Emotional memory and psychopathology

A leading model for studying how the brain forms memories about unpleasant experiences is fear conditioning. A cumulative body of work has identified major components of the neural system mediating this form of learning. The pathways involve transmission of sensory information from processing areas in the thalamus and cortex to the amygdala. The amygdala's lateral nucleus receives and integrates the sensory inputs from the thalamic and cortical areas, and the central nucleus provides the interface with motor systems controlling specific fear responses in various modalities (behavioural, autonomic, endocrine). Internal connections within the amygdala allow the lateral and central nuclei to communicate. Recent studies have begun to identify some sites of plasticity in the circuitry and the cellular mechanisms involved in fear conditioning. Through studies of fear conditioning, our understanding of emotional memory is being taken to the level of cells and synapses in the brain. Advances in understanding emotional memory hold out the possibility that emotional disorders may be better defined and treatment improved.     

An anatomically constrained neural network model of fear conditioning.

Conditioning of fear reactions to an auditory conditioned stimulus (CS) paired with a footshock unconditioned stimulus/stimuli (UCS) involves CS transmission to the amygdala from the auditory thalamus, the auditory cortex, or both. This article presents a simple neural network model of this neural system. The model consists of modules of mutually inhibitory nonlinear units representing the different relevant anatomical structures of the thalamo-amygdala and thalamo-cortico-amygdala circuitry. Frequency-specific changes produced by fear conditioning were studied at the behavioral level (stimulus generalization) and the single-unit level (receptive fields). The findings mirror effects observed in conditioning studies of animals. This computational model provides an initial grounding for explorations of how emotional information and behavior are related to anatomical and physiological observations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala

Fear conditioning is a paradigm that has been used as a model for emotional learning in animals. The cellular correlate of fear conditioning is thought to be associative N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity within the amygdala. Here we show that glutamatergic synaptic transmission to inhibitory interneurons in the basolateral amygdala is mediated solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast to AMPA receptors at inputs to pyramidal neurons, these receptors have an inwardly rectifying current-voltage relationship, indicative of a high permeability to calcium. Tetanic stimulation of inputs to interneurons caused an immediate and sustained increase in the efficacy of these synapses. This potentiation required a rise in postsynaptic calcium, but was independent of NMDA receptor activation. The potentiation of excitatory inputs to interneurons was reflected as an increase in the amplitude of the GABA(A)-mediated inhibitory synaptic current in pyramidal neurons. These results demonstrate that excitatory synapses onto interneurons within a fear conditioning circuit show NMDA-receptor independent long-term potentiation. This plasticity might underlie the increased synchronization of activity between neurons in the basolateral amygdala after fear conditioning.     

Retrieval of emotional memories.

Long-term memories are influenced by the emotion experienced during learning as well as by the emotion experienced during memory retrieval. The present article reviews the literature addressing the effects of emotion on retrieval, focusing on the cognitive and neurological mechanisms that have been revealed. The reviewed research suggests that the amygdala, in combination with the hippocampus and prefrontal cortex, plays an important role in the retrieval of memories for emotional events. The neural regions necessary for online emotional processing also influence emotional memory retrieval, perhaps through the reexperience of emotion during the retrieval process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A role for the Ras signalling pathway in synaptic transmission and long-term memory

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.     

The current status of adjuvant hormonal therapy combined with radiation therapy for localised prostate cancer

The limbic system comprises the hippocampal formation, fornix, mamillary bodies, thalamus, and other integrated structures. It is involved in complex functions including memory and emotion and in diseases such as temporal lobe epilepsy. Volume measurements of the amygdala and hippocampus have been used reliably to study patients with temporal lobe epilepsy but have not extended to other limbic structures. We performed volume measurements of hippocampus, amygdala, fornix and mamillary bodies in healthy individuals. Measurements of the amygdala, hippocampus, fornix and mamillary bodies revealed significant differences in volume between right and left sides (P < 0.001). The intraclass coefficient of variation for measurements was high for all structures except the mamillary bodies. Qualitative image assessment of the same structures revealed no asymmetries between the hemispheres. This technique can be applied to the study of disorders affecting the limbic system.     

Synaptic transmission and plasticity in the amygdala. An emerging physiology of fear conditioning circuits

Numerous studies in both rats and humans indicate the importance of the amygdala in the acquisition and expression of learned fear. The identification of the amygdala as an essential neural substrate for fear conditioning has permitted neurophysiological examinations of synaptic processes in the amygdala that may mediate fear conditioning. One candidate cellular mechanism for fear conditioning is long-term potentiation (LTP), an enduring increase in synaptic transmission induced by high-frequency stimulation of excitatory afferents. At present, the mechanisms underlying the induction and expression of amygdaloid LTP are only beginning to be understood, and probably involve both the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subclasses of glutamate receptors. This article will examine recent studies of synaptic transmission and plasticity in the amygdala in an effort to understand the relationships of these processes to aversive learning and memory.     

Neural mechanisms of emotion.

When viewed from an evolutionary perspective, the neural mechanisms of emotion can be seen to be distributed across the brainstem, limbic, paralimbic, and neocortical regions. Descending and ascending connections among these levels are discussed in relation to 3 types of emotional processes: peripheral effects on patterned bodily responses, central effects on cognitive processing, and subjective emotional experience. Descending influences from the higher to the lower levels allow for an increasing coordination and flexibility of emotional responses, culminating in patterned activity across the peripheral endocrine, autonomic, and motor systems. Ascending influences from lower to higher levels provide preparatory modulation of cortical pathways, thus enabling perceptual and cognitive processing that is adaptive given the current emotional state. The bodily feelings of emotion are a function of cortical interoceptive sensory fields, activated by centrally generated signals or peripheral inputs from the body. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural dynamics underlying impaired autonomic and conditioned responses following amygdala and orbitofrontal lesions.

A neural model is presented that explains how outcome-specific learning modulates affect, decision-making, and Pavlovian conditioned approach responses. The model addresses how brain regions responsible for affective learning and habit learning interact and answers a central question: What are the relative contributions of the amygdala and orbitofrontal cortex to emotion and behavior? In the model, the amygdala calculates outcome value while the orbitofrontal cortex influences attention and conditioned responding by assigning value information to stimuli. Model simulations replicate autonomic, electrophysiological, and behavioral data associated with three tasks commonly used to assay these phenomena: Food consumption, Pavlovian conditioning, and visual discrimination. Interactions of the basal ganglia and amygdala with sensory and orbitofrontal cortices enable the model to replicate the complex pattern of spared and impaired behavioral and emotional capacities seen following lesions of the amygdala and orbitofrontal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intrinsic and thalamic excitatory inputs onto songbird LMAN neurons differ in their pharmacological and temporal properties

In passerine songbirds, the lateral portion of the magnocellular nucleus of the anterior neostriatum (LMAN) plays a vital role in song learning, possibly by encoding sensory information and providing sensory feedback to the vocal motor system. Consistent with this, LMAN neurons are auditory, and, as learning progresses, they evolve from a broadly tuned initial state to a state of strong preference for the bird's own song and acute sensitivity to the temporal order of this song. Moreover, normal synaptic activity in LMAN is required during sensory learning for accurate tutor song copying to occur (). To explore cellular and synaptic properties of LMAN that may contribute to this crucial stage of song acquisition, we developed an acute slice preparation of LMAN from zebra finches in the early stages of sensory learning (18-25 days posthatch). We used this preparation to examine intrinsic neuronal properties of LMAN neurons at this stage and to identify two independent excitatory inputs to these neurons and compare each input's pharmacology and short-term synaptic plasticity. LMAN neurons had immature passive membrane properties, well-developed spiking behavior, and received excitatory input from two sources: afferents from the medial portion of the dorsolateral thalamus (DLM), and recurrent axon collaterals from LMAN itself ("intrinsic" input). These two inputs differed in both their pharmacology and temporal properties. Both inputs were glutamatergic, but LMAN responses to intrinsic inputs exhibited a larger N-methyl--aspartate component than responses to DLM inputs. Both inputs elicited temporal summation in response to pairs of stimuli delivered at short intervals, but -2-amino-5-phosphonovalerate (APV) significantly reduced the temporal summation only of the responses to intrinsic inputs. Moreover, responses to DLM inputs showed consistent paired-pulse depression, whereas the responses to intrinsic inputs did not. The differences between these two inputs suggest that intrinsic circuitry plays an important role in transforming DLM input patterns into the appropriate LMAN output patterns, as has been suggested for mammalian thalamocortical networks. Moreover, in LMAN, such interactions may contribute to the profound temporal and spectral selectivity that these neurons will acquire during learning.     

Amygdala beta-noradrenergic influence on hippocampal long-term potentiation in vivo

We have previously shown that hippocampal long-term potentiation (LTP), one form of synaptic plasticity that may underlie learning and memory, is attenuated by blocking neuron activity of the basolateral amygdala (BLA). In the present study we investigated the amygdala noradrenergic or cholinergic contribution to hippocampal LTP formation. When propranolol, a beta-adrenoceptor antagonist, was injected into the BLA 10 min before tetanus, the formation of LTP in the perforant path-dentate granule cell synapses was significantly impaired. Scopolamine, a muscarinic cholinergic receptor antagonist, did not affect the formation of LTP. These results suggest that amygdala beta-noradrenergic activity plays a critical role in modulation of hippocampal LTP.     

Physiological memory in primary auditory cortex: characteristics and mechanisms

"Physiological memory" is enduring neuronal change sufficiently specific to represent learned information. It transcends both sensory traces that are detailed but transient and long-term physiological plasticities that are insufficiently specific to actually represent cardinal details of an experience. The specificity of most physiological plasticities has not been comprehensively studied. We adopted receptive field analysis from sensory physiology to seek physiological memory in the primary auditory cortex of adult guinea pigs. Receptive fields for acoustic frequency were determined before and at various retention intervals after a learning experience, typified by single-tone delay classical conditioning, e.g., 30 trials of tone-shock pairing. Subjects rapidly (5-10 trials) acquire behavioral fear conditioned responses, indexing acquisition of an association between the conditioned and the unconditioned stimuli. Such stimulus-stimulus association produces receptive field plasticity in which responses to the conditioned stimulus frequency are increased in contrast to responses to other frequencies which are decreased, resulting in a shift of tuning toward or to the frequency of the conditioned stimulus. This receptive field plasticity is associative, highly specific, acquired within a few trials, and retained indefinitely (tested to 8 weeks). It thus meets criteria for "physiological memory." The acquired importance of the conditioned stimulus is thought to be represented by the increase in tuning to this stimulus during learning, both within cells and across the primary auditory cortex. Further, receptive field plasticity develops in several tasks, one-tone and two-tone discriminative classical and instrumental conditioning (habituation produces a frequency-specific decrease in the receptive field), suggesting it as a general process for representing the acquired meaning of a signal stimulus. We have proposed a two-stage model involving convergence of the conditioned and unconditioned stimuli in the magnocellular medial geniculate of the thalamus followed by activation of the nucleus basalis, which in turn releases acetylcholine that engages muscarinic receptors in the auditory cortex. This model is supported by several recent findings. For example, tone paired with NB stimulation induces associative, specific receptive field plasticity of at least a 24-h duration. We propose that physiological memory in auditory cortex is not "procedural" memory, i.e., is not tied to any behavioral conditioned response, but can be used flexibly.     

Selective effects of triazolam on memory for emotional, relative to neutral, stimuli: Differential effects on gist versus detail.

Benzodiazepines are known to reduce learning and memory performance, presumably through their facilitation of GABAergic neurotransmission, but the effects of these drugs specifically on memory for emotional material has not been addressed in humans. The effects of a benzodiazepine (triazolam, 0.25 mg) on nonincidental memory for emotional stimuli were assessed in 20 healthy volunteers (10 female). Triazolam reduced the normally facilitative effect of emotion on memory. The drug specifically affected memory for the gist of stimuli while leaving detail memory relatively unaffected. This pattern of performance is similar to that seen in patients with amygdala damage. Results suggest an effect of GABAergic neurotransmission at the level of the amygdala on memory modulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synchronization, decrease in strength of pattern, illusory contours, and neon-color effect

The data are reviewed concerning synaptic plasticity of the hippocampal monosynaptic pathways evoked by afferent activation which simulates activity of neurons in theta-rhythm. Activation with short high-frequency bursts applied with 5 Hz frequency effectively induces long-term potentiation. In contrast, activation with single pulses at 5 Hz causes the depotentiation or even long-term depression of the activated synapses. "In-phase" activation of two afferent pathways in the theta-rhythm induces long-term potentiation, while the "out-of-phase" activation induces long-term depression of a "weak" pathway. A train of 30-50 pulses at 5 Hz evokes heterosynaptic short-term depression, i.e., a suppression of all synaptic inputs for 1 min. So-called "hidden" plasticity (the enhancement of the effect of delayed activation in producing long-term depression) is also effectively evoked by the theta-like activatory patterns. Therefore, practically all known types of synaptic plasticity can be effectively evoked by the afferent activation which reproduce the pattern of the hippocampal theta-rhythm. These phenomena can underlie the theta-rhythm participation in learning and memory.     

A dose of MK801 previously shown to impair spatial learning in the radial maze attenuates primed burst potentiation in the dentate gyrus of freely moving rats.

Spatial learning but not memory performance in the radial maze is disrupted by low doses of MK801 (0.0625 mg/kg ip), a noncompetitive N-methyl-{d}-aspartate receptor channel blocker (M. L. Shapiro and C. O'Connor, 1992). The effect of this low dose of MK801 on hippocampal physiology and synaptic plasticity was assessed in 16 behaving female Sprague-Dawley rats. The drug increased the frequency (0.5 Hz), marginally reduced the amplitude of hippocampal rhythmical slow wave activity (RSA), did not alter non-RSA slow wave activity, and reduced normal synaptic transmission from the entorhinal cortex to the dentate gyrus by ～8%. Independent of these effects on normal physiology, MK801 also reduced primed burst potentiation, a form of synaptic plasticity produced by physiologically patterned stimulation, by ～20% in the same pathway. Thus, low doses of MK801 may impair spatial learning by reducing, directly or indirectly, the likelihood of synaptic plasticity in the hippocampus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Emotion, plasticity, context, and regulation: Perspectives from affective neuroscience.

The authors present an overview of the neural bases of emotion. They underscore the role of the prefrontal cortex (PFC) and amygdala in 2 broad approach- and withdrawal-related emotion systems. Components and measures of affective style are identified. Emphasis is given to affective chronometry and a role for the PFC in this process is proposed. Plasticity in the central circuitry of emotion is considered, and implications of data showing experience-induced changes in the hippocampus for understanding psychopathology and stress-related symptoms are discussed. Two key forms of affective plasticity are described—context and regulation. A role for the hippocampus in context-dependent normal and dysfunctional emotional responding is proposed. Finally, implications of these data for understanding the impact on neural circuitry of interventions to promote positive affect and on mechanisms that govern health and disease are considered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cortical pathways to the mammalian amygdala

The amygdaloid nuclear complex is critical for producing appropriate emotional and behavioral responses to biologically relevant sensory stimuli. It constitutes an essential link between sensory and limbic areas of the cerebral cortex and subcortical brain regions, such as the hypothalamus, brainstem, and striatum, that are responsible for eliciting emotional and motivational responses. This review summarizes the anatomy and physiology of the cortical pathways to the amygdala in the rat, cat and monkey. Although the basic anatomy of these systems in the cat and monkey was largely delineated in studies conducted during the 1970s and 1980s, detailed information regarding the cortico-amygdalar pathways in the rat was only obtained in the past several years. The purpose of this review is to describe the results of recent studies in the rat and to compare the organization of cortico-amygdalar projections in this species with that seen in the cat and monkey. In all three species visual, auditory, and somatosensory information is transmitted to the amygdala by a series of modality-specific cortico-cortical pathways ("cascades") that originate in the primary sensory cortices and flow toward higher order association areas. The cortical areas in the more distal portions of these cascades have stronger and more extensive projections to the amygdala than the more proximal areas. In all three species olfactory and gustatory/visceral information has access to the amygdala at an earlier stage of cortical processing than visual, auditory and somatosensory information. There are also important polysensory cortical inputs to the mammalian amygdala from the prefrontal and hippocampal regions. Whereas the overall organization of cortical pathways is basically similar in all mammalian species, there is anatomical evidence which suggests that there are important differences in the extent of convergence of cortical projections in the primate versus the nonprimate amygdala.     

Impaired fear memories are correlated with subregion-specific deficits in hippocampal and amygdalar LTP.

Inbred mouse strains have different genetic backgrounds that likely influence memory and long-term potentiation (LTP). LTP, a form of synaptic plasticity, is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired fear memory may have selective LTP deficits in different hippocampal subregions or in the amygdala. The authors assessed fear memory in 4 inbred strains: C57BL/6NCrlBR (B6), 129S1/SvImJ (129), C3H/HeJ (C3H), and DBA/2J (D2). The authors also measured LTP in the hippocampal Schaeffer collateral (SC) and medial perforant pathways (MPP) and in the basolateral amygdala. Contextual and cued fear memory, and SC and amygdalar LTP, were intact in B6 and 129, but all were impaired in C3H and D2. MPP LTP was similar in all 4 strains. Thus, SC, but not MPP, LTP correlates with hippocampus-dependent contextual memory expression, and amygdalar LTP correlates with amygdala-dependent cued memory expression, in these inbred strains. (PsycINFO Database Record (c) 2010 APA, all rights reserved)