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Lesion and inactivation studies indicate that the central amygdala (CeA) participates in the expression of cued and contextual fear, whereas the bed nucleus of the stria terminalis (BNST) is only involved in the latter. The basis for this functional dissociation is unclear because CeA and BNST form similar connections with the amygdala and brainstem fear effectors. To address this question, we recorded neurons in the anterolateral (AL) and anteromedial (AM) regions of BNST in rats subjected to auditory fear conditioning. During habituation, few neurons were responsive to the conditioned stimulus (CS). After fear conditioning, 20% of BNST-AL neurons developed inhibitory responses to the CS. In BNST-AM, 26% of neurons developed positive CS responses. The behavior of BNST-AM and -AL neurons during contextual fear paralleled their CS responsiveness: More BNST-AM neurons fired at higher rates during contextual freezing than movement, whereas the opposite was seen in BNST-AL cells. These findings point to regional differences in the activity of BNST-AL and -AM in relation to learned fear, raising the possibility that they exert opposite influences on fear output networks. However, given the similar behavior of BNST-AM and -AL neurons in relation to cued and contextual fear, it remains unclear why lesion and inactivation of BNST differentially affect these two types of fear. Either neurons in a different BNST sector, not explored here, show a different activity profile in relation to the two forms of fear or inactivation/lesion studies inadvertently affected a structure adjacent to BNST, which is involved in contextual fear.

The relative contributions of plasticity in the amygdala vs. its afferent pathways to conditioned fear remain controversial. Some believe that thalamic and cortical neurons transmitting information about the conditioned stimulus (CS) to the lateral amygdala (LA) serve a relay function. Others maintain that thalamic and/or cortical plasticity is critically involved in fear conditioning. To address this question, we developed a large-scale biophysical model of the LA that could reproduce earlier findings regarding the cellular correlates of fear conditioning in LA. We then conducted model experiments that examined whether fear memories depend on (1) training-induced increases in the responsiveness of thalamic and cortical neurons projecting to LA, (2) plasticity at the synapses they form in LA, and/or (3) plasticity at synapses between LA neurons. These tests revealed that training-induced increases in the responsiveness of afferent neurons are required for fear memory formation. However, once the memory has been formed, this factor is no longer required because the efficacy of the synapses that thalamic and cortical neurons form with LA cells has augmented enough to maintain the memory. In contrast, our model experiments suggest that plasticity at synapses between LA neurons plays a minor role in maintaining the fear memory.

Intercalated (ITC) amygdala neurons regulate fear expression by controlling impulse traffic between the input (basolateral amygdala; BLA) and output (central nucleus; Ce) stations of the amygdala for conditioned fear responses. Previously, stimulation of the infralimbic (IL) cortex was found to reduce fear expression and the responsiveness of Ce neurons to BLA inputs. These effects were hypothesized to result from the activation of ITC cells projecting to Ce. However, ITC cells inhibit each other, leading to the question of how IL inputs could overcome the inter-ITC inhibition to regulate the responses of Ce neurons to aversive conditioned stimuli (CSs). To investigate this, we first developed a compartmental model of a single ITC cell that could reproduce their bistable electroresponsive properties, as observed experimentally. Next, we generated an ITC network that implemented the experimentally observed short-term synaptic plasticity of inhibitory inter-ITC connections. Model experiments showed that strongly adaptive CS-related BLA inputs elicited persistent responses in ITC cells despite the presence of inhibitory interconnections. The sustained CS-evoked activity of ITC cells resulted from an unusual slowly deinactivating K[superscript +] current. Finally, over a wide range of stimulation strengths, brief IL activation caused a marked increase in the firing rate of ITC neurons, leading to a persistent decrease in Ce output, despite inter-ITC inhibition. Simulations revealed that this effect depended on the bistable properties and synaptic heterogeneity of ITC neurons. These results support the notion that IL inputs are in a strategic position to control extinction of conditioned fear via the activation of ITC neurons.

Memory consolidation is thought to involve the gradual transfer of transient hippocampal-dependent traces to distributed neocortical sites via the rhinal cortices. Recently, medial prefrontal (mPFC) neurons were shown to facilitate this process when their activity becomes synchronized. However, the mechanisms underlying this enhanced synchrony remain unclear. Because the hippocampus projects to the mPFC, we tested whether theta oscillations contribute to synchronize mPFC neurons during learning. Thus, we obtained field (LFP) and unit recordings from multiple mPFC sites during the acquisition of a trace-conditioning task, where a visual conditioned stimulus (CS) predicted reward delivery. In quiet waking, the activity of mPFC neurons was modulated by theta oscillations. During conditioning, CS presentation caused an increase in mPFC theta power that augmented as the CS gained predictive value for reward delivery. This increased theta power coincided with a transient theta phase locking at distributed mPFC sites, an effect that was also manifest in the timing of mPFC unit activity. Overall, these results show that theta oscillations contribute to synchronize neuronal activity at distributed mPFC sites, suggesting that the hippocampus, by generating a stronger theta source during learning, can synchronize mPFC activity, in turn facilitating rhinal transfer of its activity to the neocortex.

Manipulations that reduce or enhance the activity of basolateral amygdala (BLA) neurons in the minutes to hours after training have been shown to respectively impair or facilitate retention on the inhibitory avoidance task. Although this suggests that BLA activity is altered after emotional arousal, such changes have not been directly demonstrated. To test this, the authors devised a feline analog of the inhibitory avoidance task and recorded BLA unit activity before and after a single inescapable footshock. Single-unit recordings revealed that the firing rate of many BLA neurons gradually increased after the footshock, peaking 30-50 minutes post-shock and then subsiding to baseline levels two hours later. During this period of increased activity, the discharges of simultaneously recorded BLA cells were more synchronized than before the shock. Although it was known that pairing innocuous (conditioned stimulus, CS) and noxious stimuli modifies the responsiveness of BLA neurons to the CS, our results constitute the first demonstration that emotional arousal produces lasting increases in the spontaneous firing rates of BLA neurons. The authors propose that these changes in BLA activity may promote Hebbian interactions between coincident but spatially distributed activity patterns in BLA targets, facilitating the consolidation of emotional memories. (Contains 5 figures.)

Functional imaging studies indicate that the insula encodes the salience of stimuli and deviations from expectations, signals that can mobilize cognitive resources and facilitate learning. However, there is no information about the physiological underpinnings of these phenomena beyond changing BOLD signals. To shed light on this question, we analyzed intracerebral local field potentials (LFPs) in five patients with epilepsy of both genders performing a virtual reality task that featured varying odds of monetary rewards and losses. Upon outcome disclosure, the anterior (but not the posterior) insula generated bursts of beta oscillations whose amplitudes were lower for neutral than positive and negative outcomes, consistent with a salience signal. Moreover, beta burst power was higher when outcomes deviated from expectations, whether the outcome was better or worse than expected, indicating that the insula provides an unsigned prediction error signal. Last, in relation to insular beta bursts, many higher-order cortical areas exhibited robust changes in LFP activity that ranged from spectrally nonspecific or differentiated increases in gamma power to bursts of beta activity that closely resembled the insular beta bursts themselves. Critically, the activity of these other cortical regions was more closely tied in time to insular bursts than task events, suggesting that they are associated with particularly significant cognitive phenomena. Overall, our findings suggest that the insula signals salience and prediction errors via amplitude modulations of beta bursts, which coincide with the near simultaneous recruitment of vast cortical territories. [ABSTRACT FROM AUTHOR]

Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders (1-4). In [...]

Author(s): Sébastien Royer; Denis Paré (corresponding author) Memory is believed to depend on activity-dependent changes in the strength of synapses [1]. In part, this view is based on evidence that [...]

Uncertainty persists as to whether the amygdala is a crucial site of plasticity for classically conditioned fear or merely a sensory relay to structures generating fear responses. A recent Nature study suggests that associative synaptic changes take place in neurons of the amygdala during fear conditioning, and that these changes require dopamine-mediated modulation. Nevertheless, these findings do not prove that the amygdala is a sufficient site of plasticity for fear memory.

Much evidence implicates the serotonergic regulation of the amygdala in anxiety. Thus the present study was undertaken to characterize the influence of serotonin (5-HT) on principal neurons (PNs) of the rat lateral amygdala (LA), using whole cell recordings in vitro. Because inhibition is a major determinant of PN activity, we focused on the control of GABAergic transmission by 5-HT. IPSCs were elicited by local electrical stimulation of LA in the presence of glutamate receptor antagonists. We found that 5-HT reduces GABAA inhibitory postsynaptic currents (IPSCs) via presynaptic 5-HT1B receptors. While the presynaptic inhibition of GABA release also attenuated GABAB currents, this effect was less pronounced than for GABAA currents because 5-HT also induced a competing postsynaptic enhancement of GABAB currents. That is, GABAB currents elicited by pressure application of GABA or baclofen were enhanced by 5-HT. In addition, we obtained evidence suggesting that 5-HT differentially regulates distinct subsets of GABAergic synapses. Indeed, GABAA IPSCs were comprised of two components: a relatively 5-HT-insensitive IPSC that had a fast time course and a 5-HT-sensitive component that had a slower time course. Because the relative contribution of these two components varied depending on whether neurons were recorded at proximity versus at a distance from the stimulating electrodes, we speculate that distinct subtypes of local-circuit cells contribute the two contingents of GABAergic synapses. Overall, our results indicate that 5-HT is a potent regulator of synaptic inhibition in LA. NEW & NOTEWORTHY We report that 5-HT, acting via presynaptic 5-HT1B receptors, attenuates GABAA IPSCs by reducing GABA release in the lateral amygdala (LA). In parallel, 5-HT enhances GABAB currents postsynaptically, such that GABAB inhibitory postsynaptic currents (IPSCs) are relatively preserved from the presynaptic inhibition of GABA release. We also found that the time course of 5-HT-sensitive and -insensitive GABAA IPSCs differ. Together, these results indicate that 5-HT is a potent regulator of synaptic inhibition in LA. [ABSTRACT FROM AUTHOR]

It is almost axiomatic in neuroscience that postsynaptically induced NMDA-dependent long-term potentiation (LTP) is a cellular substrate of memory. As a result, memory impairments caused by experimental reductions of NMDA currents are often interpreted as evidence that this form of plasticity is involved in memory formation. However, a recent Nature study indicates that not all NMDA-dependent LTP is induced postsynaptically.