Molecular Mechanisms of Fear Learning and Memory
2011; Cell Press; Volume: 147; Issue: 3 Linguagem: Inglês
10.1016/j.cell.2011.10.009
ISSN1097-4172
AutoresJoshua P. Johansen, Christopher K. Cain, Linnaea Ostroff, J.E. LeDoux,
Tópico(s)Neuroendocrine regulation and behavior
ResumoPavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias. Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias. Fear is the emotion that is best understood in terms of brain mechanisms. Because fear plays a prominent role, either directly or indirectly, in a variety of psychiatric conditions, understanding its neural basis is of great importance. The term “fear” refers to a subjective feeling state and to the behavioral and physiological responses that occur in response to threatening environmental situations. The objectively measurable behavioral and physiological responses are the subject of scientific investigations of fear in laboratory animals. Research on fear has been successful in large part because of a behavioral paradigm, which is well suited for neurobiological analysis: Pavlovian fear conditioning. Fear conditioning is valuable as a neurobiological tool because it involves a specific stimulus, under the control of the experimenter, that reliably elicits a measurable set of behavioral and physiological responses once learning has occurred. In fear conditioning, an emotionally neutral conditioned stimulus, such as a tone, is paired with an emotionally potent, innately aversive unconditioned stimulus, (e.g., an electric shock) during a conditioning or acquisition phase (Figure 1). This procedure is referred to as auditory fear conditioning. The assessment of conditioning then involves measuring conditioned responses elicited by the auditory conditioned stimulus independent of the unconditioned stimulus during a memory test phase. This somewhat artificial procedure mimics real-life experiences in which the unconditioned stimulus causes pain or other harm and the conditioned stimulus occurs in connection with the harmful one. For example, a rat that is wounded by a cat but escapes may well form a memory of the sound of rustling leaves as the cat was about to attack. Pavlovian conditioning is believed to take place by the convergence of pathways transmitting the conditioned stimulus and unconditioned stimulus. In fear conditioning, the key circuits involve sensory areas that process the conditioned stimulus and unconditioned stimulus, regions of the amygdala that undergo plasticity during learning, and regions that control the expression of specific conditioned responses (Figure 2; LeDoux, 2000LeDoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (3294) Google Scholar, Fanselow and Poulos, 2005Fanselow M.S. Poulos A.M. The neuroscience of mammalian associative learning.Annu. Rev. Psychol. 2005; 56: 207-234Crossref PubMed Scopus (243) Google Scholar, Maren, 2005Maren S. Synaptic mechanisms of associative memory in the amygdala.Neuron. 2005; 47: 783-786Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, Davis and Whalen, 2001Davis M. Whalen P.J. The amygdala: vigilance and emotion.Mol. Psychiatry. 2001; 6: 13-34Crossref PubMed Scopus (1224) Google Scholar, Kim and Jung, 2006Kim J.J. Jung M.W. Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review.Neurosci. Biobehav. Rev. 2006; 30: 188-202Crossref PubMed Scopus (181) Google Scholar). These pathways converge in the LA, where synaptic plasticity that enhances the response of LA neurons to the conditioned stimulus occurs. As a result, the conditioned stimulus is then able to flow from the LA to the central nucleus of the amygdala (CE). The LA connects with the CE directly and indirectly by way of the basal (B) and intercalated masses of the amygdala. Pathways from CE to downstream areas then control defensive behavior (freezing) and autonomic and endocrine responses. Recent studies implicate the prelimbic cortex in fear expression as well, possibly by way of its connections to B and, from there, to CE (Sotres-Bayon and Quirk, 2010Sotres-Bayon F. Quirk G.J. Prefrontal control of fear: more than just extinction.Curr. Opin. Neurobiol. 2010; 20: 231-235Crossref PubMed Scopus (115) Google Scholar). In this Review, we examine recent research on cellular and molecular mechanisms in LA that contribute to auditory fear conditioning. We focus on the LA because molecular changes in this area have been shown to make essential contributions to the formation, storage, and expression of the memory of the experience (see Rodrigues et al., 2004bRodrigues S.M. Farb C.R. Bauer E.P. LeDoux J.E. Schafe G.E. Pavlovian fear conditioning regulates Thr286 autophosphorylation of Ca2+/calmodulin-dependent protein kinase II at lateral amygdala synapses.J. Neurosci. 2004; 24: 3281-3288Crossref PubMed Scopus (70) Google Scholar, Pape and Pare, 2010Pape H.C. Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.Physiol. Rev. 2010; 90: 419-463Crossref PubMed Scopus (219) Google Scholar, Sah et al., 2008Sah P. Westbrook R.F. Lüthi A. Fear conditioning and long-term potentiation in the amygdala: what really is the connection?.Ann. N Y Acad. Sci. 2008; 1129: 88-95Crossref PubMed Scopus (43) Google Scholar). Although molecular changes occur in other areas of the amygdala and in other areas of the brain, the molecular contributions to LA plasticity as it relates to fear learning are understood in the greatest detail. We restrict the discussion to molecular mechanisms that have been linked directly to the behavioral expression of conditioning, as opposed to mechanisms that underlie long-term potentiation (LTP), in which synaptic plasticity is induced by electrical or chemical stimulation of LA circuits. LTP has provided a rich array of candidate mechanisms for the plasticity processes that could occur during actual fear learning but will not be the focus of this Review (see Pape and Pare, 2010Pape H.C. Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.Physiol. Rev. 2010; 90: 419-463Crossref PubMed Scopus (219) Google Scholar, Sah et al., 2008Sah P. Westbrook R.F. Lüthi A. Fear conditioning and long-term potentiation in the amygdala: what really is the connection?.Ann. N Y Acad. Sci. 2008; 1129: 88-95Crossref PubMed Scopus (43) Google Scholar, Sigurdsson et al., 2007Sigurdsson T. Doyère V. Cain C.K. LeDoux J.E. Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory.Neuropharmacology. 2007; 52: 215-227Crossref PubMed Scopus (137) Google Scholar, and Dityatev and Bolshakov, 2005Dityatev A.E. Bolshakov V.Y. Amygdala, long-term potentiation, and fear conditioning.Neuroscientist. 2005; 11: 75-88Crossref PubMed Scopus (32) Google Scholar for reviews on this topic). LTP will only be mentioned when findings are directly relevant to auditory fear conditioning. Unique molecular mechanisms are known to underlie different stages of memory formation. Therefore, we have organized the Review by these stages—specifically, the acquisition, consolidation, and reconsolidation of fear memories. Molecular mechanisms of fear extinction will not be discussed here (for reviews, see Myers and Davis, 2007Myers K.M. Davis M. Mechanisms of fear extinction.Mol. Psychiatry. 2007; 12: 120-150Crossref PubMed Scopus (375) Google Scholar, Quirk and Mueller, 2008Quirk G.J. Mueller D. Neural mechanisms of extinction learning and retrieval.Neuropsychopharmacology. 2008; 33: 56-72Crossref PubMed Scopus (476) Google Scholar, Sotres-Bayon et al., 2006Sotres-Bayon F. Cain C.K. LeDoux J.E. Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex.Biol. Psychiatry. 2006; 60: 329-336Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, Herry et al., 2010Herry C. Ferraguti F. Singewald N. Letzkus J.J. Ehrlich I. Lüthi A. Neuronal circuits of fear extinction.Eur. J. Neurosci. 2010; 31: 599-612Crossref PubMed Scopus (99) Google Scholar, and Pape and Pare, 2010Pape H.C. Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.Physiol. Rev. 2010; 90: 419-463Crossref PubMed Scopus (219) Google Scholar). The stages of memory formation and storage are distinguished by measuring the effects of various manipulations—often pharmacological—on fear-conditioned responses at different times with respect to training or testing (see Rodrigues et al., 2004bRodrigues S.M. Farb C.R. Bauer E.P. LeDoux J.E. Schafe G.E. Pavlovian fear conditioning regulates Thr286 autophosphorylation of Ca2+/calmodulin-dependent protein kinase II at lateral amygdala synapses.J. Neurosci. 2004; 24: 3281-3288Crossref PubMed Scopus (70) Google Scholar). Table 1 summarizes the phases and how drug manipulations are used to assess effects on a particular phase. We limit our discussion to studies that manipulated molecular processes directly in the LA. Other studies that target multiple brain structures (such as genetic knockout and systemic drug studies) are discussed in Rodrigues et al., 2004bRodrigues S.M. Farb C.R. Bauer E.P. LeDoux J.E. Schafe G.E. Pavlovian fear conditioning regulates Thr286 autophosphorylation of Ca2+/calmodulin-dependent protein kinase II at lateral amygdala synapses.J. Neurosci. 2004; 24: 3281-3288Crossref PubMed Scopus (70) Google Scholar, Pape and Pare, 2010Pape H.C. Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.Physiol. Rev. 2010; 90: 419-463Crossref PubMed Scopus (219) Google Scholar, Sah et al., 2008Sah P. Westbrook R.F. Lüthi A. Fear conditioning and long-term potentiation in the amygdala: what really is the connection?.Ann. N Y Acad. Sci. 2008; 1129: 88-95Crossref PubMed Scopus (43) Google Scholar, Silva, 2003Silva A.J. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory.J. Neurobiol. 2003; 54: 224-237Crossref PubMed Scopus (147) Google Scholar, Mayford and Kandel, 1999Mayford M. Kandel E.R. Genetic approaches to memory storage.Trends Genet. 1999; 15: 463-470Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, and Sweatt, 2003Sweatt J.D. Mechanisms of Memory. Elsevier Academic Press, New York2003Google Scholar.Table 1Relation of Time Course of Drug Administration to Different Aspects of Fear ConditioningAcquisitionIf a drug given before, but not after, training affects STM and LTM, it is said to disrupt acquisition.ConsolidationIf drug given before or after training has no effect on STM but impairs LTM, it is said to disrupt consolidation.ReconsolidationIf drug given after retrieval of a consolidated memory has no effect within several (2–4) hr after but impairs memory later (usually 24 hr or longer), it is said to disrupt reconsolidation. Open table in a new tab Learning is the basis of memory. If there is no learning, there can be no memory later. This is true in a psychological description of memory and also appears to be true when looking at the molecules that initiate memory formation. Disruption of molecular mechanisms that mediate memory acquisition invariably affect long-term memories as well. We thus start our exploration of the cellular and molecular mechanisms of fear memory formation by considering the acquisition/training phase of fear conditioning during which learning occurs. A common view in neuroscience is that learning involves so-called Hebbian synaptic plasticity. This view is based on Donald Hebb's influential proposal, which can be paraphrased as follows: a synaptic input can be strengthened when activity in the presynaptic neuron co-occurs with activity (membrane depolarization, especially depolarizations that produce action potentials) in the postsynaptic neuron (Hebb, 1949Hebb D.O. The Organization of Behavior. John Wiley and Sons, New York1949Google Scholar, Brown et al., 1990Brown T.H. Kairiss E.W. Keenan C.L. Hebbian synapses: biophysical mechanisms and algorithms.Annu. Rev. Neurosci. 1990; 13: 475-511Crossref PubMed Google Scholar, Sejnowski, 1999Sejnowski T.J. The book of Hebb.Neuron. 1999; 24: 773-776Abstract Full Text Full Text PDF PubMed Google Scholar). Implicit in Hebb's original formulation was the idea that associative plasticity can be implemented if a strong presynaptic input produces activity in the postsynaptic neuron at the same time that another presynaptic input weakly stimulates the neuron. As a result, the weak input is strengthened by its temporal relationship with the strong input. The Hebbian hypothesis is especially appealing as an explanation for how simple associative learning, such as that taking place in fear conditioning, might occur. In a Hebbian model of fear conditioning, strong depolarization of LA pyramidal cells evoked by the aversive unconditioned stimulus leads to strengthening of coactive conditioned stimulus inputs onto the same neurons (Blair et al., 2001Blair H.T. Schafe G.E. Bauer E.P. Rodrigues S.M. LeDoux J.E. Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning.Learn. Mem. 2001; 8: 229-242Crossref PubMed Scopus (307) Google Scholar, LeDoux, 2000LeDoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (3294) Google Scholar, Paré, 2002Paré D. Mechanisms of Pavlovian fear conditioning: has the engram been located?.Trends Neurosci. 2002; 25 (discussion 437–438): 436-437Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, Sah et al., 2008Sah P. Westbrook R.F. Lüthi A. Fear conditioning and long-term potentiation in the amygdala: what really is the connection?.Ann. N Y Acad. Sci. 2008; 1129: 88-95Crossref PubMed Scopus (43) Google Scholar). Existing data support the idea that LA associative plasticity and fear memory formation are triggered by unconditioned stimulus-induced activation of LA neurons. Thus, unconditioned stimulus-evoked depolarization is necessary for the enhancement of conditioned stimulus-elicited neural responses in LA after conditioned-unconditioned stimuli pairing (Rosenkranz and Grace, 2002aRosenkranz J.A. Grace A.A. Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning.Nature. 2002; 417: 282-287Crossref PubMed Scopus (183) Google Scholar), and pairing a conditioned stimulus with direct depolarization of LA pyramidal neurons as an unconditioned stimulus supports fear conditioning (Johansen et al., 2010bJohansen J.P. Hamanaka H. Monfils M.H. Behnia R. Deisseroth K. Blair H.T. LeDoux J.E. Optical activation of lateral amygdala pyramidal cells instructs associative fear learning.Proc. Natl. Acad. Sci. USA. 2010; 107: 12692-12697Crossref PubMed Scopus (62) Google Scholar). Though there is evidence that Hebbian plasticity in LA may not entirely explain fear conditioning (see below), it is clear that synaptic plasticity at conditioned stimulus input pathways to the LA does occur with fear conditioning. Supporting this, in vivo studies demonstrate an enhancement of auditory stimulus-evoked responses in LA neurons after fear conditioning, (see Maren and Quirk, 2004Maren S. Quirk G.J. Neuronal signalling of fear memory.Nat. Rev. Neurosci. 2004; 5: 844-852Crossref PubMed Scopus (541) Google Scholar, LeDoux, 2000LeDoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (3294) Google Scholar, Blair et al., 2001Blair H.T. Schafe G.E. Bauer E.P. Rodrigues S.M. LeDoux J.E. Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning.Learn. Mem. 2001; 8: 229-242Crossref PubMed Scopus (307) Google Scholar, and Pape and Pare, 2010Pape H.C. Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.Physiol. Rev. 2010; 90: 419-463Crossref PubMed Scopus (219) Google Scholar for review). Further, in vitro experiments find a strengthening of putative auditory thalamo-LA and cortico-LA synapses following the pairing of a conditioned stimulus with an unconditioned stimulus (Clem and Huganir, 2010Clem R.L. Huganir R.L. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure.Science. 2010; 330: 1108-1112Crossref PubMed Scopus (103) Google Scholar, McKernan and Shinnick-Gallagher, 1997McKernan M.G. Shinnick-Gallagher P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro.Nature. 1997; 390: 607-611Crossref PubMed Scopus (436) Google Scholar, Rumpel et al., 2005Rumpel S. LeDoux J. Zador A. Malinow R. Postsynaptic receptor trafficking underlying a form of associative learning.Science. 2005; 308: 83-88Crossref PubMed Scopus (303) Google Scholar, Schroeder and Shinnick-Gallagher, 2005Schroeder B.W. Shinnick-Gallagher P. Fear learning induces persistent facilitation of amygdala synaptic transmission.Eur. J. Neurosci. 2005; 22: 1775-1783Crossref PubMed Scopus (36) Google Scholar). Also supporting the idea that enhancement of synaptic strength in the LA is important for fear learning, LTP is occluded in amygdala slices from fear-conditioned animals (Schroeder and Shinnick-Gallagher, 2004Schroeder B.W. Shinnick-Gallagher P. Fear memories induce a switch in stimulus response and signaling mechanisms for long-term potentiation in the lateral amygdala.Eur. J. Neurosci. 2004; 20: 549-556Crossref PubMed Scopus (21) Google Scholar, Schroeder and Shinnick-Gallagher, 2005Schroeder B.W. Shinnick-Gallagher P. Fear learning induces persistent facilitation of amygdala synaptic transmission.Eur. J. Neurosci. 2005; 22: 1775-1783Crossref PubMed Scopus (36) Google Scholar, Tsvetkov et al., 2002Tsvetkov E. Carlezon W.A. Benes F.M. Kandel E.R. Bolshakov V.Y. Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala.Neuron. 2002; 34: 289-300Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), suggesting that LTP-induced changes in synaptic strength occur in LA during fear learning. In the remainder of this section, we will examine the mechanisms mediating possible Hebbian forms of synaptic plasticity in LA during the acquisition of fear conditioning. Hebbian mechanisms can be defined as those that are directly engaged by or regulate coordinated pre- and postsynaptic activity. We will then consider how other mechanisms, specifically monoamine transmitters, could modulate Hebbian plasticity in LA. NMDA-Type Ionotropic Glutamate Receptors. Hebbian plasticity is believed to involve N-methyl-d-aspartate receptors (NMDARs) located on postsynaptic neurons in LA. NMDARs are known to be coincidence detectors of presynaptic activity (for example, in conditioned stimulus input synapses) and postsynaptic depolarization (evoked by the unconditioned stimulus, for example) (Malenka and Nicoll, 1999Malenka R.C. Nicoll R.A. Long-term potentiation—a decade of progress?.Science. 1999; 285: 1870-1874Crossref PubMed Scopus (1653) Google Scholar). As a result of correlated pre- and postsynaptic activity, NMDARs pass calcium, and this is thought to be important for synaptic plasticity and possibly memory formation (Malenka and Nicoll, 1999Malenka R.C. Nicoll R.A. Long-term potentiation—a decade of progress?.Science. 1999; 285: 1870-1874Crossref PubMed Scopus (1653) Google Scholar). Auditory inputs are indeed presynaptic to glutamate receptors, including NMDARs, in LA and use glutamate as a transmitter (see LeDoux, 2000LeDoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (3294) Google Scholar for review). Further, LA cells that receive auditory inputs also receive unconditioned stimulus inputs (Romanski et al., 1993Romanski L.M. Clugnet M.C. Bordi F. LeDoux J.E. Somatosensory and auditory convergence in the lateral nucleus of the amygdala.Behav. Neurosci. 1993; 107: 444-450Crossref PubMed Scopus (191) Google Scholar, Johansen et al., 2010bJohansen J.P. Hamanaka H. Monfils M.H. Behnia R. Deisseroth K. Blair H.T. LeDoux J.E. Optical activation of lateral amygdala pyramidal cells instructs associative fear learning.Proc. Natl. Acad. Sci. USA. 2010; 107: 12692-12697Crossref PubMed Scopus (62) Google Scholar), and broad spectrum NMDAR antagonists (such as APV) microinjected into the LA and basal amygdala disrupt the acquisition of fear learning (Gewirtz and Davis, 1997Gewirtz J.C. Davis M. Second-order fear conditioning prevented by blocking NMDA receptors in amygdala.Nature. 1997; 388: 471-474Crossref PubMed Scopus (138) Google Scholar, Maren et al., 1996Maren S. Aharonov G. Stote D.L. Fanselow M.S. N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats.Behav. Neurosci. 1996; 110: 1365-1374Crossref PubMed Scopus (236) Google Scholar, Miserendino et al., 1990Miserendino M.J. Sananes C.B. Melia K.R. Davis M. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala.Nature. 1990; 345: 716-718Crossref PubMed Scopus (446) Google Scholar, Rodrigues et al., 2001Rodrigues S.M. Schafe G.E. LeDoux J.E. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning.J. Neurosci. 2001; 21: 6889-6896PubMed Google Scholar). APV also disrupts normal synaptic transmission in the LA (Li et al., 1996Li X.F. Stutzmann G.E. LeDoux J.E. Convergent but temporally separated inputs to lateral amygdala neurons from the auditory thalamus and auditory cortex use different postsynaptic receptors: in vivo intracellular and extracellular recordings in fear conditioning pathways.Learn. Mem. 1996; 3: 229-242Crossref PubMed Google Scholar) and interferes with the expression of previously acquired fear memories (Rodrigues et al., 2001Rodrigues S.M. Schafe G.E. LeDoux J.E. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning.J. Neurosci. 2001; 21: 6889-6896PubMed Google Scholar). This finding raises the possibility that APV reduces the acquisition of fear conditioning by inhibiting synaptic transmission instead of blocking second messenger signaling downstream of NMDARs. However, microinjections in LA of an antagonist that targets the GluN2b (formerly called NR2B) subunit of the NMDAR reduce the acquisition of fear conditioning without affecting expression of fear memories or normal synaptic transmission (Rodrigues et al., 2001Rodrigues S.M. Schafe G.E. LeDoux J.E. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning.J. Neurosci. 2001; 21: 6889-6896PubMed Google Scholar, Bauer et al., 2002Bauer E.P. Schafe G.E. LeDoux J.E. NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala.J. Neurosci. 2002; 22: 5239-5249PubMed Google Scholar). Further, viral-mediated knockdown of the cell adhesion molecule neuroligin-1 in LA attenuates fear memory formation, possibly by reducing NMDAR number (Kim et al., 2008Kim J. Jung S.Y. Lee Y.K. Park S. Choi J.S. Lee C.J. Kim H.S. Choi Y.B. Scheiffele P. Bailey C.H. et al.Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals.Proc. Natl. Acad. Sci. USA. 2008; 105: 9087-9092Crossref PubMed Scopus (53) Google Scholar). Thus, in spite of the effects of APV on synaptic transmission and fear expression, NMDARs at conditioned stimulus input synapses in LA may indeed serve as coincidence detectors of pre- and postsynaptic activity to initiate associative plasticity during fear conditioning. Although postsynaptic NMDARs may contribute to Hebbian synaptic plasticity by facilitating an LTP-like processes involving calcium influx, there is a form of NMDAR-dependent LTP that is induced and expressed presynaptically in LA (Fourcaudot et al., 2009Fourcaudot E. Gambino F. Casassus G. Poulain B. Humeau Y. Lüthi A. L-type voltage-dependent Ca(2+) channels mediate expression of presynaptic LTP in amygdala.Nat. Neurosci. 2009; 12: 1093-1095Crossref PubMed Scopus (32) Google Scholar, Humeau et al., 2003Humeau Y. Shaban H. Bissière S. Lüthi A. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain.Nature. 2003; 426: 841-845Crossref PubMed Scopus (135) Google Scholar). This provides a potential alternate mechanism for NMDAR activation during fear learning that is non-Hebbian in nature (i.e., does not require postsynaptic depolarization) and should be taken into consideration when discussing the effects of pharmacological manipulations of the NMDAR in the LA. When a pairing protocol is used, LTP can become independent of NMDAR activation and instead depend on calcium entry through voltage-gated calcium channels (Weisskopf et al., 1999Weisskopf M.G. Bauer E.P. LeDoux J.E. L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala.J. Neurosci. 1999; 19: 10512-10519Crossref PubMed Google Scholar) in LA. However, in real learning in whole animals, calcium influx through both NMDARs and VGCCs may be required, though VGCCs appear to be involved in consolidation and not acquisition of fear conditioning (Bauer et al., 2002Bauer E.P. Schafe G.E. LeDoux J.E. NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala.J. Neurosci. 2002; 22: 5239-5249PubMed Google Scholar, McKinney and Murphy, 2006McKinney B.C. Murphy G.G. The L-Type voltage-gated calcium channel Cav1.3 mediates consolidation, but not extinction, of contextually conditioned fear in mice.Learn. Mem. 2006; 13: 584-589Crossref PubMed Scopus (30) Google Scholar, Shinnick-Gallagher et al., 2003Shinnick-Gallagher P. McKernan M.G. Xie J. Zinebi F. L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning.Ann. N Y Acad. Sci. 2003; 985: 135-149Crossref PubMed Google Scholar). Ca2+/Calmodulin-Dependent Protein Kinase II. As mentioned, Hebbian processes can activate NMDA receptors, leading to calcium elevation in postsynaptic cells. An increase in intracellular calcium levels is known to lead to autophosphorylation of Ca2+/Calmodulin (Cam)-dependent protein kinase II (CaMKII), and this process is integral to memory formation in a variety of learning paradigms (Silva, 2003Silva A.J. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory.J. Neurobiol. 2003; 54: 224-237Crossref PubMed Scopus (147) Google Scholar). CaMKII phosphorylation has been shown to increase in dendritic spines in the LA following fear learning, and prevention of CaMKII activation blocks the acquisition of fear (Rodrigues et al., 2004aRodrigues S.M. Schafe G.E. LeDoux J.E. Molecular mechanisms underlying emotional learning and memory in the lateral amygdala.Neuron. 2004; 44: 75-91Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). CaMKII autophosphorylation can then engage a number of intracellular events in LA neurons, which may result directly or indirectly in fear memories (see working model of molecular processes in LA mediating fear conditioning in Figure 3). Non-NMDA-Type Ionotropic Glutamate Receptors. Autophosphorylated CaMKII can directly influence STM formation by phosphorylating the serine 831 (ser831) site on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate re
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