Search PubMed⌕ Search

Biomedical subjects

J E LeDoux

Publications and source records attributed to J E LeDoux.

At least 19 recordsLinked to original sources
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↗
PubMed1996

Topographic projections from the periamygdaloid cortex to select subregions of the lateral nucleus of the amygdala in the rat.

Information from most of the sensory modalities enters the amygdala via the lateral nucleus. The olfactory information, however, arrives at the amygdala through the superficial nuclei, including the periamygdaloid cortex. To find out whether the olfactory information can modulate the processing of sensory information in the lateral nucleus we injected Phaseolus vulgaris leucoagglutinin, an anterograde axonal tracer, into the different divisions of the periamygdaloid cortex. We found that the PAC division of the periamygdaloid cortex projects to the ventrolateral and medial divisions, but not the dorsolateral division, of the lateral amygdaloid nucleus. Therefore, the projection from the PAC to the lateral nucleus provides a route, by which the olfactory information may become associated with other sensory modalities. Also, together with our previous finding that the lateral nucleus projects to the periamygdaloid cortex, the present data demonstrate that the lateral nucleus and the PAC are reciprocally connected.

Amygdala↗
PubMed1996

GABAA and GABAB receptors differentially regulate synaptic transmission in the auditory thalamo-amygdala pathway: an in vivo microiontophoretic study and a model.

Stimulation of the medical geniculate body elicits extracellular single unit responses in the lateral nucleus of the amygdala that are dependent upon glutamatergic neurotransmission [Li et al. (1995) Exp. Brain Res., 105-87-100]. In the present study, we examined the contribution of inhibitory amino acid transmission to these excitatory responses. Antagonists of GABAA or GABAB receptors were delivered microiontophoretically to cells activated by stimulation of the medial geniculate body. Blockade of GABAA receptors with bicuculline resulted in a pronounced increase in evoked short latency unit responses (4-8 ms). In some cases, cells that were not responsive to the stimulation became responsive in the presence of bicuculline. In contrast, delivery of GABAB antagonists, Phaclofen or 2-OH-saclofen, did not affect these short-latency responses. Using paired-pulse stimulation, both short (< 30 ms) and longer (> 50 ms) latency inhibitory processes were revealed. GABAA blockade eliminated the short latency inhibition and GABAB blockade eliminated the longer latency inhibition in most cells. These results suggest that the activation of GABAA and GABAB receptors differentially regulate glutamatergic synaptic transmission in the auditory thalamo-amygdala pathway. Moreover, our findings suggest that at least part of this regulation is via a feedforward mechanism. We tested the sufficiency of feedforward inhibition to account for the data using a simple computational model that incorporates the results presented here.

Amygdala↗
PubMed1996

Partial disruption of fear conditioning in rats with unilateral amygdala damage: correspondence with unilateral temporal lobectomy in humans.

Conditioned fear in rats was assessed for the effects of pretraining amygdala lesions (unilateral vs. bilateral) across unconditioned stimulus (US) modalities (white noise vs. shock). In contrast to sham controls, unilateral amygdala lesions significantly reduced conditioned freezing responses, whereas bilateral amygdala lesions resulted in a nearly complete lack of freezing to both the conditioned stimulus (CS) and the context. The lesion effects were more pronounced for CS conditioning but were consistent across US modalities. It was concluded that white noise can serve as an effective US and that unilateral amygdala lesions attenuate but do not eliminate conditioned fear in rats. The results support our interpretation of a recent fear conditioning study in humans (K. S. LaBar, J. E. LeDoux, D. D. Spencer, & E. A. Phelps, 1995).

Animals↗
PubMed1995

Intrinsic connections of the rat amygdaloid complex: projections originating in the basal nucleus.

The amygdaloid complex is involved in associational processes, such as the formation of emotional memories about sensory stimuli. However, the anatomical connections through which the different amygdaloid nuclei process incoming information and communicate with the other amygdaloid nuclei, is poorly understood. As part of an ongoing project aimed at elucidating the intrinsic connections of the rat amygdaloid complex, we injected the anterograde tracer PHA-L (Phaseolus vulgaris-leucoagglutinin) into different rostrocaudal levels of the basal nucleus of the amygdala in 21 rats and analyzed the distribution of labeled fibers and terminals throughout the amygdaloid complex. The connectional analysis, together with cytoarchitectonic observations, suggested that contrary to previous notions the basal nucleus in the rat has three divisions: magnocellular, intermediate, and parvicellular. The magnocellular division has heavy reciprocal connections with the lateral portion of the parvicellular division and the intermediate division projects weakly to the parvicellular division, whereas the projection from the medial portion of the parvicellular division to the intermediate division is heavy and the lateral and medial portions of the parvicellular division are only weakly interconnected, as are the magnocellular and intermediate divisions. The main intraamygdaloid targets of the basal nucleus projections are the nucleus of the lateral olfactory tract, the anterior amygdaloid area, the medial and capsular divisions of the central nucleus, the anterior cortical nucleus, and the amygdalohippocampal area. Our findings provide the most detailed understanding of the intra-amygdala connections of the basal nucleus to date and show that the connections within the basal nucleus and between the basal nucleus and other amygdaloid areas are more widespread and topographically organized than previously recognized.

Amygdala↗
PubMed1995

Brain mechanisms in human classical conditioning: a PET blood flow study.

Five healthy male subjects participated in a classical conditioning experiment, and positron emission tomography (PET) was used to compare regional cerebral blood flow before and after conditioning. The subjects participated in three different experimental phases. In the first (habituation) phase they listened to 24 repetitions of a tone with random intervals. In the second (acquisition) phase, the tone was paired with a brief shock to the wrist. In the third (extinction) phase, the tone was presented alone again. 15OPET scans were taken during the habituation and extinction phases. Because the habituation and extinction phases were similar, any difference in blood flow to the tones presented during extinction probably reflected conditioning that occurred during the acquisition phase. Statistical parametric mapping (SPM) analysis of the PET data showed significantly increased activation in the right hemisphere in the orbito-frontal cortex, dorsolateral prefrontal cortex, inferior and superior frontal cortices, and inferior and middle temporal corticies. The only activated areas in the left hemisphere were area 19 and the superior frontal cortex. The results are interpreted as evidence for the involvement of cortical areas in human classical conditioning.

Acoustic Stimulation↗