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 behavioural 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 CNO-mediated activation of CCK-GABA neurons did not alter open field or tail suspension performance and only slightly increased anxiety in the elevated plus maze. Though 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.
Significance Statement CCK-GABA neurons are thought to play an important role in pathologies such as schizophrenia, but their contributions to behavior in the healthy states are poorly understood. Here we report a novel method for selectively targeting CCK-GABA neurons and manipulating their activity during behavioural tasks. Our data demonstrate that activating CCK-GABA neurons subtly affects emotional behavior but surprisingly enhances multiple memory and cognitive processes.
Footnotes
The authors report no conflicts of interest.
Funding Sources: PW 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. JK was supported by a NSERC Discovery grant (MOP 491009) and a CIHR grant (MOP 496401). G.M.P was funded by the postdoctoral fellowship from the Brazilian National Council for Scientific and Technological Development (CNPq). RPB is supported by a Canada Research Chair and the University of Toronto Centre for the Study of Pain. RPB is supported by a NSERC Discovery grant (RGPIN-2016-05538), the Canada Research Chair in Sensory Plasticity and Reconsolidation and the University of Toronto Centre for the Study of Pain. PJ and NWP are supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (ZIA-ES102805).
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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