NMDA receptor blockade in the dorsolateral striatum impairs consolidation but not retrieval of habit memory.

The present study investigated whether N-methyl-d-aspartate (NMDA) receptors in the dorsolateral striatum (DLS) mediate consolidation and retrieval of habit memory. Adult male Long-Evans rats were trained in a response learning version of a water plus-maze task in which rats were reinforced to make a habitual and consistent body-turn response at the maze choice point in order to mount a hidden escape platform. Prior research indicates that acquisition, consolidation, and retrieval in this task requires DLS function. The present study consisted of two experiments. In Experiment 1, rats received intra-DLS post-training injections of the NMDA receptor antagonist 2-amino-5- phosphonopentanoic acid (AP5; 2 µg/side) to examine the role of NMDA receptors in consolidation of habit memory. In Experiment 2, different groups of rats received a single pre-retrieval injection of AP5 in the DLS (AP5; 2 µg/side) during the last day of maze training to examine the potential role of NMDA receptors in retrieval of habit memory. Results indicated that post-training intra-DLS AP5 injections impaired memory consolidation. However, administration of AP5 at the same dose that impaired consolidation had no effect on memory retrieval. The findings are consistent with previous research indicating a role for NMDA receptors in the DLS in memory consolidation, and suggest that NMDA-dependent synaptic activity in the DLS may not be a critical component of habit memory retrieval.

Chronic corticosterone administration in adolescence enhances dorsolateral striatum-dependent learning in adulthood.

Previous evidence indicates a link between early life stress (ELS) in humans and a predisposition to psychopathologies that are characterized in part by maladaptive habitual behaviors. Stress and anxiety influence the relative use of mammalian memory systems implicated in these disorders. Specifically, cognitive memory functions of the hippocampus are typically impaired by stress/anxiety, whereas habit memory functions of the dorsolateral striatum (DLS) are enhanced. A stress/anxiety bias toward habit memory has largely been demonstrated in adult rodents and humans, and the effects of ELS on the later use of DLS-dependent habit memory in adult rodents have not been extensively examined. The present study addressed this question by chronically elevating corticosterone (CORT) during adolescence, and investigated the effects of this treatment on DLS-dependent habit learning in adulthood. In experiment 1, adolescent rats received a single daily injection of either CORT (5 mg/kg) or vehicle (cVEH) over 5 days and then matured undisturbed before training as adults in a DLS-dependent water plus-maze task. Rats administered CORT injections during adolescence displayed a strong trend toward enhanced learning during adulthood relative to vehicle-treated rats. Adolescent CORT administration also increased anxiety-like behavior in adulthood in an elevated plus-maze. In experiment 2, adolescent CORT administration enhanced task acquisition in adulthood, and this effect was blocked by concurrent administration of the glucocorticoid antagonist mifepristone (30 mg/kg). Taken together, these findings suggest that chronic elevation of glucocorticoids during adolescence are sufficient to facilitate habit learning in adulthood, and indicate that glucocorticoid function may be a potential underlying mechanism by which ELS influences subsequent habitual behaviors.

Behavioral and Neural Mechanisms of Latent Extinction: A Historical Review.

The present paper provides a comprehensive review of latent extinction. In maze learning situations, latent extinction involves confining an animal to a previously reinforced goal location without food. When returned to the starting position after latent extinction, the animal typically shows a response decrement. Such findings have suggested that latent extinction is sufficient to invoke extinction learning, despite the animal having been prevented from making the original response. The majority of research on latent extinction was conducted between 19491980 and focused on what is being learned during the latent placements. Stimulus-response (S-R) theorists attempted to explain latent extinction via novel S-R mechanisms, namely, the fractional anticipatory response (rG). However, research did not support the role of rG in latent extinction. Cognitive expectancy theorists provided a simpler, more adequate explanation for latent extinction, more consistent with the data. Specifically, latent extinction might instill a change in expectation (i.e., animals learn to expect absence of reinforcement). Evidence also suggests that latent extinction involves place learning mechanisms and is sensitive to modulation via certain experimental factors. More recent work has uncovered some of the neural mechanisms of latent extinction. The hippocampus is critically involved in latent extinction, whereas other brain regions typically implicated in regular "response extinction" in the maze, such as the dorsolateral striatum, are not required for latent extinction. Similar to other kinds of learning, latent extinction requires NMDA receptor activity, suggesting the involvement of synaptic plasticity. Consistent with a multiple memory systems perspective, research on latent extinction supports the hypothesis that extinction learning is not a unitary process but rather there are different kinds of extinction learning mediated by distinct neural systems.

Neural systems and the emotion-memory link.

The present brief review for this Special Issue summarizes some of the original research on the emotional modulation of memory. The review begins by highlighting the pioneering research from James L. McGaugh and colleagues demonstrating modulatory effects of post-training drug administration on memory consolidation, in particular the stress hormone epinephrine. The subsequent discovery of a critical role for the basolateral amygdala in emotional modulation of memory is described. Within the context of a multiple systems approach to memory focusing on selective roles for the hippocampus and dorsolateral striatum in cognitive and habit memory, the original studies indicating that robust emotional arousal can bias animals and humans toward the predominant use of habit memory are reviewed. This effect of emotional arousal on the relative use of multiple memory systems depends on a modulatory role of the basolateral amygdala. Finally, we briefly consider how an emotion-induced enhancement of dorsolateral striatal-dependent memory may be relevant to understanding maladaptive habitual behaviors in certain human psychopathologies.

NMDA receptors in the basolateral amygdala mediate acquisition and extinction of an amphetamine conditioned place preference.

Previous work from our laboratory has indicated that temporary inactivation of the basolateral amygdala (BLA) with bupivacaine blocks acquisition, consolidation, and retrieval of an amphetamine conditioned place preference (CPP). The present study was designed to extend this line of investigation by examining whether N-methyl-D-aspartate (NMDA) receptors in the BLA mediate acquisition and extinction of an amphetamine CPP. Adult male Long-Evans rats received bilateral intra-BLA injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 1.25 µg, 2.5 µg, or 5.0 µg) or saline prior to each session of CPP acquisition (Experiment 1). In addition, separate groups of rats received intra-BLA injections of the sodium channel blocker bupivacaine (Experiment 2), AP5 (1.25 µg, 2.5 µg, or 5.0 µg; Experiment 3), or saline prior to each session of CPP extinction training. Results indicated that intra-BLA injection of bupivacaine or AP5 (2.5 or 5.0 µg) disrupted acquisition of an amphetamine CPP. In addition, neural inactivation of the BLA with bupivacaine blocked extinction of CPP. Finally, intra-BLA AP5 injections (2.5 or 5.0 µg) were sufficient to block CPP extinction. The present findings indicate that NMDA receptor activity in the BLA is critical for acquisition and extinction of an amphetamine CPP and may be relevant to understanding the neural mechanisms underlying some aspects of drug seeking and addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

There Is More Than One Kind of Extinction Learning.

The view that different kinds of memory are mediated by dissociable neural systems has received extensive experimental support. Dissociations between memory systems are usually observed during initial acquisition, consolidation, and retrieval of memory, however increasing evidence also indicates a role for multiple memory systems in extinction behavior. The present article reviews a recent series of maze learning experiments that provide evidence for a multiple memory systems approach to extinction learning and memory. Evidence is described indicating that: (1) the hippocampus and dorsolateral striatum (DLS) mediate different kinds of extinction learning; (2) the effectiveness of different extinction protocols depends on the kind of memory being extinguished; and (3) whether a neural system is involved in extinction is also determined by the extinction protocol and kind of memory undergoing extinction. Based on these findings, a novel hypothetical model regarding the role of multiple memory systems in extinction is presented. In addition, the relevance of this multiple memory systems approach to other learning paradigms involving extinction (i.e., extinction of conditioned fear) and for treating human psychopathologies characterized by maladaptive memories (e.g., drug addiction and relapse) is briefly considered.

The role of the dorsal striatum in extinction: A memory systems perspective.

The present review describes a role for the dorsal striatum in extinction. Evidence from brain lesion and pharmacological studies indicate that the dorsolateral region of the striatum (DLS) mediates extinction in various maze learning and instrumental learning tasks. Within the context of a multiple memory systems view, the role of the DLS in extinction appears to be selective. Specifically, the DLS mediates extinction of habit memory and is not required for extinction of cognitive memory. Thus, extinction mechanisms mediated by the DLS may involve response-produced inhibition (e.g. inhibition of existing stimulus-response associations or formation of new inhibitory stimulus-response associations), as opposed to cognitive mechanisms (e.g. changes in expectation). Evidence also suggests that NMDA-dependent forms of synaptic plasticity may be part of the mechanism through which the DLS mediates extinction of habit memory. In addition, in some learning situations, DLS inactivation enhances extinction, suggesting a competitive interaction between multiple memory systems during extinction training. Consistent with a multiple memory systems perspective, it is suggested that the DLS represents one of several distinct neural systems that specialize in extinction of different kinds of memory. The relevance of these findings to the development of behavioral and pharmacological therapies that target the maladaptive habit-like symptoms in human psychopathology is also briefly considered.

Enhancing and impairing extinction of habit memory through modulation of NMDA receptors in the dorsolateral striatum.

The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder).

Differential effects of neural inactivation of the dorsolateral striatum on response and latent extinction.

The present study examined the role of the dorsolateral striatum (DLS) in extinction behavior. Male Long-Evans rats were initially trained on the straight alley maze, in which they were reinforced to traverse a straight runway and retrieve food reward at the opposite end of the maze. After initial acquisition, animals were given extinction training using 1 of 2 distinct protocols: response extinction or latent extinction. For response extinction, the animal was released from the same starting position and had the opportunity to perform the originally reinforced approach response to the goal end of the maze, which no longer contained food. For latent extinction, the animal was confined to the original goal location without food, allowing the animal to form a new cognitive expectation (i.e., that the goal location is no longer reinforced). Immediately before response or latent extinction training, animals received bilateral intra-DLS administration of the sodium channel blocker bupivacaine or control injections of physiological saline. Results indicated that neural inactivation of the DLS with bupivacaine impaired response extinction, but did not influence latent extinction. The dissociation observed indicates that the DLS selectively mediates extinction mechanisms involving suppression of the original response, as opposed to cognitive mechanisms involving a change in expectation. (PsycINFO Database Record

Enhancement of striatum-dependent memory by conditioned fear is mediated by beta-adrenergic receptors in the basolateral amygdala.

Emotional arousal can have a profound impact on various learning and memory processes. For example, unconditioned emotional stimuli (e.g., predator odor or anxiogenic drugs) enhance dorsolateral striatum (DLS)-dependent habit memory. These effects critically depend on a modulatory role of the basolateral complex of the amygdala (BLA). Recent work indicates that, like unconditioned emotional stimuli, exposure to an aversive conditioned stimulus (CS) (i.e., a tone previously paired with shock) can also enhance consolidation of DLS-dependent habit memory. The present experiments examined whether noradrenergic activity, particularly within the BLA, is required for a fear CS to enhance habit memory consolidation. First, rats underwent a fear conditioning procedure in which a tone CS was paired with an aversive unconditioned stimulus. Over the course of the next five days, rats received training in a DLS-dependent water plus-maze task, in which rats were reinforced to make a consistent body-turn response to reach a hidden escape platform. Immediately after training on days 1-3, rats received post-training systemic (Experiment 1) or intra-BLA (Experiment 2) administration of the ß-adrenoreceptor antagonist, propranolol. Immediately after drug administration, half of the rats were re-exposed to the tone CS in the conditioning context (without shock). Post-training CS exposure enhanced consolidation of habit memory in vehicle-treated rats, and this effect was blocked by peripheral (Experiment 1) or intra-BLA (Experiment 2) propranolol administration. The present findings reveal that noradrenergic activity within the BLA is critical for the enhancement of DLS-dependent habit memory as a result of exposure to conditioned emotional stimuli.

The dorsolateral striatum selectively mediates extinction of habit memory.

Previous research has indicated a role for the dorsolateral striatum (DLS) in acquisition and retrieval of habit memory. However, the neurobiological mechanisms guiding extinction of habit memory have not been extensively investigated. The present study examined whether the dorsolateral striatum (DLS) is involved in extinction of habit memory in a food-rewarded response learning version of the plus-maze in adult male Long-Evans rats (experiment 1). In addition, to determine whether the role of this brain region in extinction is selective to habit memory, we also examined whether the DLS is required for extinction of hippocampus-dependent spatial memory in a place learning version of the plus-maze (experiment 2). Following acquisition in either task, rats received two days of extinction training, in which the food reward was removed from the maze. The number of perseverative trials (a trial in which the rat made the same previously reinforced body-turn) and latency to reach the previously correct food well were used as measures of extinction. Animals were given immediate post-training intra-DLS administration of the sodium channel blocker bupivacaine or vehicle to determine the effect of DLS inactivation on consolidation of extinction memory in each task. In the response learning task, post-training DLS inactivation impaired consolidation of extinction memory. Injections of bupivacaine delayed 2 h post-training did not affect extinction, indicating a time-dependent effect of neural inactivation on consolidation of extinction memory in this task. In contrast, post-training DLS inactivation did not impair, but instead slightly enhanced, extinction memory in the place learning task. The present findings indicate a critical role for the DLS in extinction of habit memory in the response learning task, and may be relevant to understanding the neural mechanisms through which maladaptive habits in human psychopathologies (e.g. drug addiction) may be suppressed.

Hippocampus NMDA receptors selectively mediate latent extinction of place learning.

Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical "response extinction," animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In "latent extinction," animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)-dependent response learning and hippocampus-dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long-Evans rats were trained in a response learning task in a water plus-maze, in which animals were reinforced to make a consistent body-turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra-hippocampal infusions of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were effective at extinguishing memory in the place learning task. In addition, intra-hippocampal AP5 (7.5 µg) impaired latent extinction, but not response extinction, suggesting that hippocampal NMDA receptors are selectively involved in latent extinction. © 2016 Wiley Periodicals, Inc.

Memory Systems and the Addicted Brain.

The view that anatomically distinct memory systems differentially contribute to the development of drug addiction and relapse has received extensive support. The present brief review revisits this hypothesis as it was originally proposed 20 years ago (1) and highlights several recent developments. Extensive research employing a variety of animal learning paradigms indicates that dissociable neural systems mediate distinct types of learning and memory. Each memory system potentially contributes unique components to the learned behavior supporting drug addiction and relapse. In particular, the shift from recreational drug use to compulsive drug abuse may reflect a neuroanatomical shift from cognitive control of behavior mediated by the hippocampus/dorsomedial striatum toward habitual control of behavior mediated by the dorsolateral striatum (DLS). In addition, stress/anxiety may constitute a cofactor that facilitates DLS-dependent memory, and this may serve as a neurobehavioral mechanism underlying the increased drug use and relapse in humans following stressful life events. Evidence supporting the multiple systems view of drug addiction comes predominantly from studies of learning and memory that have employed as reinforcers addictive substances often considered within the context of drug addiction research, including cocaine, alcohol, and amphetamines. In addition, recent evidence suggests that the memory systems approach may also be helpful for understanding topical sources of addiction that reflect emerging health concerns, including marijuana use, high-fat diet, and video game playing.

The Memory System Engaged During Acquisition Determines the Effectiveness of Different Extinction Protocols.

Previous research indicates that extinction of rodent maze behavior may occur without explicit performance of the previously acquired response. In latent extinction, confining an animal to a previously rewarded goal location without reinforcement is typically sufficient to produce extinction of maze learning. However, previous studies have not determined whether latent extinction may be successfully employed to extinguish all types of memory acquired in the maze, or whether only specific types of memory may be vulnerable to latent extinction. The present study examined whether latent extinction may be effective across two plus-maze tasks that depend on anatomically distinct neural systems. Adult male Long-Evans rats were trained in a hippocampus-dependent place learning task (Experiment 1), in which animals were trained to approach a consistent spatial location for food reward. A separate group of rats were trained in a dorsolateral striatum-dependent response learning task (Experiment 2), in which animals were trained to make a consistent egocentric body-turn response for food reward. Following training, animals received response extinction or latent extinction. For response extinction, animals were given the opportunity to execute the original running approach response toward the empty food cup. For latent extinction, animals were confined to the original goal locations with the empty food cup, thus preventing them from making the original running approach response. Results indicate that, relative to no extinction, latent extinction was effective at extinguishing memory in the place learning task, but remained ineffective in the response learning task. In contrast, typical response extinction remained very effective at extinguishing memory in both place and response learning tasks. The present findings confirm that extinction of maze learning may occur with or without overt performance of the previously acquired response, but that the effectiveness of latent extinction may depend on the type of memory being extinguished. The findings suggest that behavioral treatments modeled after response extinction protocols may be especially useful in alleviating human psychopathologies involving striatum-dependent memory processes (e.g., drug addiction and relapse).

Differential effects of massed and spaced training on place and response learning: A memory systems perspective.

Studies employing brain lesion or intracerebral drug infusions in rats have demonstrated a double dissociation between the roles of the hippocampus and dorsolateral striatum in place and response learning. The hippocampus mediates a rapid cognitive learning process underlying place learning, whereas the dorsolateral striatum mediates a relatively slower learning process in which stimulus-response habits underlying response learning are acquired in an incremental fashion. One potential implication of these findings is that hippocampus-dependent learning may benefit from a relative massing of training trials, whereas dorsal striatum-dependent learning may benefit from a relative distribution of training trials. In order to examine this hypothesis, the present study compared the effects of massed (30s inter-trial interval; ITI) or spaced (30min ITI) training on acquisition of a hippocampus-dependent place learning task, and a dorsolateral striatum-dependent response task in a plus-maze. In the place task rats swam from varying start points (N or S) to a hidden escape platform located in a consistent spatial location (W). In the response task rats swam from varying start points (N or S) to a hidden escape platform located in the maze arm consistent with a body-turn response (left). In the place task, rats trained with the massed trial schedule acquired the task quicker than rats trained with the spaced trial schedule. In the response task, rats trained with the spaced trial schedule acquired the task quicker than rats trained with the massed trial schedule. The double dissociation observed suggests that the reinforcement parameters most conducive to effective learning in hippocampus-dependent and dorsolateral striatum-dependent learning may have differential temporal characteristics.

The influence of cannabinoids on learning and memory processes of the dorsal striatum.

Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system.

Post-training re-exposure to fear conditioned stimuli enhances memory consolidation and biases rats toward the use of dorsolateral striatum-dependent response learning.

In a dual-solution task that can be acquired using either hippocampus-dependent "place" or dorsolateral striatum-dependent "response" learning, emotional arousal induced by unconditioned stimuli (e.g. anxiogenic drug injections or predator odor exposure) biases rats toward response learning. In the present experiments emotionally-arousing conditioned stimuli were used to modulate the relative use of multiple memory systems. In Experiment 1, adult male Long-Evans rats initially received three standard fear-conditioning trials in which a tone (2 kHz, 75 dB) was paired with a brief electrical shock (1 mA, 2s). On day 2, the rats were trained in a dual-solution plus-maze task to swim from the same start arm (South) to a hidden escape platform always located in the same goal arm (East). Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli (i.e. tone and context) without shock. On day 3, the relative use of place or response learning was assessed on a probe trial in which rats were started from the opposite start arm (North). Post-training re-exposure to fear-conditioned stimuli produced preferential use of a response strategy. In Experiment 2, different rats received fear conditioning and were then trained in a single-solution task that required the use of response learning. Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli without shock. Re-exposure to fear-conditioned stimuli enhanced memory consolidation in the response learning task. Thus, re-exposure to fear-conditioned stimuli biases rats toward the use of dorsolateral striatum-dependent response learning and enhances memory consolidation of response learning.

Reward-based spatial learning in unmedicated adults with obsessive-compulsive disorder.

OBJECTIVE: The authors assessed the functioning of mesolimbic and striatal areas involved in reward-based spatial learning in unmedicated adults with obsessive-compulsive disorder (OCD). METHOD: Functional MRI blood-oxygen-level-dependent response was compared in 33 unmedicated adults with OCD and 33 healthy, age-matched comparison subjects during a reward-based learning task that required learning to use extramaze cues to navigate a virtual eight-arm radial maze to find hidden rewards. The groups were compared in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudorandomly to experimentally prevent learning. RESULTS: Both groups learned to navigate the maze to find hidden rewards, but group differences in neural activity during navigation and reward processing were detected in mesolimbic and striatal areas. During navigation, the OCD group, unlike the healthy comparison group, exhibited activation in the left posterior hippocampus. Unlike healthy subjects, participants in the OCD group did not show activation in the left ventral putamen and amygdala when anticipating rewards or in the left hippocampus, amygdala, and ventral putamen when receiving unexpected rewards (control condition). Signal in these regions decreased relative to baseline during unexpected reward receipt among those in the OCD group, and the degree of activation was inversely associated with doubt/checking symptoms. CONCLUSIONS: Participants in the OCD group displayed abnormal recruitment of mesolimbic and ventral striatal circuitry during reward-based spatial learning. Whereas healthy comparison subjects exhibited activation in this circuitry in response to the violation of reward expectations, unmedicated OCD participants did not and instead over-relied on the posterior hippocampus during learning. Thus, dopaminergic innervation of reward circuitry may be altered, and future study of anterior/posterior hippocampal dysfunction in OCD is warranted.

Changes in corticostriatal connectivity during reinforcement learning in humans.

Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement-learning algorithm to participants' choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial-by-trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning.

Habit learning and memory in mammals: behavioral and neural characteristics.

Goal-direct behavior and habit learning represent two forms of instrumental learning; whereas the former is rapidly acquired and regulated by its outcome, the latter is reflexive, elicited by antecedent stimuli rather than their consequences. Habit learning can be generally defined as the acquisition of associations between stimuli and responses. Habits are acquired via experience-dependent plasticity, occurring repeatedly over the course of days or years and becoming remarkably fixed. The distinction between habit learning, as a product of a procedural learning brain system, and a declarative learning system for encoding facts and episodes is based on the hypothesis that memory is composed of multiple systems that have distinct neuroanatomy and operating principles. Here we review recent research analyzing the main behavioral and neural characteristics of habit learning. In particular, we focus on the distinction between goal-directed and habitual behavior, and describe the brain areas and neurotransmitters systems involved in habit learning. The emotional modulation of habit learning in rodents and primates is reviewed, and the implications of habit learning in psychopathology are briefly described.