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Biomedical subjects

J E LeDoux

Publications and source records attributed to J E LeDoux.

At least 37 records · Page 2Linked to original sources
PubMed1999

L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala.

Long-term potentiation (LTP) in the amygdala is a leading candidate mechanism to explain fear conditioning, a prominent model of emotional memory. LTP occurs in the pathway from the auditory thalamus to the lateral amygdala, and during fear conditioning LTP-like changes occur in the synapses of this pathway. Nevertheless, LTP has not been investigated in the thalamoamygdala pathway using in vitro recordings; hence little is known about the underlying mechanisms. We therefore examined thalamoamygdala LTP in vitro using visualized whole-cell patch recording. LTP at these synapses was dependent on postsynaptic calcium entry, similar to synaptic plasticity in other regions of the brain. However, unlike many forms of synaptic plasticity, thalamoamygdala LTP was independent of NMDA receptors, despite their presence at these synapses, and instead was dependent on L-type voltage-gated calcium channels. This was true when LTP was induced by pairing presynaptic activity with either action potentials or constant depolarization in the postsynaptic cell. In addition, the LTP was associative, in that it required concurrent pre- and postsynaptic activity, and it was synapse specific. Thus, although this LTP is different from that described at other synapses in the brain, it is nonetheless well suited to mediate classical fear conditioning.

Afferent Pathways↗
PubMed1999

GABAergic antagonists block the inhibitory effects of serotonin in the lateral amygdala: a mechanism for modulation of sensory inputs related to fear conditioning.

Neurons in the lateral amygdala (LA) receive glutamatergic sensory input from the auditory thalamus and auditory cortex, and these inputs can be modulated by serotonin (5-HT). In the present study, we examined whether serotonergic inhibition of glutamatatergic excitation in the LA occurs via activation of GABAergic interneurons. Single-unit extracellular activity in the LA was recorded in response to iontophoretically applied glutamate. Concurrent application of 5-HT reduced the number of glutamate-evoked action potentials in the majority of neurons tested. GABA antagonists were then iontophoresed with both glutamate and 5-HT. Of the neurons that were inhibited by 5-HT, concurrent application of the GABA antagonists significantly reversed this effect. Application of the GABA antagonists alone had little or no effect on basal neuronal activity. We conclude that the 5-HT-induced inhibition of glutamatergic activity occurs in part through activation of serotonergic receptors on GABAergic interneurons.

Action Potentials↗
PubMed1999

Contribution of ventrolateral prefrontal cortex to the acquisition and extinction of conditioned fear in rats.

The ventrolateral, agranular insular portion of prefrontal cortex (PFC) in rats is involved in visceral functions and has been shown to be involved in emotional processes. However, its contribution to aversive learning has not been well defined. Classical fear conditioning has been a powerful tool for illuminating some of the primary neural structures involved in aversive emotional learning. We measured both the acquisition and the extinction of conditioned fear following lesions of the ventrolateral PFC of rats. Lesions reduced fear reactivity to contextual stimuli associated with conditioning without affecting CS acquisition, and had no effect on response extinction. Ventrolateral PFC may normally be involved in the processing of contextual information while not being directly involved in extinction processes within the aversive domain.

Animals↗
PubMed1999

Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations.

Previous findings have demonstrated that systemic dopaminergic manipulations impair the retrieval of Pavlovian conditioned fear. A second-order fear-conditioning paradigm was used to test whether the dopaminergic projection from the ventral tegmental area (VTA) to the lateral and basal amygdala (LBA) can affect conditioned fear. Phase 1 entailed conditioned stimulus-unconditioned stimulus (CS1-US) pairings. In Phase 2, drugs were infused in either the LBA or VTA prior to pairings of CS2 (a second cue) with CS1. In Phase 3, freezing behavior elicited by CS2 was tested without drugs. Infusions of the D2 agonist quinpirole into the VTA or of the D1 antagonist SCH 23390 into the LBA caused a decrease in freezing to CS2. Both manipulations decrease D1 receptor activation in the LBA. Infusions of the D1 agonist SKF 38393 into the LBA had no effect. This pattern of results is consistent with the hypothesis that the VTA-LBA dopaminergic projection modulates the retrieval of an association between a CS and footshock US.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1999

Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy.

This study investigated whether 21 days of restraint stress (6 hr/day) and the subsequent hippocampal dendritic atrophy would affect fear conditioning, a memory task with hippocampal-dependent and hippocampal-independent components. Restraint-stressed rats were injected daily (21 days) with tianeptine (10 mg/kg; to prevent hippocampal atrophy) or vehicle then tested on fear conditioning (Days 23-25, with 2 tone-shock pairings) and open field (Day 25). Restraint stress enhanced freezing to context (hippocampal-dependent behavior) and tone (hippocampal-independent) and decreased open-field exploration, irrespective of whether tianeptine was given. Results confirmed that stress produced CA3 dendritic atrophy and tianeptine prevented it. Moreover, CA3 dendritic atrophy was not permanent but reversed to control levels by 10 days after the cessation of restraint stress. These data argue that different neural substrates underlie spatial recognition memory and fear conditioning.

Animals↗
PubMed1999

Distinct populations of NMDA receptors at subcortical and cortical inputs to principal cells of the lateral amygdala.

Fear conditioning involves the transmission of sensory stimuli to the amygdala from the thalamus and cortex. These input synapses are prime candidates for sites of plasticity critical to the learning in fear conditioning. Because N-methyl-D-aspartate (NMDA)-dependent mechanisms have been implicated in fear learning, we investigated the contribution of NMDA receptors to synaptic transmission at putative cortical and thalamic inputs using visualized whole cell recording in amygdala brain slices. Whereas NMDA receptors are present at both of these pathways, differences were observed. First, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor-mediated component of the synaptic response, relative to the NMDA component, is smaller at thalamic than cortical input synapses. Second, thalamic NMDA responses are more sensitive to Mg2+. These findings suggest that there are distinct populations of NMDA receptors at cortical and thalamic inputs to the lateral amygdala. Differences such as these might underlie unique contributions of the two pathways to fear conditioning.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1998

Serotonin modulation of sensory inputs to the lateral amygdala: dependency on corticosterone.

The lateral nucleus of the amygdala (LA) receives excitatory (glutamatergic) inputs from thalamic and cortical sensory processing areas and is believed to be involved in evaluation of the affective significance of sensory events. We examined whether serotonin (5-HT) affects excitatory transmission in auditory afferents to the LA and, if so, whether this modulation of sensory transmission is regulated by the stress hormone corticosterone (CORT). Neuronal activity in the LA was elicited via iontophoretic ejection of L-glutamate or synaptically via electrical stimulation of auditory afferent pathways. In the intact rat, iontophoretically applied 5-HT inhibited both synaptically and glutamate-evoked action potentials in most neurons examined. However, after adrenalectomy (ADX), which eliminates endogenous CORT, 5-HT no longer inhibited evoked activity in the LA. High-CORT doses given to ADX animals reinstated the inhibition of excitatory transmission of 5-HT, whereas low-CORT doses had little effect. Immunocytochemical labeling of the glucocorticoid receptor in the intact rat demonstrated nuclear staining throughout several amygdala regions, including the LA. However, after ADX, no nuclear labeling was visible. With a high replacement dose of CORT (5 or 10 mg) after ADX, dense nuclear staining returned, but with a low replacement dose (1 mg/kg), there was only light nuclear staining. Thus, the ability of 5-HT to modulate glutamatergic activity in auditory pathways to the amygdala is dependent on the presence of CORT and possibly glucocorticoid activation. Via this mechanism, 5-HT modulates the processing of sensory information within the LA and thus may regulate amygdala-related functions.

Adrenalectomy↗
PubMed1998

Differential effects of amygdala lesions on early and late plastic components of auditory cortex spike trains during fear conditioning.

In auditory fear conditioning, pairing of a neutral acoustic conditioned stimulus (CS) with an aversive unconditioned stimulus (US) results in an enhancement of neural responses to the CS in the amygdala and auditory cortex. It is not clear, however, whether cortical plasticity governs neural changes in the amygdala or vice versa, or whether learning in these two structures is determined by independent processes. We examined this issue by recording single-cell activity in the auditory cortex (areas Te1, Te1v, and Te3) of freely behaving, amygdalectomized rats using a movable bundle of microwires. Amygdala damage did not affect short-latency (0-50 msec) tone responses, nor did it interfere with conditioning-induced increases of these onset responses. In contrast, lesions of the amygdala interfered with the development of late (500-1500 msec) conditioned tone responses that were not present before conditioning. Furthermore, whereas onset conditioned responses in the control group remained elevated after 30 extinction trials (presentation of CS alone), onset responses in lesioned animals returned to their preconditioning firing level after approximately 10 extinction trials. These results suggest that the amygdala enables the development of long-latency (US anticipatory) responses and prevents the extinction of short-latency onset responses to threatening stimuli. The findings further suggest that auditory cortex cells may participate differently in explicit and implicit memory networks.

Acoustic Stimulation↗
PubMed1998

Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study.

Echoplanar functional magnetic resonance imaging (fMRI) was used in normal human subjects to investigate the role of the amygdala in conditioned fear acquisition and extinction. A simple discrimination procedure was employed in which activation to a visual cue predicting shock (CS+) was compared with activation to another cue presented alone (CS-). CS+ and CS- trial types were intermixed in a pseudorandom order. Functional images were acquired with an asymmetric spin echo pulse sequence from three coronal slices centered on the amygdala. Activation of the amygdala/periamygdaloid cortex was observed during conditioned fear acquisition and extinction. The extent of activation during acquisition was significantly correlated with autonomic indices of conditioning in individual subjects. Consistent with a recent electrophysiological recording study in the rat (Quirk et al., 1997), the profile of the amygdala response was temporally graded, although this dynamic was only statistically reliable during extinction. These results provide further evidence for the conservation of amygdala function across species and implicate an amygdalar contribution to both acquisition and extinction processes during associative emotional learning tasks.

Adolescent↗
PubMed1997

Fear conditioning induces associative long-term potentiation in the amygdala.

Long-term potentiation (LTP) is an experience-dependent form of neural plasticity believed to involve mechanisms that underlie memory formation. LTP has been studied most extensively in the hippocampus, but the relation between hippocampal LTP and memory has been difficult to establish. Here we explore the relation between LTP and memory in fear conditioning, an amygdala-dependent form of learning in which an innocuous conditioned stimulus (CS) elicits fear responses after being associatively paired with an aversive unconditioned stimulus (US). We have previously shown that LTP induction in pathways that transmit auditory CS information to the lateral nucleus of the amygdala (LA) increases auditory-evoked field potentials in this nucleus. Now we show that fear conditioning alters auditory CS-evoked responses in LA in the same way as LTP induction. The changes parallel the acquisition of CS-elicited fear behaviour, are enduring, and do not occur if the CS and US remain unpaired. LTP-like associative processes thus occur during fear conditioning, and these may underlie the long-term associative plasticity that constitutes memory of the conditioning experience.

Amygdala↗
PubMed1997

AMPA receptor facilitation accelerates fear learning without altering the level of conditioned fear acquired.

Rats treated with the AMPA receptor-facilitating drug 1-(quinoxolin-6-ylcarbonyl)piperidine (BDP-12) during training acquired fear conditioning to a tone faster than vehicle-treated controls. The effect on acquisition was dependent on the dose given. BDP-12-treated rats and vehicle-treated controls reached the same level of conditioned fear and extinguished at the same rate. The dissociation of learning rate from these other normally covariant measures suggests that the drug had a specific and isolated effect on acquisition. Controls for drug effects on stimulus sensitivity, locomotor activity, generalized fearfulness, and other performance factors support this interpretation. The known action of BDP-12 on receptor dynamics suggests that its effect on acquisition may be attributed to specific modulation of an AMPA and NMDA receptor-dependent plasticity mechanism. The finding that the drug accelerates acquisition but does not affect the level of conditioned fear acquired parallels the effect of the drug on long-term potentiation (LTP) (increasing the rate but not the ceiling of potentiation) and suggests that common mechanisms may underlie fear conditioning and LTP.

Animals↗
PubMed1997

NMDA and AMPA receptors in the lateral nucleus of the amygdala are postsynaptic to auditory thalamic afferents.

Projections from the medial geniculate body (MGB) to the lateral nucleus of the amygdala (LA) have been implicated in the conditioning of emotional reactions to acoustic stimuli. Anatomical and physiological studies indicate that this pathway uses the excitatory amino acid L-glutamate as a transmitter. Recent physiological studies have demonstrated that synaptic transmission in the thalamo-amygdala pathway requires the activation of both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, two of the major classes of ionotrophic glutamate receptors. In order to characterize the nature of thalamoamygdala interactions, we examined the synaptic associations between thalamic afferents and amygdala neurons that contain at least one glutamate receptor subtype. Thalamic afferents to the amygdala were identified by lesion-induced anterograde degeneration and anterograde transport of biotinylated dextran-amine, while postsynaptic glutamate receptors were labeled immunocytochemically using antisera directed the R1 subunit of the NMDA receptor and the GluR1 and GluR2/3 subunits of the AMPA receptors. Both methods demonstrated that the majority (77%) of thalamic afferents contact dendritic spines, and most (60%) of these spines express at least one glutamate receptor subtype. To a lesser extent, identified afferents also contacted small and large dendritic shafts, and many of these were immunoreactive. Thalamic afferents terminated on approximately the same proportion (60%) of immunoreactive targets for each glutamate receptor studied. These data provide morphological evidence that thalamic afferents directly synapse onto amygdala neurons that express glutamate receptors and suggest ways in which thalamic afferents activate and influence amygdala circuitry.

Afferent Pathways↗
PubMed1997

Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala.

The amygdala is located in the medial aspects of the temporal lobe. In spite of the fact that the amygdala has been implicated in a variety of functions, ranging from attention to memory to emotion, it has not attracted neuroscientists to the same extent as its laminated neighbours, in particular the hippocampus and surrounding cortex. However, recently, principles of information processing within the amygdala, particularly in the rat, have begun to emerge from anatomical, physiological and behavioral studies. These findings suggest that after the stimulus enters the amygdala, the highly organized intra-amygdaloid circuitries provide a pathway by which the representation of a stimulus becomes distributed in parallel to various amygdaloid nuclei. As a consequence, the stimulus representation may become modulated by different functional systems, such as those mediating memories from past experience or knowledge about ongoing homeostatic states. The amygdaloid output nuclei, especially the central nucleus, receive convergent information from several other amygdaloid regions and generate behavioral responses that presumably reflect the sum of neuronal activity produced by different amygdaloid nuclei.

Amygdala↗
PubMed1997

Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala.

Single neurons were recorded in freely behaving rats during fear conditioning from areas of auditory cortex that project to the lateral nucleus of the amygdala (LA). The latency and rate of conditioning and extinction were analyzed, and the results were compared to previous recordings from LA itself. Auditory cortex neurons took more trials to learn, and they responded more slowly than LA neurons within trials. Short-latency plasticity in LA, therefore, reflects inputs from the auditory thalamus rather than the auditory cortex. Unlike LA cells, some auditory cortex cells showed late conditioned responses that seemed to anticipate the unconditioned stimulus, while others showed extinction-resistant memory storage. Thus, rapid conditioning of fear responses to potentially dangerous stimuli depends on plasticity in the amygdala, while cortical areas may be particularly involved in higher cognitive (mnemonic and attentional) processing of fear experiences.

Acoustic Stimulation↗
PubMed1997

Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli.

The GABAa agonist, muscimol (0.5 microgram in 0.5 microliter saline), or vehicle was infused into the lateral and basal amygdala nuclei prior to fear conditioning or testing in rats. Rats given muscimol before conditioning and saline before testing showed much less freezing to the conditioned stimulus (CS) and the context than did controls given saline before training and testing. Rats given saline before training and muscimol prior to testing also showed low levels of freezing to the CS and the context. In follow-up procedures, rats with acquisition initially blocked by pretraining muscimol infusions froze in a manner similar to that of controls when retrained and retested with saline infusions. Rats trained with saline but tested with muscimol presumably became conditioned but could express the learning. When retested with saline, they froze in the same manner as controls. Thus, activity in the lateral and basal amygdala appears to play an essential role in the acquisition and expression of fear conditioning.

Amygdala↗
PubMed1997

Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats.

The conditioning of fear responses to a simple acoustic stimulus (pure tone) paired with footshock can be mediated by the transmission of auditory information to the lateral nucleus of the amygdala from either the auditory thalamus or the auditory cortex. We examined the processing capacity of the thalamo-amygdala pathway by making lesions of the auditory cortex and testing the extent to which conditioned fear responses generalized to tones other than the one paired with footshock. Two studies were performed, one in an anatomically constrained computational model of the fear conditioning network and the other in rats. Stimulus generalization was unaffected in both. These findings support the validity of the model as an approach to studying the neural basis of conditioned fear learning, and in addition suggest that the thalamo-amygdala pathway, possibly by the use of population coding, is capable of performing at least crude stimulus discriminations.

Acoustic Stimulation↗