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Amygdala circuitry mediating reversible and bidirectional control of anxiety
Open accessAbstract
Anxiety—a sustained state of heightened apprehension in the absence of immediate threat—becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)—achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA—exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA–CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.
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“without impaired locomotion (Supplementary Fig. 4)”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plain- Asserted: passes — The authors put it forward as true.
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“A higher proportion of CeL neurons expressed c-fos in the ChR2:BLA-CeA group relative to the eYFP:BLA-CeA group (F2,9=4.54, p=0.04)”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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“Illumination of BLA terminals in CeL elicited excitatory responses in both weakly- and strongly-connected CeL cells (n=16; Fig. 2c).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plaindirectn = 16- Asserted: passes — The authors put it forward as true.
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“in acute slices time-locked light-evoked excitatory responses were abolished upon bath application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline-2,3-dione (NBQX) and (2R)-amino-5-phosphonopentanoate (AP5) (Supplementary Fig. 10).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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“Indeed, we observed potent spiking inhibition in CeM cells upon illumination of BLA-CeL terminals (Fig. 2d; F2,11=15.35, p=0.004).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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“BLA somata inhibition did not induce an anxiogenic response, perhaps owing to the simultaneous decrease in direct BLA-CeM excitatory input.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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“as well as increased center time in the OFT (F1,105=24.46, p<0.00001; Fig. 1d,e), reflecting anxiety reduction”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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“Photostimulation of BLA terminals in the CeA (ChR2:BLA-CeA) increased open-arm time (F1,42=69.09, p<0.00001; Fig. 1b,c)”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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“Thus, the in vivo illumination of BLA-CeA projections that triggered acute anxiolysis was found to excite CeL neurons without activating all BLA somata nonspecifically.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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“the eNpHR3.0:BLA-CeA group showed elevated levels of c-fos expression, relative to the eYFP:BLA-CeA and eNpHR3.0:BLA(somata) groups, in the CeM (p<0.05; Supplementary Fig. 12)”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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In the paper
“Selective illumination of eNpHR3.0-expressing axon terminals reduced the probability of both spontaneously occurring (frequency: F1,8=32.99, p=0.00024; amplitude: F1,8=21.96, p=0.001; Supplementary Fig. 13) and electrically-evoked (F1,10=10.79, p=0.006; Fig. 4a) vesicle release, without preventing spiking at the soma (Supplementary Fig. 14).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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“Of the BLA neurons sampled (n=18, Supplementary Fig. 7); 44% projected to the CeL alone and 17% projected to the CeM alone, with only one cell observed to project to both the CeL and the CeM.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plainn = 18- Asserted: passes — The authors put it forward as true.
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“the very same CeM neurons (n=7) showed net excitation upon broad illumination of BLA inputs to the CeM (Fig. 2e), but showed net inhibition upon selective illumination of BLA inputs to the CeL (Fig. 2f).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“We also found that the eNpHR3.0:BLA-CeA group showed reduced open-arm time and probability of open-arm entry on EPM (F1,40=21.08, p<0.00001; and F1,40=19.93, p<0.00001, respectively; Fig. 4b,c) and center-time in the OFT (F1,100=18.919, p<0.00001; Fig. 4d,e) during photostimulation when compared to the eYFP and BLA(somata) groups, without altering locomotor activity”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
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In the paper
“The primary output region of the amygdala is the CeM23,24 which (when chemically or electrically excited) mediates autonomic and behavioral responses associated with fear and anxiety via projections to the brainstem25.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
What the sources say
- Not checked yetcites [23] Krettek, J. E. & Price, J. L. A description of the amygdaloid complex in the rat and cat with observations on intra-amygdaloid axonal connections. J. Comp. Neurol. 178, 255–279 (1978) source
- Not checked yetcites [24] Krettek, J. E. & Price, J. L. Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J. Comp. Neurol. 178, 225–253 (1978) source
- Not checked yetcites [25] Davis, M. in The Amygdala: A Functional Analysis (ed. Aggleton, J. P. ) 213–288 (Oxford Univ. Press, 2000) source
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In the paper
“our findings do not exclude downstream or parallel circuits including the BNST28, the insular and prefrontal cortices29, and the septal-hippocampal circuit30”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
What the sources say
- Not checked yetcites [28] Davis, M., Walker, D. L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010) source
- Not checked yetcites [29] Shin, L. M. & Liberzon, I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191 (2010) source
- Not checked yetcites [30] Gray, J. A. & McNaughton, N. The neuropsychology of anxiety: reprise. Nebr. Symp. Motiv. 43, 61–134 (1996)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Quantitative analyses of confocal images were performed with both staining and analysis blind to experimental condition.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Methods Summary > Opsin expression validation and immunohistochemistry
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In the paper
“but no detectable difference between the ChR2:BLA-CeA and eYFP:BLA-CeA groups, indicating that the bevelled cannula shielding effectively prevented BLA somata photostimulation.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“The BLA is primarily glutamatergic (~90%)20, 21 while the CeA, which encompasses the centrolateral (CeL) and centromedial (CeM) nuclei, consists of ~95% GABAergic medium spiny neurons22.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
What the sources say
- Not checked yetcites [20] Carlsen, J. Immunocytochemical localization of glutamate decarboxylase in the rat basolateral amygdaloid nucleus, with special reference to GABAergic innervation of amygdalostriatal projection neurons. J. Comp. Neurol. 273, 513–526 (1988) source
- Not checked yetcites [21] Smith, Y. & Pare, D. Intra-amygdaloid projections of the lateral nucleus in the cat: PHA-L anterograde labeling combined with postembedding GABA and glutamate immunocytochemistry. J. Comp. Neurol. 342, 232–248 (1994) source
- Not checked yetcites [22] McDonald, A. J. Cytoarchitecture of the central amygdaloid nucleus of the rat. J. Comp. Neurol. 208, 401–418 (1982) source
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In the paper
“Opsin expression was specific to BLA glutamatergic neurons, and was not observed in intercalated cells (Supplementary Fig. 6).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These data are consistent with reports implicating CeA involvement in anxiety9,11,12”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
What the sources say
- Not checked yetcites [9] Kalin, N. H., Shelton, S. E. & Davidson, R. J. The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate. J. Neurosci. 24, 5506–5515 (2004) source
- Not checked yetcites [11] Etkin, A., Prater, K. E., Schatzberg, A. F., Menon, V. & Greicius, M. D. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch. Gen. Psychiatry 66, 1361–1372 (2009) source
- Not checked yetcites [12] Lyons, A. M. & Thiele, T. E. Neuropeptide Y conjugated to saporin alters anxiety-like behavior when injected into the central nucleus of the amygdala or basomedial hypothalamus in BALB/cJ mice. Peptides 31, 2193–2199 (2010) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“for example, stress induces CeL release of corticotropin releasing hormone (CRH) in the BNST28.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
What the sources say
- Not checked yetcites [28] Davis, M., Walker, D. L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data demonstrate that the light-induced anxiolytic effects were caused by the activation of BLA-CeA synapses, and not attributable to BLA projections to distal targets passing through the CeA.”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“two well-validated27 anxiety assays: the elevated-plus maze (EPM) and the open-field test (OFT; Fig. 1a–e).”
§ Amygdala circuitry mediating reversible and bidirectional control of anxiety > Abstract
What the sources say
- Not checked yetcites [27] Carola, V., D’Olimpio, F., Brunamonti, E., Mangia, F. & Renzi, P. Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav. Brain Res. 134, 49–57 (2002) source
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In the citing paper
“Conventionally used AAV backbones which include a commonly used neuronal expression cassette composed of 1.3 kb CaMKIIα promoter (which shows comparable expression efficiency with 0.4 kb CaMKIIα promoter [10] used in CWB), WPRE, and human growth hormone polyadenylation signal [23-25] has a capacity of 2.4 kb.”
From Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons (2014) · cites this paper as [23]
Experimental — accuracy not yet measuredIn the citing paper
“In addition to a role in fear and threat conditioning, the amygdala also regulates anxiety.”
From A framework for understanding the emerging role of corticolimbic-ventral striatal networks in OCD-associated repetitive behaviors (2015) · cites this paper as Tye et al., 2011
In the citing paper
“This contrast notwithstanding, the neural systems implicated in anxiety by rodent studies are consistent with those identified in human patients26-34, underscoring the utility and translatability of these rodent studies.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [33]
In the citing paper
“Moreover, photoactivation of BLA somata increases measures of innate anxiety33, as well as learned inhibitory avoidance80.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [33]
In the citing paper
“For example, photostimulation of excitatory basolateral amygdala projections to central amygdala resulted in an acute anxiolytic effect that rapidly dissipated upon cessation of stimulation (Tye et al., 2011).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Tye et al., 2011
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Metadata
- Authors
- Tye, K. M., Prakash, R., Kim, S.-Y., Fenno, L. E., Grosenick, L., Zarabi, H., Thompson, K. R., Gradinaru, V., Ramakrishnan, C., & Deisseroth, K.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Deisseroth, Karl
- ORCID
- Venue
- Nature
- Published
- 2011-03
- Volume
- 471
- Issue
- 7338
- Pages
- 358-362
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3154022
- OpenAlex
- W2060978874
- Semantic Scholar
- ffc80185f7540e58c28aead0cf3752801f320eb3
- Cited by
- 1,289
- References
- 32
- Citations by year
- 2026: 62 · 2025: 73 · 2024: 86 · 2023: 73 · 2022: 76 · 2021: 97 · 2020: 91 · 2019: 84 · 2018: 85 · 2017: 70 · 2016: 100 · 2015: 97 · 2014: 92 · 2013: 76 · 2012: 87
- FWCI
- 47.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Institutes of Health (DP1OD000616)
- National Institute of Mental Health (F32MH088010, R01MH075957)
- National Institute on Drug Abuse (R01DA020794)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP2DK102256)
- 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, amygdala, central amygdala, basolateral amygdala, neural circuits, anxiolytic effects, bidirectional control, optogenetic stimulation, optogenetic inhibition, channelrhodopsin, halorhodopsin, fear memory, anxiety disorders, rats, mice
- MeSH terms
- Amygdala, Animals, Anxiety, Anxiety Disorders, Light, Models, Neurological, Neural Pathways, Neurons, Stress, Physiological, Synapses, Halorhodopsins, Mice
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