Abstract
The central amygdala has a rich repertoire of neuropeptides and neuropeptide receptors. The diverse ways in which they modulate neuronal activity and influence synaptic activity are discussed here mostly in the context of fear and anxiety-related behaviour but also with respect to nociception, hunger and satiety and chronic alcohol exposure that often come together with anxiety. It appears that neuropeptides exert rather specific effects on behaviour and physiology that can be quite different from the effects evoked by opto- or chemogenetical stimulation of the central amygdala neurons that synthesise them or express their receptors. Also, neuropeptides might work synergistically or antagonistically to fine-tune the final outcome of sensory processing in the central amygdala and bring about appropriate physiological and behavioural responses to threat. Taken together, we propose that neuropeptide signalling in the central amygdala mainly serves to establish or maintain emotional homeostasis in response to threatening and other sensory stimuli.

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Andero R, Dias BG, Ressler KJ (2014) A role for Tac2 , NkB, and Nk3 receptor in normal and Dysregulated fear memory consolidation. Neuron 83:444–454
Bajo M, Cruz MT, Siggins GR et al (2008) Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc Natl Acad Sci 105:8410–8415
Bernard JF, Bandler R (1998) Parallel circuits for emotional coping behaviour: new pieces in the puzzle. J Comp Neurol 401:429–436
Betley JN, Cao ZFH, Ritola KD, Sternson SM (2013) Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155:1337–1350
Beyer CE, Dwyer JM, Platt BJ et al (2010) Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation. Psychopharmacology 209:303–311
Bosch OJ (2005) Brain oxytocin correlates with maternal aggression: link to anxiety. J Neurosci 25:6807–6815
Brown MR, Gray TS (1988) Peptide injections into the amygdala of conscious rats: effects on blood pressure, heart rate and plasma catecholamines. Regul Pept 21:95–106
Cai H, Haubensak W, Anthony TE, Anderson DJ (2014) Central amygdala PKC-δ+ neurons mediate the influence of multiple anorexigenic signals. Nat Neurosci 17:1240–1248
Campos CA, Bowen AJ, Roman CW, Palmiter RD (2018) Encoding of danger by parabrachial CGRP neurons. Nature 555:617–622
Ciocchi S, Herry C, Grenier F et al (2010) Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468:277–282
Cruz MT, Herman MA, Kallupi M, Roberto M (2012) Nociceptin/orphanin FQ blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid release in central amygdala is enhanced after chronic ethanol exposure. Biol Psychiatry 71:666–676
Davidson S, Lear M, Shanley L et al (2011) Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism. Neuropsychopharmacology 36:2211–2221
Do-Monte FH, Quiñones-Laracuente K, Quirk GJ (2015) A temporal shift in the circuits mediating retrieval of fear memory. Nature 519:460–463
Donaldson ZR, Young LJ (2008) Oxytocin, vasopressin, and the neurogenetics of sociality. Science 322:900–904
Douglass AM, Kucukdereli H, Ponserre M et al (2017) Central amygdala circuits modulate food consumption through a positive-valence mechanism. Nat Neurosci 20:1384–1394
Duvarci S, Pare D (2014) Amygdala microcircuits controlling learned fear. Neuron 82:966–980
Fadok JP, Krabbe S, Markovic M et al (2017) A competitive inhibitory circuit for selection of active and passive fear responses. Nature 542:96–100
Gilpin NW, Misra K, Herman MA et al (2011) Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence. Biol Psychiatry 69:1091–1099
Gilpin NW, Roberto M (2012) Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence. Neurosci Biobehav Rev 36:873–888
Guzmán-Ramos K, Bermúdez-Rattoni F (2012) Interplay of amygdala and insular cortex during and after associative taste aversion memory formation. Rev Neurosci 23:463–471
Han JS, Adwanikar H, Li Z et al (2010) Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats. Mol Pain 6:1744-8069-6–10
Han S, Soleiman MT, Soden ME et al (2015) Elucidating an affective pain circuit that creates a threat memory. Cell 162:363–374
Haubensak W, Kunwar PS, Cai H et al (2010) Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468:270–276
Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuro-Psychopharmacol Biol Psychiatry 29:1201–1213
Hökfelt T (1991) Neuropeptides in perspective: the last ten years. Neuron 7:867–879
Huber D, Veinante P, Stoop R (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308:245–248
Iemolo A, Ferragud A, Cottone P, Sabino V (2015) Pituitary adenylate cyclase-activating peptide in the central amygdala causes anorexia and body weight loss via the melanocortin and the TrkB systems. Neuropsychopharmacology 40:1846–1855
Iemolo A, Seiglie M, Blasio A et al (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nucleus of the amygdala induces anxiety via melanocortin receptors. Psychopharmacology 233:3269–3277
Jin W-Y, Liu Z, Liu D, Yu L-C (2010) Antinociceptive effects of galanin in the central nucleus of amygdala of rats, an involvement of opioid receptors. Brain Res 1320:16–21
Johansen JP, Cain CK, Ostroff LE, LeDoux JE (2011) Molecular mechanisms of fear learning and memory. Cell 147:509–524
Keifer OP, Hurt RC, Ressler KJ, Marvar PJ (2015) The physiology of fear: reconceptualizing the role of the central amygdala in fear learning. Physiology 30:389–401
Knobloch HS, Charlet A, Hoffmann LC et al (2012) Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73:553–566
Ku Y-H, Tan L, Li L-S, Ding X (1998) Role of corticotropin-releasing factor and substance P in pressor responses of nuclei controlling emotion and stress. Peptides 19:677–682
Kuo D-Y, Yang S-F, Chu S-C et al (2010) The effect of protein kinase C-delta knockdown on anti-free radical enzyme and neuropeptide Y gene expression in phenylpropanolamine-treated rats. J Neurochem 114:1217–1230
Li H, Penzo MA, Taniguchi H et al (2013) Experience-dependent modification of a central amygdala fear circuit. Nat Neurosci 16:332–339
Li S-Y, Huo M-L, Wu X-Y et al (2017) Involvement of galanin and galanin receptor 1 in nociceptive modulation in the central nucleus of amygdala in normal and neuropathic rats. Sci Rep 7:15317
Lu Y-C, Chen Y-Z, Wei Y-Y et al (2015) Neurochemical properties of the synapses between the parabrachial nucleus-derived CGRP-positive axonal terminals and the GABAergic neurons in the lateral capsular division of central nucleus of amygdala. Mol Neurobiol 51:105–118
Manning M, Stoev S, Chini B et al (2008) Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. In: Neumann ID, Landgraf R (eds) Progress in brain research. Elsevier, pp 473–512
McCormick K, Baillie GS (2014) Compartmentalisation of second messenger signalling pathways. Curr Opin Genet Dev 27:20–25
Missig G, Mei L, Vizzard MA et al (2017) Parabrachial pituitary adenylate cyclase-activating polypeptide activation of amygdala endosomal extracellular signal–regulated kinase signaling regulates the emotional component of pain. Biol Psychiatry 81:671–682
Missig G, Roman CW, Vizzard MA et al (2014) Parabrachial nucleus (PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: implication for the sensory and behavioral effects of pain. Neuropharmacology 86:38–48
Namburi P, Beyeler A, Yorozu S et al (2015) A circuit mechanism for differentiating positive and negative associations. Nature 520:675–678
Narváez M, Millón C, Borroto-Escuela D et al (2015) Galanin receptor 2-neuropeptide Y Y1 receptor interactions in the amygdala lead to increased anxiolytic actions. Brain Struct Funct 220:2289–2301
Neugebauer V, Galhardo V, Maione S, Mackey SC (2009) Forebrain pain mechanisms. Brain Res Rev 60:226–242
Nie Z (2004) Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303:1512–1514
Penzo MA, Robert V, Li B (2014) Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala. J Neurosci 34:2432–2437
Penzo MA, Robert V, Tucciarone J et al (2015) The paraventricular thalamus controls a central amygdala fear circuit. Nature 519:455–459
Pleil KE, Rinker JA, Lowery-Gionta EG et al (2015) NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci 18:545–552
Rickenbacher E, Perry RE, Sullivan RM, Moita MA (2017) Freezing suppression by oxytocin in central amygdala allows alternate defensive behaviours and mother-pup interactions. eLife 6:e24080
Roberto M, Cruz MT, Gilpin NW et al (2010) Corticotropin releasing factor–induced amygdala gamma-aminobutyric acid release plays a key role in alcohol dependence. Biol Psychiatry 67:831–839
Rodrigues SM, Schafe GE, LeDoux JE (2004) Molecular mechanisms underlying emotional learning and memory in the lateral amygdala. Neuron 44:75–91
Roesler R, Kent P, Luft T et al (2014) Gastrin-releasing peptide receptor signaling in the integration of stress and memory. Neurobiol Learn Mem 112:44–52
Roesler R, Kent P, Schröder N et al (2012) Bombesin receptor regulation of emotional memory. Rev Neurosci 23:571–586
Sajdyk TJ, Shekhar A, Gehlert DR (2004) Interactions between NPY and CRF in the amygdala to regulate emotionality. Neuropeptides 38:225–234
Sanford CA, Soden ME, Baird MA et al (2017) A central amygdala CRF circuit facilitates learning about weak threats. Neuron 93:164–178
Schiff HC, Bouhuis AL, Yu K et al (2018) An insula–central amygdala circuit for guiding tastant-reinforced choice behavior. J Neurosci 38:1418–1429
Shi C-J, Cassell MD (1998) Cortical, thalamic, and amygdaloid connections of the anterior and posterior insular cortices. J Comp Neurol 399:440–468
Stoop R, Hegoburu C, van den BE (2015) New opportunities in vasopressin and oxytocin research: a perspective from the amygdala. Annu Rev Neurosci 38:369–388
Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11:823–836
Van den Burg EH, Stindl J, Grund T et al (2015) Oxytocin stimulates extracellular Ca2+ influx through TRPV2 channels in hypothalamic neurons to exert its anxiolytic effects. Neuropsychopharmacology 40:2938–2947
Veinante P, Freund-Mercier M-J (1997) Distribution of oxytocin- and vasopressin-binding sites in the rat extended amygdala: a histoautoradiographic study. J Comp Neurol 383:305–325
Viviani D, Charlet A, van den Burg E et al (2011) Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333:104–107
Watanabe MA, Kucenas S, Bowman TA et al (2010) Angiotensin II and CRF receptors in the central nucleus of the amygdala mediate hemodynamic response variability to cocaine in conscious rats. Brain Res 1309:53–65
Wilensky AE, Schafe GE, Kristensen MP, LeDoux JE (2006) Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J Neurosci 26:12387–12396
Wu X, Zhang J-T, Liu J et al (2015) Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats. J Neurochem 135:787–798
Yeung M, Treit D (2012) The anxiolytic effects of somatostatin following intra-septal and intra-amygdalar microinfusions are reversed by the selective sst2 antagonist PRL2903. Pharmacol Biochem Behav 101:88–92
Yu K, Ahrens S, Zhang X et al (2017) The central amygdala controls learning in the lateral amygdala. Nat Neurosci 20:1680–1685
Zhang S, Qi J, Li X et al (2015) Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons. Nat Neurosci 18:386–392
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EvdB is supported by a Swiss Federal grant from the Commission of Technology and Innovation.
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van den Burg, E.H., Stoop, R. Neuropeptide signalling in the central nucleus of the amygdala. Cell Tissue Res 375, 93–101 (2019). https://doi.org/10.1007/s00441-018-2862-6
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DOI: https://doi.org/10.1007/s00441-018-2862-6


