EXCITATION OF DIVERSE CLASSES OF CHOLECYSTOKININ-EXPRESSING INTERNEURONS IN THE BASAL AMYGDALA FACILITATES FEAR EXTINCTION
01/29/2020
Kinga Müller1, 3, Laura Rovira-Esteban1, Tibor Andrási1, Ozge Gunduz-Cinar2, Aaron Limoges2, Emma Brockway2, Lief Fenno4, Yoon Seok Kim4, Charu Ramakrishnan4, Karl Deisseroth4, Andrew Holmes2, Norbert Hájos1
1 Institute of Experimental Medicine, Hungarian Academy of Sciences;
2 National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA;
3 János Szentágothai School of Neurosciences, Semmelweis University, Budapest, Hungary;
4 Stanford University, California, USA
Impairment in fear extinction is discernible in many neuropsychiatric diseases, like trauma- or stressor related disorders. It is known that local interneurons (IN) in the basal nucleus of the amygdala (BA) play a critical role in fear related memory processes, such as fear memory extinction. However, during fear extinction the exact role of certain subpopulations of BA INs, such as cholecystokinin-expressing interneurons (CCK INs) is still unclear. In this study our aim was to characterize the physiological, morphological and molecular properties of CCK INs in the BA and assess their contribution to fear extinction. Hence, we used the INTRSECT (INTronic Recombinase Sites Enabling Combinatorial Targeting) viral strategy to genetically manipulate and label BA CCK INs. Electrophysiological recordings confirmed that this strategy targeted only GABAergic cells and a significant proportion of these cells expressed functional type 1 cannabinoid receptors, a defining characteristic of CCK-expressing basket cells (CCKBCs). Further electrophysiological and immunohistochemical analysis revealed that the EYFP was also expressed in neurogliaform neurons (58%), parvalbumin-containing axo-axonic (18%) and basket cells (9%), in addition to CCKBCs (15%). At the behavioral level, in vivo optogenetic photostimulation of the targeted population during extinction learning led to reduced freezing on a light-free extinction retrieval test, indicating the facilitation of extinction memory formation; whereas photosilencing was without effect. Our data thus show that CCK is expressed in functionally diverse IN populations in the BA. Importantly, we provided the first direct evidence that CCK-expressing INs in the BA can modulate extinction memory acquisition.