Hunger promotes fear extinction by activation of an amygdala microcircuit
Open accessAbstract
Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders.
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The Y4 receptor, which is mainly activated by peripheral PP, modulates anxiety and fear-related disorders in rodents.
“The Y 4 receptor, which is mainly activated by peripheral PP, modulates anxiety and fear-related disorders in rodents [174,185,186].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [185]
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Cites
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444 · see citing works
THE AMYGDALA MODULATES THE CONSOLIDATION OF MEMORIES OF EMOTIONALLY AROUSING EXPERIENCES
McGaugh, J. L. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144157 · Cited by 2,296 · see citing works
Effects of an expanding-spaced vs massed exposure schedule on fear reduction and return of fear
Rowe, M. K., & Craske, M. G. (1998) · Behaviour Research and Therapy · doi:10.1016/s0005-7967(97)10016-x · Cited by 1,778 · see citing works
Neural Mechanisms of Extinction Learning and Retrieval
Quirk, G. J., & Mueller, D. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301555 · Cited by 1,645 · see citing works
Ricardo, J. A., & Koh, E. T. (1978) · Brain Research · doi:10.1016/0006-8993(78)91125-3 · Cited by 1,362 · see citing works
Myers, K. M., & Davis, M. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001939 · Cited by 1,277 · see citing works
Pape, H.-C., & Pare, D. (2010) · Physiological Reviews · doi:10.1152/physrev.00037.2009 · Cited by 994 · see citing works
Deconstruction of a neural circuit for hunger
Atasoy, D., Betley, J. N., Su, H. H., & Sternson, S. M. (2012) · Nature · doi:10.1038/nature11270 · Cited by 969 · see citing works
Amygdala inhibitory circuits and the control of fear memory
Ehrlich, I., Humeau, Y., Grenier, F., Ciocchi, S., Herry, C., & Lüthi, A. (2009) · Neuron · doi:10.1016/j.neuron.2009.05.026 · Cited by 878 · see citing works
Parallel, Redundant Circuit Organization for Homeostatic Control of Feeding Behavior
Betley, J. N., Cao, Z. F. H., Ritola, K., & Sternson, S. M. (2013) · Cell · doi:10.1016/j.cell.2013.11.002 · Cited by 591 · see citing works
Genetic identification of a neural circuit that suppresses appetite
Carter, M. E., Soden, M. E., Zweifel, L. S., & Palmiter, R. D. (2013) · Nature · doi:10.1038/nature12596 · Cited by 587 · see citing works
Neuropeptide, Y, peptide YY and pancreatic polypeptide in the gut-brain axis
Holzer, P., Reichmann, F., & Farzi, A. (2012) · Neuropeptides · doi:10.1016/j.npep.2012.08.005 · Cited by 501 · see citing works
Neuronal circuits of fear extinction
Herry, C., Ferraguti, F., Singewald, N., Letzkus, J. J., Ehrlich, I., & Lüthi, A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07101.x · Cited by 484 · see citing works
Amygdala intercalated neurons are required for expression of fear extinction
Likhtik, E., Popa, D., Apergis-Schoute, J., Fidacaro, G. A., & Paré, D. (2008) · Nature · doi:10.1038/nature07167 · Cited by 474 · see citing works
Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation
Wu, Q., Boyle, M. P., & Palmiter, R. D. (2009) · Cell · doi:10.1016/j.cell.2009.04.022 · Cited by 465 · see citing works
From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior
Williams, K. W., & Elmquist, J. K. (2012) · Nature Neuroscience · doi:10.1038/nn.3217 · Cited by 421 · see citing works
Hippocampal Inactivation Disrupts the Acquisition and Contextual Encoding of Fear Extinction
Corcoran, K., Desmond, T., Frey, K., & Maren, S. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2246-05.2005 · Cited by 390 · see citing works
Bard, J., Walker, M. W., Branchek, T. A., & Weinshank, R. L. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.45.26762 · Cited by 377 · see citing works
Central amygdala PKC-δ+ neurons mediate the influence of multiple anorexigenic signals
Cai, H., Haubensak, W. E., Anthony, T. E., & Anderson, D. J. (2014) · Nature Neuroscience · doi:10.1038/nn.3767 · Cited by 369 · see citing works
Synaptic correlates of fear extinction in the amygdala
Amano, T., Ünal, Ç. T., & Paré, D. (2010) · Nature Neuroscience · doi:10.1038/nn.2499 · Cited by 369 · see citing works
The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y
Kask, A., Harro, J., von Hörsten, S., Redrobe, J. P., Dumont, Y., & Quirion, R. (2002) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(01)00066-5 · Cited by 358 · see citing works
Glucocorticoids reduce phobic fear in humans
Soravia, L. M., Heinrichs, M., Aerni, A., Maroni, C., Schelling, G., Ehlert, U., Roozendaal, B., & de Quervain, D. J. ‐. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509184103 · Cited by 357 · see citing works
Synaptic Mechanisms of Associative Memory in the Amygdala
Maren, S. (2005) · Neuron · doi:10.1016/j.neuron.2005.08.009 · Cited by 341 · see citing works
Neural bases of food-seeking: affect, arousal and reward in corticostriatolimbic circuits
BALLEINE, B. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.08.061 · Cited by 326 · see citing works
Hypothalamic Survival Circuits: Blueprints for Purposive Behaviors
Sternson, S. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.018 · Cited by 313 · see citing works
Hippocampal involvement in contextual modulation of fear extinction
Ji, J., & Maren, S. (2007) · Hippocampus · doi:10.1002/hipo.20331 · Cited by 297 · see citing works
Mueller, D., Porter, J. T., & Quirk, G. J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3248-07.2008 · Cited by 284 · see citing works
NPY and Y receptors: lessons from transgenic and knockout models
Lin, S., Boey, D., & Herzog, H. (2004) · Neuropeptides · doi:10.1016/j.npep.2004.05.005 · Cited by 282 · see citing works
Self-citationNeuronal circuits that regulate feeding behavior and metabolism
Sohn, J., Elmquist, J. K., & Williams, K. W. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.05.003 · Cited by 273 · see citing works
Doux, L. (2012) · doi:10.1016/b978-0-444-53860-4.00021-0 · Cited by 241 · see citing works
Hobin, J. A., Ji, J.-Z., & Maren, S. (2006) · Hippocampus · doi:10.1002/hipo.20144 · Cited by 211 · see citing works
To Favor Survival Under Food Shortage, the Brain Disables Costly Memory
Plaçais, P.-Y., & Préat, T. (2013) · Science · doi:10.1126/science.1226018 · Cited by 202 · see citing works
Robinson, M. J. F., Warlow, S. M., & Berridge, K. C. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2013-14.2014 · Cited by 180 · see citing works
Y4 receptor knockout rescues fertility in ob/ob micePreprint
Sainsbury, A., Schwarzer, C., Couzens, M., Jenkins, A. B., Oakes, S. R., Ormandy, C. J., & Herzog, H. (2002) · Genes & Development · doi:10.1101/gad.979102 · Cited by 170 · see citing works
Self-citationTasan, R. O., Nguyen, N. K., Weger, S., Sartori, S. B., Singewald, N., Heilbronn, R., Herzog, H., & Sperk, G. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0430-10.2010 · Cited by 152 · see citing works
Self-citationCan fear extinction be enhanced? A review of pharmacological and behavioral findings
Fitzgerald, P. J., Seemann, J. R., & Maren, S. (2013) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.12.007 · Cited by 152 · see citing works
Different Fear States Engage Distinct Networks within the Intercalated Cell Clusters of the Amygdala
Busti, D., Geracitano, R., Whittle, N., Dalezios, Y., Mańko, M., Kaufmann, W. A., Sätzler, K., Singewald, N., Capogna, M., & Ferraguti, F. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6100-10.2011 · Cited by 134 · see citing works
The Role of Neuropeptide Y in the Expression and Extinction of Fear-Potentiated Startle
Gutman, A. R., Yang, Y., Ressler, K. J., & Davis, M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2305-08.2008 · Cited by 134 · see citing works
Fasting Launches CRTC to Facilitate Long-Term Memory Formation in <i>Drosophila</i>
Hirano, Y., Masuda, T., Naganos, S., Matsuno, M., Ueno, K., Miyashita, T., Horiuchi, J., & Saitoe, M. (2013) · Science · doi:10.1126/science.1227170 · Cited by 129 · see citing works
NMDA receptors and fear extinction: implications for cognitive behavioral therapy
Davis, M. (2011) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2011.13.4/mdavis · Cited by 118 · see citing works
Physiological identification and infralimbic responsiveness of rat intercalated amygdala neurons
Amir, A., Amano, T., & Paré, D. (2011) · Journal of Neurophysiology · doi:10.1152/jn.00136.2011 · Cited by 110 · see citing works
Holmes, A., & Quirk, G. J. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.10.003 · Cited by 107 · see citing works
Medial prefrontal cortical innervation of the intercalated nuclear region of the amygdala
Pinard, C. R., Mascagni, F., & McDonald, A. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.036 · Cited by 90 · see citing works
Gehlert, D. R., Schober, D. A., Beavers, L. S., Gadski, R. A., Hoffman, J. A., Smiley, D. L., Chance, R. E., Lundell, I., & Larhammar, D. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09120-5 · Cited by 82 · see citing works
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 · see citing works
Self-citationBacchi, F., Mathé, A. A., Jiménez, P., Stasi, L. P., Arban, R., Gerrard, P. A., & Caberlotto, L. (2006) · Peptides · doi:10.1016/j.peptides.2006.07.020 · Cited by 79 · see citing works
Tasan, R. O., Lin, S., Hetzenauer, A., Singewald, N., Herzog, H., & Sperk, G. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2008.11.048 · Cited by 71 · cited 5× · see citing works
“Interestingly, Y4 receptors are highly expressed in the NTS and peripheral PP injection results in fast activation of NTS neurons (Tasan et al., 2009).”
InfluentialNPY controls fear conditioning and fear extinction by combined action on Y1 and Y2 receptors
Verma, D., Tasan, R. O., Herzog, H., & Sperk, G. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01872.x · Cited by 67 · see citing works
Self-citationLach, G., & de Lima, T. C. M. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.04.005 · Cited by 64 · see citing works
Self-citationFendt, M., Bürki, H., Imobersteg, S., Lingenhöhl, K., McAllister, K. H., Orain, D., Uzunov, D. P., & Chaperon, F. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1610-8 · Cited by 61 · see citing works
McGuire, J. F., Lewin, A. B., & Storch, E. A. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.934677 · Cited by 57 · cited 1× · see citing works
“…targeting the catecholaminergic system by yohimbine or L-DOPA but also release of stress hormones, such as glucocorticoids, have been shown to facilitate fear extinction learning in rodents and humans (Fitzgerald et al., 2014; Holmes and Quirk, 2010; McGuire et al., 2014; Soravia et al., 2006).”
Cardiac function in neuropeptide Y Y4 receptor-knockout mice
Smith-White, M. A., Herzog, H., & Potter, E. K. (2002) · Regulatory Peptides · doi:10.1016/s0167-0115(02)00160-x · Cited by 29 · see citing works
Self-citation
Flagged first, then by citations
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Lach, G., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2018) · Neurotherapeutics · doi:10.1007/s13311-017-0585-0 · Cited by 573 · see citing works
Self-citationNeuropeptide Y: a stressful review
Reichmann, F., & Holzer, P. (2016) · Neuropeptides · doi:10.1016/j.npep.2015.09.008 · Cited by 490 · see citing works
Gut hormones in microbiota-gut-brain cross-talk
Sun, L.-J., Li, J.-N., & Nie, Y.-Z. (2020) · Chinese Medical Journal · doi:10.1097/cm9.0000000000000706 · Cited by 145 · see citing works
Speed dependent descending control of freezing behavior in Drosophila melanogaster
Zacarias, R., Namiki, S., Card, G. M., Vasconcelos, M. L., & Moita, M. A. (2018) · Nature Communications · doi:10.1038/s41467-018-05875-1 · Cited by 106 · see citing works
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Diehl, M. M., Bravo-Rivera, C., & Quirk, G. J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.010 · Cited by 95 · see citing works
Fülling, C., Lach, G., Bastiaanssen, T. F. S., Fouhy, F., O'Donovan, A. N., Ventura-Silva, A.-P., Stanton, C., Dinan, T. G., & Cryan, J. F. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.02.013 · Cited by 36 · see citing works
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- Authors
- Verma, D., Wood, J., Lach, G., Herzog, H., Sperk, G., & Tasan, R.
- Affiliations
- Innsbruck Medical University (AT)
- Ministry of Education (BR)
- Garvan Institute of Medical Research (AU)
- Corresponding author
- Tasan, Ramon
- Venue
- Neuropsychopharmacology
- Published
- 2015-06-11
- Volume
- 41
- Issue
- 2
- Pages
- 431-439
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4579557
- OpenAlex
- W1608810417
- Cited by
- 69
- References
- 52
- Citations by year
- 2025: 11 · 2024: 4 · 2023: 7 · 2022: 2 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 4 · 2015: 4
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropsychopharmacology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (P22830)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- hunger, fear extinction, fasting, feedforward inhibition, basolateral amygdala, central amygdala, Y4 receptor, appetite, fear memory consolidation, anxiety disorders, exposure therapy, fear conditioning
- MeSH terms
- Amygdala, Animals, Appetite, Conditioning, Psychological, Extinction, Psychological, Fear, Food Deprivation, Hunger, Immunohistochemistry, Male, Memory, Short-Term, Mice, Inbred C57BL, Neural Inhibition, Neurons, Mental Recall, Receptors, Neuropeptide Y, Mice, Knockout, Tissue Culture Techniques, Memory, Long-Term
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