- Email: [email protected]
Affective Neuroscience: Amygdala's Role in Experiencing Fear
Dispatch R75
16. Lawley, T.D., Chan, K., Thompson, L.J., Kim, C.C., Govoni, G.R., and Monack, D.M. (2006). Genome-wide screen for Salmonella genes required for long-term systemic infection of the mouse. PLoS Pathog. 2, e11. 17. Chain, P.S., Carniel, E., Larimer, F.W., Lamerdin, J., Stoutland, P.O., Regala, W.M., Georgescu, A.M., Vergez, L.M., Land, M.L., Motin, V.L., et al. (2004). Insights into the
evolution of Yersinia pestis through whole-genome comparison with Yersinia pseudotuberculosis. Proc. Natl. Acad. Sci. USA 101, 13826–13831.
1Department of Immunobiology and 2Howard Hughes Medical Institute, Yale University
Affective Neuroscience: Amygdala’s Role in Experiencing Fear A new neuropsychological study of a rare patient provides novel evidence that amygdala lesions can virtually abolish the experience of fear, illuminating neurobiological mechanisms of fear experience. Stephan Hamann When a fear-inducing stimulus such as a crawling spider frightens us, a complex cascade of processes is initiated across multiple brain regions and pathways. Although basic mechanisms of fear learning and expression have been characterized in humans and non-human animal models [1,2], current understanding of many aspects of emotional processing remains incomplete. This is particularly true for the brain systems that mediate the experience of fear and other emotions. The amygdala, a small almond-shaped group of nuclei in the anterior temporal lobe, is a critically important orchestrator of emotional processes, particularly negative emotions such as fear. For example, the amygdala is critical for learning new fear associations, processing emotional attributes of aversive and appetitive stimuli [3], boosting long-term memory for emotional events [4], and recognizing fearful facial expressions. In contrast to its clear role in other fear-related phenomena, however, the amygdala has not been shown to have an essential role in the actual experience of fear, that is, what it feels like to be afraid, along with the behavioral and physiological manifestations of fear. Indeed, the limited available evidence has suggested that the ability to experience fear persists even after complete loss of the amygdala in humans [5], notwithstanding anecdotal clinical reports of diminished fear experience in some amygdala lesion patients. A study reported recently in Current Biology [6] revisited the role of the
amygdala in the experience of fear in an extensive and systematic case study of a rare patient with selective bilateral amygdala lesions. The striking findings of this study suggest that, contrary to previous reports, the human amygdala does indeed play a critical role in triggering the experience of fear, and that loss of the amygdala can result in a virtual absence of behavioral fear reactions and fear experience even in the face of potent fear elicitors. These findings have important implications for understanding neural mechanisms underlying fear and have broader implications for theoretical models of emotion. Feinstein et al. [6] investigated fear induction and experience in patient SM, A
School of Medicine, New Haven, CT 06520, USA. E-mail: [email protected], ruslan. [email protected]
DOI: 10.1016/j.cub.2010.12.008
a 44-year old woman with complete bilateral amygdala lesions due to Urbach-Wiethe disease, a disorder caused by loss-of-function mutations of the extracellular matrix protein 1 (ECM1) gene. Previous studies of this patient yielded a veritable mother lode of novel and influential findings regarding the emotional and social functions of the human amygdala [7,8]. SM’s brain lesions (Figure 1A, blue regions) are relatively limited to the amygdala and overlap completely with brain regions preferentially active during processing of fear-inducing stimuli, as determined in recent metaanalysis of multiple neuroimaging studies (Figure 1A, red regions) [9]. Using a multi-pronged experimental approach, the authors systematically probed SM’s behavioral and subjective responses to a wide range of stimuli and situations that potently elicit fear in healthy individuals (Figure 1B), complementing these experimental studies by carefully assessing SM’s fear experiences across her lifetime.
B
Frightening Frightening people/ animals Neuropsychological situations testing Experience sampling Fear Frightening Behavioral/ Psychiatric elicitation films clinical assessment MRI Memories/ interviews Autobiographical/relative interviews Current Biology
Figure 1. Overlap of lesions with neuroimaging studies of fear and converging strategies to identify fear deficits in patient SM. (A) SM’s amygdala lesions (blue regions) overlap completely with a neuroimaging meta-analysis brain map that summarizes the regions most consistently associated with fear (red regions) [9]. (B) The experimental strategy for investigating SM’s fear deficits focused on systematically establishing her lack of fear in multiple domains: across multiple potent fear elicitors, in everyday life and assessed clinically, and across her lifetime through extensive interviews. These combined findings provide substantial new evidence that bilateral amygdala lesions can produce a specific and virtually complete deficit in the experience of fear [6].
Current Biology Vol 21 No 2 R76
Memory retrieval
External stimuli
Insula Emotion simulation
Amygdala
Prefrontal & other cortical regions
Brainstem nuclei
Hypothalamus
Autonomic/ endocrine responses
Emotional experience
Current Biology
Figure 2. Multiple pathways to the experience of fear and locus of impairment from bilateral amygdala lesions. In the intact human brain, the experience of fear can be triggered by external stimuli or by memory recall of fear-inducing stimuli. Two main pathways ultimately lead to fear elicitation via autonomic and endocrine outputs from the hypothalamus and brainstem periaqueductal gray (PAG) region. In the amygdala pathway, fear-inducing stimuli and memories activate amygdala nuclei that directly project to the hypothalamus and PAG. A secondary route can bypass the amygdala, and involves simulation or reactivation of learned emotional states in the insula and other cortical regions. SM’s bilateral amygdala lesions eliminated the direct amygdala route (orange rectangle), as well as the emotion simulation route (pink rectangle), possibly because the early onset of her lesions in childhood interfered with the emotional learning required to develop the emotion simulation route [6]. An interesting prediction of this model is that direct stimulation of hypothalamus/PAG through interoceptive stimulation should still be able to elicit fear experience in SM.
To overcome the challenge of inducing fear repeatedly in an ethical manner, the investigators developed a variety of clever and potent fear elicitors, including handling live snakes, watching intensely frightening films, and visiting an infamously frightening haunted house. Comprehensive examination of multiple aspects of fear experience was crucial to the success of their approach, in part because it countered a serious potential concern: due to substantial individual differences in emotional response, even normal individuals may not respond to particular fear-inducing stimuli [10]. The experimental results were clear and compelling. In each test of fear induction, SM demonstrated a complete lack of the subjective fear experience and
behavioral signs of fear such as threat avoidance. Importantly, as predicted, her emotion impairments were specific to fear, leaving other emotions such as disgust or sadness unaffected. An intriguing feature of SM’s behavior is that she is fascinated by fear-inducing stimuli, rather than treating them as affectively neutral. When confronted with fear-inducing stimuli such as snakes and frightening people, she felt compelled to approach and touch them. This behavior underscores an essential qualitative difference between her responses and those of normal individuals. Her compulsion to approach threats is the opposite of the amygdala’s normal adaptive role, compelling organisms away from threat,
and parallels abnormal exploratory behavior towards fear-inducing stimuli previously reported in amygdala-lesioned monkeys [11,12]. Further study is warranted to understand the neurobiological basis for this abnormal behavior, and how it may relate to superficially similar normal behavior such as thrill-seeking, a related behavior linked with other regions such as the insula and hippocampus [13]. Regarding emotions in real-life situations, as an adult, SM has unfortunately experienced several harrowing, life-threatening events, including physical assault. When interviewed, in her descriptions of her emotional reactions during these episodes, she consistently conveys a pervasive and abnormal absence of fear and concern. Her complete lack of fear behaviors and highly impoverished fear experience across multiple contexts is clearly abnormal. Interestingly, SM’s amygdala lesions are thought to have occurred in childhood. She can recall fully-fledged fear experiences from before the age of 10, but not afterwards, suggesting that she once could feel fear, but now can feel fear no more. SM’s case shows that living without fear, like the inability to feel pain, has dangerous consequences that vividly illustrate the lost ability’s adaptive role. How can one reconcile these findings with previous reports that suggested the amygdala is not important for the experience of fear? While a full answer to this question awaits further study, Feinstein et al. [6] note that there is an additional neural route to triggering fear that bypasses the amygdala. This emotional simulation route [14,15], in which memory representations of previously experienced emotions are reactivated, can directly activate the hypothalamus and brainstem nuclei (Figure 2), bypassing the amygdala. In SM’s case, the authors speculate that, because the development of the simulation route requires amygdala-dependent emotional learning, this route was insufficiently developed by the time she sustained her amygdala lesions. Thus, SM’s fear deficits are thought to arise from the disruption of both the direct amygdala route (Figure 2; orange rectangle) and the secondary emotion simulation route (Figure 2; pink rectangle). The ability of some patients with bilateral amygdala lesions to demonstrate fear experience and fear behaviors may
Dispatch R77
therefore reflect the operation of the intact emotion simulation route. These findings suggest several next steps. First, because SM is a single case, it will be essential to pursue these issues with other amygdala lesion patients, ideally from a developmental perspective. Because physiological fear responses were not assessed in SM, another important outstanding question concerns whether her autonomic and endocrine responses also show a fear impairment, paralleling findings in amygdalectomized monkeys showing blunted stress hormone responses [16]. Finally, these findings also have important implications for theoretical views of how emotion is organized in the mind and brain. Patient SM’s prominent and highly specific fear impairments provide some of the clearest neuropsychological support to date for the neural validity of categorical or basic emotion views of emotion. Such views propose a limited set of emotions that have been shaped by evolution to deal with recurrent adaptive situations, such as escaping predators [17,18]. The common thread linking SM’s impairments is their relation to fear and threat, a pattern that would not be predicted from other theories such as dimensional theories, which emphasize explanations based on component dimensions such as arousal and valence over categorical distinctions [19]. More broadly, the findings and conclusions of Feinstein et al. [6] argue against theoretical views that conceptualize fear as a unitary psychological construct, or as mediated by a single neurobiological mechanism, instantiated in the amygdala. Instead, multiple pathways and mechanisms mediate the induction
and experience of fear, recruiting multiple brain regions, including the amygdala, hypothalamus, periaqueductal gray (brainstem), as well as the insula and other cortical regions (Figure 2). As suggested by the interconnections in Figure 2, the regions involved in fear processing interact dynamically, for example, in response to the salience of threats and other contextual factors. For example, in a study where subjects played a computerized cat-and-mouse game in a MRI scanner, when a virtual predator grew closer and subjective dread of real pain inflicted by the predator increased, fMRI activity shifted from ventromedial prefrontal cortex towards the periaqueductal gray [20]. Integrating provocative insights from careful single-case neuropsychological studies [6] with the ability of neuroimaging to characterize normal function and online dynamics offers a promising strategy for uncovering the complex mechanisms underlying the human experience of fear and other emotions. References
1. LeDoux, J. (2007). The amygdala. Curr. Biol. 17, R868–R874. 2. Davis, M., and Whalen, P.J. (2001). The amygdala: vigilance and emotion. Mol. Psych. 6, 13–34. 3. Hamann, S.B., Ely, T.D., Hoffman, J.M., and Kilts, C.D. (2002). Ecstasy and agony: Activation of the human amygdala in positive and negative emotion. Psychol. Sci. 13, 135–141. 4. McGaugh, J.L. (2003). Memory and Emotion: The Making of Lasting Memories (London: The Orion Publishing Group). 5. Anderson, A.K., and Phelps, E.A. (2002). Is the human amygdala critical for the subjective experience of emotion? Evidence of intact dispositional affect in patients with amygdala lesions. J. Cogn. Neurosci. 14, 709–720. 6. Feinstein, J., Adolphs, R., Damasio, A., and Tranel, D. (2011). The human amygdala and the induction and experience of fear. Curr. Biol. 21, 34–38. 7. Buchanan, T.W., Tranel, D., and Adolphs, R. (2009). The human amygdala in social function. In The Human Amygdala, P.W. Whalen and
Microtubule Dynamics: Patronin, Protector of the Minus End It has long been surmised that cellular microtubules are capped at the minus ends to prevent their depolymerization. A recent study provides the first definitive identification of a minus-end-specific capping protein, termed Patronin, which protects the microtubule arrays of both mitotic and interphase cells. Brian P. O’Rourke and David J. Sharp* Microtubules form complex and dynamic arrays with integral roles in
membrane trafficking, cell division, morphogenesis and migration. The proper assembly and function of the microtubule cytoskeleton relies upon
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
19.
20.
E.A. Phelps, eds. (New York: Oxford University Press), pp. 289–320. Kennedy, D.P., Gla¨scher, J., Tyszka, J.M., and Adolphs, R. (2009). Personal space regulation by the human amygdala. Nat. Neurosci. 12, 1226–1227. Vytal, K., and Hamann, S. (2010). Neuroimaging support for discrete neural correlates of basic emotions: A voxel-based meta-analysis. J. Cogn. Neurosci. 22, 2864–2885. Hamann, S., and Canli, T. (2004). Individual differences in emotion processing. Curr. Opin. Neurobiol. 14, 233–238. Chudasama, Y., Izquierdo, A., and Murray, E.A. (2009). Distinct contributions of the amygdala and hippocampus to fear expression. Eur. J. Neurosci. 30, 2327–2337. Machado, C.J., Kazama, A.M., and Bachevalier, J. (2009). Impact of amygdala, orbitalfrontal, or hippocampal lesions on threat avoidance and emotional reactivity in nonhuman primates. Emotion 9, 147–163. Joseph, J.E., Liu, X., Jiang, Y., Lynam, D., and Kelly, T.H. (2009). Neural correlates of emotional reactivity in sensation seeking. Psychol. Sci. 20, 215–223. Damasio, A.R. (1999). The Feeling of What Happens: Body, Emotion and the Making of Consciousness (London: Heinemann). Barsalou, L.W. (2009). Simulation, situated conceptualization, and prediction. Phil. Trans. R. Soc. B 364, 1281–1289. Machado, C.J., and Bachevalier, J. (2008). Behavioral and hormonal reactivity to threat: Effects of selective amygdala, hippocampal or orbital frontal lesions in monkeys. Psychoneuroendocrinology 33, 926–941. Ekman, P. (1992). Are there basic emotions? Psychol. Rev. 99, 550–553. Cosmides, L., and Tooby, J. (2000). Evolutionary psychology and the emotions. In Handbook of Emotions 2nd ed., M. Lewis and J.M. Haviland-Jones, eds. (New York: Guilford Press), pp. 91–115. Fontaine, J.R., Scherer, K.R., Roesch, E.B., and Ellsworth, P.C. (2007). The world of emotions is not two-dimensional. Psychol. Sci. 18, 1050–1057. Mobbs, D., Petrovic, P., Marchant, J.L., Hassabis, D., Weiskopf, N., Seymour, B., Dolan, R.J., and Frith, C.D. (2007). When fear is near: Threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 317, 1079–1083.
Psychology Department, Emory University, Atlanta, GA 30322, USA. E-mail: [email protected] DOI: 10.1016/j.cub.2010.12.007
the tight regulatory control of the polymerization dynamics of microtubule ends [1]. Our understanding of the mechanisms controlling microtubule plus-end dynamics has advanced rapidly, aided by the discovery of numerous plus-end-binding proteins [2]. By contrast, the regulation and behavior of the minus end has remained far more mysterious. However, we may be in for a change. A recent paper published in Cell by Goodwin and Vale [3] provides the first definitive identification of
16. Lawley, T.D., Chan, K., Thompson, L.J., Kim, C.C., Govoni, G.R., and Monack, D.M. (2006). Genome-wide screen for Salmonella genes required for long-term systemic infection of the mouse. PLoS Pathog. 2, e11. 17. Chain, P.S., Carniel, E., Larimer, F.W., Lamerdin, J., Stoutland, P.O., Regala, W.M., Georgescu, A.M., Vergez, L.M., Land, M.L., Motin, V.L., et al. (2004). Insights into the
evolution of Yersinia pestis through whole-genome comparison with Yersinia pseudotuberculosis. Proc. Natl. Acad. Sci. USA 101, 13826–13831.
1Department of Immunobiology and 2Howard Hughes Medical Institute, Yale University
Affective Neuroscience: Amygdala’s Role in Experiencing Fear A new neuropsychological study of a rare patient provides novel evidence that amygdala lesions can virtually abolish the experience of fear, illuminating neurobiological mechanisms of fear experience. Stephan Hamann When a fear-inducing stimulus such as a crawling spider frightens us, a complex cascade of processes is initiated across multiple brain regions and pathways. Although basic mechanisms of fear learning and expression have been characterized in humans and non-human animal models [1,2], current understanding of many aspects of emotional processing remains incomplete. This is particularly true for the brain systems that mediate the experience of fear and other emotions. The amygdala, a small almond-shaped group of nuclei in the anterior temporal lobe, is a critically important orchestrator of emotional processes, particularly negative emotions such as fear. For example, the amygdala is critical for learning new fear associations, processing emotional attributes of aversive and appetitive stimuli [3], boosting long-term memory for emotional events [4], and recognizing fearful facial expressions. In contrast to its clear role in other fear-related phenomena, however, the amygdala has not been shown to have an essential role in the actual experience of fear, that is, what it feels like to be afraid, along with the behavioral and physiological manifestations of fear. Indeed, the limited available evidence has suggested that the ability to experience fear persists even after complete loss of the amygdala in humans [5], notwithstanding anecdotal clinical reports of diminished fear experience in some amygdala lesion patients. A study reported recently in Current Biology [6] revisited the role of the
amygdala in the experience of fear in an extensive and systematic case study of a rare patient with selective bilateral amygdala lesions. The striking findings of this study suggest that, contrary to previous reports, the human amygdala does indeed play a critical role in triggering the experience of fear, and that loss of the amygdala can result in a virtual absence of behavioral fear reactions and fear experience even in the face of potent fear elicitors. These findings have important implications for understanding neural mechanisms underlying fear and have broader implications for theoretical models of emotion. Feinstein et al. [6] investigated fear induction and experience in patient SM, A
School of Medicine, New Haven, CT 06520, USA. E-mail: [email protected], ruslan. [email protected]
DOI: 10.1016/j.cub.2010.12.008
a 44-year old woman with complete bilateral amygdala lesions due to Urbach-Wiethe disease, a disorder caused by loss-of-function mutations of the extracellular matrix protein 1 (ECM1) gene. Previous studies of this patient yielded a veritable mother lode of novel and influential findings regarding the emotional and social functions of the human amygdala [7,8]. SM’s brain lesions (Figure 1A, blue regions) are relatively limited to the amygdala and overlap completely with brain regions preferentially active during processing of fear-inducing stimuli, as determined in recent metaanalysis of multiple neuroimaging studies (Figure 1A, red regions) [9]. Using a multi-pronged experimental approach, the authors systematically probed SM’s behavioral and subjective responses to a wide range of stimuli and situations that potently elicit fear in healthy individuals (Figure 1B), complementing these experimental studies by carefully assessing SM’s fear experiences across her lifetime.
B
Frightening Frightening people/ animals Neuropsychological situations testing Experience sampling Fear Frightening Behavioral/ Psychiatric elicitation films clinical assessment MRI Memories/ interviews Autobiographical/relative interviews Current Biology
Figure 1. Overlap of lesions with neuroimaging studies of fear and converging strategies to identify fear deficits in patient SM. (A) SM’s amygdala lesions (blue regions) overlap completely with a neuroimaging meta-analysis brain map that summarizes the regions most consistently associated with fear (red regions) [9]. (B) The experimental strategy for investigating SM’s fear deficits focused on systematically establishing her lack of fear in multiple domains: across multiple potent fear elicitors, in everyday life and assessed clinically, and across her lifetime through extensive interviews. These combined findings provide substantial new evidence that bilateral amygdala lesions can produce a specific and virtually complete deficit in the experience of fear [6].
Current Biology Vol 21 No 2 R76
Memory retrieval
External stimuli
Insula Emotion simulation
Amygdala
Prefrontal & other cortical regions
Brainstem nuclei
Hypothalamus
Autonomic/ endocrine responses
Emotional experience
Current Biology
Figure 2. Multiple pathways to the experience of fear and locus of impairment from bilateral amygdala lesions. In the intact human brain, the experience of fear can be triggered by external stimuli or by memory recall of fear-inducing stimuli. Two main pathways ultimately lead to fear elicitation via autonomic and endocrine outputs from the hypothalamus and brainstem periaqueductal gray (PAG) region. In the amygdala pathway, fear-inducing stimuli and memories activate amygdala nuclei that directly project to the hypothalamus and PAG. A secondary route can bypass the amygdala, and involves simulation or reactivation of learned emotional states in the insula and other cortical regions. SM’s bilateral amygdala lesions eliminated the direct amygdala route (orange rectangle), as well as the emotion simulation route (pink rectangle), possibly because the early onset of her lesions in childhood interfered with the emotional learning required to develop the emotion simulation route [6]. An interesting prediction of this model is that direct stimulation of hypothalamus/PAG through interoceptive stimulation should still be able to elicit fear experience in SM.
To overcome the challenge of inducing fear repeatedly in an ethical manner, the investigators developed a variety of clever and potent fear elicitors, including handling live snakes, watching intensely frightening films, and visiting an infamously frightening haunted house. Comprehensive examination of multiple aspects of fear experience was crucial to the success of their approach, in part because it countered a serious potential concern: due to substantial individual differences in emotional response, even normal individuals may not respond to particular fear-inducing stimuli [10]. The experimental results were clear and compelling. In each test of fear induction, SM demonstrated a complete lack of the subjective fear experience and
behavioral signs of fear such as threat avoidance. Importantly, as predicted, her emotion impairments were specific to fear, leaving other emotions such as disgust or sadness unaffected. An intriguing feature of SM’s behavior is that she is fascinated by fear-inducing stimuli, rather than treating them as affectively neutral. When confronted with fear-inducing stimuli such as snakes and frightening people, she felt compelled to approach and touch them. This behavior underscores an essential qualitative difference between her responses and those of normal individuals. Her compulsion to approach threats is the opposite of the amygdala’s normal adaptive role, compelling organisms away from threat,
and parallels abnormal exploratory behavior towards fear-inducing stimuli previously reported in amygdala-lesioned monkeys [11,12]. Further study is warranted to understand the neurobiological basis for this abnormal behavior, and how it may relate to superficially similar normal behavior such as thrill-seeking, a related behavior linked with other regions such as the insula and hippocampus [13]. Regarding emotions in real-life situations, as an adult, SM has unfortunately experienced several harrowing, life-threatening events, including physical assault. When interviewed, in her descriptions of her emotional reactions during these episodes, she consistently conveys a pervasive and abnormal absence of fear and concern. Her complete lack of fear behaviors and highly impoverished fear experience across multiple contexts is clearly abnormal. Interestingly, SM’s amygdala lesions are thought to have occurred in childhood. She can recall fully-fledged fear experiences from before the age of 10, but not afterwards, suggesting that she once could feel fear, but now can feel fear no more. SM’s case shows that living without fear, like the inability to feel pain, has dangerous consequences that vividly illustrate the lost ability’s adaptive role. How can one reconcile these findings with previous reports that suggested the amygdala is not important for the experience of fear? While a full answer to this question awaits further study, Feinstein et al. [6] note that there is an additional neural route to triggering fear that bypasses the amygdala. This emotional simulation route [14,15], in which memory representations of previously experienced emotions are reactivated, can directly activate the hypothalamus and brainstem nuclei (Figure 2), bypassing the amygdala. In SM’s case, the authors speculate that, because the development of the simulation route requires amygdala-dependent emotional learning, this route was insufficiently developed by the time she sustained her amygdala lesions. Thus, SM’s fear deficits are thought to arise from the disruption of both the direct amygdala route (Figure 2; orange rectangle) and the secondary emotion simulation route (Figure 2; pink rectangle). The ability of some patients with bilateral amygdala lesions to demonstrate fear experience and fear behaviors may
Dispatch R77
therefore reflect the operation of the intact emotion simulation route. These findings suggest several next steps. First, because SM is a single case, it will be essential to pursue these issues with other amygdala lesion patients, ideally from a developmental perspective. Because physiological fear responses were not assessed in SM, another important outstanding question concerns whether her autonomic and endocrine responses also show a fear impairment, paralleling findings in amygdalectomized monkeys showing blunted stress hormone responses [16]. Finally, these findings also have important implications for theoretical views of how emotion is organized in the mind and brain. Patient SM’s prominent and highly specific fear impairments provide some of the clearest neuropsychological support to date for the neural validity of categorical or basic emotion views of emotion. Such views propose a limited set of emotions that have been shaped by evolution to deal with recurrent adaptive situations, such as escaping predators [17,18]. The common thread linking SM’s impairments is their relation to fear and threat, a pattern that would not be predicted from other theories such as dimensional theories, which emphasize explanations based on component dimensions such as arousal and valence over categorical distinctions [19]. More broadly, the findings and conclusions of Feinstein et al. [6] argue against theoretical views that conceptualize fear as a unitary psychological construct, or as mediated by a single neurobiological mechanism, instantiated in the amygdala. Instead, multiple pathways and mechanisms mediate the induction
and experience of fear, recruiting multiple brain regions, including the amygdala, hypothalamus, periaqueductal gray (brainstem), as well as the insula and other cortical regions (Figure 2). As suggested by the interconnections in Figure 2, the regions involved in fear processing interact dynamically, for example, in response to the salience of threats and other contextual factors. For example, in a study where subjects played a computerized cat-and-mouse game in a MRI scanner, when a virtual predator grew closer and subjective dread of real pain inflicted by the predator increased, fMRI activity shifted from ventromedial prefrontal cortex towards the periaqueductal gray [20]. Integrating provocative insights from careful single-case neuropsychological studies [6] with the ability of neuroimaging to characterize normal function and online dynamics offers a promising strategy for uncovering the complex mechanisms underlying the human experience of fear and other emotions. References
1. LeDoux, J. (2007). The amygdala. Curr. Biol. 17, R868–R874. 2. Davis, M., and Whalen, P.J. (2001). The amygdala: vigilance and emotion. Mol. Psych. 6, 13–34. 3. Hamann, S.B., Ely, T.D., Hoffman, J.M., and Kilts, C.D. (2002). Ecstasy and agony: Activation of the human amygdala in positive and negative emotion. Psychol. Sci. 13, 135–141. 4. McGaugh, J.L. (2003). Memory and Emotion: The Making of Lasting Memories (London: The Orion Publishing Group). 5. Anderson, A.K., and Phelps, E.A. (2002). Is the human amygdala critical for the subjective experience of emotion? Evidence of intact dispositional affect in patients with amygdala lesions. J. Cogn. Neurosci. 14, 709–720. 6. Feinstein, J., Adolphs, R., Damasio, A., and Tranel, D. (2011). The human amygdala and the induction and experience of fear. Curr. Biol. 21, 34–38. 7. Buchanan, T.W., Tranel, D., and Adolphs, R. (2009). The human amygdala in social function. In The Human Amygdala, P.W. Whalen and
Microtubule Dynamics: Patronin, Protector of the Minus End It has long been surmised that cellular microtubules are capped at the minus ends to prevent their depolymerization. A recent study provides the first definitive identification of a minus-end-specific capping protein, termed Patronin, which protects the microtubule arrays of both mitotic and interphase cells. Brian P. O’Rourke and David J. Sharp* Microtubules form complex and dynamic arrays with integral roles in
membrane trafficking, cell division, morphogenesis and migration. The proper assembly and function of the microtubule cytoskeleton relies upon
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
19.
20.
E.A. Phelps, eds. (New York: Oxford University Press), pp. 289–320. Kennedy, D.P., Gla¨scher, J., Tyszka, J.M., and Adolphs, R. (2009). Personal space regulation by the human amygdala. Nat. Neurosci. 12, 1226–1227. Vytal, K., and Hamann, S. (2010). Neuroimaging support for discrete neural correlates of basic emotions: A voxel-based meta-analysis. J. Cogn. Neurosci. 22, 2864–2885. Hamann, S., and Canli, T. (2004). Individual differences in emotion processing. Curr. Opin. Neurobiol. 14, 233–238. Chudasama, Y., Izquierdo, A., and Murray, E.A. (2009). Distinct contributions of the amygdala and hippocampus to fear expression. Eur. J. Neurosci. 30, 2327–2337. Machado, C.J., Kazama, A.M., and Bachevalier, J. (2009). Impact of amygdala, orbitalfrontal, or hippocampal lesions on threat avoidance and emotional reactivity in nonhuman primates. Emotion 9, 147–163. Joseph, J.E., Liu, X., Jiang, Y., Lynam, D., and Kelly, T.H. (2009). Neural correlates of emotional reactivity in sensation seeking. Psychol. Sci. 20, 215–223. Damasio, A.R. (1999). The Feeling of What Happens: Body, Emotion and the Making of Consciousness (London: Heinemann). Barsalou, L.W. (2009). Simulation, situated conceptualization, and prediction. Phil. Trans. R. Soc. B 364, 1281–1289. Machado, C.J., and Bachevalier, J. (2008). Behavioral and hormonal reactivity to threat: Effects of selective amygdala, hippocampal or orbital frontal lesions in monkeys. Psychoneuroendocrinology 33, 926–941. Ekman, P. (1992). Are there basic emotions? Psychol. Rev. 99, 550–553. Cosmides, L., and Tooby, J. (2000). Evolutionary psychology and the emotions. In Handbook of Emotions 2nd ed., M. Lewis and J.M. Haviland-Jones, eds. (New York: Guilford Press), pp. 91–115. Fontaine, J.R., Scherer, K.R., Roesch, E.B., and Ellsworth, P.C. (2007). The world of emotions is not two-dimensional. Psychol. Sci. 18, 1050–1057. Mobbs, D., Petrovic, P., Marchant, J.L., Hassabis, D., Weiskopf, N., Seymour, B., Dolan, R.J., and Frith, C.D. (2007). When fear is near: Threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 317, 1079–1083.
Psychology Department, Emory University, Atlanta, GA 30322, USA. E-mail: [email protected] DOI: 10.1016/j.cub.2010.12.007
the tight regulatory control of the polymerization dynamics of microtubule ends [1]. Our understanding of the mechanisms controlling microtubule plus-end dynamics has advanced rapidly, aided by the discovery of numerous plus-end-binding proteins [2]. By contrast, the regulation and behavior of the minus end has remained far more mysterious. However, we may be in for a change. A recent paper published in Cell by Goodwin and Vale [3] provides the first definitive identification of