Embracing Complexity in Defensive Networks
2019; Cell Press; Volume: 103; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2019.05.024
ISSN1097-4199
AutoresDrew B. Headley, Vasiliki Kanta, Pinelopi Kyriazi, Denis Paré,
Tópico(s)Memory and Neural Mechanisms
ResumoThe neural basis of defensive behaviors continues to attract much interest, not only because they are important for survival but also because their dysregulation may be at the origin of anxiety disorders. Recently, a dominant approach in the field has been the optogenetic manipulation of specific circuits or cell types within these circuits to dissect their role in different defensive behaviors. While the usefulness of optogenetics is unquestionable, we argue that this method, as currently applied, fosters an atomistic conceptualization of defensive behaviors, which hinders progress in understanding the integrated responses of nervous systems to threats. Instead, we advocate for a holistic approach to the problem, including observational study of natural behaviors and their neuronal correlates at multiple sites, coupled to the use of optogenetics, not to globally turn on or off neurons of interest, but to manipulate specific activity patterns hypothesized to regulate defensive behaviors. The neural basis of defensive behaviors continues to attract much interest, not only because they are important for survival but also because their dysregulation may be at the origin of anxiety disorders. Recently, a dominant approach in the field has been the optogenetic manipulation of specific circuits or cell types within these circuits to dissect their role in different defensive behaviors. While the usefulness of optogenetics is unquestionable, we argue that this method, as currently applied, fosters an atomistic conceptualization of defensive behaviors, which hinders progress in understanding the integrated responses of nervous systems to threats. Instead, we advocate for a holistic approach to the problem, including observational study of natural behaviors and their neuronal correlates at multiple sites, coupled to the use of optogenetics, not to globally turn on or off neurons of interest, but to manipulate specific activity patterns hypothesized to regulate defensive behaviors. Neuron invited us to contribute a review on the role of the amygdala in anxiety. However, many comprehensive reviews have been published on this topic recently (Calhoon and Tye, 2015Calhoon G.G. Tye K.M. Resolving the neural circuits of anxiety.Nat. Neurosci. 2015; 18: 1394-1404Crossref PubMed Scopus (270) Google Scholar, Lüthi and Lüscher, 2014Lüthi A. Lüscher C. Pathological circuit function underlying addiction and anxiety disorders.Nat. Neurosci. 2014; 17: 1635-1643Crossref PubMed Scopus (129) Google Scholar, McCullough et al., 2016McCullough K.M. Morrison F.G. Ressler K.J. Bridging the gap: towards a cell-type specific understanding of neural circuits underlying fear behaviors.Neurobiol. Learn. Mem. 2016; 135: 27-39Crossref PubMed Scopus (27) Google Scholar, Tovote et al., 2015Tovote P. Fadok J.P. Lüthi A. Neuronal circuits for fear and anxiety.Nat. Rev. Neurosci. 2015; 16: 317-331Crossref PubMed Scopus (700) Google Scholar). Thus, instead of writing a review whose sole merit over prior ones would be that it includes the latest findings, we elected to present a critical appraisal of the general approach and directions in this active field of research. We hope that colleagues and other readers will find our paper useful. Defensive behaviors are a class of innate response dispositions retained by natural selection because they promote survival in the face of threats such as predators and aggressive con-specifics. Of course, organisms do not inherit the survival strategies themselves but the neuronal networks and physiological mechanisms that support them. As was noted early on (Darwin, 1872Darwin C. The Expression of Emotions in Man and Animals.First Edition. John Murray, 1872Crossref Google Scholar), many defensive behaviors and their precipitating conditions are similar in different mammalian species. As for physical attributes, this kinship likely resulted from the fact that they emerged from small variations to an overall design shared between species. Defensive behaviors have been classified in different ways including the nature of the threatening events (Gross and Canteras, 2012Gross C.T. Canteras N.S. The many paths to fear.Nat. Rev. Neurosci. 2012; 13: 651-658Crossref PubMed Scopus (298) Google Scholar), the ecological conditions they evolved to accommodate (Mobbs, 2018Mobbs D. The ethological deconstruction of fear(s).Curr. Opin. Behav. Sci. 2018; 19: 32-37Crossref Scopus (6) Google Scholar), and the proximity of the threat (Fanselow, 2018Fanselow M.S. Emotion, motivation and function.Curr. Opin. Behav. Sci. 2018; 19: 105-109Crossref Scopus (4) Google Scholar, Perusini and Fanselow, 2015Perusini J.N. Fanselow M.S. Neurobehavioral perspectives on the distinction between fear and anxiety.Learn. Mem. 2015; 22: 417-425Crossref PubMed Scopus (154) Google Scholar). The latter dimension is often used to distinguish fear and anxiety. According to this widespread view, fear occurs when organisms are faced with imminent proximal threats, causing short-lasting defensive responses such as fight or flight. By contrast, anxiety is usually defined as a long-lived state of apprehension that arises when unpredictable or uncertain perils are anticipated. However, the terms fear and anxiety imply the conscious experience of aversive states whose existence in other mammals than humans cannot be ascertained (LeDoux, 2017LeDoux J.E. Semantics, surplus meaning, and the science of fear.Trends Cogn. Sci. 2017; 21: 303-306Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The repertoire of defensive behaviors is relatively limited. It includes vocalizations warning con-specifics of a threat, fast coordinated movements orienting the body toward unexpected stimuli, and behaviors minimizing the likelihood of detection by a predator (freezing) or, if detected, captured (escape) or killed (fight). These behaviors are associated with changes in autonomic tone (e.g., heart rate, blood pressure) and endocrine activity, which mobilize organisms for confrontations and allow them to intimidate potential aggressors (piloerection). Notably, defensive behaviors are also associated with attention systems that allow anticipation and rapid detection of threats (Ohman et al., 2001aOhman A. Flykt A. Esteves F. Emotion drives attention: detecting the snake in the grass.J. Exp. Psychol. Gen. 2001; 130: 466-478Crossref PubMed Google Scholar, Ohman et al., 2001bOhman A. Lundqvist D. Esteves F. The face in the crowd revisited: a threat advantage with schematic stimuli.J. Pers. Soc. Psychol. 2001; 80: 381-396Crossref PubMed Google Scholar). Moreover, through experience, they can become associated with new stimuli. Defensive behaviors are adapted to the nature and proximity of the threats. Generally, proximal and imminent threats require organisms to rapidly weigh different options and thus allow less flexibility in the selection of a defensive strategy. For instance, while behavioral freezing or retreat are efficient ways for animals to survive encounters with distant predators, fighting or fleeing are the only possible responses when the predator’s attack is imminent. In contrast, when threats are not immediate, defensive behaviors exhibit flexibility and context dependence. For instance, foraging rats seeking to minimize the risk of predation consider multiple factors such as current metabolic needs, familiarity with the environment, and the accessibility of escape routes (Mobbs et al., 2018Mobbs D. Trimmer P.C. Blumstein D.T. Dayan P. Foraging for foundations in decision neuroscience: insights from ethology.Nat. Rev. Neurosci. 2018; 19: 419-427Crossref PubMed Scopus (55) Google Scholar). Choi and Kim, 2010Choi J.S. Kim J.J. Amygdala regulates risk of predation in rats foraging in a dynamic fear environment.Proc. Natl. Acad. Sci. USA. 2010; 107: 21773-21777Crossref PubMed Scopus (97) Google Scholar foraging task vividly illustrates the adaptable and changing character of defensive strategies. In this task, hungry rats are confronted with a mechanical predator when they leave the safety of their nest to retrieve food pellets in an elongated arena. It was noted that when rats fail to retrieve food on a given trial, they are more “hesitant” on the next trial, that is, they wait longer before leaving their nest or do not forage altogether (Amir et al., 2015Amir A. Lee S.C. Headley D.B. Herzallah M.M. Paré D. Amygdala signaling during foraging in a hazardous environment.J. Neurosci. 2015; 35: 12994-13005Crossref PubMed Google Scholar, Amir et al., 2018Amir A. Headley D.B. Lee S.C. Haufler D. Paré D. Vigilance-associated gamma oscillations coordinate the ensemble activity of basolateral amygdala neurons.Neuron. 2018; 97: 656-669.e7Abstract Full Text Full Text PDF PubMed Google Scholar). Furthermore, after initiating foraging, they often show signs of “indecision,” alternating between moving toward or away from the food pellet, (Amir et al., 2015Amir A. Lee S.C. Headley D.B. Herzallah M.M. Paré D. Amygdala signaling during foraging in a hazardous environment.J. Neurosci. 2015; 35: 12994-13005Crossref PubMed Google Scholar, Amir et al., 2018Amir A. Headley D.B. Lee S.C. Haufler D. Paré D. Vigilance-associated gamma oscillations coordinate the ensemble activity of basolateral amygdala neurons.Neuron. 2018; 97: 656-669.e7Abstract Full Text Full Text PDF PubMed Google Scholar), suggesting that even rodents continuously evaluate circumstances when selecting a course of action. Evidence of such flexibility was also obtained in aversive conditioning paradigms. In this case, rats display different defensive strategies depending on the features of the environment. In a standard conditioning chamber, aversive conditioned stimuli (CS) appear to reflexively elicit behavioral freezing. However, if the chamber also allows rats to avoid the anticipated shock, either by moving to a different part of the chamber or by stepping onto a platform, trained rats eventually show marked trial-to-trial variations in defensive strategy. They may first freeze and then escape, or escape without first freezing, and they do so at variable latencies from CS onset (Bravo-Rivera et al., 2014Bravo-Rivera C. Roman-Ortiz C. Brignoni-Perez E. Sotres-Bayon F. Quirk G.J. Neural structures mediating expression and extinction of platform-mediated avoidance.J. Neurosci. 2014; 34: 9736-9742Crossref PubMed Scopus (103) Google Scholar, Kyriazi et al., 2018Kyriazi P. Headley D.B. Paré D. Multi-dimensional coding by basolateral amygdala neurons.Neuron. 2018; 99: 1315-1328.e5Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). In another striking example of context specificity, while rat dams conditioned to fear an odor froze to the presentation of the odor when tested alone, in the presence of their pups, the dams did not freeze but remained in contact with their pups or attacked the odor source (Rickenbacher et al., 2017Rickenbacher E. Perry R.E. Sullivan R.M. Moita M.A. Freezing suppression by oxytocin in central amygdala allows alternate defensive behaviours and mother-pup interactions.eLife. 2017; 6: e24080Crossref PubMed Scopus (29) Google Scholar). At the other end of the imminence spectrum are anticipatory defensive strategies (Mobbs, 2018Mobbs D. The ethological deconstruction of fear(s).Curr. Opin. Behav. Sci. 2018; 19: 32-37Crossref Scopus (6) Google Scholar) where in the absence of actual threats, but facing the possibility one might appear, organisms display increased alertness and vigilant scanning of their environment. This state, where processing time is the longest, calls upon prior experiences in the current or similar environments, including the availability of escape routes should one be needed, all the while taking the organism’s current metabolic needs into account. One task that engages these faculties is the Barnes maze, where animals are placed in an open arena and learn the location of an escape port. To understand the neural basis of defensive behaviors, it is important to use tasks that span their spectrum. This helps disambiguate the neural processes involved in the production of specific behaviors from those supporting the processing of threatening stimuli. For instance, since threat proximity determines which defensive behavior is selected, tasks with a continuum of threat imminence have proved particularly insightful. In humans, a Pac-Man-like game, requiring subjects to avoid an artificial predator in a maze, elicited activation of the ventromedial prefrontal cortex when the threat was far away and of the periaqueductal gray when it was near (Mobbs et al., 2007Mobbs D. Petrovic P. Marchant J.L. Hassabis D. Weiskopf N. Seymour B. Dolan R.J. Frith C.D. When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans.Science. 2007; 317: 1079-1083Crossref PubMed Scopus (562) Google Scholar). In mice, serial cues that signaled the imminence of a shock evoked freezing followed by escape, and these behaviors were supported by different populations of central amygdala neurons (Fadok et al., 2017Fadok J.P. Krabbe S. Markovic M. Courtin J. Xu C. Massi L. Botta P. Bylund K. Müller C. Kovacevic A. et al.A competitive inhibitory circuit for selection of active and passive fear responses.Nature. 2017; 542: 96-100Crossref PubMed Scopus (172) Google Scholar). It is also important to distinguish arousal and attention from threat processing. One way to do this is to use tasks that feature both aversive and appetitive elements, allowing one to assess the specificity of neural activity or manipulations with respect to valence, arousal, or behavior. As discussed in detail below, only by contrasting the activity of the same neurons with respect to multiple variables can we assess what they encode. Not only do individuals show flexible expression of defensive behaviors, particularly with distal or anticipated threats, but they also vary in their disposition to express defensive behaviors. Numerous studies have reported on this phenomenon in multiple species. For instance, such differences were noted in the stimulus generalization (Duvarci et al., 2009Duvarci S. Bauer E.P. 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In support of this notion, comparing the incidence of anxiety disorders in homo- versus heterozygotic twins has revealed that the heritability of panic and phobic and generalized anxiety disorders is around 30%–40% (Hettema et al., 2001Hettema J.M. Neale M.C. Kendler K.S. A review and meta-analysis of the genetic epidemiology of anxiety disorders.Am. J. Psychiatry. 2001; 158: 1568-1578Crossref PubMed Scopus (978) Google Scholar). Moreover, selective breeding of rodents for low or high anxiety-like behaviors results in markedly different behavioral phenotypes within a few generations (Landgraf and Wigger, 2002Landgraf R. Wigger A. High vs low anxiety-related behavior rats: an animal model of extremes in trait anxiety.Behav. Genet. 2002; 32: 301-314Crossref PubMed Scopus (0) Google Scholar). 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While it is beyond the scope of the present paper to review the wide range of gene-environment interactions described so far, it is important to remind ourselves that they are ultimately expressed in neuronal networks. Given that multiple genes are involved in the genetic heritability of anxiety disorders (Sharma et al., 2016Sharma S. Powers A. Bradley B. Ressler K.J. Gene × environment determinants of stress- and anxiety-related disorders.Annu. Rev. Psychol. 2016; 67: 239-261Crossref PubMed Scopus (70) Google Scholar; and, likely, defensive behaviors) and considering that these genes regulate functions as disparate as monoamine or cholinergic signaling, neural development, stress or sex hormones, inflammatory disease pathways, and even the immune system (Daskalakis et al., 2018Daskalakis N.P. Rijal C.M. King C. Huckins L.M. Ressler K.J. Recent genetics and epigenetics approaches to PTSD.Curr. Psychiatry Rep. 2018; 20: 30Crossref PubMed Scopus (46) Google Scholar), it is likely that widespread alterations in multiple neuronal networks underlie individual differences in the disposition to express defensive behaviors. Contrasting with the heterogeneity of human anxiety disorders and the multifaceted nature of defensive behaviors, current research on the neural substrates of “anxiety” in rodents heavily relies on a handful of behavioral assays, most often the elevated plus maze (EPM) and open-field (OF) tests. These two tests rely on the assumption that, as occurs during foraging in the wild, rodents are conflicted by the motivation to explore an open, naturally threatening area where needed resources might be located, or to stay in an enclosed, safe area where resources are scarce. Time in the open versus closed arms of the EPM and in the center versus near the walls of the OF are the main variables measured, with lower times in the EPM’s open arms and OF’s center indicating higher “anxiety.” However, these tests are notoriously unreliable. Beginning in the 1970s, many questioned the usefulness of these assays (see Ennaceur and Chazot, 2016Ennaceur A. Chazot P.L. Preclinical animal anxiety research - flaws and prejudices.Pharmacol. Res. Perspect. 2016; 4: e00223Crossref PubMed Scopus (31) Google Scholar for a long list of critical reviews). Well-documented shortcomings include low test-retest reliability, inconsistent results depending on the duration of the tests (Fonio et al., 2012Fonio E. Golani I. Benjamini Y. Measuring behavior of animal models: faults and remedies.Nat. 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Central amygdala PKC-δ(+) neurons mediate the influence of multiple anorexigenic signals.Nat. Neurosci. 2014; 17: 1240-1248Crossref PubMed Scopus (187) Google Scholar). Previously, it had been reported that these PKC-δ+ cells inhibit conditioned freezing (Ciocchi et al., 2010Ciocchi S. Herry C. Grenier F. Wolff S.B. Letzkus J.J. Vlachos I. Ehrlich I. Sprengel R. Deisseroth K. Stadler M.B. et al.Encoding of conditioned fear in central amygdala inhibitory circuits.Nature. 2010; 468: 277-282Crossref PubMed Scopus (591) Google Scholar, 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 (527) Google Scholar), leading to the expectation that optogenetically exciting PKC-δ+ neurons would decrease freezing and result in more exploration of the open areas in the EPM and OF. Yet, one study reported the opposite (Botta et al., 2015Botta P. Demmou L. Kasugai Y. Markovic M. Xu C. Fadok J.P. Lu T. Poe M.M. Xu L. Cook J.M. et al.Regulating anxiety with extrasynaptic inhibition.Nat. Neurosci. 2015; 18: 1493-1500Crossref PubMed Scopus (97) Google Scholar) while the other found an increase in open arm exploration of the EPM but no change in the OF (Cai et al., 2014Cai H. Haubensak W. Anthony T.E. Anderson D.J. Central amygdala PKC-δ(+) neurons mediate the influence of multiple anorexigenic signals.Nat. Neurosci. 2014; 17: 1240-1248Crossref PubMed Scopus (187) Google Scholar). To complicate matters further, optogenetic manipulations might appear to have “anxiolytic” effects in the OF or EPM, not because they reduce “anxiety,” but because they regulate a different function such as predation, which is incompatible with cautious exploratory behavior. Thus, reducing the many facets of anxiety to a few behavioral readouts of ambiguous significance is not a viable path forward. It seems more promising to consider multiple variables such as stretch-attend behaviors, defecation, and the stimulus generalization of fear responses, which are more reliably correlated across rodent strains and species (Botta et al., 2015Botta P. Demmou L. Kasugai Y. Markovic M. Xu C. Fadok J.P. Lu T. Poe M.M. Xu L. Cook J.M. et al.Regulating anxiety with extrasynaptic inhibition.Nat. Neurosci. 2015; 18: 1493-1500Crossref PubMed Scopus (97) Google Scholar, O’Leary et al., 2013O’Leary T.P. Gunn R.K. Brown R.E. What are we measuring when we test strain differences in anxiety in mice?.Behav. Genet. 2013; 43: 34-50Crossref PubMed Scopus (0) Google Scholar). Studying the generalization of fear responses (in time, to other stimuli or contexts) is a particularly promising path forward given that generalization is a hallmark of anxiety disorders (Dunsmoor and Paz, 2015Dunsmoor J.E. Paz R. Fear generalization and anxiety: behavioral and neural mechanisms.Biol. Psychiatry. 2015; 78: 336-343Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar) and that rodents, like humans, exhibit marked individual differences in their propensity to generalization (e.g., Duvarci et al., 2009Duvarci S. Bauer E.P. Paré D. The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear.J. Neurosci. 2009; 29: 10357-10361Crossref PubMed Scopus (157) Google Scholar). When a stimulus arrives at the periphery, a wave of activity cascades and reverberates throughout the nervous system. Threatening stimuli in particular quickly recruit neuromodulatory systems of the brainstem and basal forebrain, altering the transmission of sensory information and the state of the entire brain through multiple pre- and post-synaptic mechanisms (Brunton et al., 2017Brunton L.L. Knollmann B.C. Hilal-Dandan R. The Pharmacological Basis of Therapeutics. McGraw Hill, 2017Google Scholar, McCormick et al., 1991McCormick D.A. Pape H.C. Williamson A. Actions of norepinephrine in the cerebral cortex and thalamus: implications for function of the central noradrenergic system.Prog. Brain Res. 1991; 88: 293-305Crossref PubMed Google Scholar, Steriade, 1995Steriade M. Brain activation, then (1949) and now: coherent fast rhythms in corticothalamic networks.Arch. Ital. Biol. 1995; 134: 5-20PubMed Google Scholar). Thus, the impact of threatening stimuli is not limited to the few defensive networks current research focuses on. Case in point: when Fos expression was correlated across 84 brain regions during recall of contextual fear, 80% of them were found to participate (Vetere et al., 2017Vetere G. Kenney J.W. Tran L.M. Xia F. Steadman P.E. Parkinson J. Josselyn S.A. Frankland P.W. Chemogenetic interrogation of a brain-wide fear memory network in mice.Neuron. 2017; 94: 363-374.e4Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Similarly, FosTRAP labeling revealed that cued fear conditioning (FC) recruits numerous brain areas, including cortical, thalamic, hypothalamic, and brainstem regions (DeNardo et al., 2019DeNardo L.A. Liu C.D. Allen W.E. Adams E.L. Friedmann D. Fu L. Guenthner C.J. Tessier-Lavigne M. Luo L. Temporal evolution of cortical ensembles promoting remote memory retrieval.Nat. Neurosci. 2019; 22: 460-469Crossref PubMed Scopus (70) Google Scholar). Moreover, human functional imaging studies indicate that threats orchestrate a brain-wide rearrangement of activity patterns (de Voogd et al., 2018de Voogd L.D. Kanen J.W. Neville D.A. Roelofs K. Fernandez G. Hermans E.J. Eye-movement intervention enhances extinction via amygdala deactivation.J. Neurosci. 2018; 38: 8694-8706Crossref PubMed Scopus (19) Google Scholar). The case of conditioned fear vividly illustrates how the processing of threatening stimuli depends on a broadly distributed network. While early stud
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