Long-term potentiation in the amygdala: a mechanism for emotional learning and memory

doi:10.1016/S0166-2236(99)01465-4

Trends in Neurosciences

Volume 22, Issue 12, 1 December 1999, Pages 561-567

https://doi.org/10.1016/S0166-2236(99)01465-4 Get rights and content

Abstract

In the mammalian brain, LTP is an enduring form of synaptic plasticity that is posited to have a role in learning and memory. Compelling new evidence for this view derives from studies of LTP in the amygdala, a brain structure that is essential for simple forms of emotional learning and memory, such as Pavlovian fear conditioning in rats. More specifically, antagonists of the NMDA receptor block both amygdaloid LTP induction and fear conditioning, fear conditioning induces increases in amygdaloid synaptic transmission that resemble LTP, and genetic modifications that disrupt amygdaloid LTP eliminate fear conditioning. Collectively, these results provide the most-convincing evidence to date that LTP mediates learning and memory in mammals.

Section snippets

Neural circuitry of fear conditioning

It has been recognized for decades that the amygdala is involved in emotional processes⁷, including aversively motivated learning8, 9 (see Ref. 10 for an excellent review of amygdaloid anatomy). The major amygdaloid nuclei and projections are shown in Fig. 1. Recent anatomical and behavioral evidence indicates that there are at least two distinct subsystems within the amygdala that are important for Pavlovian fear conditioning11, 12. The first subsystem of the amygdala consists of the lateral,

Fear memories are formed and stored in the basolateral amygdala

Much evidence indicates that the BLA is the crucial neural locus for the formation and storage of fear memories. Selective lesions of the BLA abolish both acquisition and expression of conditional fear in several behavioral paradigms27, 28. In addition, BLA lesions yield deficits in conditional fear when they are made up to one month after training29, 30 or after extensive overtraining³¹. Similar to permanent lesions, manipulations that temporarily disable amygdaloid neurons prevent both the

Amygdaloid neurons exhibit LTP

The first examination of synaptic plasticity in the amygdala was performed by Racine and colleagues in awake, behaving rats. In this preparation, ‘tetanic’ LTP (which is contrasted with ‘behavioral’ LTP) was induced in the amygdala by applying high-frequency electrical stimulation to the pyriform cortex⁴¹. This LTP consisted of a long-term enhancement in the amplitude of stimulus-elicited extracellular field potentials recorded in the amygdala. More recently, tetanic LTP has been reported in

Glutamate receptors in the amygdala are essential for fear conditioning

The important role for glutamate receptors in amygdaloid LTP suggests a role for these receptors in the acquisition and expression of Pavlovian fear conditioning. Consistent with this view, several laboratories have now demonstrated that the infusion of NMDA-receptor antagonists, such as (±)-2-amino-5-phosphonovaleric acid (APV), into the BLA prevents the acquisition of conditional fear responses, including freezingr53, 54, 55 and fear-potentiated startle56, 57. Moreover, it has been reported

Fear conditioning induces LTP in the amygdala

The ability of NMDA-receptor antagonists to block both the induction of tetanic LTP in the amygdala and the acquisition of fear conditioning suggests that a process akin to tetanic LTP might underlie the acquisition of conditional fear in awake, behaving rats. Two recent studies are consistent with this possibility. In the first study, LeDoux and colleagues found that fear conditioning in response to an auditory CS enhanced auditory-elicited potentials in the BLA in a manner that was similar to

Molecular basis of amygdaloid LTP and fear conditioning

A novel and exciting approach to examining the relationship between synaptic plasticity mechanisms, and learning and memory involves the use of genetically modified animals. In the past few years, many mice have been engineered with genetic manipulations that either disable or eliminate key proteins in the intracellular biochemical cascades that mediate LTP. While these studies have largely focused on the relationship of hippocampal LTP to behavior, several recent investigations using

Associative LTP as a mechanism for Pavlovian fear conditioning

If LTP in the amygdala is a synaptic mechanism for the acquisition of conditional fear, then it is of interest to consider how such a mechanism might operate during learning. In the hippocampus, tetanic LTP exhibits a property known as associativity (for example, see Ref. 71). Thus, LTP can be induced in ‘weak’ synaptic pathways if activity in these pathways is paired with activity in a ‘strong’ pathway. This associative property of LTP can accommodate CS–US association formation in the

Concluding remarks

An abundance of evidence indicates that neurons in the amygdala are essential for simple forms of emotional learning and memory, such as Pavlovian fear conditioning in rats. In the amygdala, LTP is an enduring form of synaptic plasticity that has been posited to have a role in Pavlovian fear conditioning. As this article illustrates, this view is supported by compelling new evidence that NMDA-receptor antagonists block both amygdaloid LTP induction and fear conditioning, fear conditioning

Acknowledgements

The author’s research was supported by a grant from the National Institute of Mental Health (R29MH57865). The author thanks two anonymous referees for helpful comments on a previous version of this manuscript.

References (77)

J. LeDoux
Biol. Psychiatry
(1998)
L.W. Swanson et al.
Trends Neurosci.
(1998)
M. Davis
Trends Neurosci.
(1994)
S. Maren
Behav. Brain Res.
(1997)
J. Iwata
Brain Res.
(1987)
B.S. Kapp
Brain Res.
(1982)
G.J. Quirk
Neuron
(1995)
S. Maren
Brain Res.
(1991)
J.P. Pascoe et al.
Behav. Brain Res.
(1985)
G.J. Quirk
Neuron
(1997)

Cited by (357)

Fear conditioning and extinction distinctively alter bidirectional synaptic plasticity within the amygdala of an animal model of post-traumatic stress disorder
2024, Neurobiology of Stress
Synaptic plasticity in the amygdala plays an essential role in the formation and inhibition of fear memory; however, this plasticity has mainly been studied in the lateral amygdala, making it largely uninvestigated in other subnuclei. Here, we investigated long-term potentiation (LTP) and long-term depression (LTD) in the basolateral amygdala (BLA) to the medial division of the central amygdala (CEm) synapses of juvenile C57BL/6N (B6) and 129S1/SvImJ (S1) mice. We found that in naïve B6 and S1 mice, LTP was not induced at the BLA to CEm synapses, whereas fear conditioning lowered the threshold for LTP induction in these synapses of both B6 and S1 mice. Interestingly, fear extinction disrupted the induction of LTP at the BLA to CEm synapses of B6 mice, whereas LTP was left intact in S1 mice. Both low-frequency stimulation (LFS) and modest LFS (mLFS) induced LTD in naïve B6 and S1 mice, suggesting that the BLA to CEm synapses express bidirectional plasticity. Fear conditioning disrupted both types of LTD induction selectively in S1 mice and LFS-LTD, presumably NMDAR-dependent LTD was partially recovered by fear extinction. However, mLFS-LTD which has been known to be endocannabinoid receptor 1 (CB1R)-dependent was not induced after fear extinction in both mouse strains. Our observations suggest that fear conditioning enhances LTP while fear extinction diminishes LTP at the BLA to the CEm synapses of B6 mice with successful extinction. Considering that S1 mice showed strong fear conditioning and impaired extinction, strong fear conditioning in the S1 strain may be related to disrupted LTD, and impaired extinction may be due to constant LTP and weak LFS-LTD at the BLA to CEm synapses. Our study contributes to the further understanding of the dynamics of synaptic potentiation and depression between the subnuclei of the amygdala in juvenile mice after fear conditioning and extinction.
Chemogenetic regulation of the TARP-lipid interaction mimics LTP and reversibly modifies behavior
2023, Cell Reports
Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, is believed to underlie memory formation. Hebbian, postsynaptically expressed LTP requires TARPγ-8 phosphorylation for synaptic insertion of AMPA receptors (AMPARs). However, it is unknown whether TARP-mediated AMPAR insertion alone is sufficient to modify behavior. Here, we report the development of a chemogenetic tool, ExSYTE (Excitatory SYnaptic Transmission modulator by Engineered TARPγ-8), to mimic the cytoplasmic interaction of TARP with the plasma membrane in a doxycycline-dependent manner. We use this tool to examine the specific role of synaptic AMPAR potentiation in amygdala neurons that are activated by fear conditioning. Selective expression of active ExSYTE in these neurons potentiates AMPAR-mediated synaptic transmission in a doxycycline-dependent manner, occludes synaptically induced LTP, and mimics freezing triggered by cued fear conditioning. Thus, chemogenetic controlling of the TARP-membrane interaction is sufficient for LTP-like synaptic AMPAR insertion, which mimics fear conditioning.
Know thy SEFL: Fear sensitization and its relevance to stressor-related disorders
2022, Neuroscience and Biobehavioral Reviews
Extreme stress can cause long-lasting changes in affective behavior manifesting in conditions such as post-traumatic stress disorder (PTSD). Understanding the biological mechanisms that govern trauma-induced behavioral dysregulation requires reliable and rigorous pre-clinical models that recapitulate multiple facets of this complex disease. For decades, Pavlovian fear conditioning has been a dominant paradigm for studying the effects of trauma through an associative learning framework. However, severe stress also causes long-lasting nonassociative fear sensitization, which is often overlooked in Pavlovian fear conditioning studies. This paper synthesizes recent research on the stress-enhanced fear learning (SEFL) paradigm, a valuable rodent model that can dissociate associative and nonassociative effects of stress. We discuss evidence that the SEFL paradigm produces nonassociative fear sensitization that is distinguishable from Pavlovian fear conditioning. We also discuss key biological variables, such as age and sex, neural circuit mechanisms, and crucial gaps in knowledge. We argue that nonassociative fear sensitization deserves more attention within current PTSD models and that SEFL provides a valuable complement to Pavlovian conditioning research on trauma-related pathology.
5-HT<inf>7</inf> receptors enhance inhibitory synaptic input to principal neurons in the mouse basal amygdala
2021, Neuropharmacology
The basal amygdala (BA) has been implicated in encoding fear and its extinction. The level of serotonin (5-HT) in the BA increases due to arousal and stress related to aversive stimuli. The effects of 5-HT₇ receptor (5-HT₇R) activation and blockade on the activity of BA neurons have not yet been investigated. In the present study, a transgenic mouse line carrying green fluorescent protein (GFP) reporter gene was used to identify neurons that express the 5-HT₇R. GFP immunoreactivity was present mainly in cells that also expressed GAD67 or parvalbumin (PV), the phenotypic markers for GABAergic interneurons. Most cells showing GFP fluorescence demonstrated firing patterns characteristic of BA inhibitory interneurons. Activation of 5-HT₇Rs resulted in a depolarization and/or occurrence of spontaneous spiking activity of BA interneurons that was accompanied by an increase in the mean frequency and mean amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from BA principal neurons. These effects were blocked by a specific 5-HT₇R antagonist, SB269970 and were absent in slices from 5-HT₇R knockout mice. Activation of 5-HT₇Rs also decreased the mean frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from BA principal neurons, which was blocked by the GABA_A receptor antagonist picrotoxin. Neither inhibitory nor excitatory miniature postsynaptic currents (mIPSCs/mEPSCs) were affected by 5-HT₇R activation. These results show that in the BA 5-HT₇Rs stimulate an activity-dependent enhancement of inhibitory input from local interneurons to BA principal neurons and provide insights about the possible involvement of BA serotonergic receptors in neuronal mechanisms underlying fear memory.
Microglial activation in the right amygdala-entorhinal-hippocampal complex is associated with preserved spatial learning in App<sup>NL-G-F</sup> mice
2021, NeuroImage
In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo.
In 30 App^NL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, ¹⁸F-GE-180) and β-amyloid-PET (¹⁸F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in App^NL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance.
Voxel-wise analyses in App^NL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning.
Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of App^NL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.
Evaluation of adenosine A1 receptor agonists as neuroprotective countermeasures against Soman intoxication in rats
2021, Toxicology and Applied Pharmacology
Soman, an organophosphorus (OP) compound, disrupts nervous system function through inactivation of acetylcholinesterase (AChE), the enzyme that breaks down acetylcholine at synapses. Left untreated, a state of prolonged seizure activity (status epilepticus, SE) is induced, causing widespread neuronal damage and associated cognitive and behavioral impairments. Previous research demonstrated that therapeutic stimulation of A1 adenosine receptors (A1ARs) can prevent or terminate soman-induced seizure. This study examined the ability of three potent A1AR agonists to provide neuroprotection and, ultimately, prevent observable cognitive and behavioral deficits following exposure to soman. Sprague Dawley rats were challenged with a seizure-inducing dose of soman (1.2 x LD₅₀) and treated 1 min later with one of the following A1AR agonists: (6)-Cyclopentyladenosine (CPA), 2-Chloro-N6-cyclopentyladenosine (CCPA) or N-bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (cdENBA). An active avoidance shuttle box task was used to evaluate locomotor responses to aversive stimuli at 3, 7 and 14 days post-exposure. Animals treated with CPA, CCPA or cdENBA demonstrated a higher number of avoidance responses and a faster reaction to the aversive stimulus than the soman/saline control group across all three sessions. Findings suggest that A1AR agonism is a promising neuroprotective countermeasure, capable of preventing the long-term deficits in learning and memory that are characteristic of soman intoxication.

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewLong-term potentiation in the amygdala: a mechanism for emotional learning and memory

Abstract

Section snippets

Neural circuitry of fear conditioning

Fear memories are formed and stored in the basolateral amygdala

Amygdaloid neurons exhibit LTP

Glutamate receptors in the amygdala are essential for fear conditioning

Fear conditioning induces LTP in the amygdala

Molecular basis of amygdaloid LTP and fear conditioning

Associative LTP as a mechanism for Pavlovian fear conditioning

Concluding remarks

Acknowledgements

Biol. Psychiatry

Trends Neurosci.

Trends Neurosci.

Behav. Brain Res.

Brain Res.

Brain Res.

Neuron

Brain Res.

Behav. Brain Res.

Neuron

Neuron

Brain Res.

Neuron

Neurobiol. Learn. Mem.

Neuron

Behav. Neural Biol.

Cell

J. Neuropsychiatry Clin. Neurosci.

Psychonomic Bull. Rev.

Mol. Neurobiol.

Proc. Natl. Acad. Sci. U. S. A.

Proc. Natl. Acad. Sci. U. S. A.

Am. J. Physiol.

J. Comp. Physiol. Psychol.

Psychol. Rep.

Annu. Rev. Psych.

J. Neurosci.

J. Neurosci.

J. Neurosci.

Science

Behav. Neurosci.

J. Neurosci.

J. Neurosci.

Behav. Neurosci.

Behav. Neurosci.

Behav. Neurosci.

J. Neurosci.

J. Neurosci.

Review
Long-term potentiation in the amygdala: a mechanism for emotional learning and memory