The Roles of the Amygdala and the Hippocampus in Fear Conditioning Bachelor Degree Project in Cognitive Neuroscience

................................................................................................ 2 Introduction............................................................................................4 Classical Conditioning........................................................................ 4 Fear Conditioning.............................................................................. 6 Contextual Fear Conditioning................................................................ 7 Aim of the Paper..............................................................................9 Amygdala’s Role in Fear...........................................................................12 Anatomy of the Amygdala...................................................................17 Amygdala Involvement in Memory Storage...............................................20 The Role of the Hippocampus in Fear Conditioning.............................................23 Hippocampus as an Input and Output Structure in Fear Conditioning.................28 Hippocampus as a Memory Structure in Fear Conditioning.............................30 Hippocampal Ensembles Represent the Context..........................................32 The Interaction between the Amygdala and the Hippocampus................................. 35 Discussion.............................................................................................38 References.............................................................................................44 THE ROLES OF THE AMYGDALA AND THE HIPPOCAMPUS IN FEAR CONDITIONING 4 Introduction One major goal of cognitive neuroscience is to identify and gather more understanding of the neural substrates that underlie learning and memory. In order to survive in an environment, an organism must be able to learn the structure of the environment, such as the existence of stimuli and its relationship to other stimuli. It is because of the organisms’ ability to memorize and learn about stimuli that the organism possesses the ability to adapt its behavior to the surrounding environment. To be able to study the learning processes of an organism, scientific methods have been used in which the organism is exposed to two different kind of stimuli during a period of time. First is an organism exposed to a learning experience, then at a later time, is the organism re-exposed to a specific experience that reveals the modification that the learning experience has produced. The question is whether the relation between the two experiences has modified the organism in a manner that can be detected at the second time of experience. The study of this learning process is mostly known as classical conditioning, a process in which an organism’s innate response to a stimulus becomes expressed in response to a previously neutral stimulus (Rescorla, 1988). Classical Conditioning The pioneering discovery of classical conditioning was accidently discovered by the Russian physiologist Ivan Pavlov when he studied dogs salivating in response to being fed. What he noticed was that his dogs would begin to salivate when the lab assistant entered the room even when not bringing them food. According to the contemporary terminology, the food worked as an unconditioned stimulus (US) whereas the salivary secretions worked as an unconditioned response (UR). These findings contributed to the understanding that there are some innate THE ROLES OF THE AMYGDALA AND THE HIPPOCAMPUS IN FEAR CONDITIONING 5 species-typical responses that will be expressed automatically, as the ability to learn and memorize according to the environment (McLeod, 2007). Pavlov understood that the dogs somehow had learned to associate the food with his lab assistant and that the change in behavior must be the result of learning processes. Thus, the lab assistant that originally had been a neutral stimulus (didn’t evoke any response) had become associated with a US, the food. He conducted an experiment in which he instead of the lab assistant, rang a bell as a neutral stimulus when delivering the food for the dogs. The experiment created an association between the neutral stimulus (the bell) and the US (food), and the neutral stimulus became a conditioned stimulus (CS) as the response was learned. Pavlov and his systematic studies of classical conditioning are now one of the most widely used methods to study learning and memory processes (McLeod, 2007). In behaviorist terms, classical conditioning suggests that learning is an association that is created between two stimuli presented close in time (McLeod, 2007; Diamond & Rose, 1994). Specifically, an initially neutral stimulus (CS), such as a sound, is paired with a motivationally stronger stimulus (US), either a reward or a punishment (food or shock), that in turn evokes a behavioral response. As a result of the learning of relationship between the CS and US, the organism shows an enhanced response to the CS, also referred to as a conditioned response (CR), and the outcome is that an association has been created between the CS and US (Diamond & Rose, 1994; Rescorla, 1988). The evocation of the CR is a good indicator that learning processes have occurred (Bouton & Moody, 2004). THE ROLES OF THE AMYGDALA AND THE HIPPOCAMPUS IN FEAR CONDITIONING 6 Fear Conditioning Fear conditioning is a form of classical conditioning, the difference, is that the US is unpleasant and used to investigate the neural mechanisms of emotional learning across a wide range of species, especially in rats. The fear conditioning experiment tests a rat’s response to a specific stimulus and measures how the responses change after learning. In the pre-training stage, the rat receives a light or a tone (CS), which is a neutral stimulus that does not evoke any fearful response in the rat. However, as the rat receives a foot shock (US), it elicits a startleor freezing response (Davis, 1992; Phelps, 2006; Phelps & LeDoux, 2005). The startle and freezing response serves as a defensive behavioral system critical for protection against dangerous environmental threats, thus interrupting the ongoing behavior and increases attention toward the aversive stimuli. The rat does not have to learn to perform these responses, thus the response is implicit and an innate warning of danger (Bolles & Fanselow, 1980; Davis, 1992; Fendt & Fanselow, 1999). These natural fear responses to the shock are the UR. After a few pairings of the CS and the US, the rat learns to associate the two, a process also known as acquisition (Blanchard & Blanchard, 1972). Eventually, the CS alone, without the US will prompt a fear CR in the rats. The CS and the resulting CR can subsequently be unpaired by presenting the CS alone many times, without the US. The neutral stimulus will then stop being associated with the aversive stimulus and just be a neutral stimulus again. At this point, the CR is considered extinguished (Davis, 1992; Fendt & Fanselow, 1999; Phelps, 2006; Phelps & LeDoux, 2005). By the use of fear conditioning, researchers have made a lot of progress in mapping the neural circuitry and processes critical for fear learning. Converging evidence now indicates that the amygdala is the central structure in the circuitry for the expression of fear CRs (Davis, 1992; Phelps, 2006). This research has identified not only the amygdala's critical role in fear THE ROLES OF THE AMYGDALA AND THE HIPPOCAMPUS IN FEAR CONDITIONING 7 conditioning, but also the involvement of specific synaptic connections in the acquisition and storage of memories of fear conditioning in animals (Davis, 1992; LeDoux, 2000, 2012; McGaugh & Roozendaal, 2002; Rodrigues, Schafe, & LeDoux, 2004; Fanselow & Poulos, 2005) and humans (LeDoux, 2012; Phelps, 2006; Phelps & LeDoux, 2005). In animal studies, the convergence between CS and US occurs in the lateral nucleus of the amygdala, which leads to the formation of the CS-US association. Another important region that has been shown to be a site of fear acquisition and memory storage is the central nucleus of the amygdala (LeDoux, 2012; Wilensky, Schafe, Kristensen, & LeDoux, 2006). Studies of fear conditioning on human subjects are consistent with the findings of animal models. Thus, functional magnetic resonance imaging (fMRI) has provided evidence of the occurrence of an increased blood oxygenation level-dependent (BOLD) signal in the amygdala when neutral stimuli became associated with an aversive event. The CR, which has been measured using skin conductance responses (SCRs) as an indication of arousal to the CS event, correlated with the magnitude of amygdala activation (Büchel, Morris, Dolan, & Friston, 1998; LaBar & Phelps, 1998; Phelps, 2006). All of these results provide evidence of the amygdala’s involvement in fear conditioning in humans. ContextDependent Fear Conditioning An emotional CR can also be elicited by placing an animal in the same chamber in which the aversive US has previously been experienced, but without the occurrence of the US. Thus, the memory for the CS has become context-specific, or as it will be referred to here, contextual fear conditioned (for reviews see: Fanselow, 2000; Phillips, & LeDoux, 1992; Squire, 1992). In this situation, the CR is not elicited by a stimulus that is explicitly paired with the US, it’s instead paired with the contextual information of the chamber where the US occurred. The UR are then THE ROLES OF THE AMYGDALA AND THE HIPPOCAMPUS IN FEAR CONDITIONING 8 re-experienced when the animal return to the chamber (Hobin, Goosens, & Maren, 2003; Phillips, & LeDoux, 1992). Although most research has examined the processes of the amygdala, considerable evidence has been obtained which indicates that the hippocampus is crucial for the development of emotionally significant fear conditioning in relation to contextual information (Phelps, 2004; Bouton & Moody, 2004; Hobin et al., 2003; Phillips, & LeDoux, 1992). The amygdala has been shown to interact with the declarative (conscious) memories of the hippocampus to strengthen the unconscious and conscious memories for emotional events (Phelps, 2004). For example, a woman is walking down the street, she sees a neighbor’s dog further down the road that she is afraid of and with this knowledge in mind, she decides to change her path. The reason she’s afraid of this particular dog could be for the reason the dog once bit her and, in that case, her fear response was acquired through normal fear conditioning. The dog acted as a CS and became paired with the dog bite (US), resulting in fear (UR) and an acquired fear response to avoid the dog (CR). However, it is also possible that the woman has learned about the emotional significance of stimuli through a neighbor that previously has told her that the dog is dangerous and might bite her. In this case, she has learned the emotional significance of the aversive stimuli unconsciously through verbal communication that requires the hippocampus for acquisition and retrieval when the fearful stimulus is present. This type of verbal learning, in which humans learn to fear and avoid a stimulus through instruction of an aversive experience, shows the amygdalamediated strengthening of memory for specific events, which depends on the hippocampus (Phelps, 2004). For this reason, the hippocampus has been the target of several studies investigating the contextual acquisition and extinction of fear conditioning but also the retrieval of the fearful memories. As the hippocampus receives inputs from all the cortical areas that THE ROLES OF THE AMYGDALA AND THE HIPPOCAMPUS IN FEAR CONDITIONING 9 integrate sensory information, this might underlie the function of contextual processing (Bouton, Westbrook, Corcoran, & Maren, 2006; Phillips, & LeDoux, 1992).