@article{acaddf377313448baba4eee5e8759f72,
title = "Behavioral effect of chemogenetic inhibition is directly related to receptor transduction levels in Rhesus monkeys",
abstract = "We used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male rhesus monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hSyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD-transduced cells using stereological analysis of mCherry-immunolabeled neurons. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared with monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histo-logical analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.",
keywords = "Chemogenetics, DREADD, Prefrontal, Stereology, Working memory",
author = "Upright, {Nicholas A.} and Brookshire, {Stephen W.} and Wendy Schnebelen and Damatac, {Christienne G.} and Hof, {Patrick R.} and Browning, {Philip G.F.} and Croxson, {Paula L.} and Rudebeck, {Peter H.} and Baxter, {Mark G.}",
note = "Funding Information: Received June 1, 2018; revised July 23, 2018; accepted Aug. 1, 2018. Author contributions: P.R.H., P.G.F.B., P.L.C., P.H.R., and M.G.B. designed research; N.U., S.W.B., W.S., C.G.D., P.G.B., P.L.C., P.H.R., and M.G.B. performed research; N.A.U., S.W.B., W.S., C.G.D., and M.G.B. analyzed data; N.U., S.W.B., W.S., P.L.C., P.H.R., and M.G.B. wrote the paper. This work was supported by the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai as well as by NIH Grants R21NS096936 (M.G.B., P.L.C.) and T32AG04688 (N.A.U.). We thank Scott Russo, Eric Nestler, and BryanRothforadvice,toJianJinforsynthesizingCNOHClandCompound21,andtheNIMHChemicalSynthesisand Drug Supply Program for providing CNO. The authors declare no competing financial interests. *N.A.U., SW.B., AND W.S. contributed equally to this work. Correspondence should be addressed to Dr. Mark Baxter, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029. E-mail: mark.baxter@mssm.edu. DOI:10.1523/JNEUROSCI.1422-18.2018 Copyright {\textcopyright} 2018 the authors 0270-6474/18/387969-07$15.00/0 Funding Information: This work was supported by the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai as well as by NIH Grants R21NS096936 (M.G.B., P.L.C.) and T32AG04688 (N.A.U.). We thank Scott Russo, Eric Nestler, and Bryan Roth for advice, to Jian Jin for synthesizing CNO HCl and Compound 21, and the NIMH Chemical Synthesis and Drug Supply Program for providing CNO. Publisher Copyright: {\textcopyright} 2018 the authors.",
year = "2018",
month = sep,
day = "12",
doi = "10.1523/JNEUROSCI.1422-18.2018",
language = "English",
volume = "38",
pages = "7969--7975",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "37",
}