Regulation of Fear Behavior by Microcircuits within the Mouse Amygdala
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Abstract
Background: The amygdala is a core structure in the mammalian brain that processes emotion and memory. Its complex neuronal composition and intricate microcircuit mechanisms play key roles in behaviors such as fear, anxiety, and reward. The diversity of neuronal types and the dynamics of these microcircuits provide the neural foundation for the encoding and extinction of fear memories.
Aim: This is a retrospective review article summarizing recent research on the amygdala and fear behavior in mice, which is of significant importance in helping people to comprehensively understand and recognize that the amygdala is the core regulator of fear behavior.
Methodology: An extensive and systematic search of electronic databases (Medline, PubMed, Web of Science) using keywords related to the amygdala and the technologies involved in the study such as “mouse amygdala,” “basolateral amygdala (BLA),” “central amygdala (CeA),” “fear extinction,” “fear learning,” and “microcircuits.” Articles meeting the selection criteria were included as candidate references.
Results: By integrating recent findings from optogenetics, chemogenetics, and single-cell sequencing, this review reveals the interactions between glutamatergic projection neurons and GABAergic interneurons in the amygdala, the functional division between subnuclei, and the neural basis of cross-brain area coordination. Additionally, it discusses the technical challenges in amygdala research and future directions, providing theoretical support for understanding the pathophysiology of emotional disorders.
Conclusion: The amygdala is intimately linked to emotional health, playing a critical role in understanding the mechanisms underlying the development of psychiatric disorders such as anxiety, depression, addiction, and post-traumatic stress disorder (PTSD). Despite advances in methodologies such as in vivo calcium imaging, neural circuit tracing, and electrophysiological techniques, which are progressively uncovering the underlying mechanisms of amygdalar regulation of emotional behaviors, the intrinsic microcircuitry of the amygdala remains highly complex. Significant gaps persist, necessitating further exploration and refinement to elucidate unresolved aspects of its functional architecture and behavioral modulation.
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Ledoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155-184. Available from: https://doi.org/10.1146/annurev.neuro.23.1.155
Krabbe S, Gründemann J, Lüthi A. Amygdala inhibitory circuits regulate associative fear conditioning. Biol Psychiatry. 2018;83(10):800-809. Available from: https://doi.org/10.1016/j.biopsych.2017.10.006
Maren S. Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala. Brain Res. 2015;1621:231-238. Available from: https://psycnet.apa.org/record/2014-53947-001
Herry C, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich I, Lüthi A. Neuronal circuits of fear extinction. Eur J Neurosci. 2010;31(4):599-612. Available from: https://doi.org/10.1111/j.1460-9568.2010.07101.x
Barad M, Gean P, Lutz B. The role of the amygdala in the extinction of conditioned fear. Biol Psychiatry. 2006;60(4):322-328. Available from: https://doi.org/10.1016/j.biopsych.2006.05.029
Paré D, Amano T, Unal CT. Synaptic correlates of fear extinction in the amygdala. Nat Neurosci. 2010;13(4):489-494. Available from: https://doi.org/10.1038/nn.2499
Ehrlich I, Humeau Y, Grenier F, et al. Amygdala inhibitory circuits and the control of fear memory. Neuron. 2009;62(6):757-771. Available from: https://doi.org/10.1016/j.neuron.2009.05.026
Lucas EK, Clem RL. GABAergic interneurons: The orchestra or the conductor in fear learning and memory? Brain Res Bull. 2018;141:13-19. Available from: https://doi.org/10.1016/j.brainresbull.2017.11.016
Duvarci S, Paré D. Amygdala microcircuits controlling learned fear. Neuron. 2014;82(5):966-980. Available from: https://doi.org/10.1016/j.neuron.2014.04.042
Namkung H, Thomas KL, Hall J, Sawa A. Parsing neural circuits of fear learning and extinction across basic and clinical neuroscience: Towards better translation. Neurosci Biobehav Rev. 2022;134:104502. Available from: https://doi.org/10.1016/j.neubiorev.2021.12.025
Warlow SM, Berridge KC. Incentive motivation: ‘Wanting’ roles of central amygdala circuitry. Behav Brain Res. 2021;411:113376. Available from: https://doi.org/10.1016/j.bbr.2021.113376
Hunt S, Sun Y, Kucukdereli H, Sah P. Intrinsic circuits in the lateral central amygdala. eNeuro. 2017;4(1):316-367. Available from: https://doi.org/10.1523/eneuro.0367-16.2017
Vereczki VK, Muller K, Krizsan E, Máté Z, Fekete Z, Rovira-Esteban L, et al. Total number and ratio of GABAergic neuron types in the mouse lateral and basal amygdala. J Neurosci. 2021;41(21):4575-4595. Available from: https://doi.org/10.1523/jneurosci.2700-20.2021
Yau JO, Chaichim C, Power JM, McNally GP. The roles of basolateral amygdala parvalbumin neurons in fear learning. J Neurosci. 2021;41(44):9223-9234. Available from: https://doi.org/10.1523/jneurosci.2461-20.2021
Esber GR, Holland PC. The basolateral amygdala is necessary for negative prediction errors to enhance cue salience, but not to produce conditioned inhibition. Eur J Neurosci. 2014;40(9):3328-3337. Available from: https://doi.org/10.1111/ejn.12695
Keifer OJ, Hurt RC, Ressler KJ, Marvar PJ. The physiology of fear: Reconceptualizing the role of the central amygdala in fear learning. Physiol (Bethesda). 2015;30(5):389-401. Available from: https://doi.org/10.1152/physiol.00058.2014
Hagihara KM, Bukalo O, Zeller M, Aksoy-Aksel A, Karalis N, Limoges A, et al. Intercalated amygdala clusters orchestrate a switch in fear state. Nature. 2021;594(7863):403-407. Available from: https://doi.org/10.1038/s41586-021-03593-1
Hájos N. Interneuron types and their circuits in the basolateral amygdala. Front Neural Circuits. 2021;15:687257. Available from: https://doi.org/10.3389/fncir.2021.687257
Polepalli JS, Gooch H, Sah P. Diversity of interneurons in the lateral and basal amygdala. NPJ Sci Learn. 2020;5:10. Available from: https://doi.org/10.1038/s41539-020-0071-z
Liu J, Hu T, Zhang M, Xu CY, Yuan MY, Li RX. Differential efferent projections of GABAergic neurons in the basolateral and central nucleus of amygdala in mice. Neurosci Lett. 2021;745:135621. Available from: https://doi.org/10.1016/j.neulet.2020.135621
Sun Y, Gooch H, Sah P. Fear conditioning and the basolateral amygdala [version 1; peer review: awaiting peer review]. F1000Research. 2020;9:53. Available from: https://doi.org/10.12688/f1000research.21201.1
Servonnet A, Hernandez G, El Hage C, Rompré PP, Samaha AN. Optogenetic activation of the basolateral amygdala promotes both appetitive conditioning and the instrumental pursuit of reward cues. J Neurosci. 2020;40(8):1732-1743. Available from: https://doi.org/10.1523/jneurosci.2196-19.2020
Zhang X, Kim J, Tonegawa S. Amygdala reward neurons form and store fear extinction memory. Neuron. 2020;105(6):1077-1093. Available from: https://doi.org/10.1016/j.neuron.2019.12.025
Choi K, Park K, Lee S, Yi JH, Woo C, Kang SJ, et al. Auditory fear conditioning facilitates neurotransmitter release at lateral amygdala to basal amygdala synapses. Biochem Biophys Res Commun. 2021;584:39-45. Available from: https://doi.org/10.1016/j.bbrc.2021.11.014
Spampanato J, Polepalli J, Sah P. Interneurons in the basolateral amygdala. Neuropharmacology. 2011;60(5):765-773. Available from: https://doi.org/10.1016/j.neuropharm.2010.11.006
Wolff SB, Grundemann J, Tovote P, Krabbe S, Jacobson GA, Müller C, et al. Amygdala interneuron subtypes control fear learning through disinhibition. Nature. 2014;509(7501):453-458. Available from: https://doi.org/10.1038/nature13258
McDonald AJ, Zaric V. Extrinsic origins of the somatostatin and neuropeptide Y innervation of the rat basolateral amygdala. Neuroscience. 2015;294:82-100. Available from: https://doi.org/10.1016/j.neuroscience.2015.03.004
Zimmerman JM, Maren S. NMDA receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian fear conditioning in rats. Eur J Neurosci. 2010;31(9):1664-1670. Available from: https://doi.org/10.1111/j.1460-9568.2010.07223.x
Morrison DJ, Rashid AJ, Yiu AP, Yan C, Frankland PW, Josselyn SA. Parvalbumin interneurons constrain the size of the lateral amygdala engram. Neurobiol Learn Mem. 2016;135:91-99. Available from: https://doi.org/10.1016/j.nlm.2016.07.007
Ciocchi S, Herry C, Grenier F, et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature. 2010;468(7321):277-282. Available from: https://doi.org/10.1038/nature09559
Duvarci S, Popa D, Paré D. Central amygdala activity during fear conditioning. J Neurosci. 2011;31(1):289-294. Available from: https://doi.org/10.1523/jneurosci.4985-10.2011
Watabe AM, Ochiai T, Nagase M, Takahashi Y, Sato M, Kato F. Synaptic potentiation in the nociceptive amygdala following fear learning in mice. Mol Brain. 2013;6:11. Available from: https://doi.org/10.1186/1756-6606-6-11
Yu K, Ahrens S, Zhang X, Schiff H, Ramakrishnan C, Fenno L, et al. The central amygdala controls learning in the lateral amygdala. Nat Neurosci. 2017;20(12):1680-1685. Available from: https://doi.org/10.1038/s41593-017-0009-9
Jo YS, Namboodiri VMK, Stuber GD, Zweifel LS. Persistent activation of central amygdala CRF neurons helps drive the immediate fear extinction deficit. Nat Commun. 2020;11(1):422. Available from: https://doi.org/10.1038/s41467-020-14393-y
Yang T, Yu K, Zhang X, et al. Plastic and stimulus-specific coding of salient events in the central amygdala. Nature. 2023;616(7957):510-519. Available from: https://doi.org/10.1038/s41586-023-05910-2
Hartley ND, Gaulden AD, Báldi R, Winters ND, Salimando GJ, Rosas-Vidal LE, et al. Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states. Nat Neurosci. 2019;22(12):2000-2012. Available from: https://doi.org/10.1038/s41593-019-0528-7
Whittle N, Fadok J, Macpherson KP, Nguyen R, Botta P, Wolff SBE, et al. Central amygdala micro-circuits mediate fear extinction. Nat Commun. 2021;12(1):4156. Available from: https://doi.org/10.1038/s41467-021-24068-x
Adke AP, Khan A, Ahn HS, Becker JJ, Wilson TD, Valdivia S, et al. Cell-Type Specificity of Neuronal Excitability and Morphology in the Central Amygdala. eNeuro. 2021;8(1). Available from: https://doi.org/10.1523/eneuro.0402-20.2020
Ressler RL, Maren S. Synaptic encoding of fear memories in the amygdala. Curr Opin Neurobiol. 2019;54:54-59. Available from: https://doi.org/10.1016/j.conb.2018.08.012
Ressler RL, Goode TD, Evemy C, Maren S. NMDA receptors in the CeA and BNST differentially regulate fear conditioning to predictable and unpredictable threats. Neurobiol Learn Mem. 2020;174:107281. Available from: https://doi.org/10.1016/j.nlm.2020.107281
Giovanniello J, Yu K, Furlan A, Nachtrab GT, Sharma R, Chen X, Li B. A Central Amygdala-Globus Pallidus Circuit Conveys Unconditioned Stimulus-Related Information and Controls Fear Learning. J Neurosci. 2020;40(47):9043-9054. Available from: https://doi.org/10.1523/jneurosci.2090-20.2020
Penzo MA, Robert V, Tucciarone J, De Bundel D, Wang M, Van Aelst L, et al. The paraventricular thalamus controls a central amygdala fear circuit. Nature. 2015;519(7544):455-459. Available from: https://doi.org/10.1038/nature13978
McCullough KM, Chatzinakos C, Hartmann J, Missig G, Neve RL, Fenster RJ, et al. Genome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning. Nat Commun. 2020;11(1):5180. Available from: https://doi.org/10.1038/s41467-020-18985-6
Kim J, Zhang X, Muralidhar S, LeBlanc SA, Tonegawa S. Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors. Neuron. 2017;93(6):1464-1479. Available from: https://doi.org/10.1016/j.neuron.2017.02.034
Douglass AM, Kucukdereli H, Ponserre M, Markovic M, Gründemann J, Strobel C, et al. Central amygdala circuits modulate food consumption through a positive-valence mechanism. Nat Neurosci. 2017;20(10):1384-1394. Available from: https://doi.org/10.1038/nn.4623
Yu K, Garcia Da Silva P, Albeanu DF, Li B. Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors. J Neurosci. 2016;36(24):6488-6496. Available from: https://doi.org/10.1523/jneurosci.4419-15.2016
Asede D, Bosch D, Lüthi A, Ferraguti F, Ehrlich I. Sensory Inputs to Intercalated Cells Provide Fear-Learning Modulated Inhibition to the Basolateral Amygdala. Neuron. 2015;86(2):541-554. Available from: https://doi.org/10.1016/j.neuron.2015.03.008
Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Paré D. Amygdala intercalated neurons are required for expression of fear extinction. Nature. 2008;454(7204):642-645. Available from: https://doi.org/10.1038/nature07167
Asede D, Doddapaneni D, Bolton MM. Amygdala Intercalated Cells: Gate Keepers and Conveyors of Internal State to the Circuits of Emotion. J Neurosci. 2022;42(49):9098-9109. Available from: https://doi.org/10.1523/jneurosci.1176-22.2022
Tovote P, Fadok JP, Lüthi A. Neuronal circuits for fear and anxiety. Nat Rev Neurosci. 2015;16(6):317-331. Available from: https://doi.org/10.1038/nrn3945
Choi DI, Kim J, Lee H, Kim JI, Sung Y, Choi JE, et al. Synaptic correlates of associative fear memory in the lateral amygdala. Neuron. 2021;109(17):2717-2726. Available from: https://doi.org/10.1016/j.neuron.2021.07.003
Bocchio M, Nabavi S, Capogna M. Synaptic Plasticity, Engrams, and Network Oscillations in Amygdala Circuits for Storage and Retrieval of Emotional Memories. Neuron. 2017;94(4):731-743. Available from: https://doi.org/10.1016/j.neuron.2017.03.022
Kasugai Y, Vogel E, Hörtnagl H, Schönherr S, Paradiso E, Hauschild M, et al. Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning. Neuron. 2019;104(4):781-794. Available from: https://doi.org/10.1016/j.neuron.2019.08.013
Izquierdo I, Furini CRG, Myskiw JC. Fear Memory. Physiol Rev. 2016;96(2):695-750. Available from: https://doi.org/10.1152/physrev.00018.2015
Butler CW, Wilson YM, Mills SA, Gunnersen JM, Murphy M. Evidence that a defined population of neurons in lateral amygdala is directly involved in auditory fear learning and memory. Neurobiol Learn Mem. 2020;168:107139. Available from: https://doi.org/10.1016/j.nlm.2019.107139
Perumal MB, Sah P. Inhibitory Circuits in the Basolateral Amygdala in Aversive Learning and Memory. Front Neural Circuits. 2021;15:633235. Available from: https://doi.org/10.3389/fncir.2021.633235
Ogden KK, Khatri A, Traynelis SF, Heldt SA. Potentiation of GluN2C/D NMDA Receptor Subtypes in the Amygdala Facilitates the Retention of Fear and Extinction Learning in Mice. Neuropsychopharmacology (New York, N.Y.). 2014;39(3):625-637. Available from: https://doi.org/10.1038/npp.2013.241
Courtin J, Bitterman Y, Müller S, Hinz J, Hinz J. A neuronal mechanism for motivational control of behavior. Science (New York, N.Y.). 2022;375(6576):eabg7277.378-389. Available from: https://doi.org/10.1126/science.abg7277
Chen APF, Chen L, Shi KW, Cheng E, Ge S, Xiong Q. Nigrostriatal dopamine modulates the striatal-amygdala pathway in auditory fear conditioning. Nat Commun. 2023;14(1):7231. Available from: https://doi.org/10.1038/s41467-023-43066-9
Botta P, Fushiki A, Vicente AM, Hammond LA, Mosberger AC. An Amygdala Circuit Mediates Experience-Dependent Momentary Arrests during Exploration. Cell. 2020;183(3):605-619.e22. Available from: https://doi.org/10.1016/j.cell.2020.09.023
Choi J, Lee YB, So D, So D, Kim JY. Cortical representations of affective pain shape empathic fear in male mice. Nat Commun. 2025. Available from: https://www.nature.com/articles/s41467-025-57230-w
Jimenez JC, Su K, Goldberg AR, Luna VM, Biane JS. Anxiety Cells in a Hippocampal-Hypothalamic Circuit. Neuron. 2018;97(3):670-683.e6. Available from: https://doi.org/10.1016/j.neuron.2018.01.016
Dalmay T, Abs E, Poorthuis RB, Hartung J, Pu DL. A Critical Role for Neocortical Processing of Threat Memory. Neuron. 2019;104(6):1180-1194.e7. Available from: https://doi.org/10.1016/j.neuron.2019.09.025
Shi Y, Wu X, Zhou J, Cui W, Wang J. Single-Nucleus RNA Sequencing Reveals that Decorin Expression in the Amygdala Regulates Perineuronal Nets Expression and Fear Conditioning Response after Traumatic Brain Injury. Adv Sci (Weinh). 2022;9(7):e2104112. Available from: https://doi.org/10.1002/advs.202104112
Li M, Yang X-K, Yang J, Li T-X, Cui C. Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells. Neuron. 2024. Available from: https://doi.org/10.1016/j.neuron.2024.06.026
Bourhy L, Bourhy L, Bourhy L, Mazeraud A, Mazeraud A. Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours. Brain. 2022. Available from: https://doi.org/10.1093/brain/awab475
Avolio E, Alo R, Mele M, Carelli A, Canonaco A, Bucarelli L, et al. Amygdalar excitatory/inhibitory circuits interacting with orexinergic neurons influence differentially feeding behaviors in hamsters. Behav Brain Res. 2012;234(1):91-99. Available from: https://doi.org/10.1016/j.bbr.2012.06.013
Kim J, Pignatelli M, Xu S, et al. Antagonistic negative and positive neurons of the basolateral amygdala. Nat Neurosci. 2016;19(12):1636-1646. Available from: https://doi.org/10.1038/nn.4414
Singh S, Topolnik L. Inhibitory circuits in fear memory and fear-related disorders. Front Neural Circuits. 2023;17:1122314. Available from: https://doi.org/10.3389/fncir.2023.1122314
Heinrichs SC, Leite-Morris KA, Guy MD, Goldberg LR, Young AJ, Kaplan GB. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice. Behav Brain Res. 2013;248:80-84. Available from: https://doi.org/10.1016/j.bbr.2013.03.048
Kwon OB, Lee JH, Kim HJ, Lee S, Lee S, Jeong MJ, et al. Dopamine Regulation of Amygdala Inhibitory Circuits for Expression of Learned Fear. Neuron. 2015;88(2):378-389. Available from: https://doi.org/10.1016/j.neuron.2015.09.001