes after a particularly turbulent flight. The ability to acquire fear about particular objects or situations is part of the brain's natural defense system that serves to protect us from harm, and, in most cases, serves us well.
In many cases, however, the brain's fear system goes awry. Each year, psychological disorders that are characterized by unusually strong and persistent fearful memories, such as post-traumatic stress disorder (PTSD), take an enormous social and economic toll on our society. To begin to address these problems, we first must understand how the fear memory system of the brain works. Then we can begin to understand how the fear memory system kicks into overdrive under certain circumstances, and how to fix it when it does.
The Fear Memory System of the Brain
The fear learning system of the brain has been studied most extensively in the laboratory rat. The rat is a particularly good animal to study both fear and fear learning, since rats and other rodents have very well-defined reactions to danger. As anyone who has taken a stroll though their neighborhood park and watched the dogs chase the squirrels around surely knows, rodents "freeze" when they are in danger. This behavior has obvious advantages for the squirrel: if it freezes, particularly on a tree that has the same color as its fur, it may not be seen. In the laboratory, we take advantage of this natural response to danger to examine how animals learn to fear new things. When a rat is presented with a innocuous stimulus such as a tone that it does not initially fear, followed by a brief electrical shock to the feet, the result is simple. When the rat hears the tone again, it reacts in the same way it would react to a natural predator or any other dangerous situation by freezing. Furthermore, this freezing behavior is accompanied by a number of other well known responses to fear: increases in heart rate, blood pressure and circulating stress hormones, such as adrenaline and corticosteroids. These emotional and physical responses are all "conditioned" in the same way that Ivan Pavlov's dogs were conditioned to salivate to a bell that predicted the delivery of food.
Neuroscientists have identified many of the important structures in the brain that contribute to fear learning. One structure appears to be particularly important: the amygdala. Surgical removal of the amygdala not only produces a rat that is more likely to play with a cat, but also a rat that cannot learn to fear new things. Thus, the amygdala appears to be involved in controlling both unlearned (or innate) and learned fear reactions. How might the amygdala accomplish these tasks? We know that cells within the amygdala, and in particular the lateral nucleus of the amygdala (LA), receive information from sensory areas of the brain (i.e. sight, sound, smell, pain) and in turn send information to lower brainstem areas that are important in fear-related reactions (such as startle, heart rate, & blood pressure). So the LA appears to be well-situated to receive and integrate information about potentially threatening stimuli and to tell other areas of the brain to respond accordingly.
We also know that the activity of cells within the LA changes following fear learning. Before pairing the tone and the shock, cells in the LA respond only mildly to the tone, but after pairing, they respond vigorously. This kind of change indicates that fear learning alters the cells in some fundamental way so that they now respond appropriately to danger signals. It is this kind of change that neuroscientists typically refer to as "plasticity". Most importantly, plasticity related to fear learning has also been observed in the human amygdala. Using imaging techniques such as functional MRI , a number of different labs have observed that activity in the human amygdala increases when we learn to fear a stimulus, object, or situation. Thus, we feel quite confident that what we learn in the rat is also applicable to humans.
Cellular Mechanisms of Fear Learning
The major focus of my lab is to understand how neurons in the amygdala alter their function as a result of fear conditioning. At this stage, we have learned a great deal about which structures make up the brain's fear system, and what kinds of changes LA neurons undergo when learning to fear new things. Now, we want to understand how these changes take place at the biochemical and molecular level. In particular, we want to know, and have begun to identify, which molecules within the cells of the LA become active during fear learning, and how these activated molecules produce changes in LA cells so that we react fearfully when we encounter these situations again. A complete understanding of the cellular mechanisms of fear learning in animal models may lead to the development of new drug targets for the treatment of emotional disorders in humans.
Current Lab Projects
My lab is currently pursuing 4 interrelated questions:
What are the Genomic Mechanisms Underlying Fear Memory Consolidation in the Amygdala? First and foremost, we continue to work on questions related to memory consolidation processes in the LA. While my previous work has emphasized the role of protein kinase signaling cascades in memory consolidation of fear learning, may lab and I have recently begun to focus on examining the downstream nuclear targets of these cascades and their role in the consolidation process. Studies are underway, for example, examining the role of different immediate early genes (e.g. Arc, Egr-1) and associated late-response genes in fear memory consolidation and synaptic plasticity in the LA (see Ploski, Pierre, Smucny, Park, Monsey, Overeem & Schafe, The Journal of Neuroscience, 2008, Vol. 28; Maddox & Schafe, 2011, Learning & Memory; Ploski, Park, Monsey, Ping & Schafe, Journal of Neurochemistry, 2010; Ploski, Nguyen, Monsey, DiLeone & Schafe, PLoS ONE, 2011).
What are the Genomic Mechanisms Underlying Fear Memory Reconsolidation in the LA? A second focus of my lab has been the question of the genomic mechanisms by which fear memories are ‘reconsolidated’ in the amygdala. Several years ago, my colleague Karim Nader and I showed that fear memories appear to undergo a second consolidation process at the time of retrieval. Like memory consolidation itself, this “reconsolidation” process requires de novo protein synthesis and can be disrupted by infusion of protein synthesis inhibitors into the LA at the time of memory retrieval (see Nader, Schafe, & LeDoux, 2000, Nature). This exciting finding suggests that fear memories can be disrupted at the time of retrieval using pharmacological manipulations. Current work in my lab focuses on understanding in detail the cellular and molecular mechanisms by which LA neurons accomplish this process, and the extent to which these mechanisms are similar to those underlying initial memory consolidation (see Maddox, Monsey & Schafe, Learning & Memory, 2011,Vol. 18; Maddox & Schafe, 2011, The Journal of Neuroscience; Ploski, Nguyen, Monsey, DiLeone & Schafe, PLoS ONE, 2011).
What are the Epigenomic Mechanisms Underlying Fear Memory Consolidation & Reconsolidation in the LA? Recent evidence indicates that ‘epigenetic’ mechanisms, including DNA methylation and modifications of chromatin structure, are critical for learning and memory. Epigenetic modifications have long been studied in the context of developmental biology, where they are thought to promote static, enduring alterations in gene expression that are independent of alterations in the underlying DNA sequence itself. In the adult brain, these same epigenetic processes have been suggested to play a more dynamic role in functions ranging from memory to addiction to psychopathology. Recently, my lab has begun to examine the role of epigenetic alterations in memory consolidation and reconsolidation of auditory Pavlovian fear memories and associated neural plasticity in the LA. We have shown, for example, that both auditory fear conditioning and retrieval of an auditory fear memory regulate the acetylation of histone H3 and DNA methyltransferase (DNMT)-3A expression in the LA. Further, pharmacological manipulation DNMT or histone acetyltransferase (HAT) activity impairs memory consolidation and reconsolidation of an auditory fear memory and associated training and retrieval-related neural plasticity in the LA (Monsey, Ota, Akingbade, Hong & Schafe, 2011, Plos ONE, Vol. 6; Maddox & Schafe, 2011, Learning & Memory, Vol. 18; Maddox, Watts, & Schafe, 2013, Learning & Memory, Vol. 20; Maddox, Watts, & Schafe, 2013, Neurobiology of Learning & Memory, Vol. 107). Current studies are focused on examination of the chromatin and methylation states of genes in the LA (e.g. Arc/Arg3.1, Egr-1) following both fear conditioning and fear memory retrieval using chromatin and methylated DNA immunoprecipitation techniques.
How does exposure to chronic stress regulate fear memory consolidation and reconsolidation processes? My previous and current work has largely focused on molecular mechanisms underlying consolidation, reconsolidation and associated synaptic plasticity in the fear memory system. One of my long-term goals, however, is to move my research program in a more translational direction. Within the last two decades, we’ve learned a lot, for example, about how exposure to chronic stress, both developmentally and as an adult, can profoundly affect emotional behavior and the brain. In pre-clinical models, exposure to chronic stress has been shown to lead to dendritic atrophy and loss of neurons in the hippocampus and the medial prefrontal cortex, two areas which are known to be critical for emotional regulation. Conversely, chronic stress has been shown to promote long-lasting dendritic hypertrophy in amygdala neurons. These opposing morphological changes are also reflected at the functional level in human clinical populations, and have been proposed to underlie the development of certain types of anxiety disorders. Surprisingly few studies, however, have focused their efforts on examining the molecular mechanisms by which chronic stress affects amygdala structure and function. My previous and current work in the fear memory system has laid the groundwork for asking these important questions. To that end, my lab has recently observed that a history of chronic exposure to the stress-associated adrenal steroid corticosterone persistently (e.g. > 2 weeks) upregulates the expression of the memory-related IEGs Arc/Arg3.1 and Egr-1 in the LA and enhances the consolidation of an auditory fear memory; that is, STM is unaffected, while LTM is significantly enhanced (Monsey, Kronman, Boyle, Zhang, Nguyen, Taylor, & Schafe, 2013, PloS ONE). Our findings suggest that a history of chronic exposure to stress can regulate gene expression and fear memory consolidation processes in the LA in a long-lasting manner. Further, we have begun to ask whether these genomic and behavioral effects of chronic CORT/stress exposure may result from alterations in the epigenetic ‘landscape’ of the amygdala. For example, does chronic exposure to stress, either developmentally or as an adult, alter the expression of HATs, HDACs and DNMTs in the LA? Does stress upregulate synaptic plasticity genes in the LA via modifications in chromatin structure? Does stress alter the methylation patterns of genes that promote and/or suppress memory and synaptic plasticity in the LA? Do the effects of stress on epigenetic markers in the LA vary as a function of sex? What effect does a history of chronic stress have on fear memory reconsolidation processes? Can the behavioral, genomic and epigenomic effects of chronic stress be reversed by pharmacological interventions? Collectively, these future studies have the potential to lay the groundwork for novel pharmacological approaches based on the targeting of epigenetic processes for fear and stress-related psychiatric disorders, such as PTSD, in which acquired and persistently reactivated fear memories play a prominent role.
Some Recommended Reading
The following books/papers are recommended for additional reading. A select list of primary research articles from our lab is also listed under the "Papers" tab (above):
LeDoux, J.E. (1996). The Emotional Brain. Simon & Schuster.
Maren, S. & Quirk, G.J. (2004) Neuronal signalling of fear memory. Neuron, 5, 844-52.
Rodrigues, S.M., Schafe, G.E., & LeDoux, J.E. (2004). Molecular mechanisms underlying emotional learning and memory in the lateral amygdala. Neuron, 44, 75-91.
Maren, S. (2011). Seeking a spotless mind: extinction, deconsolidation, and erasure of fear memory. Neuron, 70, 830-45.
Roozendaal, B., McEwen, B.S., & Chattarji, S. (2001). Stress, memory and the amygdala. Nature Reviews Neuroscience, 10, 423-33