Associative Learning Signals in the Brain

W.S. Sossin, J.-C. Lacaille, V.F. Castellucci & S. Belleville (Eds.) Progress in Brain Research, Vol. 169 ISSN 0079-6123 Copyright r 2008 Elsevier B.V. All rights reserved CHAPTER 19 Associative learning signals in the brain Wendy A. SuzukiÃ Center for Neural Science, New York University, New York, NY 10003, USA Abstract: Associative memory is defined as memory for the relationship between two initially unrelated items, like a name and an unfamiliar face. Associative memory is not only one of the most common forms of memory used in everyday situations, but is highly dependent on the structures of the medial temporal lobe (MTL). The goal of this chapter is to review the patterns of neural activity shown to underlie the formation of new associative memories in the MTL, as well as to examine how other extra- MTL areas participate in the learning process. Other areas implicated in various aspects of associative learning include the motor-related areas of the frontal lobe, prefrontal cortex, and striatum. The question of how the MTL and the other cortical and subcortical structures may interact during associative learning will be discussed. Keywords: hippocampus; striatum; prefrontal cortex; SEF; FEF; premotor cortex Introduction 2004) or relational memory (Eichenbaum and Cohen, 2001). One form of declarative/relational In 1957, the description of the now well-known memory that has been the focus of extensive amnesic patient H.M. provided some of the first experimental research is associative memory, clues to the mnemonic functions of the medial defined as memory for the relationship between temporal lobe (MTL) (Scoville and Milner, 1957). initially unrelated items. Findings from both the The impairment observed in patient H.M. was experimental and clinical literature show that profound and initially described as global amnesia, damage to the MTL impairs long-term associative that is, extending to all forms of learning and memory for a variety of different kinds of memory. Subsequent and detailed study of patient information (Murray et al., 1993, 1998; Vargha- H.M. together with other human amnesic patients Khadem et al., 1997; Bayley and Squire, 2002; with MTL damage revealed that the memory Stark et al., 2002; Stark and Squire, 2003; Liu impairment was not global, but instead was more et al., 2004), and neurophysiological studies have limited to particular forms of learning and demonstrated a role of the MTL, in particular the memory including learning and memory for facts perirhinal cortex in the long-term storage of (semantic memory) and events (episodic memory) associative information (Sakai and Miyashita, collectively referred to as declarative (Squire et al., 1991; Murray et al., 1993; Sobotka and Ringo, 1993; Naya et al., 1996, 2003; Booth and Rolls, 1998). In addition to a role in long-term memory ÃCorresponding author. Tel.: +1 212 998 3734; for new associations, findings from lesion studies Fax: +1 212 995 4011; E-mail: [email protected] also suggest an important role of the MTL in the DOI: 10.1016/S0079-6123(07)00019-2 305 306 initial formation of new associative memories (i.e., subsequently to the tone CS, such that the associative learning; Murray et al., 1993, 1998). enhanced response to the US appeared to shift The goal of this chapter is twofold. The first goal forward gradually in time towards the CS pre- is to review the associative learning signals that sentation with learning. Although it was later have been reported in the MTL across species shown that delay conditioning (where there is no including rabbits, rats, and primates. This review temporal gap between the CS and US presenta- will show that similar patterns of associative tion) is not dependent on intact hippocampal learning signals have been reported across species, function, similar dynamic changes in neural though the most thorough description to date has activity were subsequently reported in trace con- been done in the non-human primate model ditioning paradigms where there is a temporal gap systems. The second related question concerns the between the CS and US presentation. In contrast other brain areas beyond the MTL that may also to delay conditioning, trace conditioning is highly contribute to associative learning. While many dependent on the integrity of the hippocampus studies have shown clear impairments in associa- (Solomon et al., 1986; Moyer et al., 1990; Kim tive learning following MTL damage, the impair- et al., 1995; McEchron et al., 2000). ment is typically not complete suggesting that In one key study, hippocampal learning-related other brain areas may also be contributing to activity was examined as animal learned a trace associative learning functions. Indeed, in tasks of conditioning task where a tone was paired with an conditional motor association learning where air-puff unconditioned response (McEchron and monkeys are required to associate a particular Disterhoft, 1997). This group showed that com- visual stimulus with a particular motor response pared to the unpaired control group, hippocampal (i.e., touch right or touch left), strong associative cells in the paired trace conditioning group learning signals have been reported not only in the exhibited enhanced responses to the US a full day hippocampus but also throughout other motor- before the first day animals expressed learning of related areas in the frontal lobe and striatum. The the CS–US pairing. While the behavioral condi- second part of this chapter will compare and tioned responses remained asymptotic on the contrast the associative learning signals across 2 days following learning, the enhanced neural these extra-MTL brain areas. The question of how responses to the CS and US declined back to the MTL and these extra-MTL brain areas might control levels in the 2 days after learning. The cooperate, compete, and generally interact during authors suggested that this pattern of neural new associative learning will also be discussed. activity may reflect the relatively transient role of the hippocampus in the consolidation of the CS–US association, though the relationship Associative learning in the medial temporal lobe between the decline and hippocampal activity and consolidation of the CS–US association was not One of the earliest and most dramatic demonstra- examined directly. tions of dynamic learning-related neural signals In contrast to studies of associative learning in in the brain came in the 1970s when Berger and the rabbit hippocampus which have focused on colleagues (Berger et al., 1976; Berger and classical conditioning paradigms, the vast majority Thompson, 1978) recorded multi-unit activity in of studies in the rodent hippocampus have focused the hippocampus in rabbits during a delay eye- on the neurophysiological correlates of spatial blink conditioning task where the air-puff uncon- navigation and spatial memory. We have known ditioned stimulus (US) co-terminated with the since the 1970s with the seminal description of end of the conditioned stimulus (CS) presentation O’Keefe and Dostrovsky (1971) that cells in the (a tone). They showed that compared to the rat hippocampus signal the relative position of responses in unpaired control animals, hippocam- the rat in the environment (place cells). While pal neurons in conditioned animals developed early theories suggested that place cells represent enhanced responses, first to the air-puff US and a spatial cognitive map of the environment 307 (O’Keefe and Nadel, 1978), more recent theories session followed by another swim session, during have suggested that spatial information is one which a novel hidden platform was introduced in particularly striking example of a more general the maze. This group reported that many hippo- category of relational information that is highly campal pyramidal cells fired vigorously the first dependent on the hippocampus (Eichenbaum and time the rat encountered the novel platform Cohen, 2001). Early studies done by Wilson and location and the activity decreased as the animal Mcnaughton (1993) showed that the spatially gained more experience with that platform loca- selective activity could develop very quickly as a tion. The decreased activity paralleled a decrease rat entered a novel environment. However, fewer in swim time to find the platform, indicative of studies have attempted to examine these dynamic learning. This transient increase followed by a changes in hippocampal activity in a situation decrease with learning could play a role in where behavioral learning could be monitored. signaling novel spatial information. One study recorded from hippocampal place While the findings in rabbits and rats suggest cells as rats were exposed to either a familiar set that striking changes in neural activity can of arms in a modified T-maze or during the first accompany various forms of associative or spa- 3 days of exposure to a novel set of arms (Frank tial/relational learning, less is known about the et al., 2004). On the first exposure to a novel arm, precise timing of these neural changes relative to after an initial period of inactivity, strong and clearly defined behavioral learning. To address selective place-cell activity developed very quickly. this question, two groups used conditional motor Overall, the most dramatic change in place-field associative learning tasks to examine learning- activity in the novel arm occurred on days 1 and 2 related patterns of hippocampal activity in mon- and stabilized by day 3. To understand the keys (Cahusac et al., 1993; Wirth et al., 2003). relationship between the rapid development of This particular associative learning paradigm place-cell activity and learning, the authors com- was chosen because previous studies showed pared various measures of place-cell activity to that post-training lesions to the MTL in monkeys a behavioral measure of familiarity defined by impair the ability to learn novel conditional motor running speed. This analysis was based on the associations, while well-learned associations observation that animals typically run more slowly remain unaffected (Rupniak and Gaffan, 1987; in order to explore novel environments and speed Murray and Wise, 1996; Wise and Murray, 1999; up in familiar environments.

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