GABAergic mechanisms regulated by miR-33 encode state-dependent fear
Open accessAbstract
Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning. We found that heightened activity of hippocampal extrasynaptic GABAA receptors, believed to impair fear and memory, actually enabled their state-dependent encoding and retrieval. This effect required protein kinase C-βII and was influenced by miR-33, a microRNA that regulates several GABA-related proteins. In the extended hippocampal circuit, extrasynaptic GABAA receptors promoted subcortical, but impaired cortical, activation during memory encoding of context fear. Moreover, suppression of retrosplenial cortical activity, which normally impairs retrieval, had an enhancing effect on the retrieval of state-dependent fear. These mechanisms can serve as treatment targets for managing access to state-dependent memories of stressful experiences.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
miR-33a suppresses several gamma-aminobutyric acid (GABA)-related proteins, thereby regulating state-dependent memory.
“In addition, miR-33a has been shown to suppress several gamma-aminobutyric acid (GABA)-related proteins, thereby regulating state-dependent memory 42) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [42]
The Results section reports that miR-33 overexpression reduced several GABA-related proteins and that miR-33 levels influenced the threshold for GABAA receptor–mediated state-dependent fear. Our copy calls the microRNA miR-33, however, and does not identify it specifically as miR-33a. (LLM, conf=0.80)
Experimental — accuracy not yet measuredHippocampal δGABAARs may be involved in state-dependency of learning and memory.
“There is some evidence that a global knockout of δGABAARs impairs discrimination learning [68], and that the hippocampal δGABAARs may be involved in state-dependency of learning and memory [82], both of which are suggestive of a role for δGABAARs in handling memory interference.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [82]
δGABAARs play a role in handling memory interference.
“There is some evidence that a global knockout of δGABAARs impairs discrimination learning [68], and that the hippocampal δGABAARs may be involved in state-dependency of learning and memory [82], both of which are suggestive of a role for δGABAARs in handling memory interference.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [82]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.617 · Cited by 12,052 · see citing works
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037/0735-7044.106.2.274 · Cited by 3,292 · see citing works
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037//0735-7044.106.2.274 · Cited by 3,262 · see citing works
Modality-Specific Retrograde Amnesia of Fear
Kim, J. J., & Fanselow, M. S. (1992) · Science · doi:10.1126/science.1585183 · Cited by 2,483 · see citing works
MiR-33 Contributes to the Regulation of Cholesterol Homeostasis
Rayner, K. J., Suárez, Y., Dávalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., & Fernández-Hernando, C. (2010) · Science · doi:10.1126/science.1189862 · Cited by 1,260 · see citing works
Abel, T., Nguyen, P. V., Barad, M., Deuel, T. A. S., Kandel, E. R., & Bourtchouladze, R. (1997) · Cell · doi:10.1016/s0092-8674(00)81904-2 · Cited by 1,217 · see citing works
Crouching as an index of fear.
Blanchard, R. J., & Blanchard, D. C. (1969) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0026779 · Cited by 1,077 · see citing works
GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition
Jacob, T. C., Moss, S. J., & Jurd, R. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2370 · Cited by 695 · see citing works
Extrasynaptic GABAA Receptors: Their Function in the CNS and Implications for Disease
Brickley, S. G., & Módy, I. (2012) · Neuron · doi:10.1016/j.neuron.2011.12.012 · Cited by 674 · see citing works
A Neural Circuit for Memory Specificity and Generalization
Xu, W., & Südhof, T. C. (2013) · Science · doi:10.1126/science.1229534 · Cited by 634 · see citing works
Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning
Impey, S., Smith, D. M., Obrietan, K. H., Donahue, R. J., Wade, C. B., & Storm, D. R. (1998) · Nature Neuroscience · doi:10.1038/2830 · Cited by 520 · see citing works
Dissociation and hypnotizability in posttraumatic stress disorder
(1988) · American Journal of Psychiatry · doi:10.1176/ajp.145.3.301 · Cited by 373 · see citing works
Maren, S., Aharonov, G., Stote, D. L., & Fanselow, M. S. (1996) · Behavioral Neuroscience · doi:10.1037//0735-7044.110.6.1365 · Cited by 372 · see citing works
Maren, S., Aharonov, G., Stote, D. L., & Fanselow, M. S. (1996) · Behavioral Neuroscience · doi:10.1037/0735-7044.110.6.1365 · Cited by 325 · see citing works
Bozon, B., Davis, S., & Laroche, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00674-3 · Cited by 317 · see citing works
Chandra, D., Jia, F., Liang, J., Peng, Z., Suryanarayanan, A., Werner, D. F., Spigelman, I., Houser, C. R., Olsen, R. W., Harrison, N. L., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604304103 · Cited by 315 · see citing works
Orsini, C. A., Kim, J. H., Knapska, E., & Maren, S. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4095-11.2011 · Cited by 315 · see citing works
Alcohol and Recall: State-Dependent Effects in Man
Goodwin, D. W., Powell, B. J., Bremer, D. A., Hoine, H., & Stern, J. A. (1969) · Science · doi:10.1126/science.163.3873.1358 · Cited by 289 · see citing works
Banigan, M. G., Kao, P. F., Kozubek, J. A., Winslow, A. R., Medina, J., Costa, J., Schmitt, A., Schneider, A., Cabral, H., Cagsal‐Getkin, O., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0048814 · Cited by 267 · see citing works
Davis, M. (1979) · Psychopharmacology · doi:10.1007/bf00426027 · Cited by 263 · see citing works
Ephus: multipurpose data acquisition software for neuroscience experiments
Suter, B. A. (2010) · Frontiers in Neural Circuits · doi:10.3389/fncir.2010.00100 · Cited by 255 · see citing works
Moreau, M. P., Bruse, S. E., David-Rus, R., Buyske, S., & Brzustowicz, L. M. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.09.039 · Cited by 249 · see citing works
Radulović, J., Kammermeier, J., & Spiess, J. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07452.1998 · Cited by 245 · see citing works
Sathyan, P., Golden, H. B., & Miranda, R. C. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1269-07.2007 · Cited by 245 · see citing works
Lal, A., Thomas, M. P., Altschuler, G. M., Navarro, F., O’Day, E. M., Li, X. L., Concepcion, C. P., Han, Y.-C., Thiery, J., Rajani, D. K., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002363 · Cited by 245 · see citing works
GABA Potency at GABAA Receptors Found in Synaptic and Extrasynaptic Zones
Mortensen, M., Patel, B., & Smart, T. G. (2012) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2012.00001 · Cited by 244 · see citing works
Fear-enhancing effects of septal oxytocin receptors
Guzmán, Y. F., Tronson, N. C., Jovasevic, V., Sato, K., Guedea, A. L., Mizukami, H., Nishimori, K., & Radulovic, J. (2013) · Nature Neuroscience · doi:10.1038/nn.3465 · Cited by 215 · see citing works
Self-citationThe brain-specific microRNA miR-128b regulates the formation of fear-extinction memory
Lin, Q., Wei, W., Coelho, C. M., Li, X., Baker-Andresen, D., Dudley, K., Ratnu, V. S., Boskovic, Z., Kobor, M. S., Sun, Y. E., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2891 · Cited by 200 · see citing works
Corcoran, K. A., Donnan, M. D., Tronson, N. C., Guzmán, Y. F., Gao, C., Jovasevic, V., Guedea, A. L., & Radulović, J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2107-11.2011 · Cited by 177 · see citing works
Self-citationState-Dependent Learned Valuation Drives Choice in an Invertebrate
Pompilio, L., Kacelnik, A., & Behmer, S. T. (2006) · Science · doi:10.1126/science.1123924 · Cited by 170 · see citing works
Isolation of microRNA targets using biotinylated synthetic microRNAs
Ørom, U. A., & Lund, A. H. (2007) · Methods · doi:10.1016/j.ymeth.2007.04.007 · Cited by 167 · see citing works
A genuine layer 4 in motor cortex with prototypical synaptic circuit connectivity
Yamawaki, N., Borges, K., Suter, B. A., Harris, K. D., & Shepherd, G. M. G. (2014) · eLife · doi:10.7554/elife.05422 · Cited by 141 · see citing works
Self-citationMicroRNA-182 Regulates Amygdala-Dependent Memory Formation
Griggs, E. M., Young, E. J., Rumbaugh, G., & Miller, C. A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2873-12.2013 · Cited by 140 · see citing works
Molecular regulation of cognitive functions and developmental plasticity: impact of GABAAreceptors
Möhler, H. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04454.x · Cited by 137 · see citing works
Conditioned responses in curarized striate muscle in dogs.
Girden, E., & Culler, E. (1937) · Journal of comparative psychology · doi:10.1037/h0058634 · Cited by 130 · see citing works
Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders
Penzes, P., Buonanno, A., Passafaro, M., Sala, C., & Sweet, R. A. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12261 · Cited by 125 · see citing works
Sengupta, J. N., Pochiraju, S., Kannampalli, P., Bruckert, M., Addya, S., Yadav, P., Miranda, A., Shaker, R., & Banerjee, B. (2012) · Pain · doi:10.1016/j.pain.2012.09.002 · Cited by 100 · see citing works
IQGAP1 Regulates NR2A Signaling, Spine Density, and Cognitive Processes
Gao, C., Frausto, S. F., Guedea, A. L., Tronson, N. C., Jovasevic, V., Leaderbrand, K., Corcoran, K. A., Guzmán, Y. F., Swanson, G. T., & Radulović, J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1300-11.2011 · Cited by 96 · see citing works
Self-citationScopolamine Selectively Disrupts the Acquisition of Contextual Fear Conditioning in Rats
Anagnostaras, S., Maren, S., & Fanselow, M. S. (1995) · Neurobiology of Learning and Memory · doi:10.1006/nlme.1995.0001 · Cited by 96 · see citing works
Merchán, F., Boualem, A., Crespi, M. D., et al. (2009) · Genome biology · doi:10.1186/gb-2009-10-12-r136 · Cited by 90 · see citing works
Historical context of state dependent learning and discriminative drug effects
Overton, D. A. (1991) · Behavioural Pharmacology · doi:10.1097/00008877-199109000-00002 · Cited by 88 · see citing works
Protein kinase C regulation of GABAA receptors
Song, M., & Messing, R. O. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4339-x · Cited by 79 · see citing works
Dissociative states in multiple personality disorder: A quantitative study
Silberman, E. K., Putnam, F. W., Weingartner, H., Braun, B. G., & Post, R. M. (1985) · Psychiatry Research · doi:10.1016/0165-1781(85)90062-9 · Cited by 67 · see citing works
Milenkovic, I., Vasiljevic, M., Maurer, D., Höger, H., Klausberger, T., & Sieghart, W. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.019 · Cited by 62 · see citing works
State dependent learning in humans
Bustamante, J. A., Jordán, A., Vila, M., et al. (1970) · Physiology & Behavior · doi:10.1016/0031-9384(70)90281-7 · Cited by 57 · see citing works
Zhao, C., Huang, C., Weng, T., Xiao, X., Mā, H., & Liu, L. (2012) · BMC Research Notes · doi:10.1186/1756-0500-5-91 · Cited by 51 · see citing works
Clinical implications of state-dependent learning
Reus, V. I., Weingartner, H., & Post, R. M. (1979) · American Journal of Psychiatry · doi:10.1176/ajp.136.7.927 · Cited by 51 · see citing works
Medrihan, L., Ferrea, E., Greco, B., Baldelli, P., & Benfenati, F. (2014) · Cerebral Cortex · doi:10.1093/cercor/bhu141 · Cited by 46 · see citing works
Paradoxical Fear-Increasing Effects of Tranquilizers: Evidence of Repression of Memory in the Rat
Stein, L., & Berger, B. D. (1969) · Science · doi:10.1126/science.166.3902.253 · Cited by 39 · see citing works
Huh, K. H., Guzmán, Y. F., Tronson, N. C., Guedea, A. L., Gao, C., & Radulović, J. (2009) · Learning & Memory · doi:10.1101/lm.1240109 · Cited by 35 · see citing works
Self-citationEvidence that mnesic states govern normal and disordered memory
Colpaert, F. C., Koek, W., & Slot, L. A. B. (2001) · Behavioural Pharmacology · doi:10.1097/00008877-200112000-00002 · Cited by 35 · see citing works
Piri, M., Rostampour, M., Nasehi, M., & Zarrindast, M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.08.003 · Cited by 24 · see citing works
Weafer, J. J., Gallo, D. A., & de Wit, H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090423 · Cited by 15 · see citing works
Drug-induced state-dependent learning
Koek, W. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e328348ed3b · Cited by 12 · see citing works
Long-term climbing fibre activity induces transcription of microRNAs in cerebellar Purkinje cells
Barmack, N. H., Qian, Z., & Yakhnitsa, V. (2014) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0508 · Cited by 10 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [48]Franklin K Paxinos G The Mouse Brain in Stereotaxic Coordinates Elsevier 2004
Cited by
Sorted by citations
An emerging circuit pharmacology of GABAA receptors
Engin, E., Benham, R. S., & Rudolph, U. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.04.003 · Cited by 225 · see citing works
Price, N. L., Singh, A. K., Rotllan, N., Goedeke, L., Wing, A., Canfrán-Duque, A., Diaz-Ruiz, A., Araldi, E., Baldán, Á., Camporez, J.-P., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.074 · Cited by 110 · see citing works
Maurel, O. M., Torrisi, S. A., Barbagallo, C., Purrello, M., Salomone, S., Drago, F., Ragusa, M., & Leggio, G. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105157 · Cited by 44 · see citing works
Radulovic, J., Lee, R., & Ortony, A. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00259 · Cited by 26 · see citing works
microRNA-33 controls hunger signaling in hypothalamic AgRP neurons
Price, N. L., Fernández-Tussy, P., Varela, L., Cardelo, M. P., Shanabrough, M., Aryal, B., de Cabo, R., Suárez, Y., Horvath, T. L., & Fernández-Hernando, C. (2024) · Nature Communications · doi:10.1038/s41467-024-46427-0 · Cited by 25 · see citing works
“Other studies have shown that miR-33 in speci fi c subsetsofneuronscanregulatestatedependentmemoryandadaptive thermogenesis through repression of gamma-aminobutyric acid (GABA) A receptor subunits, but an impact on obesity was not observed 37,38 .”
BackgroundHorie, T., Baba, O., Nishino, T., Yamashita, Y., Tsujisaka, Y., & Ono, K. (2026) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv22045 · Cited by 5 · see citing works
- Authors
- Jovasevic, V., Corcoran, K. A., Leaderbrand, K., Yamawaki, N., Guedea, A. L., Chen, H. J., Shepherd, G. M. G., & Radulovic, J.
- Affiliations
- Northwestern University (US)
- Venue
- Nature Neuroscience
- Published
- 2015-08-17
- Volume
- 18
- Issue
- 9
- Pages
- 1265-1271
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4880671
- OpenAlex
- W1187096858
- Cited by
- 88
- References
- 55
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 16 · 2017: 14 · 2016: 8 · 2015: 3
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Yale University
- Northwestern University
- National Institutes of Health (NS061963)
- National Institute of Mental Health (R01MH078064, MH-078064)
- National Institute of Neurological Disorders and Stroke (NS061963, R01NS061963, NS087479, R21NS087479, R37NS061963)
- 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
- contextual fear conditioning, extrasynaptic GABAA receptors, miR-33, protein kinase C beta II, hippocampus, retrosplenial cortex, memory retrieval, memory encoding, microRNA regulation, anxiety disorders
- MeSH terms
- Animals, Conditioning, Psychological, Dose-Response Relationship, Drug, Fear, Hippocampus, Isoxazoles, Male, Mice, Inbred C57BL, Organ Culture Techniques, Receptors, GABA-A, GABA Agonists, MicroRNAs, Mice, GABAergic Neurons
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
