Jarid Goodman

Emotional modulation of multiple memory systems: implications for the neurobiology of post-traumatic stress disorder

Abstract In lower animals and humans, stress/anxiety can enhance dorsal striatal-dependent habit memory, at the expense of hippocampal-dependent cognitive memory. The present review considers the potential for this ‘stress/anxiety-induced habit bias’ to explain some aspects of post-traumatic stress disorder (PTSD). In rats, anxiety induced by peripheral or intra-amygdala infusions of anxiogenic drugs can enhance habit memory and impair cognitive memory. In tasks in which both habit and cognitive memory processes may provide a learned solution, stress and drug-induced anxiety favors the use of habit memory. The effect of stress and anxiety on the use of multiple memory systems in rats depends on the functional integrity of the basolateral amygdala. Thus, under robust emotional arousal, amygdala activation can modulate the relative use of memory systems in a manner that favors habit memory. We propose a similar mechanism may underlie the development and persistence of some PTSD symptoms. The traumatic memories of PTSD patients can be deficient in hippocampus-dependent contextual or autobiographical aspects, and enhanced in responding to trauma-related cues, which we suggest may reflect increased involvement of the dorsal striatum. We briefly consider the potential role of a stress/anxiety-induced habit bias with regard to other psychopathologies, including obsessive-compulsive disorder and drug addiction.

Emotional arousal and multiple memory systems in the mammalian brain.

Emotional arousal induced by stress and/or anxiety can exert complex effects on learning and memory processes in mammals. Recent studies have begun to link study of the influence of emotional arousal on memory with earlier research indicating that memory is organized in multiple systems in the brain that differ in terms of the “type” of memory they mediate. Specifically, these studies have examined whether emotional arousal may have a differential effect on the “cognitive” and stimulus-response “habit” memory processes sub-served by the hippocampus and dorsal striatum, respectively. Evidence indicates that stress or the peripheral injection of anxiogenic drugs can bias animals and humans toward the use of striatal-dependent habit memory in dual-solution tasks in which both hippocampal and striatal-based strategies can provide an adequate solution. A bias toward the use of habit memory can also be produced by intra-basolateral amygdala (BLA) administration of anxiogenic drugs, consistent with the well documented role of efferent projections of this brain region in mediating the modulatory influence of emotional arousal on memory. In some learning situations, the bias toward the use of habit memory produced by emotional arousal appears to result from an impairing effect on hippocampus-dependent cognitive memory. Further research examining the neural mechanisms linking emotion and the relative use of multiple memory systems should prove useful in view of the potential role for maladaptive habitual behaviors in various human psychopathologies.

Factors that influence the relative use of multiple memory systems

Neurobehavioral evidence supports the existence of at least two anatomically distinct “memory systems” in the mammalian brain that mediate dissociable types of learning and memory; a “cognitive” memory system dependent upon the hippocampus and a “stimulus‐response/habit” memory system dependent upon the dorsolateral striatum. Several findings indicate that despite their anatomical and functional distinctiveness, hippocampal‐ and dorsolateral striatal‐dependent memory systems may potentially interact and that, depending on the learning situation, this interaction may be cooperative or competitive. One approach to examining the neural mechanisms underlying these interactions is to consider how various factors influence the relative use of multiple memory systems. The present review examines several such factors, including information compatibility, temporal sequence of training, the visual sensory environment, reinforcement parameters, emotional arousal, and memory modulatory systems. Altering these parameters can lead to selective enhancements of either hippocampal‐dependent or dorsolateral striatal‐dependent memory, and bias animals toward the use of either cognitive or habit memory in dual‐solution tasks that may be solved adequately with either memory system. In many learning situations, the influence of such experimental factors on the relative use of memory systems likely reflects a competitive interaction between the systems. Research examining how various factors influence the relative use of multiple memory systems may be a useful method for investigating how these systems interact with one another.

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 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.

Glucocorticoid enhancement of dorsolateral striatum-dependent habit memory requires concurrent noradrenergic activity.

Previous findings indicate that post-training administration of glucocorticoid stress hormones can interact with the noradrenergic system to enhance consolidation of hippocampus- or amygdala-dependent cognitive/emotional memory. The present experiments were designed to extend these findings by examining the potential interaction of glucocorticoid and noradrenergic mechanisms in enhancement of dorsolateral striatum (DLS)-dependent habit memory. In experiment 1, different groups of adult male Long-Evans rats received training in two DLS-dependent memory tasks. In a cued water maze task, rats were released from various start points and were reinforced to approach a visibly cued escape platform. In a response-learning version of the water plus-maze task, animals were released from opposite starting positions and were reinforced to make a consistent egocentric body-turn to reach a hidden escape platform. Immediately post-training, rats received peripheral injections of the glucocorticoid corticosterone (1 or 3 mg/kg) or vehicle solution. In both tasks, corticosterone (3 mg/kg) enhanced DLS-dependent habit memory. In experiment 2, a separate group of animals received training in the response learning version of the water plus-maze task and were given peripheral post-training injections of corticosterone (3 mg/kg), the β-adrenoreceptor antagonist propranolol (3 mg/kg), corticosterone and propranolol concurrently, or control vehicle solution. Corticosterone injections again enhanced DLS-dependent memory, and this effect was blocked by concurrent administration of propranolol. Propranolol administration by itself (3 mg/kg) did not influence DLS-dependent memory. Taken together, the findings indicate an interaction between glucocorticoid and noradrenergic mechanisms in DLS-dependent habit memory. Propranolol administration may be useful in treating stress-related human psychopathologies associated with a dysfunctional DLS-dependent habit memory system.

Buspirone blocks the enhancing effect of the anxiogenic drug RS 79948-197 on consolidation of habit memory

Previous findings indicate that post-training administration of the anxiogenic α(2)-adrenoceptor antagonist RS 79948-197 facilitates the consolidation of dorsal striatal-dependent habit memory. The present study examined the effect of concurrent administration of the anxiolytic serotonin 5-HT(1A) receptor partial agonist buspirone on anxiety-induced facilitation of habit memory. Male Long-Evans rats were trained in a response learning version of a water plus-maze task that requires animals to learn to make the same body turn response on each trial in order to reach a hidden escape platform. Immediately following training on days 1-3, rats received peripheral injections of either saline, buspirone (1.5 mg/kg, 2.0 mg/kg, or 5.0 mg/kg), RS 79948-197 (0.1 mg/kg), or RS 79948-197 and buspirone together. Post-training injections of RS 79948-197 alone significantly enhanced memory consolidation. The highest dose of buspirone (5.0 mg/kg) also enhanced response learning. However, concurrent administration of a dose of buspirone (1.5 mg/kg) that itself had no effect on acquisition blocked the memory enhancing effects of RS 79948-197. These findings suggest that the facilitation of habit memory observed following drug-induced anxiety can be prevented by co-administration of an anxiolytic agent.

Peripheral and intra-dorsolateral striatum injections of the cannabinoid receptor agonist WIN 55,212-2 impair consolidation of stimulus-response memory.

The endocannabinoid system plays a major role in modulating memory. In the present study, we examined whether cannabinoid agonists influence the consolidation of stimulus-response/habit memory, a form of memory dependent upon the dorsolateral striatum (DLS). In Experiment 1, rats were trained in a cued platform water maze task in which animals were released from different start points and in order to escape had to find a cued platform which was moved to various spatial locations across trials. Immediately following training, rats received an i.p. injection of the cannabinoid receptor agonist WIN 55,212-2 (1 or 3mg/kg) or a vehicle solution. In Experiment 2, rats were trained in a forced-response version of the water plus-maze task in which a consistent body-turn response was reinforced across trials. Immediately following training, rats received an i.p. injection of WIN 55,212-2 (3 mg/kg) or vehicle. In Experiment 3, rats were trained in the cued platform task and after training received bilateral intra-DLS WIN 55,212-2 (100 ng/.5 μL or 200 ng/.5 μL) or vehicle. In Experiments 1-3, the higher doses of WIN 55,212-2 were associated with significant memory impairments, relative to vehicle-treated controls. The results indicate that peripheral or intra-DLS administration of a cannabinoid receptor agonist impairs consolidation of DLS-dependent memory. The findings are discussed within the context of previous research encompassing cannabinoids and DLS-dependent learning and memory processes, and the possibility that cannabinoids may be used to treat some habit-like human psychopathologies (e.g. posttraumatic stress disorder) is considered.

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.

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 β-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.