Regulating anxiety with extrasynaptic inhibition

Botta, Paolo; Demmou, Lynda; Kasugai, Yu; Markovic, Milica; Xu, Chun; Fadok, Jonathan P; Lu, Tingjia; Poe, Michael M; Xu, Li; Cook, James M; Rudolph, Uwe; Sah, Pankaj; Ferraguti, Francesco; Lüthi, Andreas

doi:10.1038/nn.4102

Cited by 192Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Regulating anxiety with extrasynaptic inhibition

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Botta, Paolo, Demmou, Lynda, Kasugai, Yu, Markovic, Milica, Xu, Chun, Fadok, Jonathan P, Lu, Tingjia, Poe, Michael M +6 more·2015·Nature Neuroscience

DOI 10.1038/nn.4102PMC PMC4607767

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Abstract

Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ(+) neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes.

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Selective knockdown of α5GABAARs in the small CeA PKC-delta+ population leads to increased anxiety-like responses by increasing spontaneous activity of these neurons.
“One group reported that selective knockdown of α5GABAARs in this small CeA population leads to increased anxiety-like responses by increasing the spontaneous activity of these neurons [4].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [4]
α5GABAARs have been implicated in anxiety, fear and/or response to chronic stress.
“In addition, γ2GABAARs [11], α1GABAARs [10, 12], α3GABAARs [13] (but see [14-16] for contradictory findings), and more recently, α5GABAARs [16-18, 4] have been implicated in anxiety, fear and/or response to chronic stress.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [4]
α5GABAARs in a small neuronal population in the central amygdala can regulate anxiety behaviors.
“However, a recent study showed that α5GABAARs in a small neuronal population in the central amygdala can regulate anxiety behaviors [4].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [4]

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Kaneda, M., Farrant, M., & Cull-Candy, S. G. (1995) · The Journal of Physiology · doi:10.1113/jphysiol.1995.sp020739 · Cited by 248 · see citing works
Electrophysiological characteristics of amygdaloid central nucleus neurons during Pavlovian fear conditioning in the rabbit
Pascoe, J. P., & Kapp, B. S. (1985) · Behavioural Brain Research · doi:10.1016/0166-4328(85)90087-7 · Cited by 233 · cited 1× · see citing works
“conditioning learning (Pascoe and Kapp 1985; Ciocchi, Herry et al. 2010).”
Mechanisms of Inhibition within the Telencephalon: “Where the Wild Things Are”
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“There is a myriad of heterogeneity among PNs due to their molecular markers, connectivity, sub-cellular targeting, cellular properties and behavioral function (Freund and Buzsaki 1996; Somogyi and Klausberger 2005; Ehrlich, Humeau et al. 2009; Pape and Pare 2010; Fishell and Rudy 2011; Spampanato, De Maria et al. 2012…”
GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1
Bedford, F. K., Kittler, J. T., Muller, É., Thomas, P., Uren, J. M., Merlo, D., Wisden, W., Triller, A., Smart, T. G., & Moss, S. J. (2001) · Nature Neuroscience · doi:10.1038/nn0901-908 · Cited by 231 · see citing works
Patterns of mRNA and protein expression for 12 GABAA receptor subunits in the mouse brain
Hörtnagl, H., Tasan, R. O., Wieselthaler, A., Kirchmair, E., Sieghart, W., & Sperk, G. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.01.008 · Cited by 229 · see citing works
Osteogenic sarcoma of bones and soft tissues in older persons. A clinicopathologic analysis of 117 patients older than 60 years
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Central Amygdala Activity during Fear Conditioning
Duvarci, S., Popa, D., & Paré, D. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4985-10.2011 · Cited by 202 · see citing works
Fear Conditioning Potentiates Synaptic Transmission onto Long-Range Projection Neurons in the Lateral Subdivision of Central Amygdala
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Transneuronal propagation of mutant huntingtin contributes to non–cell autonomous pathology in neurons
Pecho‐Vrieseling, E., Rieker, C., Fuchs, S., Bleckmann, D., Esposito, M. S., Botta, P., Goldstein, C., Bernhard, M., Galimberti, I., Müller, M. M., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3761 · Cited by 185 · see citing works
Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors
Wang, D.-S., Zurek, A. A., Lecker, I., Yu, J., Abramian, A. M., Avramescu, S., Davies, P. A., Moss, S. J., Lu, W.-Y., & Orser, B. A. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.08.022 · Cited by 182 · see citing works
The role of stress in symptom exacerbation among IBS patients
Blanchard, E. B., Lackner, J. M., Jaccard, J. J., Rowell, D., Carosella, A. M., Powell, C., Sanders, K. A., Krasner, S. S., & Kuhn, E. R. (2008) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2007.10.010 · Cited by 167 · see citing works
Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons
Ade, K. K., Janssen, M. J., Ortinski, P. I., & Vicini, S. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3908-07.2008 · Cited by 164 · see citing works
Distinct γ2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABAAReceptors and Gephyrin
Alldred, M. J., Mulder-Rosi, J., Lingenfelter, S. E., Chen, G., & Lüscher, B. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4011-04.2005 · Cited by 152 · see citing works
Quantitative localisation of synaptic and extrasynaptic GABAAreceptor subunits on hippocampal pyramidal cells by freeze‐fracture replica immunolabelling
Kasugai, Y., Swinny, J. D., Roberts, J. D. B., Dalezios, Y., Fukazawa, Y., Sieghart, W., Shigemoto, R., & Somogyi, P. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07473.x · Cited by 149 · see citing works
GABAA receptors containing the α5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear
Yee, B. K., Hauser, J., Dolgov, V. V., Keist, R., Möhler, H., Rudolph, U., & Feldon, J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03642.x · Cited by 132 · see citing works
Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors
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Training‐induced changes in the expression of GABAA‐associated genes in the amygdala after the acquisition and extinction of Pavlovian fear
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Dendritic Calcium Spikes Are Tunable Triggers of Cannabinoid Release and Short-Term Synaptic Plasticity in Cerebellar Purkinje Neurons
Rancz, E. A., & Häusser, M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5284-05.2006 · Cited by 122 · see citing works
Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of the conditional fear.
Goosens, K. A., & Maren, S. (2003) · Behavioral Neuroscience · doi:10.1037/0735-7044.117.4.738 · Cited by 112 · cited 1× · see citing works
“Furthermore, acute and reversible inactivation of CEA using the GABAA receptor agonist muscimol during fear conditioning, or local blockade of NMDA receptors, caused impairment in acquisition of conditioned fear responses (Wilensky, Schafe et al. 2000; Goosens and Maren 2003).”
Intact Synaptic GABAergic Inhibition and Altered Neurosteroid Modulation of Thalamic Relay Neurons in Mice Lacking δ Subunit
Porcello, D. M., Huntsman, M. M., Mihalek, R., Homanics, G. E., & Huguenard, J. R. (2003) · Journal of Neurophysiology · doi:10.1152/jn.00899.2002 · Cited by 110 · see citing works
Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition
Hauser, J., Rudolph, U., Keist, R., Möhler, H., Feldon, J., & Yee, B. K. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001554 · Cited by 109 · see citing works
An Orally Bioavailable, Functionally Selective Inverse Agonist at the Benzodiazepine Site of GABAA α5 Receptors with Cognition Enhancing Properties
Chambers, M. S., Atack, J. R., Carling, R. W., Collinson, N., Cook, S. M., Dawson, G. R., Ferris, P., Hobbs, S. C., O'Connor, D. V., Marshall, G. R., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm040863t · Cited by 109 · see citing works
The GABA A receptor α1 subunit epilepsy mutation A322D inhibits transmembrane helix formation and causes proteasomal degradation
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Novel Subunit-Specific Tonic GABA Currents and Differential Effects of Ethanol in the Central Amygdala of CRF Receptor-1 Reporter Mice
Herman, M. A., Contet, C., Justice, N. J., Vale, W., & Roberto, M. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2490-12.2013 · Cited by 105 · see citing works
Long‐term potentiation in freely moving rats reveals asymmetries in thalamic and cortical inputs to the lateral amygdala
Doyère, V., Schafe, G. E., Sigurdsson, T., & LeDoux, J. E. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02707.x · Cited by 101 · see citing works
GABA-Independent GABA A Receptor Openings Maintain Tonic Currents
Wlodarczyk, A. I., Sylantyev, S., Herd, M. B., Kersanté, F., Lambert, J. J., Rusakov, D. A., Linthorst, A. C. E., Semyanov, A. V., Belelli, D., Pavlov, I., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4193-12.2013 · Cited by 94 · cited 1× · see citing works
“…extrasynaptic inhibition in CEA PKC δ + neurons was largely insensitive to the competitive GABA A R antagonist SR95531 (1 – 50 μM) suggests either that extrasynaptic GABA A Rs exhibit a very high affinity for GABA 18,19 and/or that they can open in a spontaneous, ligand-independent manner 20,21 .”
Phasic activation of locus ceruleus neurons by the central nucleus of the amygdala
Bouret, S., Duvel, A., Onat, S., & Sara, S. J. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-08-03491.2003 · Cited by 84 · see citing works
Controlling the Elements: An Optogenetic Approach to Understanding the Neural Circuits of Fear
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Altered GABA transmission in a mouse model of increased trait anxiety
Tasan, R. O., Bukovac, A., Peterschmitt, Y., Sartori, S. B., Landgraf, R., Singewald, N., & Sperk, G. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.03.051 · Cited by 82 · cited 2× · see citing works
“Given that fear conditioning and trait anxiety are associated with decreased Gabra5 mRNA levels 24,25 , this suggests that the cell type-specific regulation of α 5 -GABA A Rs controls the excitability of CEA PKC δ + neurons in an experience-dependent manner.”
Tonically Active GABAA Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating
McCartney, M. R., Deeb, T. Z., Henderson, T. N., & Hales, T. G. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.028597 · Cited by 81 · cited 2× · see citing works
“…extrasynaptic inhibition in CEA PKC δ + neurons was largely insensitive to the competitive GABA A R antagonist SR95531 (1 – 50 μM) suggests either that extrasynaptic GABA A Rs exhibit a very high affinity for GABA 18,19 and/or that they can open in a spontaneous, ligand-independent manner 20,21 .”
Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse
Belmeguenaï, A., Botta, P., Weber, J. T., Carta, M., de Ruiter, M. M., Zeeuw, C. I. D., Valenzuela, C. F., & Hansel, C. (2008) · Journal of Neurophysiology · doi:10.1152/jn.90384.2008 · Cited by 80 · see citing works
Release Probability-Dependent Scaling of the Postsynaptic Responses at Single Hippocampal GABAergic Synapses
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Physiological properties of central amygdala neurons: species differences
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Intrinsic and extrinsic connections of the rat central extended amygdala: an in vivo electrophysiological study of the central amygdaloid nucleus
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“However, CEA receives a variety of extra-amygdaloid inputs (Ottersen and BenAri 1979; Veinante and Freund-Mercier 1998; Dong, Fukazawa et al. 2010), suggesting that it could function in parallel or independently from the BLA (Sun, Yi et al.”
Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies
Botta, P., Radcliffe, R. A., Carta, M., Mameli, M., Daly, E., Floyd, K. L., Deitrich, R. A., & Valenzuela, C. F. (2007) · Alcohol · doi:10.1016/j.alcohol.2007.04.004 · Cited by 67 · see citing works
Colocalization of peptide- and tyrosine hydroxylase-like immunoreactivities with Fos-immunoreactive neurons in rat central amygdaloid nucleus after immobilization stress
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“1984), oxytocin, vasopressin and its receptors (Veinante and FreundMercier 1995; Veinante and Freund-Mercier 1997), calcitonin- gene related peptide (CGRP) Honkaniemi (Honkaniemi 1992), galanin and its receptors Waters and Kraude (Waters and Krause 2000), somatostatin (SOM), substance P, neurotensin, cholecystokinin R…”
Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test
Navarro, J. F., Burón, E., & Martín‐López, M. (2002) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(02)00305-6 · Cited by 61 · see citing works
Distribution of pro-opiomelanocortin-derived peptides and enkephalins in the rat central nucleus of the amygdala
Gray, T. S., Cassell, M. D., & Kiss, J. Z. (1984) · Brain Research · doi:10.1016/0006-8993(84)90386-x · Cited by 60 · see citing works
Behavioral Effects of Ethanol in Cerebellum Are Age Dependent: Potential System and Molecular Mechanisms
Skike, C. E. V., Botta, P., Chin, V. S., Tokunaga, S., McDaniel, J. R., Venard, J., Diaz‐Granados, J. L., Valenzuela, C. F., & Matthews, D. B. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01303.x · Cited by 54 · see citing works
PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats
Savić, M. M., Clayton, T., Furtmüller, R., Gavrilović, I., Samardžić, J., Savic, S. D., Huck, S., Sieghart, W., & Cook, J. M. (2008) · Brain Research · doi:10.1016/j.brainres.2008.02.020 · Cited by 54 · see citing works
The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system
Carta, M., Murru, L., Botta, P., Talani, G., SECHI, G., Deriu, P. L., Sanna, E., & Biggio, G. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.05.023 · Cited by 54 · see citing works
Ethanol Decreases Purkinje Neuron Excitability by Increasing GABA Release in Rat Cerebellar Slices
Mameli, M., Botta, P., Zamudio, P. A., Zucca, S., & Valenzuela, C. F. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.144865 · Cited by 51 · see citing works
Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine
Bullock, W. M., Bolognani, F., Botta, P., Valenzuela, C. F., & Perrone‐Bizzozero, N. I. (2009) · Neurochemistry International · doi:10.1016/j.neuint.2009.07.010 · Cited by 47 · see citing works
Alcohol Excites Cerebellar Golgi Cells by Inhibiting the Na+/K+ ATPase
Botta, P., de Souza, F. M. S., Sangrey, T., Schutter, E. D., & Valenzuela, C. F. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.76 · Cited by 46 · see citing works
Mechanisms Involved in the Reduction of GABAA Receptor α1-Subunit Expression Caused by the Epilepsy Mutation A322D in the Trafficking-competent Receptor
Bradley, C. A., Taghibiglou, C., Collingridge, G. L., & Wang, Y. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801708200 · Cited by 46 · see citing works
Corticotropin-Releasing Factor Increases Dihydropyridine- and Neurotoxin-Resistant Calcium Currents in Neurons of the Central Amygdala
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Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R–/– mice
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Synaptic Plasticity in the Central Nucleus of the Amygdala
Samson, R. D., Duvarci, S., & Paré, D. (2005) · Reviews in the Neurosciences · doi:10.1515/revneuro.2005.16.4.287 · Cited by 36 · see citing works
Behavioral effects after ibotenic acid, 6-OHDA and electrolytic lesions in the central amygdala nucleus of the rat
Jellestad, F. K., Markowska, A. L., Bakke, H. K., & Walther, B. T. (1986) · Physiology & Behavior · doi:10.1016/s0031-9384(86)80004-x · Cited by 34 · see citing works
Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the α6 GABAA Receptor Subunit
Botta, P., Mameli, M., Floyd, K. L., Radcliffe, R. A., & Valenzuela, C. F. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.127894 · Cited by 33 · see citing works
Associative structure of fear memory after basolateral amygdala lesions in rats.
Rabinak, C. A., & Maren, S. (2008) · Behavioral Neuroscience · doi:10.1037/a0012903 · Cited by 30 · cited 1× · see citing works
“35 manner (Zimmerman, Rabinak et al. 2007; Rabinak and Maren 2008).”
Sensory Learning Differentially Affects GABAergic Tonic Currents in Excitatory Neurons and Fast Spiking Interneurons in Layer 4 of Mouse Barrel Cortex
Urban‐Ciećko, J., Kossut, M. M., & Mozrzymas, J. W. (2010) · Journal of Neurophysiology · doi:10.1152/jn.00988.2009 · Cited by 28 · see citing works
Sensorimotor gating and anxiety: Prepulse inhibition following acute exercise
Duley, A. R., Hillman, C. H., Coombes, S. A., & Janelle, C. M. (2007) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2007.01.006 · Cited by 27 · see citing works
Selective Influence on Contextual Memory: Physiochemical Properties Associated with Selectivity of Benzodiazepine Ligands at GABAAReceptors Containing the α5 Subunit
Harris, D. L., Clayton, T., Cook, J. M., Sahbaie, P., Halliwell, R. F., Furtmüller, R., Huck, S., Sieghart, W., & DeLorey, T. M. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701433b · Cited by 27 · see citing works
Excitation of Rat Cerebellar Golgi Cells by Ethanol: Further Characterization of the Mechanism
Botta, P., de Souza, F. M. S., Sangrey, T., Schutter, E. D., & Valenzuela, C. F. (2011) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2011.01658.x · Cited by 20 · see citing works
Receptor binding and drug modulation in anxiety
Malizia, A. (2002) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(02)00105-0 · Cited by 13 · cited 1× · see citing works
“Generalized anxiety disorders, panic anxiety, but also sleep disturbances and epilepsy, including status epilepticus, are pathologies ameliorated by enhancing inhibitory neurotransmission largely mediated by γ-aminobutyric acid (GABA), acting through GABA type A receptors (GABAARs) in the central nervous system (Maliz…”
Acute ethanol exposure inhibits silencing of cerebellar Golgi cell firing induced by granule cell axon input
Botta, P., Zucca, A., & Valenzuela, C. F. (2014) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2014.00010 · Cited by 11 · see citing works
Histoautoradiographic detection of oxytocin- and vasopressin-binding sites in the amygdala of the rat.
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Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide
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“Previous studies involving genetic or systemic pharmacological manipulations leading to reduced or completely absent α 5 - mediated extrasynaptic inhibition revealed an improved performance in a number of cognitive learning tasks and mild anxiogenic behavior 22,26-28 .”
If it reduces stress (hormones), do it!
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Distribution of oxytocin- and vasopressin-binding sites in the rat extended amygdala: a histoautoradiographic study
Veinante, P., & Freund-Mercier, M.-J. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970707)383:3

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Inhibition in the amygdala anxiety circuitry
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A molecular mechanism for choosing alcohol over an alternative reward
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Central amygdala circuits modulate food consumption through a positive-valence mechanism
Douglass, A. M., Kucukdereli, H., Ponserre, M., Marković, M., Gründemann, J., Strobel, C., Morales, P. L. A., Conzelmann, K., Lüthi, A., & Klein, R. (2017) · Nature Neuroscience · doi:10.1038/nn.4623 · Cited by 257 · see citing works
New perspectives on central amygdala function
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Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders
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GABA tone regulation and its cognitive functions in the brain
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An emerging circuit pharmacology of GABAA receptors
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“For instance, a population of GABAergic neurons in the CeL which express protein kinase Cd (PKCd neurons) increase their spontaneous activity following fear conditioning [34], and are involved in fear generalization and anxiety (Figure 1D) [4].”
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Amygdala ensembles encode behavioral states
Gründemann, J., Bitterman, Y., Lu, T., Krabbe, S., Grewe, B. F., Schnitzer, M. J., & Lüthi, A. (2019) · Science · doi:10.1126/science.aav8736 · Cited by 223 · see citing works
International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans
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“In addition, evidence is accumulating that not only a2-containing receptor subtypes, but also a5- (Botta et al., 2015; Behlke et al., 2016)- or a4- and d-containing receptor subtypes (Marowsky and Vogt, 2014) contribute to the modulation of anxiety.”
Background
A Central Amygdala CRF Circuit Facilitates Learning about Weak Threats
Sanford, C. A., Soden, M. E., Baird, M. A., Miller, S. M., Schulkin, J. A., Palmiter, R. D., Clark, M., & Zweifel, L. S. (2016) · Neuron · doi:10.1016/j.neuron.2016.11.034 · Cited by 199 · see citing works
“12 Neuron 93, 1–15, January 4, 2017 synaptic GABA release onto PKCd neurons in the CeAL protects against fear generalization (Botta et al., 2015).”
The central extended amygdala in fear and anxiety: Closing the gap between mechanistic and neuroimaging research
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Adaptive disinhibitory gating by VIP interneurons permits associative learning
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Know safety, no fear
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A Corticotropin Releasing Factor Network in the Extended Amygdala for Anxiety
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“CeA as a potent driver of anxiety-like behavior in mice (Botta et al., 2015; McCall et al., 2015; Ahrens et al., 2018; Pliota et al., 2018).”
Background
Role of the bed nucleus of the stria terminalis in aversive learning and memoryPreprint
Goode, T. D., & Maren, S. (2017) · Learning & Memory · doi:10.1101/lm.044206.116 · Cited by 138 · see citing works
“Furthermore, BNST lesions can enhance discrimination between a CS+ and CS− (Duvarci et al. 2009; Radke 2009) by attenuating fear to the CS− (also, see Botta et al. 2015; De Bundel et al. 2016; Sanford et al. 2017).”
Background
An ACC–VTA–ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences
Song, Q., Wei, A., Xu, H., Gu, Y., Jiang, Y. Q., Dong, N., Zheng, C., Wang, Q., Gao, M., Sun, S., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-023-01519-w · Cited by 128 · see citing works
“The general methods for preparing ACC and VTA slices were similar to those described previously 68,69 .”
GABAA receptors as targets for treating affective and cognitive symptoms of depression
Lüscher, B., Maguire, J. L., Rudolph, U., & Sibille, E. L. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.06.009 · Cited by 118 · see citing works
Neural circuits and mechanisms involved in fear generalization: Implications for the pathophysiology and treatment of posttraumatic stress disorder
Lopresto, D., Schipper, P., & Homberg, J. R. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.10.009 · Cited by 117 · see citing works
Benzodiazepine Modulation of GABAA Receptors: A Mechanistic Perspective
Goldschen-Ohm, M. P. (2022) · Biomolecules · doi:10.3390/biom12121784 · Cited by 117 · see citing works
The promise and perils of causal circuit manipulations
Wolff, S. B. E., & Ölveczky, B. P. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.01.004 · Cited by 115 · see citing works
Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala
De Bundel, D., Zussy, C., Espallergues, J., Gerfen, C. R., Girault, J.-A., & Valjent, E. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.210 · Cited by 112 · see citing works
“Interestingly, a recent study demonstrated that optogenetic activation of CEl PKCδ+ cells during retrieval of fear memory was anxiogenic and promoted fear generalization (58).”
Background
The central nucleus of the amygdala and the construction of defensive modes across the threat-imminence continuum
Moscarello, J. M., & Penzo, M. A. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01130-5 · Cited by 112 · see citing works
New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System
Perucca, E., Bialer, M., & White, H. S. (2023) · CNS Drugs · doi:10.1007/s40263-023-01027-2 · Cited by 114 · see citing works
“GABAA receptors containing α5 subunits are thought to contribute to anxiolytic effects [37, 51].”
Background
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 120 · see citing works
“However, optogenetic activation of PKCδ+ cells in CeL can increase fear-cue generalization and can be anxiogenic [38].”
Background
Dopamine Neurons Reflect the Uncertainty in Fear Generalization
Jo, Y. S., Heymann, G., & Zweifel, L. S. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.028 · Cited by 107 · see citing works
“Based on previous observations that the CeA plays a key role in generalized fear responses (Botta et al., 2015; Sanford et al., 2017), and that dopamine signaling in the CeA regulates threat discrimination (De Bundel et al.”
Dissecting the Roles of GABA and Neuropeptides from Rat Central Amygdala CRF Neurons in Anxiety and Fear Learning
Pomrenze, M. B., Giovanetti, S. M., Maiya, R., Gordon-Fennell, A., Kreeger, L. J., & Messing, R. O. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.083 · Cited by 93 · see citing works
“Several Fos+ neurons in the CeA and oval BNST expressed protein kinase C δ (PKCδ), a marker for a subpopulation of non-CRF neurons that when activated can drive anxiety-like behaviors in mice (Botta et al., 2015).”
Background
Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice
Chen, D., Lou, Q., Song, X.-J., Kang, F., Liu, A., Zheng, C., Li, Y., Wang, D., Qun, S., Zhang, Z., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44704-6 · Cited by 101 · see citing works
“In particular, the central nucleus of the amygdala (CeA) serves as the primary output nucleus for amygdala functions, and its increased activity is well-established as a potent driver of anxiety-like behaviors in mice 1,18 – 20 .”
Modulation of anxiety and fear via distinct intrahippocampal circuits
Engin, E., Smith, K. S., Gao, Y., Nagy, D., Foster, R. A., Tsvetkov, E., Keist, R., Crestani, F., Fritschy, J.-M., Bolshakov, V. Y., et al. (2016) · eLife · doi:10.7554/elife.14120 · Cited by 91 · see citing works
“Anxiety and fear are regulated by overlapping but somewhat distinct circuits in the brain (e.g., Jennings et al., 2013, Kheirbek et al., 2013, Botta et al., 2015).”
BackgroundInfluential
Chronic pain–induced neuronal plasticity in the bed nucleus of the stria terminalis causes maladaptive anxiety
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 88 · see citing works
Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles
Prévot, T. D., Li, G., Vidojević, A., Misquitta, K. A., Fee, C., Santrač, A., Knutson, D. E., Stephen, M. R., Kodali, R., Zahn, N. M., et al. (2019) · Complex Psychiatry · doi:10.1159/000496086 · Cited by 83 · see citing works
Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis
Müller, C. P., Kalinichenko, L. S., Tiesel, J., Witt, M., Stöckl, T., Sprenger, E., Fuchser, J., Beckmann, J., Praetner, M., Huber, S. E., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1658-6 · Cited by 85 · see citing works
“An enhanced α5-GABAA-R function was shown to be associated with anxiety in animals [7] and humans [26].”
BackgroundMethod
Input-Specific Synaptic Location and Function of the α5 GABA A Receptor Subunit in the Mouse CA1 Hippocampal Neurons
Magnin, E., Francavilla, R., Amalyan, S., Gervais, É., David, L. S., Luo, X., & Topolnik, L. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0567-18.2018 · Cited by 81 · see citing works
“However, the cell-specific knock-down of this subunit in central amygdala uncovered the anxiety-related phenotypes (Botta et al., 2015), highlighting the cell- and circuit-specific mechanisms in the 5-GABAAR function.”
Background
Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress
Zhang, T. R., Larosa, A., Raddo, M.-E. D., Wong, V., Wong, A. S., & Wong, T. P. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1958-18.2019 · Cited by 84 · see citing works
Multimodal mapping of cell types and projections in the central nucleus of the amygdala
Wang, Y., Krabbe, S., Eddison, M., Henry, F. E., Fleishman, G. M., Lemire, A. L., Wang, L., Korff, W. L., Tillberg, P. W., Lüthi, A., et al. (2023) · eLife · doi:10.7554/elife.84262 · Cited by 75 · see citing works
“…Prkcd have been shown to be suppressed by conditioned stimuli predicting an aversive stimulus ( Haubensak et al., 2010 ), to modulate anxiety ( Botta et al., 2015 ; Cai et al., 2014 ; Griessner et al., 2021 ), and to suppress food intake associated with either satiety or illness ( Cai et al.,…”
Central amygdala micro-circuits mediate fear extinction
Whittle, N., Fadok, J., Macpherson, K. P., Nguyen, R., Botta, P., Wolff, S. B. E., Müller, C., Herry, C., Tovote, P., Holmes, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24068-x · Cited by 69 · see citing works
The Neurobiology of Dispositional Negativity and Attentional Biases to Threat: Implications for Understanding Anxiety Disorders in Adults and Youth
Shackman, A. J., Stockbridge, M. D., Tillman, R. M., Kaplan, C. M., Tromp, D., Fox, A. S., & Gamer, M. (2016) · Journal of Experimental Psychopathology · doi:10.5127/jep.054015 · Cited by 78 · see citing works
“Some of these sub-components promote rapid responses to immediate danger, some promote sustained responses in the face of novelty and uncertain threat, some support both kinds of response, and still others appear to dampen fear- and anxiety-related responses (Botta et al., 2015; Daniel & Rainnie, 2016; Davis et al., 2…”
Background
GAK and PRKCD are positive regulators of PRKN-independent mitophagy
Munson, M. J., Mathai, B. J., Ng, M. Y. W., Trachsel-Moncho, L., de la Ballina, L. R., Schultz, S. W., Aman, Y., Lystad, A. H., Singh, S., Singh, S. K., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26331-7 · Cited by 77 · see citing works
A functional switch in tonic GABA currents alters the output of central amygdala corticotropin releasing factor receptor-1 neurons following chronic ethanol exposure
Herman, M. A., Contet, C., & Roberto, M. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1267-16.2016 · Cited by 72 · see citing works
“Specific inhibitory microcircuits in the central amygdala govern different aspects of fear learning (Ciocchi et al., 2010), and extrasynaptic inhibition regulates the changes in excitability underlying the encoding of generalized fear or anxiety (Botta et al., 2015).”
Background
Intrinsic Circuits in the Lateral Central Amygdala
Hunt, S., Sun, Y., Kucukdereli, H., Klein, R., & Sah, P. (2017) · eNeuro · doi:10.1523/eneuro.0367-16.2017 · Cited by 74 · see citing works
Neuronal diversity of the amygdala and the bed nucleus of the stria terminalis
Beyeler, A., & Dabrowska, J. (2020) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-12-815134-1.00003-9 · Cited by 65 · see citing works
“Accordingly, optogenetic stimulation of PKCδ neurons increases anxiety-like behavior and fear generalization, and overall degree of fear generalization correlates with spontaneous activity of PKCδ neurons (Botta et al., 2015) (Fig.”
Background
Sex-dependent anti-stress effect of an α5 subunit containing GABAA receptor positive allosteric modulator
Piantadosi, S. C., French, B. J., Poe, M. M., Timić, T., Marković, B. D., Pabba, M., Seney, M. L., Oh, H., Orser, B. A., Savić, M. M., et al. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00446 · Cited by 67 · see citing works
“Moreover a recent study in the amygdala suggests that generalization of fear and anxiety is mediated by α5-subunit containing neurons in the central nucleus of the amygdala (Botta et al., 2015).”
Background
Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states
Hartley, N. D., Gaulden, A. D., Báldi, R., Winters, N. D., Salimando, G. J., Rosas-Vidal, L. E., Jameson, A. N., Winder, D. G., & Patel, S. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0528-7 · Cited by 66 · see citing works
Releasing the Cortical Brake by Non-Invasive Electromagnetic Stimulation? rTMS Induces LTD of GABAergic Neurotransmission
Lenz, M., & Vlachos, A. (2016) · Frontiers in Neural Circuits · doi:10.3389/fncir.2016.00096 · Cited by 67 · see citing works
“Indeed, a series of animal studies support the notion that decreased inhibition improves learning (Collinson et al., 2002, 2006; Botta et al., 2015), while increased GABAergic neurotransmission impairs learning and memory formation (Davis, 1979; Sanger and Joly, 1985; McNaughton and Morris, 1987;…”
Background
Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach–Avoidance Conflict Test
Korn, C. W., Vunder, J., Miró, J., Fuentemilla, L., Hurlemann, R., & Bach, D. R. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.01.018 · Cited by 67 · see citing works
An Amygdala Circuit Mediates Experience-Dependent Momentary Arrests during Exploration
Botta, P., Fushiki, A., Vicente, A. M., Hammond, L. A., Mosberger, A. C., Gerfen, C. R., Peterka, D. S., & Costa, R. M. (2020) · Cell · doi:10.1016/j.cell.2020.09.023 · Cited by 66 · see citing works
“Classical and recent studies demonstrated that electrical and optogenetic stimulation of the main output structure of the amygdala and CEA as well as direct optogenetic stimulation of different neuronal subtypes in this brain area induces unconditional immobility and a decrease in track length (Ciocchi et al., 2010; L…”
Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice
de León-Reyes, N. S., Díaz, P. S., Nogueira, R., Ruiz-Pino, A., Nomura, Y., de Solis, C. A., Schulkin, J. A., Asok, A., & Leroy, F. (2023) · Cell · doi:10.1016/j.cell.2023.08.010 · Cited by 67 · see citing works
“The pseudo-simultaneous data yielded a decoding performance even higher (79%).”
GABAergic implications in anxiety and related disorders
Arora, I., Mal, P., Arora, P., Paul, A., & Kumar, M. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150218 · Cited by 68 · see citing works
Cell-type specific parallel circuits in the bed nucleus of the stria terminalis and the central nucleus of the amygdala of the mouse
Ye, J., & Veinante, P. (2019) · Brain Structure and Function · doi:10.1007/s00429-018-01825-1 · Cited by 65 · see citing works
Central amygdala cells for learning and expressing aversive emotional memories
Li, B. (2018) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.09.012 · Cited by 64 · see citing works
Amygdala inhibitory neurons as loci for translation in emotional memories
Shrestha, P., Shan, Z., Mamcarz, M., Ruiz, K. S. A., Zerihoun, A. T., Juan, C.-Y., Herrero-Vidal, P., Pelletier, J., Heintz, N., & Klann, E. (2020) · Nature · doi:10.1038/s41586-020-2793-8 · Cited by 64 · see citing works
Compartmentalized dendritic plasticity during associative learning
d‘Aquin, S., Szőnyi, A., Mahn, M., Krabbe, S., Gründemann, J., & Lüthi, A. (2022) · Science · doi:10.1126/science.abf7052 · Cited by 60 · see citing works
“Consistent with this, somatic inhibition undergoes anatomical and functional plasticity upon FC, resulting in a network-wide remodeling of the excitation/inhibition balance (26, 40).”
Background
Embracing Complexity in Defensive Networks
Headley, D. B., Kanta, V., Kyriazi, P., & Paré, D. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.024 · Cited by 57 · see citing works
“It seems more promising to consider multiple variables such as stretch-attend behaviors, defecation, and the stimulus generalization of fear responses, which are more reliably correlated across rodent strains and species (Botta et al., 2015; O’Leary et al., 2013).”
Background
Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors
Luo, Z.-Y., Huang, L., Lin, S., Yin, Y., Jie, W., Hu, N.-Y., Hu, Y.-Y., Guan, Y., Liu, J., You, Q.-L., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.10.021 · Cited by 58 · see citing works
A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice
Behlke, L. M., Foster, R. A., Liu, J., Benke, D., Benham, R. S., Nathanson, A. J., Yee, B. K., Zeilhofer, H. U., Engin, E., & Rudolph, U. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.49 · Cited by 57 · see citing works
Corticotropin-Releasing Factor (CRF) and Addictive Behaviors
Roberto, M., Spierling, S. R., Kirson, D., & Zorrilla, E. P. (2017) · International review of neurobiology · doi:10.1016/bs.irn.2017.06.004 · Cited by 58 · see citing works
“For example, circuitry-specific changes in CeA processing have been implicated in conditioned fear (Haubensak et al., 2010) and in anxiety (Botta et al., 2015).”
Background
Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety
Chen, X., van Gerven, J., Cohen, A. F., & Jacobs, G. E. (2018) · Acta Pharmacologica Sinica · doi:10.1038/s41401-018-0185-5 · Cited by 56 · see citing works
Selective inhibition of extra-synaptic α5-GABA A receptors by S44819, a new therapeutic agent
Etherington, L. V., Mihalik, B., Pálvölgyi, A., Ling, I., Pallagi, K., Kertész, S., Varga, P., Gunn, B. G., Brown, A. R., Livesey, M. R., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.012 · Cited by 53 · see citing works
“Furthermore, a recent report identified a large tonic current mediated by α5-GABAARs in a sub-population of central amygdala neurons that was insensitive to gabazine, but was inhibited by picrotoxin and by L-655,708, an α5-GABAAR selective NAM, suggesting that these receptors spontaneously conduct anions (Botta et al.…”
Background
Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology
Castellano, D., Shepard, R. D., & Lü, W. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.616298 · Cited by 53 · see citing works
“For example, in the central amygdala (CeA), α5containing GABAARs are associated with anxiety-like behaviors in a cell-specific manner (Haubensak et al., 2010; Botta et al., 2015).”
BackgroundInfluential
Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron–astrocyte–microglia dysregulation
Yeung, R. K., Xiang, Z., Tsang, S., Li, R., Ho, T. Y. C., Li, Q., Hui, C.-K., Sham, P. C., Qiao, M.-Q., & Xue, H. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0176-9 · Cited by 51 · see citing works
Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation
Yuan, F., Jiang, H., Yin, H., Jiang, X., Jiao, F., Chen, S., Ying, H., Chen, Y., Zhai, Q., & Guo, F. (2020) · Nature Communications · doi:10.1038/s41467-020-16662-2 · Cited by 51 · see citing works
Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome
Martín, J. Z. D. S., Donato, C., Peixoto, J., Aguirre, A., Choudhary, V., Stasi, A. M. D., Lourenço, J., Potier, M., & Bacci, A. (2020) · eLife · doi:10.7554/elife.58731 · Cited by 49 · see citing works
“extrasynaptic expression is still debated (Ali and Thomson, 2008; Botta et al., 2015; Glykys and Mody, 2010; Hannan et al., 2020; Hausrat et al., 2015; Schulz et al., 2018; Serwanski et al., 2006), mediate dendritic synaptic inhibition from neocortical MCs (Ali and Thomson, 2008) and their hippocampal counterparts (th…”
Background
Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala
Samineni, V. K., Grajales‐Reyes, J. G., Grajales‐Reyes, G. E., Tycksen, E., Copits, B. A., Pedersen, C. E., Ankudey, E. S., Sackey, J. N., Sewell, S. B., Bruchas, M. R., et al. (2021) · eLife · doi:10.7554/elife.68130 · Cited by 50 · see citing works
Neuronal basis for pain-like and anxiety-like behaviors in the central nucleus of the amygdala
Chen, W., Lien, C., & Chen, C. (2021) · Pain · doi:10.1097/j.pain.0000000000002389 · Cited by 49 · see citing works
GABAA(δ) receptor hypofunction in the amygdala-hippocampal circuit underlies stress-induced anxiety
Qin, X., Pan, H., Huang, S.-H., Zou, J., Zheng, Z.-H., Liu, X., You, W.-J., Liu, Z.-P., Cao, J., Zhang, W.-H., et al. (2021) · 中国科学通报：英文版 · doi:10.1016/j.scib.2021.09.007 · Cited by 47 · see citing works
Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice
Liu, Z.-P., He, Q.-H., Pan, H., Xu, X., Chen, W., He, Y., Zhou, J., Zhang, W., Zhang, J., Ying, X.-P., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.06.022 · Cited by 45 · see citing works
“Both receptors have been recently shown to mediate tonic inhibition in PNs of the basal amygdala and INs of the central amygdala respectively (12,26).”
Bridging the Gap : Towards a cell-type specific understanding of neural circuits underlying fear behaviors
McCullough, K. M., Morrison, F. G., & Ressler, K. J. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.07.025 · Cited by 45 · see citing works
“Pursuing the observation that increases in tonic activity in PKCd-expressing (PKCd+) neurons strongly correlate with fear generalization, Botta et al. (2015) examined the contributions of PKCd+ neurons to acute fear responses and anxiety-like behaviors.”
Background
Disinhibition, an emerging pharmacology of learning and memory
Möhler, H., & Rudolph, U. (2017) · F1000Research · doi:10.12688/f1000research.9947.1 · Cited by 44 · see citing works
Distinct circuits in rat central amygdala for defensive behaviors evoked by socially signaled imminent versus remote danger
Andraka, K., Kondrakiewicz, K., Rojek-Sito, K., Ziegart-Sadowska, K., Meyza, K. Z., Nikolaev, T., Hamed, A., Kursa, M. B., Wójcik, M., Danielewski, K., et al. (2021) · Current Biology · doi:10.1016/j.cub.2021.03.047 · Cited by 42 · see citing works
Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology
Shackman, A. J., Fox, A. S., Oler, J. A., Shelton, S. E., Oakes, T. R., Davidson, R. J., & Kalin, N. H. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.132 · Cited by 39 · see citing works
“24 – 27 Imaging studies in monkeys demonstrate that activity in the extended amygdala predicts individual differences in freezing and other components of anxious temperament.”
Background
Neuronal cell types, projections, and spatial organization of the central amygdala
O’Leary, T. P., Kendrick, R. M., Bristow, B. N., Sullivan, K. E., Wang, L., Clements, J., Lemire, A. L., & Cembrowski, M. S. (2022) · iScience · doi:10.1016/j.isci.2022.105497 · Cited by 38 · see citing works
Distinct ventral hippocampal inhibitory microcircuits regulating anxiety and fear behaviors
Li, K., Koukoutselos, K., Sakaguchi, M., & Ciocchi, S. (2024) · Nature Communications · doi:10.1038/s41467-024-52466-4 · Cited by 41 · see citing works
AgRP neurons trigger long-term potentiation and facilitate food seeking
Wang, C., Zhou, W., He, Y., Yang, T., Xu, P., Yang, Y., Cai, X., Wang, J., Liu, H., Yu, M., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-020-01161-1 · Cited by 39 · see citing works
Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit
Stamenić, T. T., Poe, M. M., Rehman, S., Santrač, A., Divović, B., Scholze, P., Ernst, M. C., Cook, J. M., & Savić, M. M. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.09.016 · Cited by 38 · see citing works
“It is less clear how these results can be linked with the recent suggestions that generalization of fear and anxiety is mediated by α5-subunit containing neurons in the central nucleus of the amygdala, where reduced expression of α5-GABAARs was proved to be anxiogenic (Botta et al., 2015), or that the anxiolytic effec…”
BackgroundInfluential
A balancing act: the role of pro‐ and anti‐stress peptides within the central amygdala in anxiety and alcohol use disorders
Walker, L. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15301 · Cited by 37 · see citing works
“Optogenetic manipulations suggest these populations may have opposing roles in fear and anxiety- like behaviours (Botta et al., 2015; Cai et al., 2014; Fadok et al., 2017; Li et al., 2013).”
Background
Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours
Bourhy, L., Mazeraud, A., Costa, L. H. A., Levy, J., Rei, D., Hecquet, E., Gabanyi, I., Bozza, F. A., Chrétien, F., Lledo, P.-M., et al. (2022) · Brain · doi:10.1093/brain/awab475 · Cited by 37 · see citing works
An active inference perspective for the amygdala complex
Sladky, R., Kargl, D., Haubensak, W. E., & Lamm, C. (2023) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2023.11.004 · Cited by 37 · see citing works
Activation of the neural pathway from the dorsolateral bed nucleus of the stria terminalis to the central amygdala induces anxiety‐like behaviors
Yamauchi, N., Takahashi, D., Sugimura, Y. K., Kato, F., Amano, T., & Minami, M. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14165 · Cited by 35 · see citing works
“These microcircuits in the CeA may play an important role in the regulation of fear and anxiety (Botta et al., 2015; Ciocchi et al., 2010).”
Background
Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments
Forkuo, G. S., Guthrie, M. L., Yuan, N. Y., Nieman, A. N., Kodali, R., Jahan, R., Stephen, M. R., Yocum, G. T., Treven, M., Poe, M. M., et al. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00159 · Cited by 30 · see citing works
Cocaine and amphetamine regulated transcript (CART) signalling in the central nucleus of the amygdala modulates stress-induced alcohol seeking
Walker, L. C., Hand, L. J., Letherby, B., Huckstep, K. L., Campbell, E. J., & Lawrence, A. J. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-00807-4 · Cited by 29 · see citing works
κ Opioid Receptor-Dynorphin Signaling in the Central Amygdala Regulates Conditioned Threat Discrimination and Anxiety
Baird, M. A., Hsu, T. Y., Wang, R., Juarez, B., & Zweifel, L. S. (2020) · eNeuro · doi:10.1523/eneuro.0370-20.2020 · Cited by 28 · see citing works
“…heterogeneous and interconnected structure that has emerged as an important central regulator for the acquisition, consolidation, and expression of conditioned threat (Ciocchi et al., 2010; Haubensak et al., 2010; Li et al., 2013) and anxiety-related behavior (Tye et al., 2011; Botta et al., 2015).”
Background
Phosphatidylinositol-3-kinase and protein kinase C are involved in the pro-cognitive and anti-anxiety effects of phytohormone abscisic acid in rats
Naderi, R., Esmaeili‐Mahani, S., & Abbasnejad, M. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.09.089 · Cited by 28 · see citing works
Expanding the canon: An inclusive neurobiology of thalamic and subthalamic fear circuits
Venkataraman, A., & Dias, B. G. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109380 · Cited by 26 · see citing works
“Thalamic neurons compute experience-dependent information to facilitate fine tuning of cortical representations and enhance contrast between safety and danger (CS+ vs CS-) leading to appropriate balance between fear expression and inhibition.”
BackgroundInfluential
Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization
Scarlata, M., Lee, S. H., Lee, D., Kandigian, S. E., Hiller, A. J., Dishart, J. G., Mintz, G. E., Wang, Z., Coste, G., Mousley, A., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-43159-w · Cited by 26 · see citing works
The central extended amygdala guides survival-relevant tradeoffs: Implications for understanding common psychiatric disorders
Holley, D., & Fox, A. S. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104879 · Cited by 25 · see citing works
“Other studies have characterized a lateral Ce (CeL) microcircuit that gates conditioned freezing through projections to the medial Ce (CeM; Botta et al., 2015; Ciocchi et al., 2010; Haubensak et al., 2010).”
Background
A genetic link between discriminative fear coding by the lateral amygdala, dopamine, and fear generalization
Jones, G. L., Soden, M. E., Knakal, C. R., Lee, H. J., Chung, A. S., Merriam, E. B., & Zweifel, L. S. (2015) · eLife · doi:10.7554/elife.08969 · Cited by 24 · see citing works
“…generalized defensive responses to threat have been correlated with non-specific coding of cue information in the CeAl (Ciocchi et al., 2010), and activation of a specific population of CeAl neurons during discriminative fear conditioning results in response generalization (Botta et al., 2015).”
Background
Topographic representation of current and future threats in the mouse nociceptive amygdala
Bowen, A. J., Huang, Y. W., Chen, J., Pauli, J. L., Campos, C., & Palmiter, R. D. (2023) · Nature Communications · doi:10.1038/s41467-023-35826-4 · Cited by 24 · see citing works
NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation
Dodt, S., Widdershooven, N. V., Dreisow, M.-L., Weiher, L., Steuernagel, L., Wunderlich, F. T., Brüning, J. C., & Fenselau, H. (2024) · Nature Communications · doi:10.1038/s41467-024-49766-0 · Cited by 20 · see citing works
“Speci ﬁ cally, food intake was reduced by continuous photostimulation with a frequency of 5Hz and higher, a stimulation protocol that was found to evoke anxiety and feeding behavior 40,41 , while stimulating at 2.5Hz had no effect (Fig.”
Distinct Circuits From the Central Lateral Amygdala to the Ventral Part of the Bed Nucleus of Stria Terminalis Regulate Different Fear Memory
Zhu, Y., Xie, S., Peng, A.-B., Yu, X., Li, C., Fu, J., Shen, C.-J., Cao, S.-X., Zhang, Y., Chen, J., et al. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.08.022 · Cited by 19 · see citing works
Stress-induced anxiety-related behavior in mice is driven by enhanced excitability of ventral tegmental area GABA neurons
Mitten, E. H., Souders, A., de Velasco, E. M. F., & Wickman, K. (2024) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2024.1425607 · Cited by 20 · see citing works
“Restraint, social defeat, and conditioned shock stress can decrease GABA A R-dependent current amplitude in the amygdala (Suvrathan et al., 2014; Botta et al., 2015; Qin et al., 2022).”
Background
Behavioural pharmacology of the α5-GABA A receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models
Gacsályi, I., Móricz, K., Gigler, G., Wellmann, J., Nagy, K. E., Ling, I., Barkóczy, J., Haller, J., Lambert, J. J., Szénási, G., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.07.005 · Cited by 19 · see citing works
“Furthermore, recent work has highlighted the involvement of tonic, α5-GABAAR mediated inhibition in regulating the activity of PKCδ expressing neurons in the central amygdala (Botta et al., 2015), which is a key brain site for fear conditioning (Ciocchi et al., 2010).”
Influential
Behavioral characteristics of 5-HT2C receptor knockout mice: Locomotor activity, anxiety- and fear memory-related behaviors
Nebuka, M., Ohmura, Y., Izawa, S., Bouchekioua, Y., Nishitani, N., Yoshida, T., & Yoshioka, M. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112394 · Cited by 18 · see citing works
Pharmacological Signature and Target Specificity of Inhibitory Circuits Formed by Martinotti Cells in the Mouse Barrel Cortex
Donato, C., Victorino, D. B., Cabezas, C., Aguirre, A., Lourenço, J., Potier, M., Martín, J. Z. D. S., & Bacci, A. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1661-21.2022 · Cited by 19 · see citing works
Physiological and pharmacological properties of inhibitory postsynaptic currents mediated by α5β1γ2, α5β2γ2 and α5β3γ2 GABA A receptors
Chen, X., Keramidas, A., & Lynch, J. W. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.07.027 · Cited by 18 · see citing works
δ Subunit-containing GABAA receptor prevents overgeneralization of fear in adult mice
Zhang, W.-H., Zhou, J., Pan, H.-Q., Wang, X.-Y., Liu, W.-Z., Zhang, J.-Y., Yin, X.-P., & Pan, B.-X. (2017) · Learning & Memory · doi:10.1101/lm.045856.117 · Cited by 17 · see citing works
“presented at an interval of 40 sec (Botta et al. 2015).”
BackgroundInfluential
PKCδ-positive GABAergic neurons in the central amygdala exhibit tissue-type plasminogen activator: role in the control of anxiety
Douceau, S., Lemarchand, E., Hommet, Y., Lebouvier, L., Joséphine, C., Bemelmans, A., Maubert, E., Agin, V., & Vivien, D. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01455-4 · Cited by 17 · see citing works
“Accordingly, a previous study revealed that CeL PKCδ neuronal activity can modulate locomotor activity [56].”
Background
Persistent therapeutic effect of a novel α5-GABAA receptor antagonist in rodent preclinical models of vascular cognitive impairment
Gacsályi, I., Móricz, K., Gigler, G., Megyeri, K., Machado, P., & Antoni, F. A. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.015 · Cited by 17 · see citing works
Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons
Corder, K. M., Cortes, M. A., Bartley, A. F., Lear, S. A., Lubin, F. D., & Dobrunz, L. E. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200809 · Cited by 17 · see citing works
Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors
Zou, G., Chen, Q., Chen, K., Zuo, X., Ge, Y., Hou, Y., Pan, T., Pan, H., Liu, D., Zhang, L., et al. (2019) · iScience · doi:10.1016/j.isci.2019.08.018 · Cited by 18 · see citing works
Methyleugenol Potentiates Central Amygdala GABAergic Inhibition and Reduces Anxiety
Liu, Y., Fan, H.-R., Deng, S., Zhu, T., Yan, Y., Ge, W., Li, W., & Li, F. R. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.250779 · Cited by 17 · see citing works
“, 2011) such as fear and anxiety (Botta et al., 2015; Tovote et al., 2015) as well as induces pathologic anxiety traits (Shen et al.”
BackgroundMethodInfluential
To what extent is it possible to dissociate the anxiolytic and sedative/hypnotic properties of GABAA receptors modulators?
Chagraoui, A., Skiba, M., Thuillez, C., & Thibaut, F. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.08.001 · Cited by 16 · see citing works
“Moreover, anxiogenic-like effects have been reported in mice with conditional genetic deletion of α5 in the central nucleus of the amygdala (Botta et al., 2015) suggesting that the anxiolytic-like effects may involve, at least in part, modulation of the α5-GABAARs in this specific neuronal…”
Background

Modulating anxiety with extrasynaptic inhibition
Botta, P. (2014) · edoc (University of Basel) · doi:10.5451/unibas-006285666
Fear and anxiety generalization
Lewis, S. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn4032
Neuronal basis for pain-like and anxiety-like behaviors in the central nucleus of the amygdala
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A tonic for anxiety
Füzesi, T., & Bains, J. S. (2015) · Nature Neuroscience · doi:10.1038/nn.4118
Genetic dissection of an amygdala microcircuit that gates conditioned fear
Haubensak, W., Kunwar, P. S., Cai, H., Ciocchi, S., Wall, N. R., Ponnusamy, R., Biag, J., Dong, H.-W., Deisseroth, K., Callaway, E. M., et al. (2010) · Nature · doi:10.1038/nature09553 · Cited by 840 · see citing works

Authors: Botta, P., Demmou, L., Kasugai, Y., Markovic, M., Xu, C., Fadok, J. P., Lu, T., Poe, M. M., Xu, L., Cook, J. M., Rudolph, U., Sah, P., Ferraguti, F., & Lüthi, A.
Affiliations: University of Basel (CH)
Innsbruck Medical University (AT)
Friedrich Miescher Institute (CH)
University of Wisconsin–Milwaukee (US)
The University of Queensland (AU)
Harvard University (US)
Corresponding author: Lüthi, Andreas
ORCID: Botta, Paolo
Xu, Chun
Fadok, Jonathan P
Poe, Michael M
Cook, James M
Rudolph, Uwe
Sah, Pankaj
Ferraguti, Francesco
Lüthi, Andreas
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2015-08-31
Volume: 18
Issue: 10
Pages: 1493-1500
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.4102
PMC: PMC4607767
OpenAlex: W2157081213
Cited by: 192
References: 132
Citations by year: 2026: 13 · 2025: 14 · 2024: 17 · 2023: 15 · 2022: 18 · 2021: 15 · 2020: 16 · 2019: 17 · 2018: 29 · 2017: 16 · 2016: 16 · 2015: 6
FWCI: 13.41
Type: journal article
Language: en
Update notices: erratum (2015-11-25)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders: National Heart, Lung, and Blood Institute (R01HL118561)
National Institute of Mental Health (R01MH080006, R01MH096463)
National Institute of Neurological Disorders and Stroke (R01NS076517)
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 › Neurotransmitter Receptor Influence on Behavior
Keywords: anxiety, extrasynaptic inhibition, central amygdala, alpha5 GABA-A receptor, protein kinase C delta, fear generalization, aversive experience, neuronal excitability, optogenetics
MeSH terms: Amygdala, Animals, Anxiety, Conditioning, Classical, Disease Models, Animal, Immunohistochemistry, Male, Mice, Inbred C57BL, Neural Inhibition, Neurons, Stress, Psychological, Patch-Clamp Techniques, Mice, Protein Kinase C-delta, Gene Knockdown Techniques, Optogenetics

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