Amygdala Microcircuits Controlling Learned Fear
2014; Cell Press; Volume: 82; Issue: 5 Linguagem: Inglês
10.1016/j.neuron.2014.04.042
ISSN1097-4199
Autores Tópico(s)Neuroscience and Neuropharmacology Research
ResumoWe review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning. We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning. This review focuses on learned fear and its regulation by intrinsic circuits of the amygdala. As biologists, we approach fear with an evolutionary perspective. We conceive fear as a set of innate response predispositions (behavioral, endocrine, autonomic, and cognitive) to threatening stimuli. We assume that these response tendencies, or rather, the underlying anatomical substrates and physiological mechanisms, have been retained by natural selection because they promote survival and reproductive success. Thus, the neuronal basis of fear should be well conserved across species, a corollary supported by congruent findings of animal and human studies (Phelps and LeDoux, 2005Phelps E.A. LeDoux J.E. Contributions of the amygdala to emotion processing: from animal models to human behavior.Neuron. 2005; 48: 175-187Abstract Full Text Full Text PDF PubMed Scopus (1180) Google Scholar). We focus on observable correlates of fear like freezing behavior for two reasons. First, animals might not experience feelings of fear. Second, the subjective experience of fear and associated defensive behaviors likely depend on different mechanisms (LeDoux, 2014LeDoux J.E. Coming to terms with fear.Proc. Natl. Acad. Sci. USA. 2014; 111: 2871-2878Crossref PubMed Scopus (84) Google Scholar). Nevertheless, for simplicity, below we use the word fear when referring to defensive behaviors. Building on innate fear, learned fear also represents an advantageous evolutionary adaptation: the ability to learn by experience that some stimuli or circumstances predict danger or safety is key to the survival of animals in the wild. In the laboratory, the paradigm most often used to study this process is Pavlovian fear conditioning where an initially neutral stimulus (conditioned stimulus [CS]), such as tone, is paired with a noxious unconditioned stimulus (US), typically a mild foot shock. As a result, the CS acquires the ability to elicit conditioned fear responses (such as freezing) when later presented alone. Pavlovian fear conditioning is used widely, in part because it is easy to implement: just a few (typically four to five) CS-US pairings lead to the formation of a readily quantifiable memory that lasts the subjects’ lifetime (McAllister et al., 1986McAllister W.R. McAllister D.E. Scoles M.T. Hampton S.R. Persistence of fear-reducing behavior: relevance for the conditioning theory of neurosis.J. Abnorm. Psychol. 1986; 95: 365-372Crossref PubMed Google Scholar, Gale et al., 2004Gale G.D. Anagnostaras S.G. Godsil B.P. Mitchell S. Nozawa T. Sage J.R. Wiltgen B. Fanselow M.S. Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of rats.J. Neurosci. 2004; 24: 3810-3815Crossref PubMed Scopus (210) Google Scholar). Another factor behind this paradigm’s popularity is evidence that human anxiety disorders result from a dysregulation of normal fear learning mechanisms (Graham and Milad, 2011Graham B.M. Milad M.R. The study of fear extinction: implications for anxiety disorders.Am. J. Psychiatry. 2011; 168: 1255-1265Crossref PubMed Scopus (81) Google Scholar) and abnormal activity patterns in the cerebral networks that normally regulate fear learning (Shin et al., 2006aShin L.M. Rauch S.L. Pitman R.K. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD.Ann. N Y Acad. Sci. 2006; 1071: 67-79Crossref PubMed Scopus (403) Google Scholar, Bremner et al., 2008Bremner J.D. Elzinga B. Schmahl C. Vermetten E. Structural and functional plasticity of the human brain in posttraumatic stress disorder.Prog. Brain Res. 2008; 167: 171-186Crossref PubMed Scopus (164) Google Scholar). Together, these factors have contributed to make fear learning mechanisms one of the most intensely studied questions in neuroscience. Indeed, during the last decade, ∼400 papers/year have been published on this question. Since this vast literature cannot possibly be reviewed here, we will focus on a line of investigation that has been particularly active lately: the intrinsic amygdala circuits that mediate learned fear. Although we concentrate on learned fear, it should be noted that the same circuits have been implicated in the acquisition of responses driven by positively valenced reinforcers (for instance, see Tye et al., 2008Tye K.M. Stuber G.D. de Ridder B. Bonci A. Janak P.H. Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning.Nature. 2008; 453: 1253-1257Crossref PubMed Scopus (86) Google Scholar). The reader is referred to prior reviews for other aspects of fear conditioning such as mechanisms of synaptic plasticity (Pape and Pare, 2010Pape H.C. Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.Physiol. 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The amygdala is a critical component of the neural circuitry underlying fear learning (Davis, 2000Davis M. The role of the amygdala in conditioned and unconditioned fear and anxiety.in: Aggleton J.P. The Amygdala: a functional analysis. Oxford University Press, Oxford2000: 213-287Google Scholar, LeDoux, 2000LeDoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (4227) Google Scholar). It is comprised of a heterogeneous collection of nuclei, some with properties reminiscent of cortex, others of striatum. In this review, we will focus on a subset of these because they are thought to regulate conditioned fear: the basolateral complex (BLA), which includes the lateral (LA), basolateral (BL), and basomedial (BM) nuclei; the central nucleus (CeA), commonly divided in lateral (CeL) and medial (CeM) sectors; and the intercalated cell masses (ICMs). In broad strokes, LA is the main point of entry for sensory inputs into the amygdala, whereas CeM is the main source of amygdala projections to brainstem fear effector structures. However, not all sensory inputs trigger fear, in part because impulse transfer from LA to CeM is flexibly gated depending on the specific pattern of environmental cues confronting the organism (Paré et al., 2003Paré D. Royer S. Smith Y. Lang E.J. Contextual inhibitory gating of impulse traffic in the intra-amygdaloid network.Ann. N Y Acad. Sci. 2003; 985: 78-91Crossref PubMed Google Scholar). It is thought that CeL and the ICMs fulfill this function, because they receive glutamatergic inputs from BLA and send GABAergic projections to CeM. We now briefly consider the cell types and connectivity of these nuclei. The cellular composition of the BLA is often likened to that of the cerebral cortex, because it also contains a majority (∼80%) of spiny glutamatergic neurons (principal neurons; Figures 1A and 1B) and a minority (∼20%) of sparsely spiny GABAergic interneurons (Figure 1B3) (McDonald, 1992McDonald A.J. Cell types and intrinsic connections of the amygdala.in: Aggleton J.P. The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction. Wiley-Liss, New York1992: 67-96Google Scholar, Spampanato et al., 2011Spampanato J. Polepalli J. Sah P. Interneurons in the basolateral amygdala.Neuropharmacology. 2011; 60: 765-773Crossref PubMed Scopus (42) Google Scholar). While the vast majority of GABAergic neurons in the BLA are local-circuit cells, a recent study reported that a small subset located in or near the external capsule projects to the basal forebrain (McDonald et al., 2012McDonald A.J. Mascagni F. Zaric V. Subpopulations of somatostatin-immunoreactive non-pyramidal neurons in the amygdala and adjacent external capsule project to the basal forebrain: evidence for the existence of GABAergic projection neurons in the cortical nuclei and basolateral nuclear complex.Front. Neural Circuits. 2012; 6: 46Crossref PubMed Scopus (15) Google Scholar). Although some intrinsically bursting principal cells exist (Figure 1E1) (Paré et al., 1995aParé D. Pape H.-C. Dong J. Bursting and oscillating neurons of the cat basolateral amygdaloid complex in vivo: electrophysiological properties and morphological features.J. Neurophysiol. 1995; 74: 1179-1191PubMed Google Scholar), most are regular spiking neurons that exhibit a continuum of spike frequency adaptation due to the differential expression of voltage- and Ca2+-dependent K+ conductances (Figure 1E2) (Faber and Sah, 2002Faber E.S. Sah P. Physiological role of calcium-activated potassium currents in the rat lateral amygdala.J. 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A novel subpopulation of 5-HT type 3A receptor subunit immunoreactive interneurons in the rat basolateral amygdala.Neuroscience. 2007; 144: 1015-1024Crossref PubMed Scopus (23) Google Scholar). Numerically, the two main classes express parvalbumin (PV+) (Figure 1B3) or somatostatin (SOM+). However, PV+ interneurons are not distributed homogenously in the BLA: they are more numerous in BA than LA (Muller et al., 2006Muller J.F. Mascagni F. McDonald A.J. Pyramidal cells of the rat basolateral amygdala: synaptology and innervation by parvalbumin-immunoreactive interneurons.J. Comp. Neurol. 2006; 494: 635-650Crossref PubMed Scopus (91) Google Scholar). Different classes of interneurons regulate principal cells in distinct ways, because they receive different inputs and target different postsynaptic domains (Smith et al., 2000Smith Y. Paré J.F. Paré D. 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Cell-type-specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo.Neuron. 2012; 74: 1059-1074Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). For instance, PV+ interneurons receive strong inputs from principal cells, but very few from the cerebral cortex (Smith et al., 2000Smith Y. Paré J.F. Paré D. Differential innervation of parvalbumin-immunoreactive interneurons of the basolateral amygdaloid complex by cortical and intrinsic inputs.J. Comp. Neurol. 2000; 416: 496-508Crossref PubMed Scopus (110) Google Scholar). They form inhibitory synapses with the soma, axon initial segment, and proximal dendrites of projection cells (Pitkänen and Amaral, 1993Pitkänen A. Amaral D.G. Distribution of parvalbumin-immunoreactive cells and fibers in the monkey temporal lobe: the amygdaloid complex.J. Comp. Neurol. 1993; 331: 14-36Crossref PubMed Google Scholar, Sorvari et al., 1995Sorvari H. Soininen H. Paljärvi L. Karkola K. 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In fact, even among neurochemically homogeneous subtypes, the physiological properties of local-circuit cells are extremely diverse (Rainnie et al., 2006Rainnie D.G. Mania I. Mascagni F. McDonald A.J. Physiological and morphological characterization of parvalbumin-containing interneurons of the rat basolateral amygdala.J. Comp. Neurol. 2006; 498: 142-161Crossref PubMed Scopus (68) Google Scholar, Sosulina et al., 2006Sosulina L. Meis S. Seifert G. Steinhäuser C. Pape H.C. Classification of projection neurons and interneurons in the rat lateral amygdala based upon cluster analysis.Mol. Cell. Neurosci. 2006; 33: 57-67Crossref PubMed Scopus (43) Google Scholar Jasnow et al., 2009Jasnow A.M. Ressler K.J. Hammack S.E. Chhatwal J.P. Rainnie D.G. Distinct subtypes of cholecystokinin (CCK)-containing interneurons of the basolateral amygdala identified using a CCK promoter-specific lentivirus.J. Neurophysiol. 2009; 101: 1494-1506Crossref PubMed Scopus (31) Google Scholar). CeL and CeM each contain one main cell type (Hall, 1972Hall E. The amygdala of the cat: a Golgi study.Z. Zellforsch. Mikrosk. Anat. 1972; 134: 439-458Crossref PubMed Scopus (83) Google Scholar, Kamal and Tömböl, 1975Kamal A.M. Tömböl T. Golgi studies on the amygdaloid nuclei of the cat.J. Hirnforsch. 1975; 16: 175-201PubMed Google Scholar, McDonald, 1992McDonald A.J. Cell types and intrinsic connections of the amygdala.in: Aggleton J.P. The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction. Wiley-Liss, New York1992: 67-96Google Scholar) thought to be GABAergic (Paré and Smith, 1993aParé D. Smith Y. Distribution of GABA immunoreactivity in the amygdaloid complex of the cat.Neuroscience. 1993; 57: 1061-1076Crossref PubMed Scopus (100) Google Scholar, McDonald and Augustine, 1993McDonald A.J. Augustine J.R. Localization of GABA-like immunoreactivity in the monkey amygdala.Neuroscience. 1993; 52: 281-294Crossref PubMed Scopus (124) Google Scholar). Most CeM neurons have a large soma, dendrites that branch sparingly and exhibit a low to moderate density of dendritic spines. In contrast, most CeL neurons have a smaller soma, multiple primary dendrites that branch profusely and bear a high density of spines, similar to the main type of cells found in the striatum (Hall, 1972Hall E. The amygdala of the cat: a Golgi study.Z. Zellforsch. Mikrosk. Anat. 1972; 134: 439-458Crossref PubMed Scopus (83) Google Scholar), the so-called medium spiny neurons. Also similar to the striatum, local-circuit cells appear to account for a much lower proportion of neurons in CeL than BLA. As to the physiological properties of principal CeL and CeM neurons, three subtypes have been described (Martina et al., 1999Martina M. Royer S. Paré D. Physiological properties of central medial and central lateral amygdala neurons.J. Neurophysiol. 1999; 82: 1843-1854PubMed Google Scholar, Dumont et al., 2002Dumont E.C. Martina M. Samson R.D. Drolet G. Paré D. 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We will refer to the intercalated cell clusters located in the external and intermediate capsules as lateral ICMs (ICML) and medial ICMs (ICMM), respectively. Among the latter, we will distinguish between clusters located dorsally, near CeL (ICMMD) and those located ventrally, near CeM (ICMMV). The vast majority of intercalated neurons are GABAergic (Nitecka and Ben-Ari, 1987Nitecka L. Ben-Ari Y. Distribution of GABA-like immunoreactivity in the rat amygdaloid complex.J. Comp. Neurol. 1987; 266: 45-55Crossref PubMed Google Scholar, Paré and Smith, 1993aParé D. Smith Y. Distribution of GABA immunoreactivity in the amygdaloid complex of the cat.Neuroscience. 1993; 57: 1061-1076Crossref PubMed Scopus (100) Google Scholar, McDonald and Augustine, 1993McDonald A.J. Augustine J.R. Localization of GABA-like immunoreactivity in the monkey amygdala.Neuroscience. 1993; 52: 281-294Crossref PubMed Scopus (124) Google Scholar). They have a small soma (8–19 μm in diameter), a dendritic tree mostly confined to the fiber bundle where their soma is located, and a moderate to high density of dendritic spines (Figures 1B1 and 1D2) (Millhouse, 1986Millhouse O.E. The intercalated cells of the amygdala.J. Comp. Neurol. 1986; 247: 246-271Crossref PubMed Google Scholar). Compared to the rest of the amygdala, ICMs express very high levels of μ opioid and dopamine type-1 receptors (Herkenham and Pert, 1982Herkenham M. Pert C.B. Light microscopic localization of brain opiate receptors: a general autoradiographic method which preserves tissue quality.J. Neurosci. 1982; 2: 1129-1149PubMed Google Scholar, Jacobsen et al., 2006Jacobsen K.X. Höistad M. Staines W.A. Fuxe K. 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Intra-amygdaloid projections of the lateral nucleus in the cat: PHA-L anterograde labeling combined with postembedding GABA and glutamate immunocytochemistry.J. Comp. Neurol. 1994; 342: 232-248Crossref PubMed Google Scholar). Yet, paired recordings of closely spaced principal cells rarely provide evidence of connections. The explanation for this apparent contradiction resides in the spatial heterogeneity of the connections formed by principal cells with each other versus interneurons. Indeed, physiological studies have revealed that the axons of principal cells prevalently contact different types of neurons depending on the position of their targets: interneurons at proximity and other principal cells at a distance (Samson et al., 2003Samson R.D. Dumont E.C. Paré D. Feedback inhibition defines transverse processing modules in the lateral amygdala.J. Neurosci. 2003; 23: 1966-1973PubMed Google Scholar, Samson and Paré, 2006Samson R.D. Paré D. A spatially structured network of inhibitory and excitatory connections directs impulse traffic within the lateral amygdala.Neuroscience. 2006; 141: 1599-1609Crossref PubMed Scopus (13) Google Scholar). Presumably, this arrangement allows the BLA network to prevent runaway excitation locally while allowing associative interactions between distant principal cells that receive different types of inputs. Within CeA, principal neurons are also connected with each other, but via GABAergic synapses. For instance, local pressure application of glutamate in CeL evokes inhibitory postsynaptic potentials in CeL neurons (Lopez de Armentia and Sah, 2004Lopez de Armentia M. Sah P. Firing properties and connectivity of neurons in the rat lateral central nucleus of the amygdala.J. Neurophysiol. 2004; 92: 1285-1294Crossref PubMed Scopus (38) Google Scholar). Tracing studies have also revealed that CeL neurons project to CeM (Figure 1B1) but that projections from CeM to CeL are weak or do not exist (Petrovich and Swanson, 1997Petrovich G.D. Swanson L.W. Projections from the lateral part of the central amygdalar nucleus to the postulated fear conditioning circuit.Brain Res. 1997; 763: 247-254Crossref PubMed Scopus (160) Google Scholar, Jolkkonen and Pitkänen, 1998Jolkkonen E. Pitkänen A. Intrinsic connections of the rat amygdaloid complex: projections originating in the central nucleus.J. Comp. Neurol. 1998; 395: 53-72Crossref PubMed Scopus (95) Google Scholar). More recently, it was found that distinct subtypes of CeL neurons contact CeM cells projecting to different brainstem sites. In particular, CeM cells that project to the periaqueductal gray (PAG) are contacted by CeL neurons expressing oxytocin receptors (OR+), whereas CeM cells projecting to the dorsal vagal complex (DVC) receive inputs from OR− CeL neurons (Viviani et al., 2011Viviani D. Charlet A. van den Burg E. Robinet C. Hurni N. Abatis M. Magara F. Stoop R. Oxytocin selectively gates fear responses through distinct outputs from the central amygdala.Science. 2011; 333: 104-107Crossref PubMed Scopus (116) Google Scholar). It should be noted that many of the OR+ CeL neurons also express PKCδ but not SOM and conversely for OR− CeL neurons (Haubensak et al., 2010Haubensak W. Kunwar P.S. Cai H. Ciocchi S. Wall N.R. Ponnusamy R. Biag J. Dong H.W. Deisseroth K. Callaway E.M. et al.Genetic dissection of an amygdala microcircuit that gates conditioned fear.Nature. 2010; 468: 270-276Crossref PubMed Scopus (241) Google Scholar, Li et al., 2013Li H. Penzo M.A. Taniguchi H. Kopec C.D. Huang Z.J. Li B. Experience-dependent modification of a central amygdala fear circuit.Nat. Neurosci. 2013; 16: 332-339Crossref PubMed Scopus (72) Google Scholar). Locally within each intercalated cell cluster, individual neurons form inhibitory synapses with other intercalated cells, but these connections are rarely reciprocal (Geracitano et al., 2007Geracitano R. Kaufmann W.A. Szabo G. Ferraguti F. Capogna M. Synaptic heterogeneity between mouse paracapsular intercalated neurons of the amygdala.J. Physiol. 2007; 585: 117-134Crossref PubMed Scopus (36) Google Scholar, Geracitano et al., 2012Geracitano R. Fischer D. Kasugai Y. Ferraguti F. Capogna M. Functional expression of the GABA(A) receptor α2 and α3 subunits at synapses between intercalated medial paracapsular neurons of mouse amygdala.Front Neural Circuits. 2012; 6: 32Crossref PubMed Scopus (1) Google Scholar). There are also connections between different intercalated cell clusters, at least between medially located ICMs (Figure 2, link 1). However, these connections have a preferential direction from clusters located dorsolaterally (ICMMD), near CeL, to those located ventromedially (ICMMV), near CeM (Figure 2) (Royer et al., 1999Royer S. Martina M. Paré D. An inhibitory interface gates impulse traffi
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