Modulation of anxiety and fear via distinct intrahippocampal circuits
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Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus or CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry.
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Selective knockout of α2GABAARs in DG or CA3 principal neurons abolishes the anxiolytic-like effects of systemically administered diazepam.
“Selective knockout of α2GABAARs in DG or CA3 principal neurons abolishes the anxiolytic-like effects of systemically administered diazepam [43].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [43]
Reduction of α2GABAAR activity selectively in the DG improves spatial memory.
“Selective knockdown of α2GABAARs in CA1 pyramidal neurons improves contextual fear conditioning [43], whereas reduction of α2GABAAR activity selectively in the DG improves both object recognition [84] and spatial [50, 43] memory.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [43]
Selective knockdown of α2GABAARs in CA1 pyramidal neurons improves contextual fear conditioning.
“Selective knockdown of α2GABAARs in CA1 pyramidal neurons improves contextual fear conditioning [43], whereas reduction of α2GABAAR activity selectively in the DG improves both object recognition [84] and spatial [50, 43] memory.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [43]
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An emerging circuit pharmacology of GABAA receptors
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- Authors
- Engin, E., Smith, K. S., Gao, Y., Nagy, D., Foster, R. A., Tsvetkov, E., Keist, R., Crestani, F., Fritschy, J.-M., Bolshakov, V. Y., Hajos, M., Heldt, S. A., & Rudolph, U.
- Affiliations
- Harvard University (US)
- University of Tennessee Health Science Center (US)
- Section of Comparative Medicine, Yale School of Medicine, New Haven, United States
- Russian Academy of Sciences (RU)
- University of Zurich (CH)
- Corresponding author
- Engin, Elif
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-03-14
- Volume
- 5
- Pages
- e14120-e14120
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4816644
- OpenAlex
- W2300274411
- Cited by
- 91
- References
- 53
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 16 · 2020: 4 · 2019: 7 · 2018: 11 · 2017: 9 · 2016: 2
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute of Mental Health (MH080006, MH095905)
- Brain and Behavior Research Foundation (19266)
- 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 › Neural dynamics and brain function
- Keywords
- anxiety, fear, hippocampus, dentate gyrus, CA3, CA1 pyramidal neurons, conditional knockout, diazepam, hippocampal theta activity, double dissociation
- MeSH terms
- Animals, Anxiety, Brain Mapping, Fear, Hippocampus, Nerve Net, Receptors, GABA-A, Mice
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