Volume 23, Issue 5-6 - Special Issue: The emotional brain and its relation to psychopathology: Edited by Patrizia Campolongo, Carlos Tomaz, Antonella Gasbarri

No abstract available.

Acute stress and emotional arousal can enhance the consolidation of long-term memories in a manner that is dependent on β-adrenoceptor activation in the basolateral complex of the amygdala (BLA). The BLA interacts with multiple memory systems in the brain to modulate a variety of classes of memory. However, the synaptic mechanisms of this interaction remain unresolved. This review describes the evidence of modulation of memory and synaptic plasticity produced by emotional arousal, stress hormones, and pharmacological or electrophysiological stimulation of the amygdala. The amygdala modulation of local translation and/or degradation of the synaptic plasticity-related proteins, activity-regulated cytoskeletal-associated protein and calcium/calmodulin-dependent protein kinase IIα, is offered as a potential mechanism for the rapid memory consolidation that is associated with emotionally arousing events. This model shares features with synaptic tagging and the emotional tagging hypotheses.

The formation and storage of aversively motivated memories is based on plastic changes within the amygdala and other brain structures that are modulated by its activity. One of these structures is the insular cortex, which integrates environmental and interoceptive information such that memory traces can be efficient and rapidly stored. A great example of an aversively motivated learning is the taste aversion paradigm, which involves several changes at the cellular level of the amygdala and the insular cortex in order to be acquired and consolidated. So far, the interplay of these structures was described in terms of their participation during exposure to the stimuli to be associated; however, because of the cellular properties and interconnections between them, their functional interplay may go beyond the acquisition stage and the learning experience might trigger an ongoing engagement of amygdala-insular cortex reactivations in order to store the information.

The activity history of a given neuron or pathway has been suggested to influence its future responses to synaptic inputs. In particular, training in several learning tasks produces a metaplastic change, that is, a change in the ability to induce subsequent synaptic plasticity. Experimental evidence shows that the maintenance of long-term memory and long-term potentiation (LTP) requires the persistent action of the atypical protein kinase C isoform, protein kinase Mζ (PKMζ). Recent work has demonstrated that the inactivation of PKMζ in the insular cortex (IC) abolishes conditioned taste aversion (CTA) long-term memory. Our previous studies in the IC have demonstrated that the induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC projection previous to CTA training enhances the retention of this task. Moreover, recently, we have observed that CTA training blocks the subsequent induction of LTP in the Bla-IC projection. The aim of the present study was to investigate the participation of PKMζ on the CTA-dependent modification of the ability to induce subsequent LTP in the Bla-IC projection in vivo . Thus, we have delivered high-frequency stimulation in the Bla-IC projection in order to induce in vivo IC-LTP in the rats that underwent or did not have an impairment of CTA retention due to the intracortical administration of the selective PKMζ pseudosubstrate inhibitory peptide, ZIP. Our results show that the microinfusion of ZIP into the IC of the behaving rats impairs long-term memory of CTA and prevents its effects on IC-LTP. These results indicate that PKMζ is a key component of the cellular mechanisms necessary for the persistence of lasting memory traces as well as for those underlying metaplastic changes in neocortex, contributing to the persistence of aversive memories.

In recent years, our knowledge of the neurobiology of taste and smell has greatly increased; by using several learning models, we now have a better understanding of the behavioral and neurochemical basis of memory recognition. Studies have provided new evidence of some processes that depend on prior experience with the specific combination of sensory stimuli. This review contains recent research related to taste and odor recognition memory, and the goal is to highlight the role of two prominent brain structures, the insular cortex and the amygdala. These structures have an important function during learning and memory and have been associated with the differences in learning induced by the diverse degrees of emotion during taste/odor memory formation, either aversive or appetitive or when taste and odor are combined and/or potentiated. Therefore, this review includes information about certain neurochemical transmitters and their interactions during appetitive or aversive taste memory formation, taste-potentiated odor aversion memory, and conditioned odor aversion, which might be able to maintain the complex processes necessary for flavor recognition memory.

Most of the work related to the neurobiological basis of memory has been guided by the memory consolidation theory, which was derived from the seminal work of Müller and Pilzecker that was published over a century ago. This theory proposes that the transfer from short- to long-term memory is mediated by a process called consolidation, and while consolidation is taking place, the information to be stored is in a labile state. A great deal of experimentation has given strong support to this proposal, as it has been found repeatedly that interference with neural activity shortly after a learning experience impedes durable retention of that experience. A growing body of evidence, however, indicates that intense emotional experiences prevent memory loss induced by amnesic treatments, even when these treatments are administered intracerebrally shortly after the learning experience. This evidence implies that the memory consolidation theory cannot account for long-term memory formation when neural activity is disrupted while consolidation should be taking place, and it calls for new hypotheses to account for these findings.

Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested, from mild to extreme. Emotional experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote the development of memories, resulting in maladaptive outcomes such as compulsive seeking or avoidance. We have offered evidence that prefrontal cortical norepinephrine transmission is a necessary condition for motivational salience attribution to highly salient stimuli through modulation of dopamine in the nucleus accumbens, a brain area involved in motivated behaviors. Moreover, the prefrontal-accumbal catecholamine system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus is high enough to induce sustained catecholamine activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events. This system, when activated by highly salient stimuli, is likely to lead to motivational and neural processes that trigger mechanisms causing aberrant motivational salience attribution and to engage other frontal-subcortical systems, resulting in compulsion-driven behavioral disorders.

Research on the function of the nucleus accumbens, the most ventral component of the striatal complex, has traditionally focused on locomotor activity, reward, motivation and addiction. However, based on the existence of projections to the nucleus accumbens from the allocortical regions involved in spatial navigation, it has been suggested that this structure plays a role in spatial learning and memory. Lesion and neuropharmacological studies confirm this view, also revealing the complex dynamics of the receptors involved in these processes. Moreover, the effects of post-training intra-nucleus accumbens drug administrations demonstrate the necessity of off-line neural activity within this structure in order to consolidate spatial memory. Blockade of molecular processes implicated in synaptic plasticity, such as cAMP response element-binding protein (CREB)-induced transcription or extracellular matrix remodeling, provides further experimental support to this hypothesis. These observations imply that experience-dependent synaptic plasticity responsible for long-term stabilization of spatial information might occur within the nucleus accumbens, similarly to what has been observed in the hippocampus. This suggests that a comprehensive understanding of spatial memory processing should be viewed in the context of a wider neural circuit.

Serotonin (5-hydroxytryptamien, 5-HT) has been linked to emotional and motivational aspects of human behavior, including anxiety, depression, impulsivity, etc. Several clinically effective drugs exert effects via 5-HT systems. Growing evidence suggests that those effects play an important role in learning and memory. Whether the role of serotonin is related to memory and/or behavioral or emotional aspects remains an important question. A key question that remains is whether 5-HT markers (e.g., receptors) directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis. The major aim of this paper is to re-examine some recent advances regarding mammalian 5-HT receptors and transporter in light of their physiological, pathophysiological and therapeutic implications for memory. We particularly address evidence involving 5-HT systems in behavioral, pharmacological, molecular, genetic and imaging results and memory. Finally, this paper aims to summarize a portion of the evidence about serotonin, memory and emotion from animal and human studies and provide an overview of potential tools, markers and cellular and molecular candidate mechanisms. It should be noted that there are several subjects that this paper only briefly touches upon, presenting only what may be the most salient findings in the context of memory, emotion and serotonin.

The changes in serotonin type 3 (5-HT 3 ) receptor activity influence memory and emotional regulation, the two essential components underlying the successful extinction of conditioned fear. These studies determined if blocking 5-HT 3 receptors with granisetron influences the extinction of fear in male Sprague-Dawley rats. In Experiment 1, preextinction granisetron (0.5 or 1.0 mg/kg intraperitoneally) did not affect cued extinction learning but enhanced memory for the extinction session on retention test given 24 and 48 h later. In Experiment 2, granisetron injections given on days 1 and 4 during 6 days of extinction training reduced fear produced by contextual fear conditioning. Experiments 3 and 4 examined if 5-HT 3 antagonists influence extinction memory by interactions with γ-aminobutyric acid (GABA). The expression of the GABA A receptor clustering protein gephyrin was significantly elevated in the amygdala after cued fear extinction training and a subsequent extinction retention test given 24 h later. Gephyrin expression in the hippocampus but not in the amygdala or the medial prefrontal cortex was significantly reduced after contextual fear extinction sessions given 1 or 5 days after training. The current studies reveal the beneficial effects of 5-HT 3 receptor activity in improving new learning associated with extinction of fearful memories and suggest that these actions could be mediated through influences on central GABAergic systems.

Mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) act by activating NMB receptors (NMBR, BB1) and GRP receptors (GRPR, BB2), respectively. These two bombesin receptors are members of the G-protein-coupled receptor (GPCR) superfamily. In the brain, NMBR and GRPR are highly expressed in the brain areas involved in memory processing and emotional responses, such as the hippocampus and the amygdaloid nuclei. An increasing number of pharmacological and genetic studies in rodents indicate that NMBRs and GRPRs in brain regions including the dorsal hippocampus, the nucleus tractus solitarius, the basolateral amygdala, and cortical areas, regulate memory formation and expression, particularly for memories related to emotionally arousing tasks. GRPR signaling interacts with multiple protein kinase pathways as well as with other neurotransmitter, hormone, and growth factor systems in influencing memory formation. Together with evidence from human studies, the findings from rodent experiments suggest that bombesin receptors may be therapeutic targets in brain disorders involving memory dysfunction and anxiety.

Accumulating evidence has highlighted a number of important, global issues regarding the influence of estrogen on emotion and cognitive functions, including learning and memory processes, both in animal models and humans. The influence of estrogen on cognition and emotion can be explained by taking into account its modulator role on several neurotransmitter systems, acetylcholine in particular, but also catecholamines, serotonin and GABA in rodents, primates and humans. Another reason may lie in the widespread presence of the two classes (α and β) of estrogen receptors in many brain regions involved in emotion and cognition, including the hippocampal formation, amygdala and cerebral cortex. The present review reports on research conducted in our laboratory and others with the objective of identifying the action of estrogens on cognition and emotion in rodents, monkeys and humans in youth. In particular, the first section, focused on the mechanisms of estrogens action in the brain, illustrates the involvement of estrogen receptors and neurotransmitters in the cognitive and emotional processes; the second section deals with the estrogen effects on cognitive and emotional mechanisms, with particular emphasis on memory and the involvement of estrogen in emotion and cognition across the estrous/menstrual cycle.

Under basal conditions histone deacetylases (HDACs) and their associated co-repressor complexes serve as molecular ‘brake pads’ to prevent the gene expression required for long-term memory formation. Following a learning event, HDACs and their co-repressor complexes are removed from a subset of specific gene promoters, allowing the histone acetylation and active gene expression required for long-term memory formation. Inhibition of HDACs increases histone acetylation, extends gene expression profiles, and allows for the formation of persistent long-term memories for training events that are otherwise forgotten. We propose that emotionally salient experiences have utilized this system to form strong and persistent memories for behaviorally significant events. Consequently, the presence or absence of HDACs at a selection of specific gene promoters could serve as a critical barrier for permitting the formation of long-term memories.

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.

Aberrant emotional memory processing is a core, disabling feature of both specific phobias and posttraumatic stress disorder (PTSD), two psychiatric diseases of significant prevalence and morbidity whose cognitive symptoms cannot be adequately treated by current psychopharmacological tools. Elucidating the neurobiological mechanisms involved in the etiology of these diseases is of great interest for the identification of new therapeutics that improve not only the symptomatology but also the full recovery from the pathology. To this aim, several animal models have been proposed based on substantial resemblance between the behavioral alterations seen in animals and the human pathology. The purpose of this review is to describe and comment on the most commonly used rodent models of specific phobias and PTSD. A particular focus will be reserved to the cued version of fear conditioning, as the highly specific stimulus-bound conditioned fear response seems to fit well with clinical descriptions of phobic fear. Moreover, animal models of PTSD will be evaluated by referring to three elements that are considered essential in a valid model of this disease: stressor exposure, memory for the stressor, and anxiety-related behaviors. Finally, current therapeutic directions, with a focus on cannabinoid and glucocorticoid compounds, will be briefly outlined.

Stress is the main non-genetic source of psychopathology. Therefore, the identification of neurobiological bases of resilience, the resistance to pathological outcomes of stress, is a most relevant topic of research. It is an accepted view that resilient individuals are those who do not develop helplessness, or other depression-like phenotypes, following a history of stress. In the present review, we discuss the phenotypic differences between mice of the inbred C57BL/6J and DBA/2J strains that could be associated with the strain-specific resistance to helplessness observable in DBA/2J mice. The reviewed results support the hypothesis that resilience to stress-promoted helplessness develops through interactions between a specific genetic makeup and a history of stress, and is associated with an active coping style, a bias toward the use of stimulus-response learning, and specific adaptive changes of mesoaccumbens dopamine transmission under stress. Finally, evidence that compulsivity represents a side effect of the neuroadaptive processes fostering resistance to develop depressive-like phenotypes under stress is discussed.

The endocannabinoid system (ECS) plays an important role in the regulation of physiological functions, from stress and memory regulation to vegetative control and immunity. The ECS is considered a central and peripheral stress response system to emotional or physical challenges and acts through endocannabinoids (ECs), which bind to their receptors inducing subsequent effecting mechanisms. In our studies, the ECS responses have been assessed through blood concentrations of the ECs anandamide and 2-arachidonoylglycerol. In parallel, saliva cortisol was determined and the degree of perceived stress was quantified by questionnaires. This report summarizes the reactivity of the ECS in humans subjected to brief periods of kinetic stress and weightlessness during parabolic flights and to prolonged stress exposure during life onboard the International Space Station (ISS). Both conditions resulted in a significant increase in circulating ECs. Under the acute stress during parabolic flights, individuals who showed no evidence of motion sickness were in low-stress conditions and had a significant increase of plasma ECs. In contrast, highly stressed individuals with severe motion sickness had an absent EC response and a massive increase in hypothalamic-pituitary-adrenal axis activity. Likewise, chronic but well-tolerated exposure to weightlessness and emotional and environmental stressors on the ISS for 6 months resulted in a sustained increase in EC blood concentrations, which returned to baseline values after the cosmonauts’ return. These preliminary results suggest that complex environmental stressors result in an increase of circulating ECs and that enhanced EC signaling is probably required for adaptation and tolerance under stressful conditions.

Background: Endocannabinoids (ECs) are rapidly acting immune-modulatory lipid-signaling molecules that are important for adaptation to stressful and aversive situations. They are known to interact with glucocorticoids and other stress-responsive systems. Maladaptation to acute or chronic stress represents a major risk factor for the development of psychiatric disorders. In the present study, we administered stress doses of hydrocortisone in a prospective, randomized, placebo-controlled double-blind study in patients undergoing cardiac surgery (CS) to examine the relationship between the use of glucocorticoids, plasma EC levels, and the occurrence of early postoperative cognitive dysfunction (delirium) and of later development of depression. Methods: We determined plasma levels of the ECs anandamide and 2-arachidonoylglycerol (2-AG) in CS patients of the hydrocortisone (n=56) and the placebo group (n=55) preoperatively, at postoperative day (POD) 1, at intensive care unit discharge, and at 6 months after CS (n=68). Postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of the American Psychiatric Association IVth Edition (DSM-IV) criteria, and depression was determined by validated questionnaires and a standardized psychological interview (Structured Clinical Interview for DSM-IV ). Results: Stress doses of hydrocortisone did not affect plasma EC levels and the occurrence of delirium or depression. However, patients who developed delirium on POD 1 had significantly lower preoperative 2-AG levels of the neuroprotective EC 2-AG (median values, 3.8 vs. 11.3 ng/ml; p =0.03). Preoperative 2-AG concentrations were predictive of postoperative delirium (sensitivity=0.70; specificity=0.69; cutoff value=4.9 ng/ml; receiver operating characteristic curve area=0.70; 95% confidence interval=0.54–0.85). Patients with depression at 6 months after CS (n=16) had significantly lower anandamide and 2-AG levels during the perioperative period. Conclusions: A low perioperative EC response may indicate an increased risk for early cognitive dysfunction and long-term depression in patients after CS. Glucocorticoids do not seem to influence this relationship.

Three studies illustrate the relationship between memory, emotion, age, and chronic cerebrovascular disorders (CCVDs). In study A, emotion and age interact to produce secondary effects on memory functioning. In study B, emotion-related complaints are correlated with the cognition-related complaints only for high or low levels of impairment. For intermediate levels of impairment, the two components of subjective complaints are independent. In study C, there is a relationship between aging and the pathological interference by CCVD on memory productivity; young healthy persons do better than aged healthy persons who do better than patients with vascular cognitive impairment (VCI). However, memory processing is different in terms of encoding and organization of stimuli. Young healthy subjects automatically use the semantic structure of the verbal stimuli, whereas the aged healthy persons do so only after a second learning session. Patients with VCI have lost this ability. They keep encoding and organizing items according to the serial effect, the common strategy spontaneously followed by everyone when presented with unstructured stimuli. These are examples of the complex relationships that characterize memory functioning and that should be taken into account when assessing memory when the role of the age factor, the emotional factor, and an eventual CCVD factor should be specifically identified.

Defense and social mechanisms in primates seem to share, at least in infancy, common neural substrata. Among these, recent research has implicated the primate superior colliculus (SC) on tasks involving visual detection and recognition of threatening stimuli, such as snakes and faces with emotional expressions. There is also evidence that both kinds of stimuli share specific characteristics and command special attention in the primate visual system. The present review focuses on the role of the SC in these seemingly overlapping functions. We present social behavioral data from capuchin monkeys in which the bilateral lesion of the SC induced a transitory impairment of social behaviors. The findings presented here are compared with previous studies, our own and others, on social behaviors and threat detection. We argue that, although the SC may participate in both systems, its role is more prominent in the detection/recognition of threat. Social interactions more likely depend on larger and more complex neural systems, where the SC may play a key role in early infancy. The implications of these recent findings are discussed under an evolutionary perspective.

Mother-infant interactions are essential for proper neurobehavioral development of the offspring, and disruptions in those relationships may result in neuroendocrine, neurochemical and behavioral alterations at adulthood. The neural circuitries involved in mother-infant interactions have not been completely elucidated yet. The brain endocannabinoid system plays an essential role in prenatal and postnatal neurobehavioral development. Here, we will summarize and discuss the available findings about the role of endocannabinoids in three key aspects of mother-infant interactions in rodents: suckling, maternal behavior and separation-induced ultrasonic vocalizations (USVs). The studies reviewed here show that endocannabinoids are not only involved in suckling initiation and, therefore, in the feeding and growth of the offspring, but also regulate the emotional reactivity of rodent pups, as measured by the rate of isolation-induced USVs. Conversely, less information is available about endocannabinoid modulation of maternal behavior, and therefore more research in this direction is warranted. Indeed, since Cannabis sativa preparations are widely used by young people, including pregnant and lactating women, it is important to understand whether developmental exposure to cannabinoids interferes with mother-infant bond formation, potentially leading to neurodevelopmental alterations and increased vulnerability to psychopathology later in life.

Although costly in energy and time, social play is present and evolutionarily conserved in nearly all young mammals. Ontogenetic factors responsible for this particular form of supposed rewarding behavior are incompletely understood. Here, we have focused our attention on maternal glucocorticoid hormone. We used a model in which neonate rats are fed by mothers in which drinking water has been supplemented with 0.2 mg/ml corticosterone. The control groups were lactated by water-drinking mothers. Both male and female adolescent offspring of corticosterone (CORT) supplemented dams (CORT-nursed) showed an increase in social play behavior (i.e., pinning, pouncing, wrestling/boxing and social exploration) when compared to controls. No differences were observed between CORT-nursed progeny of both sexes and controls in the exploration of the arena during the social encounter. Finally, no differences were found in CORT plasma levels in basal conditions and following a social play session in both male and female CORT-nursed rats. These results indicate that variations in the maternal glucocorticoid status are able, directly or indirectly, to influence social play behavior in the offspring, although there is no direct relationship between the level of social play behavior and the intensity of adrenocortical activation.

Drug addiction is a chronic relapsing brain disease, characterized by compulsive drug use. Despite the fact that drug addiction affects millions of people worldwide, treatments for this disorder are limited in number and efficacy. In our opinion, understanding the neural underpinnings of drug addiction would open new avenues for the development of innovative treatments for this disorder. Based on an awareness that drug use and drug reward do not equal drug addiction, there has been increasing interest in developing animal models of addiction that mimick the loss of control over drug use more closely than existing models aimed at studying drug reward. The present review provides an overview of animal studies of compulsive drug use and the neural mechanisms involved. First, the employed models are summarized, with a particular emphasis on models of escalation of drug use and resistance to punishment. Next, we discuss mechanisms within the (ventral and dorsal) striatum and (central) amygdala that have recently been implicated in the compulsive seeking and taking of alcohol and cocaine. The studies discussed here provide a promising line of research that will advance our knowledge of the neural circuits involved in the self-destructive behavior that characterizes drug addiction.

The present paper reviews foundational and contemporary theories of motivated behaviors and the growing body of evidence that they require specific functional interactions within the basal ganglia. Such evidence suggests that unconditioned responses (UR), conditioned responses (CR), goal-directed actions and stimulus-response (S-R) habits are selected in the basal ganglia. Such selection depends on activation of striatal neurons by cortical and subcortical neurons encoding unconditioned stimuli (US), conditioned stimuli (CS), goals and neutral stimuli (S). These neurons project respectively to the medial nucleus accumbens (NAc) shell/olfactory tubercle, NAc core/lateral olfactory tubercle, dorsolateral striatum and dorsomedial striatum. The strength of these synapses is altered when the levels of extracellular dopamine in the basal ganglia undergo phasic increases or decreases, which signal outcomes that are, respectively, better or worse than expected. In addition, dopamine release in response to salient USs and to CSs with incentive salience increases the signal-to-noise ratio of corticostriatal neurotransmission, thus ‘energizing’ the performance of selected actions. Different actions can be selected in the striatum because the striatal neurons of the so-called direct and indirect pathways can respectively initiate and end actions through pallidum/nigral-thalamic projections to premotor and motor areas of the cortex. According to this view, the basal ganglia is thought to play a role in the action-selection processes needed for the expression of both declarative and procedural memories, but the memories of the contexts, predictive stimuli or neutral stimuli associated with free rewards or with an action’s outcomes are stored elsewhere.

Drug abuse is often seen as a unitary phenomenon, partly as a result of the discovery over the past three decades of shared mechanisms of action for addictive substances. Yet the pattern of drug taking is often very different from drug to drug. This is particularly evident in the case of ‘club drugs’, such as ketamine. Although the number of ketamine abusers is relatively small in the general population, it is quite substantial in some settings. In particular, ketamine abuse is almost exclusively limited to clubs and large music parties, which suggests a major role of context in modulating the reward effects of this drug. This review focuses on recent preclinical and clinical findings, including previously unpublished data, that provide evidence that, even under controlled conditions, ketamine reward is a function of the setting of drug taking.