Long-range connectivity defines behavioral specificity of amygdala neurons
Open accessAbstract
Memories are acquired and encoded within large-scale neuronal networks spanning different brain areas. The anatomical and functional specificity of such long-range interactions and their role in learning is poorly understood. The amygdala and the medial prefrontal cortex (mPFC) are interconnected brain structures involved in the extinction of conditioned fear. Here, we show that a defined subpopulation of basal amygdala (BA) projection neurons targeting the prelimbic (PL) subdivision of mPFC is active during states of high fear, whereas BA neurons targeting the infralimbic (IL) subdivision are recruited, and exhibit cell-type-specific plasticity, during fear extinction. Pathway-specific optogenetic manipulations demonstrate that the activity balance between pathways is causally involved in fear extinction. Together, our findings demonstrate that, although intermingled locally, long-range connectivity defines distinct subpopulations of amygdala projection neurons and indicate that the formation of long-term extinction memories depends on the balance of activity between two defined amygdala-prefrontal pathways.
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There is a dorso-ventral topographic segregation of BLA input to the mPFC; more dorsal projections (to PL) encode threat-stimulating information while more ventral projections (to IL) encode threat extinction-related information.
“There is evidence to suggest that there is a dorso-ventral topographic segregation of BLA input to the mPFC; more dorsal projections (to PL) encode threat-stimulating information while more ventral projections (to IL) encode threat extinction-related information [51].”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [51]
Optogenetic excitation of BLA→dmPFC PNs increases conditioned fear after extinction.
“Moreover, optogenetic excitation of BLA→dmPFC PNs has been shown to increase conditioned fear after extinction (19).”
From Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner (2019) · cites this paper as [19]
Extinction of the learned fear association increases activity in basal amygdala neurons targeting the infralimbic cortex.
“By contrast, extinction of the learned fear association increases activity in basal amygdala neurons targeting the infralimbic cortex105.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [105]
During auditory fear conditioning, activity in basal amygdala neurons projecting to the prelimbic cortex is increased.
“During auditory fear conditioning, activity in basal amygdala neurons projecting to the prelimbic cortex is increased105”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [105]
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Viewpoints: Dialogues on the functional role of the ventromedial prefrontal cortex
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Neural circuits underlying a psychotherapeutic regimen for fear disorders
Baek, J., Lee, S., Cho, T., Kim, S.-W., Kim, M., Yoon, Y., Kim, K. K., Byun, J., Kim, S. J., Jeong, J., et al. (2019) · Nature · doi:10.1038/s41586-019-0931-y · Cited by 161 · see citing works
How the amygdala affects emotional memory by altering brain network properties.
Hermans, E., Battaglia, F., Atsak, P., de Voogd, L. D., Fernández, G., & Roozendaal, B. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.02.005 · Cited by 152 · see citing works
“…both cell classes project strongly to the medial prefrontal cortex, neurons activated during fear expression predominantly target the prelimbic subregion of the medial prefrontal cortex, while those activated during extinction selectively target the infralimbic subregion (Senn et al., 2014).”
BackgroundNassi, J. J., Cepko, C. L., Born, R. T., & Beier, K. T. (2015) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2015.00080 · Cited by 156 · see citing works
“Other strains, such as the HSV-1 strain H129 (Zemanick et al., 1991; Sun et al., 1996), appear to transmit transsynaptically only in the anterograde direction.”
MethodInfluentialSchubert, D., Martens, G. J. M., & Kolk, S. M. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.147 · Cited by 149 · see citing works
Sangha, S., Diehl, M. M., Bergstrom, H. C., & Drew, M. R. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.11.006 · Cited by 144 · see citing works
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“…of distinct cell groups that mediate different functions (e.g., Ashwell and Ito 2014; Burgos-Robles et al. 2013; Cole et al. 2013; Heidbreder and Groenewegen 2003; Knapska et al. 2012; Maeng and Shors 2013; Martinez et al. 2013; Mendoza et al. 2014; Senn et al. 2014; Swanson and Petrovich 1998).”
Prefrontal Cortex Drives Distinct Projection Neurons in the Basolateral Amygdala
McGarry, L. M., & Carter, A. G. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.046 · Cited by 141 · see citing works
“By preferentially activating AC and AH neurons, the PFC may be able to rapidly regulate behaviors associatedwith fear andanxiety (Felix-Ortiz et al., 2013, 2016; Herry et al., 2008; Likhtik et al., 2014; Senn et al., 2014).”
Afferents to anterior cingulate areas 24a and 24b and midcingulate areas 24a′ and 24b′ in the mouse
Fillinger, C., Yalçın, İ., Barrot, M., & Veinante, P. (2016) · Brain Structure and Function · doi:10.1007/s00429-016-1290-1 · Cited by 139 · see citing works
Basolateral amygdala circuitry in positive and negative valence
O’Neill, P.-K., Gore, F., & Salzman, C. D. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.02.012 · Cited by 139 · see citing works
Architectural Representation of Valence in the Limbic System
Namburi, P., Al‐Hasani, R., Calhoon, G. G., Bruchas, M. R., & Tye, K. M. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.358 · Cited by 133 · see citing works
“…that some of the projection-target-defined populations of BLA neurons are largely nonoverlapping, such as vHPC vs mPFC-projecting BLA neurons (Senn et al, 2014), whereas other projectiontarget-defined BLA neurons are largely overlapping, especially striatal and prefrontal cortex-projecting…”
BackgroundInfluentialControl of amygdala circuits by 5-HT neurons via 5-HT and glutamate cotransmission
Sengupta, A., Bocchio, M., Bannerman, D. M., Sharp, T., & Capogna, M. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2238-16.2016 · Cited by 136 · see citing works
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
“…or -inhibiting neurons within the amygdala (Vertes 2004; Quirk et al. 2006; Hoover and Vertes 2007; Herry et al. 2008; Knapska et al. 2012; Senn et al. 2014; Adhikari et al. 2015; Rozeske et al. 2015; Giustino and Maren 2015; Gourley and Taylor 2016)—processes that are regulated by the…”
BackgroundSynaptic encoding of fear memories in the amygdala
Ressler, R. L., & Maren, S. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.08.012 · Cited by 132 · see citing works
Prefrontal cortex reactivity underlies trait vulnerability to chronic social defeat stress
Kumar, S., Hultman, R. C., Hughes, D. N., Michel, N., Katz, B. M., & Dzirasa, K. (2014) · Nature Communications · doi:10.1038/ncomms5537 · Cited by 130 · see citing works
Prefrontal–Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder
Wolf, R. C., & Herringa, R. J. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.209 · Cited by 128 · see citing works
Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress
Perusini, J. N., Meyer, E. M., Long, V., Rau, V., Nocera, N. A., Avershal, J., Maksymetz, J., Spigelman, I., & Fanselow, M. S. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.224 · Cited by 128 · see citing works
Serotonin in fear conditioning processes
Bauer, E. P. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.028 · Cited by 127 · see citing works
Sex differences in fear extinction
Velasco, E. R., Florido, A., Milad, M. R., & Andero, R. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.020 · Cited by 125 · see citing works
“Moreover, BA projections to the ventral hippocampus, or the prelimbic cortex (PrL) promote fear expression, while BA projections to the infralimbic cortex (IL) promote fear inhibition (Herry et al., 2008; Knapska et al., 2012; Senn et al., 2014).”
BackgroundConnectivity characterization of the mouse basolateral amygdalar complex
Hintiryan, H., Bowman, I., Johnson, D. L., Korobkova, L., Zhu, M., Khanjani, N., Gou, L., Gao, L., Yamashita, S., Bienkowski, M. S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22915-5 · Cited by 121 · see citing works
Pathway-Selective Adjustment of Prefrontal-Amygdala Transmission during Fear Encoding
Arruda-Carvalho, M., & Clem, R. L. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2664-14.2014 · Cited by 127 · see citing works
“In addition, due to reciprocity of mPFC-BLA connectivity (Little and Carter, 2013; Senn et al., 2014), experiments should also examine whether BLA synapses onto mPFC neurons exhibit fear-related plasticity.”
Chen, Y.-H., Wu, J., Hu, N.-Y., Zhuang, J.-P., Li, W., Zhang, S.-R., Li, X.-W., Yang, J., & Gao, T. (2021) · Journal of Clinical Investigation · doi:10.1172/jci145692 · Cited by 123 · see citing works
Déjean, C., Courtin, J., Rozeske, R. R., Bonnet, M. C., Dousset, V., Michelet, T., & Herry, C. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.03.017 · Cited by 120 · see citing works
“Conversely, optogenetic activation or inhibition of BLA neurons projecting to the IL region reduced or promoted fear recovery (79).”
BackgroundAmygdala signaling during foraging in a hazardous environment
Amir, A., Lee, S.-C., Headley, D. B., Herzallah, M. M., & Pare, D. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.0407-15.2015 · Cited by 104 · see citing works
Intercalated amygdala clusters orchestrate a switch in fear state
Hagihara, K. M., Bukalo, O., Zeller, M., Aksoy‐Aksel, A., Karalis, N., Limoges, A., Rigg, T., Campbell, T. L., Mendez, A., Weinholtz, C. A., et al. (2021) · Nature · doi:10.1038/s41586-021-03593-1 · Cited by 113 · see citing works
Hübner, C., Bosch, D., Gall, A., Lüthi, A., & Ehrlich, I. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00064 · Cited by 115 · see citing works
Self-citationParaventricular Thalamus Balances Danger and Reward
Choi, E. A., & McNally, G. P. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3320-16.2017 · Cited by 115 · see citing works
“…respond to danger relies on amygdala, hippocampal, and prefrontal circuitries, among others, that encode fear associations (Maren and Quirk, 2004; Senn et al., 2014; Tovote et al., 2015) and interface with hypothalamic and brainstem circuitries for production of scalable defensive responses…”
BackgroundGiustino, T. F., Ramanathan, K. R., Totty, M. S., Miles, O. W., & Maren, S. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.1092-19.2019 · Cited by 110 · see citing works
CAV-2—why a canine virus is a neurobiologist's best friend
Junyent, F., & Kremer, E. J. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.08.004 · Cited by 111 · see citing works
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
Artificially Enhancing and Suppressing Hippocampus-Mediated Memories
Chen, B. K., Murawski, N. J., Cincotta, C., McKissick, O. P., Finkelstein, A. B., Hamidi, A., Merfeld, E., Doucette, E., Grella, S. L., Shpokayte, M., et al. (2019) · Current Biology · doi:10.1016/j.cub.2019.04.065 · Cited by 109 · see citing works
A Discrete Dorsal Raphe to Basal Amygdala 5-HT Circuit Calibrates Aversive Memory
Sengupta, A., & Holmes, A. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.029 · Cited by 112 · see citing works
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Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction
Dunsmoor, J. E., Kroes, M. C. W., Li, J., Daw, N. D., Simpson, H. B., & Phelps, E. A. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.2713-18.2019 · Cited by 110 · see citing works
Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening
Marcus, D. J., Bedse, G., Gaulden, A. D., Ryan, J. D., Kondev, V., Winters, N. D., Rosas-Vidal, L. E., Altemus, M., Mackie, K., Lee, F. S., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.024 · Cited by 104 · see citing works
“Consistent with these findings, activation of rodent basolateral amygdala (BLA) inputs to the prelimbic PFC (plPFC), a rodent homologue of the human dmPFC, generates anxiety-like behaviors and biases behavior toward fear responses in the face of uncertainty (Burgos-Robles et al., 2017; Felix-Ortiz et al., 2015; Senn e…”
Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress
Fitzgerald, P. J., Giustino, T. F., Seemann, J. R., & Maren, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1500682112 · Cited by 101 · see citing works
Active avoidance requires inhibitory signaling in the rodent prelimbic prefrontal cortex
Diehl, M. M., Bravo-Rivera, C., Rodríguez-Romaguera, J., Pagan-Rivera, P. A., Burgos-Robles, A., Roman-Ortiz, C., & Quirk, G. J. (2018) · eLife · doi:10.7554/elife.34657 · Cited by 102 · see citing works
Asede, D., Bosch, D., Lüthi, A., Ferraguti, F., & Ehrlich, I. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.008 · Cited by 101 · see citing works
Rodent models of impaired fear extinction
Singewald, N., & Holmes, A. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5054-x · Cited by 98 · see citing works
Martinelli, D. C., Chew, K. S., Rohlmann, A., Lum, M. Y., Ressl, S., Hattar, S. S., Brünger, A. T., Missler, M., & Südhof, T. C. (2016) · Neuron · doi:10.1016/j.neuron.2016.07.002 · Cited by 98 · see citing works
“For example, ‘‘fear neurons’’ project from the BLA to the prelimbic cortex and are active during fear training, while ‘‘extinction neurons’’ project from the BLA to the infralimbic cortex and are active during fear memory extinction training (Herry et al., 2008; Senn et al., 2014).”
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“Our findings indicate that increased BLA input to the IL detected during fear extinction (Senn et al., 2014) directly affects the activity of L5 IL-CP neurons, which target the ventral PAG (Ferreira et al., 2015).”
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Efferents of anterior cingulate areas 24a and 24b and midcingulate areas 24aʹ and 24bʹ in the mouse
Fillinger, C., Yalçın, İ., Barrot, M., & Veinante, P. (2017) · Brain Structure and Function · doi:10.1007/s00429-017-1585-x · Cited by 97 · see citing works
Oscillations Synchronize Amygdala-to-Prefrontal Primate Circuits during Aversive Learning
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Walker, A. G., Wenthur, C. J., Xiang, Z., Rook, J. M., Emmitte, K. A., Niswender, C. M., Lindsley, C. W., & Conn, P. J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416196112 · Cited by 94 · see citing works
Retrieving fear memories, as time goes by…
Monte, F. H. D., Quirk, G. J., Li, B., & Penzo, M. A. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.78 · Cited by 95 · see citing works
de Kloet, S. F., Bruinsma, B., Terra, H., Heistek, T. S., Passchier, E. M. J., van den Berg, A. R., Luchicchi, A., Min, R., Pattij, T., & Mansvelder, H. D. (2021) · Nature Communications · doi:10.1038/s41467-021-22260-7 · Cited by 93 · see citing works
Illuminating circuitry relevant to psychiatric disorders with optogenetics
Steinberg, E. E., Christoffel, D. J., Deisseroth, K., & Malenka, R. C. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.004 · Cited by 92 · see citing works
“Accordingly, optogenetic inhibition of IL-projecting neurons impaired extinction learning, while inhibition of PLprojecting neurons resulted in enhanced extinction learning [27].”
Background
- Authors
- Senn, V., Wolff, S. B. E., Herry, C., Grenier, F., Ehrlich, I., Gründemann, J., Fadok, J. P., Müller, C., Letzkus, J. J., & Lüthi, A.
- Affiliations
- University of Basel (CH)
- Friedrich Miescher Institute (CH)
- Corresponding author
- Lüthi, Andreas
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 81
- Issue
- 2
- Pages
- 428-437
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1977502547
- Cited by
- 522
- References
- 38
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 35 · 2023: 35 · 2022: 40 · 2021: 55 · 2020: 45 · 2019: 52 · 2018: 55 · 2017: 47 · 2016: 30 · 2015: 49 · 2014: 34
- FWCI
- 29.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- amygdala, medial prefrontal cortex, fear extinction, long-range connectivity, prelimbic cortex, infralimbic cortex, memory extinction, optogenetic manipulation, fear conditioning
- MeSH terms
- Channelrhodopsins, Acoustic Stimulation, Action Potentials, Amygdala, Analysis of Variance, Animals, Bacterial Proteins, Biophysics, Cell Count, Conditioning, Classical, Elapid Venoms, Electric Stimulation, Extinction, Psychological, Fear, Hippocampus, Light, Luminescent Proteins, Male, Neural Pathways, Neurons, Peptides, Time Factors, Oncogene Proteins v-fos, Prefrontal Cortex, Herpesvirus 1, Human, Patch-Clamp Techniques, Mice, Biophysical Phenomena, Optogenetics, In Vitro Techniques
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