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New Research, Neuronal Excitability

Excitation of diverse classes of cholecystokinin interneurons in the basolateral amygdala facilitates fear extinction

Laura Rovira-Esteban, Ozge Gunduz-Cinar, Olena Bukalo, Aaron Limoges, Emma Brockway, Kinga Müller, Lief Fenno, Yoon Seok Kim, Charu Ramakrishnan, Tibor Andrási, Karl Deisseroth, Andrew Holmes and Norbert Hájos
eNeuro 21 October 2019, ENEURO.0220-19.2019; DOI: https://doi.org/10.1523/ENEURO.0220-19.2019
Laura Rovira-Esteban
1Laboratory of Network Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Science, 1083 Budapest, Hungary
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  • ORCID record for Laura Rovira-Esteban
Ozge Gunduz-Cinar
2Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20814, USA
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Olena Bukalo
2Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20814, USA
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Aaron Limoges
2Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20814, USA
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Emma Brockway
2Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20814, USA
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Kinga Müller
1Laboratory of Network Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Science, 1083 Budapest, Hungary
3János Szentágothai Doctoral School of Neurosciences, Semmelweis University, 1085 Budapest, Hungary
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Lief Fenno
4Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA
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Yoon Seok Kim
4Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA
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Charu Ramakrishnan
4Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA
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Tibor Andrási
1Laboratory of Network Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Science, 1083 Budapest, Hungary
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Karl Deisseroth
4Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA
5Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA
6Howard Hughes Medical Institute, Stanford University, Stanford, CA, 94305, USA
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Andrew Holmes
2Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20814, USA
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Norbert Hájos
1Laboratory of Network Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Science, 1083 Budapest, Hungary
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Abstract

There is growing evidence that interneurons orchestrate neural activity and plasticity in corticoamygdala circuits to regulate fear behaviors. However, defining the precise role of cholecystokinin-expressing interneurons (CCK INs) remains elusive due to the technical challenge of parsing this population from CCK-expressing principal neurons (CCK PNs). Here we used an intersectional genetic strategy in CCK-Cre;Dlx5/6-Flpe double-transgenic mice to study the anatomical, molecular and electrophysiological properties of CCK INs in the basal amygdala (BA) and optogenetically manipulate these cells in fear extinction. Electrophysiological recordings confirmed that this strategy targeted GABAergic cells and that a significant proportion expressed functional cannabinoid CB1 receptors; a defining characteristic of CCK-expressing basket cells. However, immunostaining showed that subsets of the genetically-targeted cells expressed either neuropeptide Y (NPY) (29%) or parvalbumin (PV) (17%), but not somatostatin (SOM) or CaMKII-α. Further morphological and electrophysiological analyses showed that four interneuron types could be identified among the EYFP-expressing cells: CCK/CB1R-expressing basket cells, neurogliaform cells, PV+ basket and PV+ axo-axonic cells. At the behavioral level, in vivo optogenetic photostimulation of the targeted population during extinction acquisition led to reduced freezing on a light-free extinction retrieval test, indicating extinction memory facilitation; whereas photosilencing was without effect. Conversely, non-selective (i.e., inclusive of INs and PNs) photostimulation or photosilencing of CCK-targeted cells, using CCK-Cre single-transgenic mice, impaired extinction. These data reveal an unexpectedly high degree of phenotypic complexity in a unique population of extinction-modulating BA INs.

Significance statement Distinct types of interneurons in the basolateral amygdala (BA) are known to control principal cell activity, allowing complex behaviors. Despite their importance, the role of cholecystokinin (CCK)-expressing inhibitory cells remains unknown. In this work, we could specifically alter the function of CCK-expressing interneurons in the BA by using an INTRSECT viral strategy. Using a combination of anatomical and electrophysiological methods, we found that CCK+ interneurons in the BA are comprised of CB1R-expressing basket cells, neurogliaform cells, parvalbumin-expressing basket as well as axo-axonic cells. Importantly, we provided the first direct evidence that CCK-expressing interneurons in the BA can modulate fear extinction learning. Our data thus show that CCK is expressed in functionally diverse interneuron populations, positioned to impact amygdala operation.

Footnotes

  • Authors report no conflict of interest.

  • Work supported by the NIAAA Intramural Research Program and by the National Research, Development and Innovation Office, Hungary (NKFIH K119742) and the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002).

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Excitation of diverse classes of cholecystokinin interneurons in the basolateral amygdala facilitates fear extinction
Laura Rovira-Esteban, Ozge Gunduz-Cinar, Olena Bukalo, Aaron Limoges, Emma Brockway, Kinga Müller, Lief Fenno, Yoon Seok Kim, Charu Ramakrishnan, Tibor Andrási, Karl Deisseroth, Andrew Holmes, Norbert Hájos
eNeuro 21 October 2019, ENEURO.0220-19.2019; DOI: 10.1523/ENEURO.0220-19.2019

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Excitation of diverse classes of cholecystokinin interneurons in the basolateral amygdala facilitates fear extinction
Laura Rovira-Esteban, Ozge Gunduz-Cinar, Olena Bukalo, Aaron Limoges, Emma Brockway, Kinga Müller, Lief Fenno, Yoon Seok Kim, Charu Ramakrishnan, Tibor Andrási, Karl Deisseroth, Andrew Holmes, Norbert Hájos
eNeuro 21 October 2019, ENEURO.0220-19.2019; DOI: 10.1523/ENEURO.0220-19.2019
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