Optical activation of lateral amygdala pyramidal cells instructs associative fear learning

The basolateral amygdala plays an important role in the acquisition and expression of both fear conditioning and fear extinction. To understand how a single structure could encode these “opposite” memories, we developed a biophysical network model of the lateral amygdala (LA) neurons during auditory fear conditioning and extinction. Membrane channel properties were selected to match waveforms and firing properties of pyramidal cells and interneurons in LA, from published in vitro studies. Hebbian plasticity was implemented in excitatory AMPA and inhibitory GABAA receptor-mediated synapses to model learning. The occurrence of synaptic potentiation versus depression was determined by intracellular calcium levels, according to the calcium control hypothesis. The model was able to replicate conditioning- and extinction-induced changes in tone responses of LA neurons in behaving rats. Our main finding is that LA activity during both acquisition and extinction can be controlled by a balance between pyramidal cell and interneuron activations. Extinction training depressed conditioned synapses and also potentiated local interneurons, thereby inhibiting the responses of pyramidal cells to auditory input. Both long-term depression and potentiation of inhibition were required to initiate and maintain extinction. The model provides insights into the sites of plasticity in conditioning and extinction, the mechanism of spontaneous recovery, and the role of amygdala NMDA receptors in extinction learning.

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Long-Term Neural Correlates of Reversible Fear Learning in the Lateral Amygdala

Journal of Neuroscience ◽

10.1523/jneurosci.3017-12.2012 ◽

2012 ◽

Vol 32 (47) ◽

pp. 16845-16856 ◽

Cited By ~ 34

Author(s):

B. An ◽

I. Hong ◽

S. Choi

Keyword(s):

Neural Correlates ◽

Fear Learning ◽

Lateral Amygdala

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Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala

Neuroscience ◽

10.1016/j.neuroscience.2005.12.055 ◽

2006 ◽

Vol 139 (3) ◽

pp. 821-829 ◽

Cited By ~ 16

Author(s):

R. Lamprecht ◽

D.S. Margulies ◽

C.R. Farb ◽

M. Hou ◽

L.R. Johnson ◽

...

Keyword(s):

Synaptic Plasticity ◽

Light Chain ◽

Myosin Light Chain Kinase ◽

Myosin Light Chain ◽

Fear Learning ◽

Lateral Amygdala

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Impact of Chronic BDNF Depletion on GABAergic Synaptic Transmission in the Lateral Amygdala

International Journal of Molecular Sciences ◽

10.3390/ijms20174310 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4310 ◽

Cited By ~ 5

Author(s):

Susanne Meis ◽

Thomas Endres ◽

Thomas Munsch ◽

Volkmar Lessmann

Keyword(s):

Synaptic Transmission ◽

Long Term Potentiation ◽

Fear Learning ◽

Inhibitory Synapses ◽

Lateral Amygdala ◽

Term Potentiation ◽

Gabaergic Synapses ◽

Bdnf Signaling ◽

The Impact

Brain-derived neurotrophic factor (BDNF) has previously been shown to play an important role in glutamatergic synaptic plasticity in the amygdala, correlating with cued fear learning. While glutamatergic neurotransmission is facilitated by BDNF signaling in the amygdala, its mechanism of action at inhibitory synapses in this nucleus is far less understood. We therefore analyzed the impact of chronic BDNF depletion on GABAA-mediated synaptic transmission in BDNF heterozygous knockout mice (BDNF+/−). Analysis of miniature and evoked inhibitory postsynaptic currents (IPSCs) in the lateral amygdala (LA) revealed neither pre- nor postsynaptic differences in BDNF+/− mice compared to wild-type littermates. In addition, long-term potentiation (LTP) of IPSCs was similar in both genotypes. In contrast, facilitation of spontaneous IPSCs (sIPSCs) by norepinephrine (NE) was significantly reduced in BDNF+/− mice. These results argue against a generally impaired efficacy and plasticity at GABAergic synapses due to a chronic BDNF deficit. Importantly, the increase in GABAergic tone mediated by NE is reduced in BDNF+/− mice. As release of NE is elevated during aversive behavioral states in the amygdala, effects of a chronic BDNF deficit on GABAergic inhibition may become evident in response to states of high arousal, leading to amygdala hyper-excitability and impaired amygdala function.

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The role of p21-activated kinase in maintaining the fear learning-induced modulation of excitation/inhibition ratio in lateral amygdala

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2021.107385 ◽

2021 ◽

Vol 179 ◽

pp. 107385

Author(s):

Blesson K. Paul ◽

Edi Barkai ◽

Raphael Lamprecht

Keyword(s):

Fear Learning ◽

Lateral Amygdala ◽

Inhibition Ratio ◽

P21 Activated Kinase

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Arc expression identifies the lateral amygdala fear memory trace

Molecular Psychiatry ◽

10.1038/mp.2015.18 ◽

2015 ◽

Vol 21 (3) ◽

pp. 364-375 ◽

Cited By ~ 24

Author(s):

L A Gouty-Colomer ◽

B Hosseini ◽

I M Marcelo ◽

J Schreiber ◽

D E Slump ◽

...

Keyword(s):

Fear Conditioning ◽

Memory Trace ◽

Fear Memory ◽

Early Gene ◽

Fear Learning ◽

Intrinsic Excitability ◽

Lateral Amygdala ◽

Neuronal Ensembles ◽

Neuronal Ensemble ◽

Distinct Subset

Abstract Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity.

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Distinct Populations of NMDA Receptors at Subcortical and Cortical Inputs to Principal Cells of the Lateral Amygdala

Journal of Neurophysiology ◽

10.1152/jn.1999.81.2.930 ◽

1999 ◽

Vol 81 (2) ◽

pp. 930-934 ◽

Cited By ~ 80

Author(s):

Marc G. Weisskopf ◽

Joseph E. LeDoux

Keyword(s):

Nmda Receptors ◽

Fear Conditioning ◽

Brain Slices ◽

Fear Learning ◽

Lateral Amygdala ◽

Sensory Stimuli ◽

Cortical Input ◽

Principal Cells ◽

Cell Recording ◽

Cortical Inputs

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 α-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.

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