many paths to fear

8
The term ‘fear’ is used to describe the feeling that arises when we experience an impend- ing threat to our survival. Considerable debate remains about the relationship between the feeling of fear and its underly- ing physiology in humans, as well as to what extent non-human animals are capable of experiencing fear. Nevertheless, there is a growing consensus among neuroscientists that understanding the neural circuits that support the behavioural and physiological responses to threat in animals and studying their functional and anatomical homo- logues in humans is a promising approach to understanding fear 1 . In this Perspective, we follow the precedent set by other behav- ioural neuroscientists in using the term ‘fear’ or ‘fear responses’ to refer to the combined behavioural and physiological responses elicited in animals by an overt threat or sig- nal of potential threat, although we acknowl- edge that the relationship of the term used in this way to the human feeling of fear remains largely unsubstantiated. Research into the neural mechanisms underlying defensive responses in animals has a long history. An important distinction is made between ‘innate fear’ responses that are activated by intrinsically threatening stimuli and ‘learned fear’ that is elicited by neutral stimuli that have been associated with innate threats. For example, animals are naturally selected to protect them- selves from dangers associated with the presence of a predator that evokes innate fear responses 2 . But similar fear behaviour can also be elicited by exposure to a cue or context associated with predator exposure — a phenomenon called fear conditioning 2,3 . Similarly, physically harmful stimuli, such as footshocks 4–6 , or other aversive stimuli, such as air puffs 7 and loud noises 8 , can support learned fear responses. Early theories of fear processing emphasized a unitary response mechanism for fear. Bolles 9 proposed that a set of innately determined defensive behav- iours (such as freezing and flight) occur in response to all classes of threatening stimuli on the basis of the observation that animals appear to express a limited set of fundamental behavioural repertoires. Later, Fanselow 10 extended this theory to argue that a unitary brain circuit underlies all types of fear. However, evidence that has accumu- lated over the past two decades suggests that the circuitry that supports fear responses is complex and involves multiple, independent circuits that process different types of fear. In particular, there is good evidence to support the existence of distinct circuits for fear of pain, fear of predators and fear of aggressive conspecifics. Here, we review these data and consider the wider implications of this segregated circuitry for understanding fear and inter- ventions aimed at its amelioration. We first discuss the anatomy of independent fear circuits and point out the crucial role of the medial hypothalamus in the integration of innate and learned fear. Then, we review data demonstrating that each fear circuit also processes or regulates important physi- ological and behavioural responses that are not related to fear and is thus likely to serve as a general circuit that controls adaptive responses to different classes of environ- mental challenge. Next, we discuss evidence that segregated fear circuits share a common memory encoding mechanism and, last, we discuss how these insights might influ- ence our understanding of fear and anxiety in humans. The amygdala as a switchboard for fear The amygdala is the brain region most implicated in fear. The mammalian amyg- dala comprises a heterogeneous set of distinct regions, called nuclei. These have been classified in various ways. One class- ification — based on anatomical location, developmental origin and local circuit architecture — partitions the region into a cortical division (cortical amygdala, basolat- eral amygdala (BLA), basomedial amygdala (BMA) and lateral amygdala (LA)) and a striatal division (medial amygdala (MEA) and central amygdala (CEA)) 11 . Following the pattern of circuitries elsewhere in the brain 12 , major connections in the amygdala run from the cortical to the striatal division, with the latter providing the major outputs of the structure. Neural activity mapping and lesion studies in rodents show that different types of threat stimuli activate and depend on different parts of the amygdala (FIG. 1). In rodents, olfactory and vomeronasal cues have a crucial role in signalling the presence of a predator 13–15 , and these signals are con- veyed through direct connections from the main and accessory olfactory bulb, respec- tively, to the MEA 16 . Thus, rats exposed to a natural predator or its odour show substan- tial activation in this nucleus, particularly in its posteroventral part (pvMEA) 13,14,17 . Consistent with these inputs being crucial for predator recognition, rats with lesions in the MEA show a substantial reduction in innate fear responses to a cat 17 or its odour 18 . Exposure to a live predator also activates two other amygdala nuclei, the LA and posterior BMA (pBMA) 17 . These nuclei receive inputs OPINION The many paths to fear Cornelius T. Gross and Newton Sabino Canteras Abstract | Fear is an emotion that has powerful effects on behaviour and physiology across animal species. It is accepted that the amygdala has a central role in processing fear. However, it is less widely appreciated that distinct amygdala outputs and downstream circuits are involved in different types of fear. Data show that fear of painful stimuli, predators and aggressive members of the same species are processed in independent neural circuits that involve the amygdala and downstream hypothalamic and brainstem circuits. Here, we discuss data supporting multiple fear pathways and the implications of this distributed system for understanding and treating fear. PERSPECTIVES NATURE REVIEWS | NEUROSCIENCE VOLUME 13 | SEPTEMBER 2012 | 651 © 2012 Macmillan Publishers Limited. All rights reserved

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  • The term fear is used to describe the feeling that arises when we experience an impend-ing threat to our survival. Considerable debate remains about the relationship between the feeling of fear and its underly-ing physiology in humans, as well as to what extent non-human animals are capable of experiencing fear. Nevertheless, there is a growing consensus among neuroscientists that understanding the neural circuits that support the behavioural and physiological responses to threat in animals and studying their functional and anatomical homo-logues in humans is a promising approach to understanding fear1. In this Perspective, we follow the precedent set by other behav-ioural neuroscientists in using the term fear or fear responses to refer to the combined behavioural and physiological responses elicited in animals by an overt threat or sig-nal of potential threat, although we acknowl-edge that the relationship of the term used in this way to the human feeling of fear remains largely unsubstantiated.

    Research into the neural mechanisms underlying defensive responses in animals has a long history. An important distinction is made between innate fear responses that are activated by intrinsically threatening stimuli and learned fear that is elicited by neutral stimuli that have been associated with innate threats. For example, animals are naturally selected to protect them-selves from dangers associated with the

    presence of a predator that evokes innate fear responses2. But similar fear behaviour can also be elicited by exposure to a cue or context associated with predator exposure a phenomenon called fear conditioning2,3. Similarly, physically harmful stimuli, such as footshocks46, or other aversive stimuli, such as air puffs7 and loud noises8, can support learned fear responses. Early theories of fear processing emphasized a unitary response mechanism for fear. Bolles9 proposed that a set of innately determined defensive behav-iours (such as freezing and flight) occur in response to all classes of threatening stimuli on the basis of the observation that animals appear to express a limited set of fundamental behavioural repertoires. Later, Fanselow10 extended this theory to argue that a unitary brain circuit underlies all types of fear. However, evidence that has accumu-lated over the past two decades suggests that the circuitry that supports fear responses is complex and involves multiple, independent circuits that process different types of fear. In particular, there is good evidence to support the existence of distinct circuits for fear of pain, fear of predators and fear of aggressive conspecifics.

    Here, we review these data and consider the wider implications of this segregated circuitry for understanding fear and inter-ventions aimed at its amelioration. We first discuss the anatomy of independent fear circuits and point out the crucial role of the

    medial hypothalamus in the integration of innate and learned fear. Then, we review data demonstrating that each fear circuit also processes or regulates important physi-ological and behavioural responses that are not related to fear and is thus likely to serve as a general circuit that controls adaptive responses to different classes of environ-mental challenge. Next, we discuss evidence that segregated fear circuits share a common memory encoding mechanism and, last, we discuss how these insights might influ-ence our understanding of fear and anxiety inhumans.

    The amygdala as a switchboard for fearThe amygdala is the brain region most implicated in fear. The mammalian amyg-dala comprises a heterogeneous set of distinct regions, called nuclei. These have been classified in various ways. One class-ification based on anatomical location, developmental origin and local circuit architecture partitions the region into a cortical division (cortical amygdala, basolat-eral amygdala (BLA), basomedial amygdala (BMA) and lateral amygdala (LA)) and a striatal division (medial amygdala (MEA) and central amygdala (CEA))11. Following the pattern of circuitries elsewhere in the brain12, major connections in the amygdala run from the cortical to the striatal division, with the latter providing the major outputs of the structure. Neural activity mapping and lesion studies in rodents show that different types of threat stimuli activate and depend on different parts of the amygdala (FIG.1). In rodents, olfactory and vomeronasal cues have a crucial role in signalling the presence of a predator1315, and these signals are con-veyed through direct connections from the main and accessory olfactory bulb, respec-tively, to the MEA16. Thus, rats exposed to a natural predator or its odour show substan-tial activation in this nucleus, particularly in its posteroventral part (pvMEA)13,14,17. Consistent with these inputs being crucial for predator recognition, rats with lesions in the MEA show a substantial reduction in innate fear responses to a cat17 or its odour18. Exposure to a live predator also activates two other amygdala nuclei, the LA and posterior BMA (pBMA)17. These nuclei receive inputs

    O P I N I O N

    The many paths to fearCornelius T.Gross and Newton Sabino Canteras

    Abstract | Fear is an emotion that has powerful effects on behaviour and physiology across animal species. It is accepted that the amygdala has a central role in processing fear. However, it is less widely appreciated that distinct amygdala outputs and downstream circuits are involved in different types of fear. Data show that fear of painful stimuli, predators and aggressive members of the same species are processed in independent neural circuits that involve the amygdala and downstream hypothalamic and brainstem circuits. Here, we discuss data supporting multiple fear pathways and the implications of this distributed system for understanding and treating fear.

    PERSPECTIVES

    NATURE REVIEWS | NEUROSCIENCE VOLUME 13 | SEPTEMBER 2012 | 651

    2012 Macmillan Publishers Limited. All rights reserved

  • Nature Reviews | Neuroscience

    SeptumHippocampus Hypothalamus

    PAG

    Olfactory

    AuditoryVisual

    Predator cues

    Aggressiveconspecic cues

    Conditioned stimulus(previously pairedwith painful stimuli)

    LA pBMA

    pvMEA

    pdMEA

    Cortical Striatal

    LABLA CEA

    Amygdala

    dmVMH vIPMD

    Predator-responsive circuit

    vIVMH dmPMD dmPAG

    dIPAG

    vIPAG(freezing)

    Innate defensiveresponses to predators

    Innate defensive responsesto aggressive conspecics

    Fear conditioning topainful stimuli

    Conspecic-responsive circuit

    vHIP LS AHN

    MPN PMV

    from visual and auditory association areas and are likely to integrate non-olfactory predator-derived sensory cues19. Consistent with this view, lesions in these nuclei also reduce innate fear responses to a cat17. Olfactory and vomeronasal inputs to MEA also have a role in the detection of conspe-cifics20. However, exposure to an aggressive conspecific activates predominantly the posterodorsal part of the MEA (pdMEA)20, suggesting that the processing of olfactory threat cues that associate with predators and conspecifics is likely to depend on different MEA subnuclei (FIG.1). The close proximity of pdMEA and pvMEA has so far prevented a functional dissection of these pathways.

    Nuclei of the cortical division of the amygdala appear to be particularly impor-tant for learned fear. The LA is one of the main sites in which associative learning between conditioned and unconditioned stimuli occurs46,21,22, and lesions or pharma-cological blockade of the LA prevent both the acquisition and the expression of con-ditioned fear to footshock46,23,24, as well as conditioned fear to predators17 (for example, in rats, fear to a context that was previously associated with a cat). The LA, in turn, pro-jects to the CEA both directly and indirectly via the BLA25 (FIG.1). Importantly, lesions or pharmacological blockade of the CEA prevent the expression of conditioned fear

    to footshock46,26, but do not interfere with conditioned fear to a predator17. By contrast, lesions of the MEA that block fear responses to a predator do not block conditioned responses to footshock27. These mapping and lesion data show that the fear-of-predator circuit and the fear-of-pain circuit are segre-gated at the level of amygdala outputs, with the former depending on outputs from the pvMEA and pBMA and the latter depending on outputs from the CEA (FIG.1). Together, these data suggest that the amygdala acts as a switchboard, gathering distinct afferent inputs that carry information about envi-ronmental threats and channelling them along distinct efferent pathways, with clearly distinct output circuits for fear of predators and fear of pain and a possible segregation of circuits that process predator cues and aggressive-conspecific cues (FIG.1).

    Parallel downstream pathways for fearThe parallel processing of different classes of fear responses continues downstream of the amygdala. Efferents from the CEA to the ventrolateral part of the periaqueductal grey (vlPAG) are crucial for suppressing ongoing motivated behaviours, promoting freezing and eliciting vocalization and analgesia46. These efferents arise in the medial subnucleus of the CEA (CEAm), which receives inhibitory projections from

    neurons in the lateral subnucleus (CEAl)2830. These CEAl projection neurons also project to the basal forebrain (specifically, to the substantia innominata), where they promote the activity of cholinergic neurons that sup-port cortical arousal and risk assessment31. Fear conditioning causes a generalized tonic upregulation of CEAl projection neurons to favour risk assessment and to suppress freezing outputs from the CEAm, whereas the presentation of a conditioned stimulus itself suppresses CEAl projection neurons to disinhibit freezing29,31. In this way, fear responses that are dependent on the CEA can be switched between outputs that favour freezing (from the vlPAG) and those that favour arousal and risk assessment (from the substantia innominata).

    Efferents from the MEA that relay olfactory information about predators and aggressive conspecifics along with efferents from the pBMA that, we propose, relay non-olfactory information about predators innervate the medial hypothalamus32,33. On the basis of anatomical tract-tracing experiments of medial hypothalamic zone projections, this zone has been divided into two networks that show a high degree of interconnection among nuclei. One net-work comprises the anterior hypothalamic nucleus (AHN), the dorsomedial part of the ventromedial nucleus (dmVMH) and

    Figure 1 | Parallel circuits mediate fear of pain, predators and aggres-sive conspecifics. Fear of pain, fear of predators and fear of aggressive conspecifics are processed in three independent neural pathways that include subnuclei of the amygdala, hypothalamus and periaqueductal grey (PAG). Predators and aggressive conspecifics elicit innate fear responses through activation of distinct nuclei of the amygdala, which are in turn con-nected to distinct regions of the ventromedial hypothalamus (VMH), dorsal premammillary nucleus (PMD) and PAG to produce stimulus-appropriate defensive behaviours. Thus, fear of predators involves a pathway that includes the lateral amygdala (LA), the posterior part of the basomedial amygdala (pBMA), the posteroventral part of the medial amygdala (pvMEA), the dorsomedial part of theVMH (dmVMH), the ventrolateral part of the PMD (vlPMD) and the dorsolateral part of the PAG (dlPAG). Fear of

    aggressive conspecifics involves a pathway including the posterodorsal part of the medial amygdala (pdMEA), the ventrolateral part of the VMH (vlVMH), the dorsomedial PMD (dmPMD) and the dorsomedial part of the PAG (dmPAG). Several additional interconnected nuclei of the medial hypotha-lamic circuits are also recruited specifically by predator threats and conspe-cific threats, including the anterior hypothalamic nucleus (AHN), medial preoptic nucleus (MPN) and ventral premammilliary nucleus (PMV). Conversely, cues that are associated with painful stimuli activate the central amygdala (CEA) to induce defensive behaviour via the ventrolateral part of the PAG (vlPAG). Thus, different classes of threatening stimuli recruit parallel and independent circuits to produce fear. BLA, basolateral amygdala; LS, lateral septum; vHIP, ventral hippocampus. Dashed arrows indicate stimulus input and behavioural output.

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  • the ventrolateral part of the dorsal pre-mammillary nucleus (vlPMD), which are highly interconnected. The second net-work includes the medial preoptic nucleus (MPN), the ventrolateral part of the VMH (vlVMH), the tuberal nucleus and the ven-tral premammillary nucleus (PMV), which are also highly interconnected12. Exposure to a predator or its odour activates the AHNdmVMHvlPMD circuit13,34 (that is, the predator-responsive medial hypo-thalamic circuit), and lesions or pharma-cological blockade of the PMD drastically reduces fear responses to a predator or its odour27,3438. Exposure to an aggres-sive conspecific, by contrast, activates the MPNvlVMHPMV network (that is, the conspecific-responsive medial hypo-thalamic circuit20,39), providing further evidence that there are separate circuits for fear of predators and conspecifics. In addition, exposure to an aggressive conspe-cific activates the dorsomedial part of the PMD39 (dmPMD), a small cell population that is distinct from the predator-activated vlPMD. Consistent with this activation, lesions of the PMD block flight, freezing and passive supine responses to an aggres-sive conspecific but not, however, upright defensive postures elicited in the defeated animal39. These data suggest that separate circuits in the PMD are responsible for fear responses to predators versus fear responses to aggressive conspecifics39.

    Importantly, the amygdala nuclei that carry olfactory and non-olfactory predator information (pvMEA and pBMA, respectively) both project to the predator-responsive medial hypothalamic circuit, predominantly via the dmVMH32,33. In addi-tion, the predator-responsive medial hypo-thalamic circuit is influenced by contextual cues from the environment, which are con-veyed from the ventral hippocampus (vHIP) via the lateral septum to the AHN40 (FIG.1). Finally, lesions of the PMD that block fear of predators have a minimal effect on defensive responses to non-predator-related threat stimuli, such as learned fear of footshock27,36, confirming a segregation of fear of predator and pain pathways.

    The CEA selectively projects to the vlPAG to promote fear responses, whereas the predator-responsive medial hypotha-lamic circuit targets the dorsolateral part of the PAG (dlPAG; FIG.1), which presents a striking activation during exposure to a live predator or its odour34 and is an important site for the organization of fear responses to predators34,41,42. Which type of fear response to predator-related cues is

    expressed depends on their degree of ambi-guity. Fear responses to an actual predator include mostly freezing and some flight behaviour2, whereas fear responses to a more ambiguous predator cue, such as its odour, are characterized mainly by risk assessment responses, including a careful scanning of the environment in a crouched position and attempts to approach the threatening stimu-lus by stretching the body2. Notably, lesions in the dorsal PAG block the entire range of fear responses to a predator, from flight and freezing to risk assessment42, raising the possibility that the degree of activation of the same circuit dictates the intensity of the fear response34.

    The dlPAG also receives projections from the deep layers of the medial superior colliculus43, and these may relay predator-related visual cues, such as looming shadows signalling the approach of aerial predators44. Similarly, electrical stimulation of the deep layers of the medial superior colliculus produces fear responses, such as freezing and flight45. Such predator-related fear responses have also been shown to be influenced by the cerebellum; for example, lesions of the cerebellar vermis reduced freezing responses in rats exposed to a cat46. The cerebellum is likely to influ-ence predator-related freezing through projections from the fastigial nucleus to the deep layers of the superior colliculus47 and to brain sites targeted by the dlPAG48. However, it remains unclear whether and through what route the cerebellum responds to predator-relatedcues.

    As discussed above, fear responses to an aggressive conspecific are associated with activation of the MPNvlVMHPMV medial hypothalamic network. This circuit is activated by pheromonal and olfactory information that is relayed in large part by the pdMEA20,32,39. Exposure to an aggressive conspecific also activates the dmPMD, and this is necessary for conspecific-related fear responses39. The link between elements of the conspecific-responsive medial hypotha-lamic circuit and the dmPMD is provided by the subfornical region of the lateral hypotha-lamic area49. The dmPMD, in turn, serves as an important interface between the conspe-cific-responsive medial hypothalamic circuit and the PAG; indeed, the activation pattern response to an aggressive conspecific in both the dorsomedial PAG (dmPAG) and lateral PAG (lPAG) matches the projection pattern from the dmPMD39 (FIG.1). Preliminary find-ings from our laboratory suggest that the dmPAG, but not the lPAG, seems to be cru-cial for the expression of both passive forms

    (that is, freezing and the typical on-the-back position maintained after the resident leaves them alone) and active forms (that is, an upright position with sparse boxing and dashing away from the resident) of social defensive responses (N.S.C., unpublished observations). Together, these data demon-strate that distinct pathways from the amyg-dala through the medial hypothalamus to the PAG control different classes and types of fear responses (FIG.1).

    More to fear than fearA notable but under-appreciated feature of the amygdala and the hypothalamic nuclei involved in fear processing is their role in the regulation of non-fear responses. Predator-responsive nuclei in the medial hypothalamus have been studied for their role in energy balance and metabolic homeostasis. Selective deletion of leptin receptors from the dmVMH, for example, causes obesity and hepatic glucose release50, a response that may reflect a more general link between predator fear and the control of sympathetic outflow, which would be important for providing the metabolic and autonomic changes necessary to prepare the animal for a life-threatening situation. In line with this view, studies have reported that exposure to predator threat is strongly associated with sustained increases in plasma glucocorticoid levels51, heart rate and blood pressure in rats52,53. Another striking feature that occurs in response to predator exposure is the profound inhibi-tion of non-fear responses. Studies using a visible burrow system have shown that a brief presentation of a cat in the open area of this habitat elicited defensive behaviours and, at the same time, suppressed non-fear behaviours (such as eating, drinking, mounting and attacking) measured over the following 24 h54. Likewise, exposure to cat odour produces a clear inhibition of mater-nal behaviour in lactating rats, and this effect is blocked by dorsal PAG lesions42. Therefore, the bulk of the responses organized by the system involved in anti-predatory defence aim to provide adequate autonomic support for impending fight or fleeing responses and, at the same time, to organize fear responses and inhibit non-fear behaviours to protect the individual from the predator threat.

    During a social attack, a subordinate intruder shows in addition to fear responses a clear submissive posture toward the dominant, resident male that is aimed at avoiding further attacks39. Social conflict is important for establishing

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  • dominantsubordinate hierarchies and is accompanied by increased plasma levels of adrenocorticotrophin (ACTH) and glucocorticoids55,56, decreased plasma lev-els of testosterone55,56, reduced immune system functioning57 and changes in body weight58,59. Behaviourally, social defeat reduces aggression and reproductive fit-ness56,60, and repeated defeats have severe consequences, such as anhedonia and a depressive-like state60,61. In addition to social defence, the conspecific-responsive medial hypothalamic circuit organizes social aggression as well as sexual and maternal behaviours6264. Interestingly, studies using immediate early gene analysis and single-unit recordings in the vlVMH during malemale and malefemale inter-actions in mice revealed that partially overlapping neuronal subpopulations are involved in aggression and mating65. Neurons in the vlVMH became activated in the dominant animal during attack and during the build-up to mating but were inhibited as mating progressed65. Optogenetic activation of these vlVMH neurons rapidly induced aggression, even towards inanimate objects or females, con-firming that vlVMH activity is sufficient to induce aggressive behaviours65. A key ques-tion will be to determine whether vlVMH cells that are activated by conspecific fear overlap with vlVMH cells that are activated during aggression or sex and whether they can influence each others activity.

    As far as the pain-related fear circuit is concerned, the CEA has also been shown to respond to pleasurable stimuli, such as food66,67, and to influence foraging, explora-tion and food consumption6769, suggesting that its role in mediating fear conditioning to pain is only one aspect of a more general involvement in processing the affective salience of physical stimuli. This opens the possibility that plasticity arising from interactions between positive and nega-tive affective circuits in the CEA might influence the appraisal of such stimuli. Fear conditioning to pain also suppresses feeding; for example, food-deprived rats suppress eating when presented with a tone (the conditioned stimulus) that had been previously paired with footshocks (the unconditioned stimulus), and this effect was blocked by lesions of the CEA70. Thus, it may be useful to consider fear pathways as multimodal response circuits that coor-dinate and adjust adaptive responses to both threats and opportunities rather than as circuits that are dedicated exclusively tofear.

    A common system for fear memoryAs discussed above, learned fear may be elicited by exposure to environmental cues that were previously associated with innate fear stimuli (such as predators and aggres-sive conspecifics) or with physically harmful or aversive stimuli (such as footshocks, air puffs and loud noises). We have presented evidence showing how distinct fear circuits process these stimuli to generate appropri-ate behavioural and physiological responses. However, there is strong evidence that a common mechanism underlies the encod-ing of learned fear for all classes of stimuli. As studies of learned fear of predator-related cues have relied nearly exclusively on con-textual cues, we restrict our discussion to contextual fear conditioning studies. We do not consider contextual conditioning to aggressive conspecifics because few studies have examined the circuits involved in this phenomenon and because aggressive con-specific encounters routinely include biting attacks that may activate the fear-of-pain pathway and thus confound a comparison of the circuitries involved.

    Contextual fear conditioning to both painful stimuli and predators requires the hippocampus and LABLA, as well as higher-order associative processing areas of the anterior cingulate cortex (ACC), retrosplenial cortex (RSP) and postrhinal cortex (POR)7175. Evidence suggests that during fear memory encoding, informa-tion about the aversive experience either from painful stimuli or predator cues may be relayed to this common cortical memory system by the PAG (FIG.2a). The vlPAG responds to painful stimuli through ascending projections from spinal cord76 and is likely to relay expectancy-modulated information to instruct associative plasticity in the amygdala during fear conditioning to painful stimuli76. In line with this view, phar-macological inhibition of the vlPAG during learning prevents fear conditioning to foot-shock76. The pathway from the vlPAG to the LA is not clearly defined but may involve projections from midline and intral-aminar thalamic nuclei to the cortical mem-ory system (FIG.2a), because midline and intralaminar thalamic nuclei and ACC pre-sent robust responses to unexpected uncon-ditioned stimuli during fear conditioning to footshocks77 and inactivation of the ACC prevented associative fear learning77.

    Similarly, activity in the dlPAG the main target of the predator-responsive medial hypothalamic circuit appears to be required for encoding contextual memory of predator cues78. Dorsal PAG stimulation

    can be used as an unconditioned stimulus in contextual fear learning79, and blockade of glutamatergic neurotransmission in the dlPAG prevents fear conditioning when chemical stimulation of the PMD is used to mimic predator exposure78. As discussed for the vlPAG, projections from the dlPAG to midline and intralaminar thalamic nuclei80 and their allied cortical targets are likely to mediate contextual fear encoding to predators (FIG.2a).

    Studies suggest that several structures within the cortical memory system are involved in encoding information about aversive experiences and associating them with contextual information during fear learning. Chemical or electrical stimula-tion of the ACC can be used as an effective unconditioned stimulus to support fear learning, whereas pharmacological inhibi-tion or antagonism of glutamate receptors in the ACC can impair or prevent such learning for both contextual and auditory fear conditioning to footshock72,73. This effect is likely to be mediated through either direct or indirect projections to the LABLA and hippocampus. Indirect paths appear to involve the RSP, as electrolytic or chemical damage to this area either before or immediately after training impaired the expression of contextual but not auditory fear conditioning74,75. The RSP is thought to influence contextual fear processing through its projections to the POR, a region shown to be involved in the association of contextual information, probably via its projections to the hippocampal formation and the LABLA71. Thus, it is likely that the ACC, RSP and POR form a cortical network that is required for effective encoding of aversive cues and their association with con-textual information in the hippocampus and LABLA (FIG.2a). The vlPMD also provides crucial information linking predator threat to context37,38 through projections to the ventral part of the anteromedial thalamic nucleus (vAMT) and on to elements of the cortical memory system, such as the ACC and RSP81 (FIG.2a). Bilateral lesions of the vAMT do not alter innate fear responses to predators but completely block contextual fear to the same stimulus81. Thus, projec-tions from multiple points along the medial hypothalamusPAG predator pathway contribute to fear memory encoding.

    The LABLA and hippocampus serve as crucial sites for memory encoding of both painful stimuli and predator threats. Lesions of the vHIP but not the dorsal hippocampus impair contextual memory for predator-related threats27. Likewise, the vHIP has

    P E R S P E C T I V E S

    654 | SEPTEMBER 2012 | VOLUME 13 www.nature.com/reviews/neuro

    2012 Macmillan Publishers Limited. All rights reserved

  • Nature Reviews | Neuroscience

    Hypothalamus

    Amygdala

    PAG

    PAG

    Olfactory

    AuditoryVisual

    Predator cues(unconditionedstimuli)

    LABLA

    pBMA

    pvMEA dmVMH vIPMD

    Predator-responsive circuit

    dIPAG

    dIPAG

    vIPAG(freezing)

    Hypothalamus

    dmVMH vIPMD

    AHN

    Predator-responsive circuit

    vIPAG

    Contextual cues(conditioned stimuli)

    ACC

    RSP

    POR

    ILNs MLNs

    vAMT

    vHIP

    Cortex Thalamus

    Painful stimuli(unconditionedstimuli)

    Amygdala

    LABLA

    pBMA

    vHIP

    CEA

    Fear conditioning topredator cues

    Fear conditioning topainful stimuli

    a Encoding of fear memory

    b Retrieval of fear memory

    Cortical Striatal

    Cortical Striatal

    Contextual cues(previously paired withpredator cues or painfulstimuli)

    CEA

    AHNLS

    LS

    Hippocampus Septum

    Hippocampus Septum

    an important role in the acquisition and expression of contextual conditioning to painful stimuli27,82. A number of studies have shown that the LABLA is involved in the acquisition of contextual conditioning to painful stimuli and their expression8386. One study85 used lesions targeting specific amygdala nuclei and showed that lesions of the LA or the BLA attenuate contextual conditioning to painful stimuli. Similarly, lesions of the LA block contextual condi-tioning to predator threats17. Therefore, the role ascribed to synapses in the LA for encoding plasticity that is crucial for fear conditioning to footshock6,22 may also hold

    for fear conditioning to predators. Notably, contextual conditioning to predators is also blocked by lesions of the pBMA but is not affected by lesions in the CEA17. By contrast, lesions of the CEA, but not of the pBMA, prevent contextual conditioning to foot-shock85. These data suggest that interactions between the LABLA and output nuclei in the CEA and pBMA may be crucial for both encoding and retrieval of distinct classes of learnedfear.

    Retrieval of fear conditioning to preda-tor stimuli and painful stimuli appear to depend on different circuits (FIG.2b). In part, these different circuits reflect the different

    behavioural and physiological responses required to deal with these threats. Contextual fear of painful stimuli is domi-nated by freezing46, whereas contextual fear of predators elicits primarily risk assessment behaviour, possibly as an effective strategy to deal with the ambiguity posed by a mov-ing threat3. Accordingly, retrieval of learned fear of painful stimuli, through projections from the LABLA to the CEA and on to the vlPAG, leads to freezing and suppres-sion of ongoing behaviours46 (FIG.2b), whereas retrieval of learned fear of preda-tors through projections from the LA to the pBMA and on to the predator-responsive

    Figure 2 | Circuits supporting the encoding and retrieval of learned fear. a | The encoding of learned fear to predator-associated or painful stimuli requires projections from the relevant areas of the periaqueductal grey (PAG) via the thalamus to cortical association areas that are involved in higher-order processing of contextual cues, including the anterior cingulate cortex (ACC), retrosplenial cortex (RSP) and postrhinal cortex (POR). The hip-pocampus and lateral amygdala (LA) have a crucial role in memory for all classes of fear. b | The hippocampus and LA are also essential for fear retrieval upon exposure to contextual cues that were previously associated with a threat. Importantly, retrieval of predator fear memory recruits the same medial hypothalamic and PAG nuclei as those involved in the processing of innate fear of predators, but the triggers for activation of the medial hypo-thalamus differ in the two conditions: during innate fear processing, inputs mainly come from the accessory olfactory system, whereas during retrieval

    of predator fear memory, the medial hypothalamus is activated by the hip-pocampus and lateral amygdala via the lateral septum (LS) and the posterior basomedial amygdala (pBMA), respectively. AHN, anterior hypothalamic nucleus; BLA, basolateral amygdala; CEA, central amygdala; dlPAG, dorsolat-eral part of the PAG; dmPAG, dorsomedial part of the PAG; dmPMD, dorso-medial part of the dorsal premammillary nucleus; dmVMH, dorsomedial part of the ventromedial hypothalamic nucleus; ILNs, intralaminar thalamic nuclei; MLNs, midline thalamic nuclei; MPN, medial preoptic nucleus; pdMEA, pos-terodorsal part of the medial amygdala; PMV, ventral premammillary nucleus; pvMEA, posteroventral part of the medial amygdala; vAMT, ventral part of the anteromedial thalamic nucleus; vHIP, ventral hippocampus; vlPAG, ventrolat-eral part of the PAG; vlPMD, ventrolateral part of the dorsal premammillary nucleus; vlVMH, ventrolateral part of the ventromedial hypothalamic nucleus. Dashed arrows indicate stimulus input and behavioural output.

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  • medial hypothalamic circuit and dlPAG leads to risk assessment behaviour17 (FIG.2b). Associations stored in the vHIP that are relevant for both types of fear stimuli could depend on projections to the LABLA and, at least for predator fear, also on projections to the lateral septum and on to the AHN40, which is an important node of the medial hypothalamic predator fear circuit. Thus, learned fear of predators engages the same medial hypothalamic circuit as that involved in innate fear of predators, a fact supported by data showing that both types of fear are disrupted by lesions or pharmacological blockade of the PMD34. Perhaps unexpect-edly, these data show that this fear circuit mediates both the freezing and flight behav-iours that dominate innate responses to a predator and the risk assessment behaviours elicited by context-induced fear of preda-tors. These data show that the notion of separate circuits for innate and learned fear needs to be revised.

    The medial prefrontal cortex, particularly the prelimbic area, has also been shown to influence the expression of contextual fear conditioning to painful stimuli87. The prelimbic area receives projections from the vHIP88 and is thought to influence the expression of contextual fear through its projection to the BLA87. However, lesions of the prelimbic area do not affect innate fear responses to predators87, and its role in fear conditioning to predator threats remains to be investigated.

    Implications for understanding human fearCan we learn something about human fear and anxiety by understanding fear circuits in rodents (BOX1)? Fear refers to the men-tal state evoked by an immediate threat, whereas anxiety describes a more diffuse feeling of worry, apprehension and rumina-tion that is associated with a perceived but non-existent threat89. Anxiety can be elicited by cues associated with threat, such as the environment in which a threat previously occurred, and some researchers have sug-gested that learned fear to contextual or lengthy auditory cues can be used to model human anxiety90. If this assumption is cor-rect, then anxiety might involve a reactiva-tion of innate fear circuits, as discussed above for fear retrieval (FIG.2b). By extension, such an argument would implicate excessive or inappropriate activity in these circuits in pathological anxiety.

    The existence of distinct circuits for processing different classes of fear sug-gests that fear and anxiety in humans may come in different flavours. Knowing which fear circuit is preferentially affected could help to tailor pharmacological or psycho-therapeutic interventions. For example, the observation that electrical stimulation of the dmVMH elicits panic in humans91 suggests a specific relation between panic attacks and the predator fear pathway (BOX1). Moreover, the recognition that each fear pathway also regulates non-fear-related responses could help us to understand links

    between human fear and other homeo-static systems. A hallmark of mood disor-ders, for example, is alterations in energy metabolism89.

    Here, we have emphasized data that support the existence of multiple distinct fear pathways and described how they are specialized to deal with different types of innate and learned environmental threats. In doing so, we have aimed to expand the traditional view of fear, which is derived from animal studies using condition-ing of discrete cues to painful stimuli, to encompass a wider range of ethological fear responses. We believe that an appreciation of the multiplicity of these fear circuits and a better understanding of how they contribute to species-specific defensive mechanisms and integrate with other body homeostatic systems is likely to go a long way to helping us determine the molecular, cellular and physiological bases of human fear and anxiety.

    Cornelius T.Gross is at the Mouse Biology Unit, European Molecular Biology Laboratory,

    via Ramarini 32, 00015 Monterotondo, Italy.

    Newton Sabino Canteras is at the Department of Anatomy, Institute of Biomedical Sciences,

    University of So Paulo, So Paulo SP 0550805000, Brazil.

    e-mails: [email protected]; [email protected]

    doi:10.1038/nrn3301Published online 1 August 2012

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    Box 1 | Evolutionary conservation of fear circuits

    The close anatomical conservation across mammalian species of the amygdala, medial hypothalamus and periaqueductal grey (PAG) nuclei that are known to be involved in fear processing in rodents suggests that similar circuits for different classes of fear also exist in other mammals, including humans. Indeed, two lines of evidence suggest that the separate circuits for processing different classes of fear may be conserved across vertebrates. First, genes that selectively mark fear circuit nuclei show similar expression patterns in diverse vertebrates. For example, steroidogenic factor 1 (SF1), the expression of which selectively marks the predator-responsive dorsomedial part of the ventromedial hypothalamic nucleus (dmVMH) region in rodents, is expressed in an orthologous region of the fish medial hypothalamus92, and the promoter region of the gene that regulates its expression in the rodent dmVMH is highly conserved across species, including humans93. Similarly, corticotropin-releasing hormone (CRH; also known as CRF), the expression of which marks the central amygdala in rodents, is also expressed in a restricted area of the forebrain of fish and primates94,95, suggesting a possible evolutionary conservation of the fear of pain pathway. Second, stimulation studies suggest functional conservation of these circuits across species. For example, electrical stimulation of the medial hypothalamus in fish can elicit flight and aggressive behaviour96. In humans, electrical stimulation of dmVMH elicited a sensation of panic and imminent death91, and people undergoing electrical stimulation of the dorsolateral PAG showed tachycardia and reported a sensation of uncertainty and being chased by someone97. Although the significance of these isolated findings in humans is not yet clear, we speculate that the predator fear circuit in humans may become activated under conditions of grave physical threat or fear of death, and that panic attacks may reflect an extreme predator-related behavioural response. Thus, there is some evidence for the anatomical conservation of fear circuitry across species, but much remains to be done to understand how these circuits have adapted to provide appropriate species-specific defensive responses.

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    AcknowledgementsThis work evolved out of discussions initiated at the Janelia Conference Can New Tools Revolutionize Understanding of Hypothalamic Neural Circuits?in October 2009 and was supported in part by funds from the European Molecular Biology Laboratory to C.G. andgrants fromFundao de Amparo Pesquisa do Estado de So Paulo (FAPESP, no. 05/59286-4) andConselho Nacional de Desenvolvimento Cientfico e Tecnolgico (CNPq) to N.S.C.

    Competing interests statementThe authors declare no competing financial interests.

    FURTHER INFORMATIONCornelius T. Grosss homepage: http://www.embl.it/research/unit/gross/index.html

    ALL LINKS ARE ACTIVE IN THE ONLINE PDF

    Procedural learning refers to the ability to gradually improve the performance of a newly acquired skill, usually over mul-tiple training sessions. It has been known for decades that procedural learning can occur in both the perceptual and motor domains1,2, with the resulting improvement in the baseline performance of a particular skill lasting for lengthy periods of time. These different forms of procedural learn-ing have been studied across a wide range of disciplines, and these investigations have improved our understanding of the pro-cesses involved.

    Intriguingly, the characteristics of per-ceptual, notably visual, and motor memory formation show striking similarities across the various stages of learning. Fast learning develops during the first training session when individuals practise a new visual or motor task and leads to the initial encod-ing or acquisition of a memory. Learning in this first session usually involves rapid improvements in the performance of the task310. Following termination of prac-tice, a learnt memory can stabilize a phenomenon referred to as consolidation which allows the memory to become resistant to interference by competing stimuli or tasks and prevents its decay (that is, forgetting)1116. Such stabilization involves modifications in the intracellular signal transduction cascades at the synap-tic level and neuronal protein synthesis, as well as reorganization of the neural networks that represent the memory17. In the context of procedural learning in the visual and motor domains, consolidation does not only refer to stabilization of the acquired memory but also to improve-ments in performance that occur after the

    end of practice (so-called offline gains), which become evident in subsequent test sessions. These offline gains occur in the absence of additional practice3,4,1824 and are influenced by sleep stages4,21,2530. Indeed, previously consolidated memories may be reactivated during sleep or wakefulness, resulting in memory modification that may be mediated by a process of reconsolida-tion3134. Thus, modification of a previ-ously consolidated memory may result in its degradation, maintenance or further strengthening12,20. Long-term retention of a memory refers to the ability to maintain the acquired performance levels following a period of weeks to months without addi-tional training3,18,3537.

    The goal of this article is to explore the commonalities in the characteristics of visual and motor memory formation in humans that have been outlined above. We also discuss similarities between learn-ing in the motor and visual domains in relation to the involvement of primary cortical areas and top-down attentional mechanisms, as well as the conditions under which learning generalizes (trans-fers) to the untrained eye or hand or to an untrained stimulus or movement. Most of the similarities that we discuss have emerged from the evaluation of texture discrimination and motor sequence learn-ing tasks18,19 (BOX1). When relevant, we mention procedural learning paradigms other than these tasks, although we do not elaborate on motor adaptation paradigms, in which individuals are subjected to externally induced perturbations and their return to pre-perturbation performance levels for a task is evaluated (for a review of these paradigms, see REF.38).

    O P I N I O N

    Common mechanisms of human perceptual and motor learningNitzan Censor, Dov Sagi and Leonardo G.Cohen

    Abstract | The adult mammalian brain has a remarkable capacity to learn in both the perceptual and motor domains through the formation and consolidation of memories. Such practice-enabled procedural learning results in perceptual and motor skill improvements. Here, we examine evidence supporting the notion that perceptual and motor learning in humans exhibit analogous properties, including similarities in temporal dynamics and the interactions between primary cortical and higher-order brain areas. These similarities may point to the existence of a common general mechanism for learning in humans.

    P E R S P E C T I V E S

    658 | SEPTEMBER 2012 | VOLUME 13 www.nature.com/reviews/neuro

    2012 Macmillan Publishers Limited. All rights reserved

    Abstract | Fear is an emotion that has powerful effects on behaviour and physiology across animal species. It is accepted that the amygdala has a central role in processing fear. However, it is less widely appreciated that distinct amygdala outputs and doThe amygdala as a switchboard for fearFigure 1 | Parallel circuits mediate fear of pain, predators and aggressive conspecifics.Fear of pain, fear of predators and fear of aggressive conspecifics are processed in three independent neural pathways that include subnuclei of the amygdala, hypothParallel downstream pathways for fearMore to fear than fearA common system for fear memoryBox 1 | Evolutionary conservation of fear circuitsImplications for understanding human fearAbstract | The adult mammalian brain has a remarkable capacity to learn in both the perceptual and motor domains through the formation and consolidation of memories. Such practice-enabled procedural learning results in perceptual and motor skill improvemeCommonalities in learning stagesBox 1 | Texture discrimination and sequential finger-tapping tasksFigure 1 | Perceptual and motor learning.The texture discrimination and sequential finger-tapping tasks (BOX1) are commonly used to study visual and motor procedural learning, respectively. Both tasks are characterized by within-session fast learning, wThe role of sleepEngaging higher-order brain areasFigure 2 | Interplay between primary cortical processing and higher-order brain areas.The primary visual cortex (V1) and primary motor cortex (M1) have important roles in perceptual and motor learning, respectively, by contributing to the retention of spConclusions and future directions