Abstract

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes. To accomplish this goal, new and improved methods for both recording and manipulating neuronal activity will be needed. In this application, we focus on technologies for manipulating neuronal activity. The major significance of this application is that we will provide an enhanced chemogenetic toolbox that allows non-invasive, multiplexed spatiotemporal control of neuronal activity in domains ranging from single synapses to ensembles of neurons. To achieve this, we will provide: Chemical actuators with improved pharmacokinetics and pharmacodyamics suited for use with current DREADDs in eukaryotes ranging from Drosophila to primates (Specific Aim #1) Photo-caged CNO and other chemical actuators to provide millisecond-scale control (Specific Aim #1) Novel DREADDs and 'split-DREADDs'targeted to distinct neuronal pathways to enable multiplexed interrogation of neuronal circuits (Specific Aims #2 and 3) Chemogenetic platforms with minimized desensitization and down-regulation (Specific Aim #3)

Public Health Relevance

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes-ultimately to provide novel approaches for diagnosing and treating neuropsychiatric diseases. To accomplish this goal, new and improved methods for both recording and manipulating neuronal activity will be needed. Here we provide a chemogenetic platform for manipulating neuronal activity which requires no specialized equipment, and is non-invasive. Further this chemogenetic platform affords multiplexed spatiotemporal control of neuronal activity in domains ranging from single synapses to ensembles of neurons. It is likely that this new chemogenetic platform will be used by large numbers of investigators to elucidate circuitry and neuronal signaling pathways responsible for many neuropsychiatric diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01MH105892-01
Application #
8819319
Study Section
Special Emphasis Panel (ZMH1-ERB-L (04))
Program Officer
Freund, Michelle
Project Start
2014-09-26
Project End
2017-06-30
Budget Start
2014-09-26
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$997,398
Indirect Cost
$310,940

  Institution

Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

McCorvy, John D; Butler, Kyle V; Kelly, Brendan et al. (2018) Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14:126-134
Mazzone, C M; Pati, D; Michaelides, M et al. (2018) Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23:143-153
Navarro, Montserrat; Olney, Jeffrey J; Burnham, Nathan W et al. (2016) Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli. Neuropsychopharmacology 41:1505-12
Hardaway, J Andrew; Jensen, Jennifer; Kim, Michelle et al. (2016) Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating. Behav Brain Res 307:25-34
Butler, Kyle V; Bohn, Kelsey; Hrycyna, Christine A et al. (2016) Non-Substrate Based, Small Molecule Inhibitors of the Human Isoprenylcysteine Carboxyl Methyltransferase. Medchemcomm 7:1016-1021
Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113:E3441-50
Zhu, Hu; Aryal, Dipendra K; Olsen, Reid H J et al. (2016) Cre-dependent DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice. Genesis 54:439-46
Bruchas, Michael R; Roth, Bryan L (2016) New Technologies for Elucidating Opioid Receptor Function. Trends Pharmacol Sci 37:279-289
Urban, Daniel J; Zhu, Hu; Marcinkiewcz, Catherine A et al. (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404-15
Marchant, Nathan J; Whitaker, Leslie R; Bossert, Jennifer M et al. (2016) Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats. Neuropsychopharmacology 41:402-9

Showing the most recent 10 out of 16 publications