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Genetic dissection of an amygdala microcircuit that gates conditioned fear
Open accessAbstract
The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ(+) neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ(-) neurons in CEl. Electrical silencing of PKC-δ(+) neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called CEl(off) units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.
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“The amygdala plays a key role in defensive behaviour and switching between defensive modes in rodents [39–42].”
From Freeze for action: neurobiological mechanisms in animal and human freezing (2017) · cites this paper as [42]
Experimental — accuracy not yet measuredIn the citing paper
“since BLA neurons excite GABAergic CeL neurons26 that provide feed-forward inhibition onto CeM “output” neurons6,18,19”
From Amygdala circuitry mediating reversible and bidirectional control of anxiety (2011) · cites this paper as [19]
In the citing paper
“For instance, a population of GABAergic neurons in the CeL which express protein kinase C-delta (PKC-delta+ neurons) increase their spontaneous activity following fear conditioning [34], and are involved in fear generalization and anxiety (Fig. 1D) [4].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [34]
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Pathological circuit function underlying addiction and anxiety disorders
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“In sharp contrast, the PKC- CeL neurons strongly project to and inhibit CeM neurons (Haubensak et al., 2010; Li et al., 2013).”
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BackgroundA Disinhibitory Microcircuit Mediates Conditioned Social Fear in the Prefrontal Cortex
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The central amygdala controls learning in the lateral amygdala
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“Protein kinase C-δ-expressing CeL neurons are required for the FC-induced LA synaptic plasticity and learning We next examined the effects of inhibiting protein kinase C-δ-expressing (PKC-δ) CeL neurons, another major population in the CeL, with the TeLC in Prkcd-Cre mice that express Cre in PKC-δ CeL neurons (Haubens…”
BackgroundInfluentialSelf-citationCircuit dynamics of adaptive and maladaptive behaviour
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“In other cases, selectivity might be achieved using an intersectional strategy of complementary elements introduced on co-injected viruses (Dymecki et al., 2010; Haubensak et al., 2010; Fujimoto et al., 2011).”
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“…of synaptic currents depict the arrangements and strengths of connections between different classes of neurons (Figure 6) (Arenkiel et al. 2007; Cruikshank et al. 2010; Dhawale et al. 2010; Haubensak et al. 2010; Kätzel et al. 2011; Ren et al. 2011; Petreanu et al. 2007, 2009; Wang et al. 2007).”
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“…direct evidence of the role of amygdala subregions in threat and fear processing comes predominantly from rodent lesion research 47 and optogenetics 48 , our present finding of a lowered threshold for reporting fear for morphed faces is consistent with prior human amygdala lesion results: patient…”
ResultLeft and right hemispheric lateralization of the amygdala in pain
Allen, H. N., Bobnar, H. J., & Kolber, B. J. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101891 · Cited by 151
Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism
Cheadle, L., Rivera, S. A., Phelps, J. S., Ennis, K. A., Stevens, B., Burkly, L. C., Lee, W.-C. A., & Greenberg, M. E. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.002 · Cited by 160
Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors
Yu, K., da Silva, P. G., Albeanu, D. F., & Li, B. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4419-15.2016 · Cited by 157
“…CeL populations, including the corticotropinreleasing hormone-expressing neurons (Day et al., 1999) and the protein kinase C- -expressing neurons (Haubensak et al., 2010), or by the long-range interactions of SOM CeL neurons with extraamygdaloid structures, such as the periaqueductal gray or the…”
BackgroundThe Basolateral Amygdala Is Essential for Rapid Escape: A Human and Rodent Study
Terburg, D., Scheggia, D., Rio, R. T. D., Klumpers, F., Ciobanu, A. C., Morgan, B. E., Montoya, E. R., Bos, P. A., Giobellina, G., van den Burg, E. H., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.028 · Cited by 158
“Recent evidence furthermore indicates that the CeL can act as a switch between passive—freezing—and active—escape—defensive behaviors, specifically due to inhibitory projections to the medial subdivision (CeM) and the brainstem (Ciocchi et al., 2010; Fadok et al., 2017; Gozzi et al., 2010; Haubensak et al., 2010; Tovo…”
BackgroundNassi, J. J., Cepko, C. L., Born, R. T., & Beier, K. T. (2015) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2015.00080 · Cited by 161
Deconstructing the Gestalt: Mechanisms of Fear, Threat, and Trauma Memory Encoding
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General anesthetics activate a potent central pain-suppression circuit in the amygdala
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Fear bradycardia and activation of the human periaqueductal grey
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“Rodent studies have shown that the amygdala plays a key role in orchestrating defensive behavior and transitioning between defensive modes (Davis and Whalen, 2001; Fendt and Fanselow, 1999; Gozzi et al., 2010; Haubensak et al., 2010).”
Optogenetic insights on the relationship between anxiety-related behaviors and social deficits
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“Perhaps Frontiers in Behavioral Neuroscience www.frontiersin.org July 2014 | Volume 8 | Article 241 | 7 FIGURE 2 | Projections from the BLA to the vHPC bidirectionally modulate anxiety-related behaviors as well as social interaction.”
BackgroundFunctional circuits of new neurons in the dentate gyrus
Vivar, C., & van Praag, H. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00015 · Cited by 153
“…rabies virus has been applied to analyze the properties of neural circuits in different parts of the central nervous system such as the amygdala (Haubensak et al., 2010), olfactory bulb (Arenkiel et al., 2011; Miyamichi et al., 2011), visual cortex (Wickersham et al., 2007b; Marshel et al.,…”
BackgroundMethodSangha, S., Diehl, M. M., Bergstrom, H. C., & Drew, M. R. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.11.006 · Cited by 151
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Quantified Coexpression Analysis of Central Amygdala Subpopulations
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“The protein kinase c- (PKC- , Prkcd)-expressing neuron population has previously been shown to directly inhibit CeM output neurons, reducing activity in response to conditioned stimuli (CS) following fear conditioning and thus playing an important role in fear extinction learning (Herry et al., 2008; Ciocchi et al., 2…”
BackgroundInfluentialIndividual differences in recovery from traumatic fear
Holmes, A., & Singewald, N. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.003 · Cited by 147
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“Information relayed to the Ce from other nuclei is extensively processed in Ce intrinsic circuits (Ciocchi et al. 2010; Duvarci et al. 2011; Ehrlich et al. 2009; Haubensak et al. 2010).”
BackgroundMalézieux, M., Klein, A. S., & Gogolla, N. (2023) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-111020-103314 · Cited by 144
Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors
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“…brain-derived neurotrophic factor (BDNF) is a positive regulator of neural plasticity in dopamine neurons to promote the actions of cocaine and other stimulants (Horger et al., 1999; Hall et al., 2003; Graham et al., 2007; Lobo et al., 2010), it plays an opposite role in the effects of morphine.”
BackgroundSynaptic encoding of fear memories in the amygdala
Ressler, R. L., & Maren, S. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.08.012 · Cited by 138
Central Amygdala Prepronociceptin-Expressing Neurons Mediate Palatable Food Consumption and Reward
Hardaway, J. A., Halladay, L. R., Mazzone, C. M., Pati, D., Bloodgood, D. W., Kim, M., Jensen, J., DiBerto, J. F., Boyt, K. M., Shiddapur, A., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.037 · Cited by 138
The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning
Keifer, O. P., Hurt, R. C., Ressler, K. J., & Marvar, P. J. (2015) · Physiology · doi:10.1152/physiol.00058.2014 · Cited by 124
“Within the amygdala, not only do both CEl and CEm cells receive inhibitory GABAergic input from ITC cells (103, 123), but CEl cells also inhibit CEm cells (33, 53).”
BackgroundClosed-loop optogenetic intervention in mice
Armstrong, C., Krook-Magnuson, E. I., Oijala, M., & Soltész, I. (2013) · Nature Protocols · doi:10.1038/nprot.2013.080 · Cited by 134
Pomrenze, M. B., Millan, E. Z., Hopf, F. W., Keiflin, R., Maiya, R., Blasio, A., Dadgar, J., Kharazia, V., de Guglielmo, G., Crawford, E. F., et al. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00487 · Cited by 130
“The anatomy of projections from CeL to CeM has been examined recently inmousemodels of fear conditioning (Ciocchi et al., 2010; Haubensak et al., 2010; Li et al., 2013), although without a focus on amygdala CRF neurons or employing CrhCre mice.”
BackgroundMethodInfluentialInduction and Expression of Fear Sensitization Caused by Acute Traumatic Stress
Perusini, J. N., Meyer, E. M., Long, V., Rau, V., Nocera, N. A., Avershal, J., Maksymetz, J., Spigelman, I., & Fanselow, M. S. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.224 · Cited by 128
Self-citationSerotonin in fear conditioning processes
Bauer, E. P. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.028 · Cited by 136
The Origins and Organization of Vertebrate Pavlovian ConditioningPreprint
Fanselow, M., & Wassum, K. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021717 · Cited by 132
“GABAergic circuitry within the CeN regulates this output (Haubensak et al. 2010).”
BackgroundSelf-citationJurek, B., Slattery, D. A., Hiraoka, Y., Liu, Y., Nishimori, K., Aguilera, G., Neumann, I. D., & van den Burg, E. H. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1345-14.2015 · Cited by 124
“F), as previously reported (Gray and Magnuson, 1992; Gray, 1993; Haubensak et al., 2010).”
MethodChen, Y.-H., Wu, J., Hu, N.-Y., Zhuang, J.-P., Li, W., Zhang, S.-R., Li, X.-W., Yang, J., & Gao, T. (2021) · Journal of Clinical Investigation · doi:10.1172/jci145692 · Cited by 126
“Since the CeM is under tonic inhibitory control from the CeL (36, 37, 80), the functional relationship rently unknown but would also be an interesting topic for future studies.”
BackgroundInfluentialOptogenetic Central Amygdala Stimulation Intensifies and Narrows Motivation for Cocaine
Warlow, S. M., Robinson, M. J. F., & Berridge, K. C. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3141-16.2017 · Cited by 129
“…significance to particular stimuli based partly on associative information (Weiskrantz, 1956; LeDoux, 2000; Balleine and Killcross, 2006; Mahler and Berridge, 2009; Haubensak et al., 2010; DiFeliceantonio and Berridge, 2012; Peck et al., 2013; Janak and Tye, 2015; Yasoshima et al., 2015).”
BackgroundThe Role of the Central Amygdala in Alcohol Dependence
Roberto, M., Kirson, D., & Khom, S. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a039339 · Cited by 112
“…(CeM) aspects that differ in neuropeptide content, origin of afferents, and target sites of efferent projections [for review (Sun et al. 1991; Petrovich et al. 1996; Pitkanen et al. 2000; Dong et al. 2001; Ciocchi et al. 2010; Davis et al. 2010; Haubensak et al. 2010; McCullough et al. 2016).”
BackgroundDéjean, C., Courtin, J., Rozeske, R. R., Bonnet, M. C., Dousset, V., Michelet, T., & Herry, C. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.03.017 · Cited by 130
“neurons facilitates the disinhibition of PAG-projecting CEm neurons during fear expression (63,68).”
BackgroundDorsal tegmental dopamine neurons gate associative learning of fear
Groessl, F., Munsch, T., Meis, S., Griessner, J., Kaczanowska, J., Pliota, P., Kargl, D., Badurek, S., Kraitsy, K., Rassoulpour, A., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0174-5 · Cited by 118
Self-citationThe role of Neuropeptide Y in fear conditioning and extinction
Tasan, R. O., Verma, D., Wood, J. C., Lach, G., Hörmer, B. A., de Lima, T. C. M., Herzog, H., & Sperk, G. (2015) · Neuropeptides · doi:10.1016/j.npep.2015.09.007 · Cited by 121
“In fact, the CEA is far from being a passive output relay, but forms in itself a highly elaborated micro-network and is capable of establishing diverse forms of plasticity (Ciocchi et al., 2010; Haubensak et al., 2010).”
BackgroundOptogenetic investigation of neural circuits in vivo
Carter, M. E., & de Lecea, L. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.12.005 · Cited by 117
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“In line with our results, pharmacogenetic silencing of CEl PKCδ+ cells during fear conditioning and subsequent testing was previously shown to increase freezing responses both during and after auditory cue presentation, suggesting generalization (5).”
BackgroundResultVisualizing an emotional valence map in the limbic forebrain by TAI-FISH
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Subcortical amygdala pathways enable rapid face processing
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Layer I Interneurons Sharpen Sensory Maps during Neonatal Development
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The intersection of stress and reward: BNST modulation of aversive and appetitive states
Ch’ng, S. S., Fu, J., Brown, R. M., McDougall, S. J., & Lawrence, A. J. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.01.005 · Cited by 118
“PKC-δ+ neurons in the CeA represent “fear off” neurons (Haubensak et al., 2010).”
Zhou, M., Liu, Z., Melin, M. D., Ng, Y. H., Xu, W., & Südhof, T. C. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0248-4 · Cited by 112
Valence coding in amygdala circuits
Pignatelli, M., & Beyeler, A. (2018) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.10.010 · Cited by 133
“Moreover, mutual inhibition was described between functionally divergent populations such as PKCδ+ and SOM+ neurons in CeA [35], as well as Rspo2 and Ppp1rb1 neurons in BLA [62●●].”
BackgroundGrogans, S. E., Bliss‐Moreau, E., Buss, K. A., Clark, L. A., Fox, A. S., Keltner, D. J., Cowen, A., Kim, J. J., Kragel, P. A., MacLeod, C., et al. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105237 · Cited by 135
“…is insufficient, as research in rodents has identified subsets of neurons in threat-relevant regions, such as the amygdala, that have a distinct impact on the behavioral and physiological responses to threat (Fadok et al., 2017; Haubensak et al., 2010; Li et al., 2013; Viviani et al., 2011).”
BackgroundHypervigilance for fear after basolateral amygdala damage in humans
Terburg, D., Morgan, B. E., Montoya, E. R., Hooge, I. T. C., Thornton, H. B., Hariri, A. R., Panksepp, J., Stein, D. J., & van Honk, J. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.46 · Cited by 112
Physiological identification and infralimbic responsiveness of rat intercalated amygdala neurons
Amir, A., Amano, T., & Paré, D. (2011) · Journal of Neurophysiology · doi:10.1152/jn.00136.2011 · Cited by 118
Neuronal types in the mouse amygdala and their transcriptional response to fear conditioning
Hochgerner, H., Singh, S., Tibi, M., Lin, Z., Skarbianskis, N., Admati, I., Ophir, O., Reinhardt, N., Netser, S., Wagner, S., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01469-3 · Cited by 110
“These neurons likely constitute one or several types described for their involvement in both fear and appetitive behaviors 12,44,45 .”
BackgroundResultThe lateral parabrachial nucleus is actively involved in the acquisition of fear memory in mice
Satô, M., Ito, M., Nagase, M., Sugimura, Y. K., Takahashi, Y., Watabe, A. M., & Kato, F. (2015) · Molecular Brain · doi:10.1186/s13041-015-0108-z · Cited by 111
“Recently, accumulating evidence revealed that, in addition to the lateral nucleus of the amygdala (LA) [2], the central amygdala (CeA) is also crucial for fear learning [8-14].”
BackgroundAnimal Models of PTSD: A Critical Review
Flandreau, E. I., & Tóth, M. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_65 · Cited by 118
Translating Across Circuits and Genetics Toward Progress in Fear- and Anxiety-Related Disorders
Ressler, K. J. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20010055 · Cited by 104
FROM THE NEUROBIOLOGY OF EXTINCTION TO IMPROVED CLINICAL TREATMENTS
Morrison, F. G., & Ressler, K. J. (2013) · Depression and Anxiety · doi:10.1002/da.22214 · Cited by 107
A Role for Tac2 , NkB, and Nk3 Receptor in Normal and Dysregulated Fear Memory Consolidation
Andero, R., Dias, B. G., & Ressler, K. J. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.028 · Cited by 104
“Enk is colocalized with PKCd in the CeL (Haubensak et al., 2010) and specific CeA-Enk deletion decreases fear expression during FC without”
BackgroundInfluentialCortico-Limbic Interactions Mediate Adaptive and Maladaptive Responses Relevant to Psychopathology
Kovner, R., Oler, J. A., & Kalin, N. H. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19101064 · Cited by 111
Asok, A., Draper, A., Hoffman, A. F., Schulkin, J. A., Lupica, C. R., & Rosen, J. B. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.79 · Cited by 103
Asede, D., Bosch, D., Lüthi, A., Ferraguti, F., & Ehrlich, I. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.008 · Cited by 109
Self-citationRodent models of impaired fear extinction
Singewald, N., & Holmes, A. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5054-x · Cited by 110
“2015) and the lateral part of the central amygdala (CeL), wherein different populations of cells are predicted to promote or oppose the expression of extinction via inputs from the paraventricular nucleus of the thalamus (PVT) (Do-Monte et al. 2015; Haubensak et al. 2010; Knobloch et al. 2012; Li et al. 2013; Penzo et…”
BackgroundInfluentialBurghardt, N. S., & Bauer, E. P. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.05.050 · Cited by 109
An Insula–Central Amygdala Circuit for Guiding Tastant-Reinforced Choice Behavior
Schiff, H. C., Bouhuis, A. L., Yu, K., Penzo, M. A., Li, H., He, M., & Li, B. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1773-17.2017 · Cited by 100
“The Som-cre (Taniguchi et al., 2011; RRID:IMSR_JAX:013044), Ai14 (Madisen et al., 2010; RRID:IMSR_JAX:007908), Prkcd-cre (Haubensak et al., 2010; RRID:IMSR_JAX:028437), and Rosa26-stopflox-tTA (Li et al., 2010) mice were described previously and were purchased from the Jackson Laboratory.”
MethodA time-dependent role of midline thalamic nuclei in the retrieval of fear memory
Padilla-Coreano, N., Do-Monte, F. H., & Quirk, G. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.037 · Cited by 100
“Furthermore, two subpopulations of reciprocally connected CeL neurons were identified (Haubensak et al., 2010), suggesting gating of CeL projections to CeM.”
BackgroundCheriyan, J., Kaushik, M. K., Ferreira, A. N., & Sheets, P. L. (2016) · eNeuro · doi:10.1523/eneuro.0002-16.2016 · Cited by 106
“Because PKC- neurons inhibit PKC- (Haubensak et al., 2010) activation of PKC- neurons by IL inputs may decrease PKC- driven inhibition of the PAG.”
BackgroundNavratilova, E., Ji, G., Phelps, C. E., Qu, C., Hein, M., Yakhnitsa, V., Neugebauer, V., & Porreca, F. (2018) · Pain · doi:10.1097/j.pain.0000000000001458 · Cited by 101
“Recordings were made from regular spiking CeLC neurons as in our previous studies(41) because they typically are peptidergic projection neurons.(16) As a measure of neuronal output, excitatory postsynaptic potential-spike coupling (E-S coupling) was measured.”
A neural substrate of compulsive alcohol use
Domi, E., Xu, L. X., Toivainen, S., Nordeman, A., Gobbo, F., Vènniro, M., Shaham, Y., Messing, R. O., Visser, E., van den Oever, M. C., et al. (2021) · Science Advances · doi:10.1126/sciadv.abg9045 · Cited by 100
Thy1-Expressing Neurons in the Basolateral Amygdala May Mediate Fear Inhibition
Jasnow, A. M., Ehrlich, D., Choi, D. C., Dabrowska, J., Bowers, M. E., McCullough, K. M., Rainnie, D. G., & Ressler, K. J. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5539-12.2013 · Cited by 93
“As activity of CeM neurons has been linked to increased conditioned freezing (Haubensak et al., 2010), our electrophysiological and be-”
BackgroundInfluentialBasal Ganglia Output Controls Active Avoidance Behavior
Hormigo, S., Vega‐Flores, G., & Castro‐Alamancos, M. A. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1842-16.2016 · Cited by 94
“…part of the neural circuitry involved in Pavlovian fear conditioning (LeDoux, 2000; Davis and Whalen, 2001; Maren, 2001; Ciocchi et al., 2010; Haubensak et al., 2010; Pape and Pare, 2010; Tye and Deisseroth, 2012), The amygdala, and its connections with the striatum, appear to have an…”
BackgroundWang, Y., Kim, J., Schmit, M. B., Cho, T. S., Fang, C., & Cai, H. (2019) · Nature Communications · doi:10.1038/s41467-019-10715-x · Cited by 95
Self-citationSleep Regulation by Neurotensinergic Neurons in a Thalamo-Amygdala Circuit
Ma, C., Zhong, P., Liu, D., Barger, Z., Zhou, L., Chang, W.-C., Kim, B., & Dan, Y. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.015 · Cited by 97
Retrieving fear memories, as time goes by…
Monte, F. H. D., Quirk, G. J., Li, B., & Penzo, M. A. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.78 · Cited by 98
Perspectives on fear generalization and its implications for emotional disorders
Jasnow, A. M., Lynch, J. F., Gilman, T. L., & Riccio, D. C. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23837 · Cited by 97
Illuminating circuitry relevant to psychiatric disorders with optogenetics
Steinberg, E. E., Christoffel, D. J., Deisseroth, K., & Malenka, R. C. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.004 · Cited by 92
“In the lateral nucleus of the CeA, a subpopulation of protein kinase C-d-expressing inhibitory neurons inhibit medial CeA neurons that project to brainstem regions important for generating freezing [25].”
BackgroundSelf-citationZhang, G., Sun, W., Zingg, B., Shen, L., He, J., Xiong, Y., Tao, H. W., & Zhang, L. I. (2017) · Neuron · doi:10.1016/j.neuron.2017.12.010 · Cited by 95
“On the other hand, tone signals may be transmitted through other pathways, e.g., via the amygdala (Ehrlich et al., 2009; Haubensak et al., 2010; Wolff et al., 2014), to form tone-specific fear memory.”
Li, J., & Sheets, P. L. (2018) · The Journal of Physiology · doi:10.1113/jp276935 · Cited by 93
“Consistent with previous studies (Rizvi et al. 1991; Finnegan et al. 2005; Haubensak et al. 2010; Penzo et al. 2014), our retrograde labelling experiments reveal that PAG-projecting neurons are distributed in the both CeL and CeM subregions of the amygdala.”
BackgroundResultInfluentialHuman fear conditioning: From neuroscience to the clinic
Fullana, M. A., Dunsmoor, J. E., Schruers, K. R. J., Savage, H. S., Bach, D. R., & Harrison, B. J. (2019) · Behaviour Research and Therapy · doi:10.1016/j.brat.2019.103528 · Cited by 96
Optogenetics and Psychiatry: Applications, Challenges, and Opportunities
Deisseroth, K. A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.12.021 · Cited by 91
Self-citationEnkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience
Henry, M. S., Gendron, L., Tremblay, M., & Drolet, G. (2017) · Neural Plasticity · doi:10.1155/2017/1546125 · Cited by 96
“(i) In rats, ENK mRNA levels are increased in CEA upon contextual fear conditioning [14] (ii) ENK knockout (KO) mice show an exaggerated immobility during auditory fear conditioning [42] (iii) ENK neurons in CEAl overlap with PKC-δ GABAergic neurons, which are involved in fear behavior [45, 66] (iv) In SWR/J mice (sho…”
Yamauchi, N., Sato, K., Sato, K., Murakawa, S., Hamasaki, Y., Nomura, H., Amano, T., & Minami, M. (2022) · Science Advances · doi:10.1126/sciadv.abj5586 · Cited by 90
Li, Y., Stam, F. J., Aimone, J. B., Goulding, M., Callaway, E. M., & Gage, F. H. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306912110 · Cited by 91
Self-citationLahoud, N., & Maroun, M. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.04.006 · Cited by 87
“, 2006) but rather engaged in fear conditioning learning (Ciocchi et al., 2010; Haubensak et al., 2010).”
BackgroundTorruella-Suárez, M. L., Vandenberg, J. R., Cogan, E. S., Tipton, G. J., Teklezghi, A. T., Dange, K., Patel, G., McHenry, J. A., Hardaway, J. A., Kantak, P. A., et al. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1466-19.2019 · Cited by 87
“Although some data have shed light on neuronal subpopulations influencing fear- and feeding-related behaviors in the CeA (Haubensak et al., 2010; Cai et al., 2014; Douglass et al., 2017), it remains unclear which CeA subpopulations and efferents influence ethanol consumption, particularly during early ethanol seeking…”
BackgroundBorgomaneri, S., Battaglia, S., Sciamanna, G., Tortora, F., & Laricchiuta, D. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.036 · Cited by 90
A comprehensive concept of optogenetics
Dugué, G. P., Akemann, W., & Knöpfel, T. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59426-6.00001-x · Cited by 94
“This important issue has only been addressed and discussed on very few occasions (Aponte et al., 2011; Haubensak et al., 2010; Lin et al., 2011).”
BackgroundControlling the Elements: An Optogenetic Approach to Understanding the Neural Circuits of Fear
Johansen, J. P., Wolff, S. B. E., Lüthi, A., & LeDoux, J. E. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.10.023 · Cited by 87
Self-citationSex differences in fear responses: Neural circuits
Bauer, E. P. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109298 · Cited by 92
GABAergic cell type diversity in the basolateral amygdala
Capogna, M. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.01.006 · Cited by 91
“Remarkably, the physiological role of some specific neurons of the amygdala in fear and extinction behaviours has been defined [8,9,10 ,11].”
Metadata
- Authors
- Haubensak, W., Kunwar, P. S., Cai, H., Ciocchi, S., Wall, N. R., Ponnusamy, R., Biag, J., Dong, H.-W., Deisseroth, K., Callaway, E. M., Fanselow, M. S., Lüthi, A., & Anderson, D. J.
- Affiliations
- California Institute of Technology (US)
- Salk Institute for Biological Studies (US)
- University of California, Los Angeles (US)
- Stanford University (US)
- Friedrich Miescher Institute (CH)
- Corresponding author
- Anderson, David J.
- ORCID
- Venue
- Nature
- Published
- 2010-11
- Volume
- 468
- Issue
- 7321
- Pages
- 270-276
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3597095
- OpenAlex
- W1981044491
- Cited by
- 840
- References
- 55
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 50 · 2023: 45 · 2022: 64 · 2021: 62 · 2020: 50 · 2019: 55 · 2018: 84 · 2017: 51 · 2016: 50 · 2015: 68 · 2014: 50 · 2013: 58 · 2012: 46
- FWCI
- 29.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (R01MH063912, R01MH085082)
- National Institute of Neurological Disorders and Stroke (RC2NS069464)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- central amygdala, fear conditioning, protein kinase C delta, GABAergic neurons, inhibitory microcircuits, disinhibition, conditioned freezing, fear memory, neuronal cell types
- MeSH terms
- Amygdala, Animals, Axonal Transport, Cells, Cultured, Conditioning, Classical, Fear, Female, gamma-Aminobutyric Acid, Genetic Techniques, Humans, Male, Mice, Transgenic, Neural Inhibition, Neural Pathways, Neurons, Synapses, Freezing Reaction, Cataleptic, Mice, Protein Kinase C-delta
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