DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates

Sascha A L Mueller; Jonathan A Oler; Patrick H Roseboom; Nakul Aggarwal; Margaux M Kenwood; Marissa K Riedel; Victoria R Elam; Miles E Olsen; Alexandra H DiFilippo; Bradley T Christian; Xing Hu; Adriana Galvan; Matthew A Boehm; Michael Michaelides; Ned H Kalin

doi:10.1016/j.crneur.2023.100111

DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates

Curr Res Neurobiol. 2023 Oct 5:5:100111. doi: 10.1016/j.crneur.2023.100111. eCollection 2023.

Authors

Sascha A L Mueller¹, Jonathan A Oler¹, Patrick H Roseboom¹, Nakul Aggarwal¹, Margaux M Kenwood², Marissa K Riedel¹, Victoria R Elam¹, Miles E Olsen¹, Alexandra H DiFilippo³, Bradley T Christian^{1

3}, Xing Hu⁴, Adriana Galvan⁴, Matthew A Boehm⁵, Michael Michaelides⁵, Ned H Kalin¹

Affiliations

¹ Department of Psychiatry and the HealthEmotions Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53719, USA.
² Department of Psychiatry, Weill Cornell Medical College, New York, NY, 10065, USA.
³ Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
⁴ Emory National Primate Research Center, Emory University, Atlanta, GA, 30329, USA.
⁵ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.

Abstract

Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [¹¹C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.

Abstract

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