Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala
Open accessAbstract
Molecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or 'Fear-Off' neurons during behaviour. We use cell-type-specific optogenetics and chemogenetics (DREADDs) to modulate activity in this population during behaviour to block or enhance fear extinction. Dissociated Thy1-eYFP neurons are isolated using FACS. RNA sequencing identifies genes strongly upregulated in RNA of this population, including Ntsr2, Dkk3, Rspo2 and Wnt7a. Pharmacological manipulation of neurotensin receptor 2 confirms behavioural effects observed in optogenetic and chemogenetic experiments. These experiments identify and validate Ntsr2-expressing neurons within the BLA, as a putative 'Fear-Off' population.
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R-Spondin 2 has been implied in the development of midbrain dopaminergic neurons and has been linked to fear extinction processes in the amygdala.
“R-Spondin 2 has been implied in the development of midbrain dopaminergic neurons (Gyllborg et al., 2018) and has been linked to fear extinction processes in the amygdala (McCullough et al., 2016).”
From Epigenome-wide DNA methylation in unipolar depression: predictive biomarker of antidepressant treatment response? (2024) · cites this paper as McCullough et al., 2016
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“On the other hand, different interneuronal subpopulations regulate the local amygdaloid circuitry (McDonald, 1982; Spampanato et al., 2011).”
BackgroundPan, H., Zhang, W., Liao, C.-Z., He, Y., Xiao, Z.-M., Qin, X., Liu, W.-Z., Wang, N., Zou, J., Liu, X., et al. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00299 · Cited by 16 · see citing works
“Previous studies have shown that activation of Thy1+ neurons in BLA (“fear-off” neurons) inhibits fear expression and promotes fear extinction (Jasnow et al., 2013; McCullough et al., 2016).”
BackgroundInfluentialDiminishing fear: Optogenetic approach toward understanding neural circuits of fear control
Luchkina, N. V., & Bolshakov, V. Y. (2017) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2017.05.005 · Cited by 15 · see citing works
Schiele, M. A., Crespo Salvador, O., Lipovsek, J., Schwarte, K., Schlosser, P., Zwanzger, P., Arolt, V., Baune, B. T., Köttgen, A., & Domschke, K. (2024) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae045 · Cited by 13 · see citing works
Identification of a stress-responsive subregion of the basolateral amygdala in male rats
Aukema, R. J., Petrie, G. N., Matarasso, A. K., Baglot, S. L., Molina, L. A., Füzesi, T., Kadhim, S., Nastase, A. S., Reyes, I. R., Bains, J. S., et al. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01927-x · Cited by 10 · see citing works
“It will be important to overlay function, connectivity, and molecular expression to identify molecular markers speci fi c to discrete subregions, which could then be pharmacologically targeted to in fl uence speci fi c behavioural or physiological processes [29, 31, 110 – 112].”
Narendra, S., Klengel, C., Hamzeh, B., Patel, D., Otten, J., Lardenoije, R., Newman, E. L., Miczek, K. A., Klengel, T., Ressler, K. J., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02231-2 · Cited by 8 · see citing works
“Chronic ethanol exposure increased Nts expression in the dorsal striatum [49], whereas ethanol decreased the expression of Nts receptors in both the nucleus accumbens (NAcc) and midbrain [50].”
BackgroundAukema, R. J., Petrie, G. N., Baglot, S. L., Gilpin, N. W., & Hill, M. N. (2024) · Neurobiology of Stress · doi:10.1016/j.ynstr.2024.100694 · Cited by 7 · see citing works
“Yet, this remains a critical gap in our understanding of stress-activated neurons in the BLA (McCullough et al., 2016a,b).”
Gilman, T. L., Dutta, S., Adkins, J. M., Cecil, C. A., & Jasnow, A. M. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.09.010 · Cited by 7 · see citing works
“reduced fear by inhibiting the consolidation of fear learning and by facilitating the consolidation of avoidance extinction (present study) and cued fear extinction (Jasnow et al., 2013; McCullough et al., 2016) - both of which require a consolidation period similar to reconsolidation.”
InfluentialAhlbrand, R., Wilson, A., Woller, P., Sachdeva, Y. S., Lai, J., Davis, N., Wiggins, J., & Sah, R. (2024) · Neurobiology of Stress · doi:10.1016/j.ynstr.2024.100617 · Cited by 5 · see citing works
“Previous work has reported segregated cell populations within the BLA that regulate “ high ” and “ low ” fear states (McCullough et al., 2016; Zhang et al., 2020), however, their contribution to CO 2 -evoked fear or differential engagement by sex is currently unknown.”
BackgroundNeuronal ensembles in the amygdala allow social information to motivate later decisions
Kietzman, H. W., Trinoskey-Rice, G., Seo, E. H., Guo, J., & Gourley, S. L. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.1848-23.2024 · Cited by 6 · see citing works
Synaptic organization and associative learning-related activity of basolateral amygdala interneurons
Báldi, R., Muthuswamy, S., Yasmin, F., Quadir, S. G., Zaidi, D., Kwon, M., Kandil, I. F., Johnson, K., Loomba, N., & Patel, S. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116295 · Cited by 5 · see citing works
Acute sleep deprivation reduces fear memories in male and female micePreprint
Foilb, A. R., Taylor-Yeremeeva, E. M., Schmidt, B. D., Ressler, K. J., & Carlezon, W. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.30.577985 · Cited by 5 · see citing works
Aukema, R. J., Petrie, G. N., Lau, B. K., Seabrook, L. T., Baglot, S. L., Christianson, J. P., Bains, J. S., Morena, M., Borgland, S. L., & Hill, M. N. (2025) · Science Advances · doi:10.1126/sciadv.adv3737 · Cited by 4 · see citing works
“Similarly, specific molecular markers may be common to multiple projection populations; for example, Thy1 + neurons in the BLA strongly project to the BST, PrL, and NAc while largely sparing projections to the CeA ( 33 ).”
Neurobiology of Posttraumatic Stress Disorder: Circuits, Genomics, and Treatment
Beatty, Z. G., Kearney, M. G., Ponomareva, O. Y., & Ressler, K. J. (2026) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-102124-033854 · Cited by 5 · see citing works
Physiological and Pathological Roles of NTSR2 in Several Organs and Diseases (Review)
Yang, Y., Zhang, W., Wei, K., Hu, F., Wu, S., Ma, Y., & Ouyang, Q. (2023) · Protein and Peptide Letters · doi:10.2174/0109298665267989231024064200 · Cited by 4 · see citing works
Projection-specific roles of basolateral amygdala Thy1 neurons in alcohol-induced place preference
Suh, J., Flanagan-Burt, Q. C., Moon, B. K., Pasqualini, A. L., Zambrano, M. A., & Ressler, K. J. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03184-w · Cited by 3 · see citing works
“Submandibular blood samples (30 – 50 ul) were collected from a subset of mice on Day 1 or Day 4 immediately upon conclusion of CPP procedure, and blood ethanol concentration (BEC) was determined using Analox Analyzer (Analox Instruments; courtesy of Klaus Miczek Laboratory).”
Ontogeny of the Corticolimbic System and the Risk of Anxiety Disorders in Adolescence
Дыгало, Н. Н. (2022) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-022-01235-1 · Cited by 2 · see citing works
Translating Across Circuits and Genetics Toward Progress in Fear- and Anxiety-Related Disorders
Ressler, K. J. (2021) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.19205 · Cited by 1 · see citing works
Multicolour optogenetics for studying the roles of cAMP and cGMP in synaptic plasticity and memory
Valencia, M. (2018) · TSpace (University of Toronto) · Cited by 1 · see citing works
Báldi, R., Muthuswamy, S., Loomba, N., & Patel, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.18.599631 · Cited by 1 · see citing works
Cardona-Jordan, K. M., Lay-Rivera, X. X., Cartagena-López, E., Bracho-Rincón, D. L., González-Bermejo, R., Monefeldt, G. A., Toro, J. P. G. D., Esquilin‐Rodriguez, C. J., Lloret-Torres, M. E., & Velázquez‐Marrero, C. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.25.620195 · Cited by 1 · see citing works
Narendra, S., Klengel, C., Hamzeh, B., Patel, D., Otten, J., Lardenoije, R., Newman, E. L., Miczek, K. A., Klengel, T., Ressler, K. J., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.07.459347
“Chronic ethanol exposure increased Nts expression in the dorsal striatum [41], whereas ethanol decreased the expression of Nts receptors in both the nucleus accumbens (NAcc) and midbrain [42].”
BackgroundAmygdala circuit mechanisms underlying alcohol seekingPreprint
Suh, J., Pasqualini, A. L., Zambrano, M. A., & Ressler, K. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.03.596970
“This is in addition to our prior work suggesting that this same population may serve as ‘Fear-off’ neurons that appear to suppress fear behavior and enhance fear extinction 19, 20 .”
BackgroundMethodResultInfluentialAnxiety and Trauma-Related Disorders
Jia, C., Li, H., & Tye, K. M. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780197640654.003.0039
Li, K., Liu, C., Wan, G., Zhang, L., Fan, R., Zhang, X., Su, Y., He, J., Liu, N., Guan, F., et al. (2025) · Animal Models and Experimental Medicine · doi:10.1002/ame2.70051
“10,11 Notably, NeuN ( Fox-3/Rbfox3 ) has remained the gold-standard marker for mature postmitotic neurons for over two decades, serving as a critical tool to assess neuronal functional integrity across both physiological and pathological contexts.”
The Role of the Immunoglobulin Superfamily of Cell Adhesion Molecules in Intellectual Disability
Zaman, N., Bui, K., & Sytnyk, V. (2026) · Cells · doi:10.3390/cells15191801
- Authors
- McCullough, K. M., Choi, D., Guo, J., Zimmerman, K., Walton, J., Rainnie, D. G., & Ressler, K. J.
- Affiliations
- Harvard University (US)
- Emory University (US)
- Corresponding author
- Ressler, Kerry J.
- Venue
- Nature Communications
- Published
- 2016-10-21
- Volume
- 7
- Issue
- 1
- Pages
- 13149-13149
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5078744
- OpenAlex
- W2532170155
- Cited by
- 51
- References
- 42
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 3
- FWCI
- 2.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (GM08605, P51OD011132)
- Yerkes National Primate Research Center, Emory University (P51RR000165)
- National Institute of Mental Health (R01MH096764, R01MH108665)
- National Institute of General Medical Sciences (T32GM008605)
- National Institute of Neurological Disorders and Stroke (T32NS096050)
- National Center for Research Resources (P51RR000165)
- 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
- CD90, basolateral amygdala, fear extinction, neurotensin receptor 2, optogenetics, chemogenetics, DREADD, cell type-specific gene expression, Wnt signaling, dissociated neurons, fear circuitry
- MeSH terms
- R-Spondins, Animals, Bacterial Proteins, Clozapine, Extinction, Psychological, Fear, Gene Expression Regulation, Injections, Intraventricular, Luminescent Proteins, Memory, Oligopeptides, Piperidines, Sensory Receptor Cells, Stereotaxic Techniques, Prefrontal Cortex, Sequence Analysis, RNA, Genes, Reporter, Receptors, Neurotensin, Thy-1 Antigens, Integrases, Thrombospondins, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Wnt Proteins, Mice, Optogenetics, Basolateral Nuclear Complex
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