@article{e7b335a93d5649b1b7986d2f4706ad09,
title = "Selective activation of cholecystokinin-expressing GABA (CCK-GABA) neurons enhances memory and cognition",
abstract = "Cholecystokinin-expressing GABAergic (CCK-GABA) neurons are perisomatic inhibitory cells that have been argued to regulate emotion and sculpt the network oscillations associated with cognition. However, no study has selectively manipulated CCK-GABA neuron activity during behavior in freely-moving animals. To explore the behavioral effects of activating CCK-GABA neurons on emotion and cognition, we utilized a novel intersectional genetic mouse model coupled with a chemogenetic approach. Specifically, we generated triple transgenic CCK-Cre;Dlx5/6-Flpe;RC::FL-hM3Dq (CCK-GABA/hM3Dq) mice that expressed the synthetic excitatory hM3Dq receptor in CCK-GABA neurons. Results showed that clozapine-N-oxide (CNO)-mediated activation of CCKGABA neurons did not alter open field (OF) or tail suspension (TS) performance and only slightly increased anxiety in the elevated plus maze (EPM). Although CNO treatment had only modestly affected emotional behavior, it significantly enhanced multiple cognitive and memory behaviors including social recognition, contextual fear conditioning, contextual discrimination, object recognition, and problem-solving in the puzzle box. Collectively, these findings suggest that systemic activation of CCK-GABA neurons minimally affects emotion but significantly enhances cognition and memory. Our results imply that CCK-GABA neurons are more functionally diverse than originally expected and could serve as a potential therapeutic target for the treatment of cognitive/memory disorders.",
keywords = "Anxiety, Cholecystokinin, Cognition, GABA, Memory, Perisomatic",
author = "Whissell, {Paul D.} and Bang, {Jee Yoon} and Ikram Khan and Xie, {Yu Feng} and Parfitt, {Gustavo M.} and Martine Grenon and Plummer, {Nicholas W.} and Patricia Jensen and Bonin, {Robert P.} and Kim, {Jun Chul}",
note = "Funding Information: P.D.W. was funded by post-doctoral fellowships from the Natural Sciences and Engineering Council of Canada (NSERC) and the Canadian Institutes of Health Research (CIHR) through the Sleep and Biological Rhythms Program. J.C.K. was supported by the NSERC Discovery Grant MOP 491009 and the CIHR Grant MOP 496401. G.M.P. was funded by the postdoctoral fellowship from the Brazilian National Council for Scientific and Technological Development (CNPq). R.P.B. is supported by a Canada Research Chair in Sensory Plasticity and Reconsolidation, the University of Toronto Centre for the Study of Pain and an NSERC Discovery grant (RGPIN-2016-05538). P.J. and N.W.P. are supported by the Intramural Research Program of the United States National Institutes of Health, National Institute of Environmental Health Sciences Grant ZIA-ES102805. ^P.D.W. and J.Y.B. contributed equally to this work. Acknowledgements: We thank Elena Soukhov for technical assistance. Funding Information: CNO was obtained from the NIH as a part of the Rapid Access to Investigative Drug Program funded by the National Institute of Neurologic Disorders and Stroke (NINDS). CNO powder was dissolved in 20% dimethylsulfoxide (DMSO)/saline to prepare a stock solution of 3 mM. In behavioral experiments, mice were weighed daily before being randomly assigned to either CNO or vehicle treatment groups. Unless otherwise stated, all drug injections were given in the intraperitoneal cavity ~10 min before each test. Mice in the CNO group received a 3 mg/kg injection of CNO whereas mice in the vehicle group received a DMSO/saline injection. The experimenters giving the injections and testing the mice were blinded to the drug condition. To ensure that CNO injection of an animal in one behavioral test did not confound the performance of that animal in another subsequent behavioral test, we made sure that different behavioral tests were separated by at least 48 h. In electrophysiology experiments, a concentration of 5 µM CNO was used. Publisher Copyright: {\textcopyright} 2019 Whissell et al.",
year = "2019",
month = jan,
day = "1",
doi = "10.1523/ENEURO.0360-18.2019",
language = "English",
volume = "6",
journal = "eNeuro",
issn = "2373-2822",
publisher = "Society for Neuroscience",
number = "1",
}