Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective

doi:10.1016/S0166-2236(00)01969-X

Trends in Neurosciences

Volume 24, Issue 9, 1 September 2001, Pages 540-546

https://doi.org/10.1016/S0166-2236(00)01969-X Get rights and content

Abstract

Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. Although considerable progress has been made in understanding the neural substrates of fear conditioning at the systems level, until recently little has been learned about the underlying cellular and molecular mechanisms. The success of systems-level work aimed at defining the neuroanatomical pathways underlying fear conditioning, combined with the knowledge accumulated by studies of long-term potentiation (LTP), has recently given way to new insights into the cellular and molecular mechanisms that underlie acquisition and consolidation of fear memories. Collectively, these findings suggest that fear memory consolidation in the amygdala shares essential biochemical features with LTP, and hold promise for understanding the relationship between memory consolidation and synaptic plasticity in the mammalian brain.

Section snippets

The amygdala and fear conditioning

Much of what we know about the fear learning system of the brain comes from studies of Pavlovian fear conditioning. In this learning paradigm, an initially neutral conditioned stimulus (CS), such as a tone, acquires the ability to elicit defensive responses after association with a noxious unconditioned stimulus (US), such as a brief electric shock to the feet. A large body of evidence suggests that the amygdala, and in particular the lateral amygdala (LA), is a likely site of the plasticity

Cellular mechanisms of fear memory storage: why is LTP important?

How might neurons within the LA store memories of the CS–US association during fear conditioning? In 1949, Hebb ²³ proposed that when two interconnected neurons fire at the same time, the synapses between them become stronger, and remain so for a long time afterwards. At the time Hebb proposed his influential theory, there was little evidence to support it. Later studies, however, showed that high-frequency stimulation of afferents to the hippocampus led to a long-term enhancement of synaptic

Biochemical mechanisms of short- and long-term fear memory

The biochemical and molecular events that underlie LTP have begun to be elucidated in detail, especially in the hippocampus 26, 27, 43, but also more recently in the LA (28, 35, 44, 45). In both structures, LTP is thought to involve activation of a variety of protein kinase signaling pathways, either directly or indirectly, by increases in intracellular Ca²⁺ in the postsynaptic cell at the time of LTP induction. Depending on the pathway and type of stimulation, either the N-methyl-D-aspartate

Is amygdala LTP a cellular mechanism of fear memory consolidation?

Collectively, the findings of recent behavioral and electrophysiological experiments are clearly consistent with the hypotheses that the amygdala is a likely site of fear memory consolidation and storage, and that this process shares essential biochemical features with an LTP-like mechanism (Fig. 1). However, because many, if not all, of these LTP studies have employed in vitro methods, it remains difficult to draw conclusions about the causal role of amygdala LTP in fear memory formation. This

A model of fear memory consolidation in the amygdala

Despite the questions that remain, at this stage we can begin to envision a model of the cellular and molecular events that underlie memory formation and consolidation of fear conditioning in the LA. In brief, the existing behavioral and electrophysiological data are consistent with a model wherein pairing of CS and US inputs onto LA principal cells during training leads to Ca²⁺ influx through the NMDA receptor 61, 62, 63, 64, 65, 66. This increase in intracellular Ca²⁺ leads to the activation

Retrieval and reconsolidation of fear memories in the amygdala

Although we have begun to piece together a model of the cellular and molecular events underlying memory formation and consolidation in the LA, it currently applies only to the initial phases of memory consolidation following training. Indeed, this model will no doubt require modification to account for the process of reconsolidation of fear conditioning, which we currently know very little about.

As discussed earlier, memory consolidation is typically thought of as a process in which labile,

Concluding remarks

Progress in elucidating the neural system underlying fear conditioning has in recent years been paralleled by great strides in our understanding of the cellular and molecular basis of synaptic plasticity, including LTP. The application of the knowledge gained by LTP studies to the fear conditioning paradigm has revealed a great deal about the cellular and molecular mechanisms of fear conditioning in the LA, suggesting that similar mechanisms might be involved. These findings provide a

Acknowledgements

This work was supported, in part, by National Institutes of Health grants: MH 46516, MH 00956, MH 39774 and MH 11902, and a grant from the W.M. Keck Foundation to New York University.

References (103)

M Fendt et al.
The neuroanatomical and neurochemical basis of conditioned fear
Neurosci. Biobehav. Rev.
(1999)
M.S Fanselow et al.
Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala
Neuron
(1999)
G.J Quirk
Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat
Neuron
(1995)
G.J Quirk
Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala
Neuron
(1997)
B.S Kapp
Amygdala central nucleus lesions: effect on heart rate conditioning in the rabbit
Physiol. Behav.
(1979)
L Cahill
Is the amygdala a locus of ‘conditioned fear’? Some questions and caveats
Neuron
(1999)
B Milner
Cognitive neuroscience and the study of memory
Neuron
(1998)
Y.Y Huang
cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase
Cell
(1994)
M.T Rogan et al.
LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit
Neuron
(1995)
Y.Y Huang et al.
Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala
Neuron
(1998)

S Maren

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

Trends Neurosci.

(1999)

T.R Soderling et al.

Postsynaptic protein phosphorylation and LTP

Trends Neurosci.

(2000)

L.C Griffith

Inhibition of calcium/calmodulin-dependent protein kinase in Drosophila disrupts behavioral plasticity

Neuron

(1993)

C Wolfman

Intrahippocampal or intraamygdala infusion of KN62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, causes retrograde amnesia in the rat

Behav. Neural Biol.

(1994)

D Jerusalinsky

Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats

Behav. Neural Biol.

(1994)

S Strack et al.

Autophosphorylation-dependent targeting of calcium/ calmodulin- dependent protein kinase II by the NR2B subunit of the N-methyl- D-aspartate receptor

J. Biol. Chem.

(1998)

S Strack

Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor

J. Biol. Chem.

(2000)

A.J Silva

Impaired learning in mice with abnormal short-lived plasticity

Curr. Biol.

(1996)

E.D Roberson et al.

Transient activation of cyclic AMP-dependent protein kinase during hippocampal long-term potentiation

J. Biol. Chem.

(1996)

J.D English et al.

Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation

J. Biol. Chem.

(1996)

J.D English et al.

A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation

J. Biol. Chem.

(1997)

K.C Martin

MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia

Neuron

(1997)

S Impey

Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus

Neuron

(1996)

S Impey

Cross talk between ERK and PKA is required for Ca²⁺ stimulation of CREB-dependent transcription and ERK nuclear translocation

Neuron

(1998)

K Morimoto

Time-dependent changes in neurotrophic factor mRNA expression after kindling and long-term potentiation in rats

Brain Res. Bull.

(1998)

M Dragunow

Brain-derived neurotrophic factor expression after long-term potentiation

Neurosci. Lett.

(1993)

K Yukawa

Expressions of CCAAT/Enhancer-binding proteins beta and delta and their activities are intensified by cAMP signaling as well as Ca²⁺/calmodulin kinases activation in hippocampal neurons

J. Biol. Chem.

(1998)

S Malkani et al.

Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats

Neuroscience

(2000)

R Bourtchuladze

Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein

Cell

(1994)

T Abel

Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory

Cell

(1997)

H.P Davis et al.

Protein synthesis and memory: a review

Psychol. Bull.

(1984)

M Davis

Neurobiology of fear responses: the role of the amygdala

J. Neuropsychiatry Clin. Neurosci.

(1997)

J.E LeDoux

Emotion circuits in the brain

Annu. Rev. Neurosci.

(2000)

L.M Romanski

Somatosensory and auditory convergence in the lateral nucleus of the amygdala

Behav. Neurosci.

(1993)

J.E LeDoux

The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning

J. Neurosci.

(1990)

P Amorapanth

Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus

Nat. Neurosci.

(2000)

S Campeau et al.

Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli

J. Neurosci.

(1995)

S Maren

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient

Behav. Neurosci.

(1996)

A.E Wilensky

The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning

J. Neurosci.

(2000)

J Muller

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

Behav. Neurosci.

(1997)

M.G McKernan et al.

Fear conditioning induces a lasting potentiation of synaptic currents in vitro

Nature

(1997)

S Maren

Auditory fear conditioning increases CS-elicited spike firing in lateral amygdala neurons even after extensive overtraining

Eur. J. Neurosci.

(2000)

M.T Rogan

Fear conditioning induces associative long-term potentiation in the amygdala

Nature

(1997)

J.E LeDoux

Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear

J. Neurosci.

(1988)

B.S Kapp

Effects of electrical stimulation of the amygdaloid central nucleus on neocortical arousal in the rabbit

Behav. Neurosci.

(1994)

K Nader

Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning

Learn. Mem.

(2001)

D.O Hebb

The Organization of Behavior

(1949)

T.V Bliss et al.

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

(1973)

D.V Madison

Mechanisms underlying long-term potentiation of synaptic transmission

Annu. Rev. Neurosci.

(1991)

E.R Kandel

Genes, synapses, and long-term memory

J. Cell. Physiol.

(1997)

Cited by (406)

Some key parameters in contextual fear conditioning and extinction in adult rats
2024, Behavioural Brain Research
Contextual fear conditioning is a behavioral paradigm used to assess hippocampal-dependent memory in experimental animals. Perception of the context depends on activation of a distinct population of neurons in the hippocampus and in hippocampal-related areas that process discrete aspects of context perception. In the absence of any putatively associated cue, the context becomes the salient element that may warn of an upcoming aversive event; and in particular conditions, animals generalize this warning to any new or similar context. In this study we evaluated the effects of the number of sessions, the number of unconditioned stimuli per acquisition session and the distribution of extinction sessions to assess fear acquisition and extinction and determine under which conditions generalization occurred in adult, male rats. We observed that the organization and spacing of sessions were relevant factors in the acquisition and extinction of contextual fear memories. Extinction occurred with significantly greater robustness when sessions were spread over two days. Furthermore, results indicated that exposure to a single 0.3 mA, 0.5 s footshock in two different sessions could produce context-specific fear, while more acquisition sessions or more footshocks within a single session produced a generalization of the fear response to a new context. Notably, when generalization occurred, successive re-exposure to the generalized context produced extinction in a similar way to the paired exposure. Together, the present findings identify clear procedural and behavioral parameters amenable to neural systems analysis of three clinically relevant outcomes of contextual fear conditioning, i.e., memory acquisition, storage and extinction.
Chemogenetic inhibition of amygdala excitatory neurons impairs rhEPO-enhanced contextual fear memory after TBI
2023, Neuroscience Letters
Erythropoietin (EPO) is a hypoxia-responsive cytokine that induces neuroprotective effect in hypoxic-ischaemic, traumatic, excitotoxic and inflammatory injuries. Recently, utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we have found that ongoing recombinant human EPO (rhEPO) administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We also demonstrated that the 1-month behavioral improvement was associated with mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. However, we did not uncover which type of cells were involved in fear memory response enhancement after rhEPO treatment in the setting of TBI with delayed hypoxemia. In this report, using chemogenetic tools in our controlled cortical impact (CCI) model, we were able to inactivate excitatory neurons and eliminate rhEPO-induced fear memory recall enhancement. In summary, these data demonstrate that rhEPO treatment initiated after TBI enhances contextual fear memory in the injured brain via activation of excitatory neurons in the amygdala.
Distinct populations of corticotropin-releasing factor (CRF) neurons mediate divergent yet complementary defensive behaviors in response to a threat
2023, Neuropharmacology
Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are adaptive and facilitate survival. Selecting appropriate defensive strategy depends on intensity, proximity, temporal threat threshold, and past experiences. Hypothalamic corticotropin-releasing factor (CRF) is a major driver of an acute stress response, whereas extrahypothalamic CRF mediates stress-related affective behaviors. In this review, we shift the focus from a monolithic role of CRF as an anxiogenic peptide to comprehensively dissecting contributions of distinct populations of CRF neurons in mediating defensive behaviors. Direct interrogation of CRF neurons of the central amygdala (CeA) or the bed nucleus of the stria terminalis (BNST) show they drive unconditioned defensive responses, such as vigilance and avoidance of open spaces. Although both populations also contribute to learned fear responses in familiar, threatening contexts, CeA-CRF neurons are particularly attuned to the ever-changing environment. Depending on threat intensities, they facilitate discrimination of salient stimuli predicting manageable threats, and prevent their generalization. Finally, hypothalamic CRF neurons mediate initial threat assessment and active defense such as escape to shelter. Overall, these three major populations of CRF neurons demonstrate divergent, yet complementary contributions to the versatile defense system: heightened vigilance, discriminating salient threats, and active escape, representing three legs of the defense tripod. Despite the ‘CRF exhaustion’ in the field of affective neuroscience, understanding contributions of specific CRF neurons during adaptive defensive behaviors is needed in order to understand the implications of their dysregulation in fear- and anxiety-related psychiatric disorders.
This article is part of the Special Issue on “Fear, Anxiety and PTSD”.
Cerebellar nuclei neurons projecting to the lateral parabrachial nucleus modulate classical fear conditioning
2023, Cell Reports
Multiple brain regions are engaged in classical fear conditioning. Despite evidence for cerebellar involvement in fear conditioning, the mechanisms by which cerebellar outputs modulate fear learning and memory remain unclear. We identify a population of deep cerebellar nucleus (DCN) neurons with monosynaptic glutamatergic projections to the lateral parabrachial nucleus (lPBN) (DCN^→lPBN neurons) in mice. While optogenetic suppression of DCN^→lPBN neurons impairs auditory fear memory, activation of DCN^→lPBN neurons elicits freezing behavior only after auditory fear conditioning. Moreover, auditory fear conditioning potentiates DCN-lPBN synapses, and subsequently, auditory cue activates lPBN neurons after fear conditioning. Furthermore, DCN^→lPBN neuron activation can replace the auditory cue but not footshock in fear conditioning. These findings demonstrate that cerebellar nuclei modulate auditory fear conditioning via transmitting conditioned stimuli signals to the lPBN. Collectively, our findings suggest that the DCN-lPBN circuit is a part of neuronal substrates within interconnected brain regions underscoring auditory fear memory.
Mannose-coated superparamagnetic iron oxide nanozyme for preventing postoperative cognitive dysfunction
2023, Materials Today Bio
Postoperative cognitive dysfunction (POCD) is associated with increased postoperative morbidity and mortality in patients. Excessive production of reactive oxygen species (ROS) and the consequent inflammatory response in the postoperative brain play crucial roles in the development of POCD. However, effective ways to prevent POCD have yet to be developed. Moreover, effective penetration of the blood-brain barrier (BBB) and maintaining viability in vivo are major challenges for preventing POCD using traditional ROS scavengers. Herein, mannose-coated superparamagnetic iron oxide nanoparticles (mSPIONs) were synthesized by co-precipitation method. The BBB penetration of mSPIONs was verified through fluorescent imaging and ICP-MS quantification. The ROS scavenging and anti-inflammatory of mSPIONs were evaluated in H₂O₂-treated J774A.1 cells and in tibial fracture mice model. The novel object recognition (NOR) and trace-fear conditioning (TFC) were used to test the cognitive function of postoperative mice. The average diameter of mSPIONs was approximately 11 nm. mSPIONs significantly reduced ROS levels in H₂O₂-treated cells and in hippocampus of surgical mice. mSPIONs administration reduced the levels of IL-1β and TNF-α in the hippocampus and inhibited surgery-upregulated HIF1-α/NF-κB signaling pathway. Moreover, mSPIONs significantly improved the cognitive function of postoperative mice. This study provides a new approach for preventing POCD using a nanozyme.
Mycobacterium vaccae protects against glucocorticoid resistance resulting from combined physical and psychosocial trauma in mice
2023, Brain, Behavior, and Immunity
Stress-related somatic and psychiatric disorders are often associated with a decline in regulatory T cell (Treg) counts and chronic low-grade inflammation. Recent preclinical evidence suggests that the latter is at least partly mediated by stress-induced upregulation of toll-like receptor (TLR)2 in newly generated neutrophils and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), as well as glucocorticoid (GC) resistance in predominantly PMN-MDSCs following stress-induced upregulation of TLR4 expression. Here we show in mice exposed to the chronic subordinate colony housing (CSC) paradigm that repeated intragastric (i.g.) administrations of a heat-killed preparation of Mycobacterium vaccae NCTC 11659, a saprophytic microorganism with immunoregulatory properties, protected against the stress-induced reduction in systemic Tregs, increase in basal and LPS-induced in vitro splenocyte viability, as well as splenic in vitro GC resistance. Our findings further support the hypothesis that i.g. M. vaccae protects against CSC-associated splenic GC resistance via directly affecting the myeloid compartment, thereby preventing the CSC-induced upregulation of TLR4 in newly generated PMN-MDSCs. In contrast, the protective effects of i.g. M. vaccae on the CSC-induced upregulation of TLR2 in neutrophils and the subsequent increase in basal and LPS-induced in vitro splenocyte viability seems to be indirectly mediated via the Treg compartment. These data highlight the potential for use of oral administration of M. vaccae NCTC 11659 to prevent stress-induced exaggeration of inflammation, a risk factor for development of stress-related psychiatric disorders.

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewMemory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective

Abstract

Section snippets

The amygdala and fear conditioning

Cellular mechanisms of fear memory storage: why is LTP important?

Biochemical mechanisms of short- and long-term fear memory

Is amygdala LTP a cellular mechanism of fear memory consolidation?

A model of fear memory consolidation in the amygdala

Retrieval and reconsolidation of fear memories in the amygdala

Concluding remarks

Acknowledgements

Neurosci. Biobehav. Rev.

Neuron

Neuron

Neuron

Physiol. Behav.

Neuron

Neuron

Cell

Neuron

Neuron

Trends Neurosci.

Trends Neurosci.

Neuron

Behav. Neural Biol.

Behav. Neural Biol.

J. Biol. Chem.

J. Biol. Chem.

Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuron

Neuron

Brain Res. Bull.

Neurosci. Lett.

J. Biol. Chem.

Neuroscience

Cell

Cell

Protein synthesis and memory: a review

Psychol. Bull.

Neurobiology of fear responses: the role of the amygdala

J. Neuropsychiatry Clin. Neurosci.

Emotion circuits in the brain

Annu. Rev. Neurosci.

Somatosensory and auditory convergence in the lateral nucleus of the amygdala

Behav. Neurosci.

The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning

J. Neurosci.

Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus

Nat. Neurosci.

Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli

J. Neurosci.

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient

Behav. Neurosci.

The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning

J. Neurosci.

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

Behav. Neurosci.

Fear conditioning induces a lasting potentiation of synaptic currents in vitro

Nature

Auditory fear conditioning increases CS-elicited spike firing in lateral amygdala neurons even after extensive overtraining

Eur. J. Neurosci.

Fear conditioning induces associative long-term potentiation in the amygdala

Nature

Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear

J. Neurosci.

Effects of electrical stimulation of the amygdaloid central nucleus on neocortical arousal in the rabbit

Behav. Neurosci.

Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning

Learn. Mem.

The Organization of Behavior

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

Mechanisms underlying long-term potentiation of synaptic transmission

Annu. Rev. Neurosci.

Genes, synapses, and long-term memory

Review
Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective