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.

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
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
Bruchas, Michael R; Roth, Bryan L (2016) New Technologies for Elucidating Opioid Receptor Function. Trends Pharmacol Sci 37:279-89
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
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
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
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
Roth, Bryan L (2016) DREADDs for Neuroscientists. Neuron 89:683-94
Hardaway, J A; Crowley, N A; Bulik, C M et al. (2015) Integrated circuits and molecular components for stress and feeding: implications for eating disorders. Genes Brain Behav 14:85-97
Chen, Xin; Choo, Hyunah; Huang, Xi-Ping et al. (2015) The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs. ACS Chem Neurosci 6:476-84
Vardy, Eyal; Robinson, J Elliott; Li, Chia et al. (2015) A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Neuron 86:936-46
English, Justin G; Roth, Bryan L (2015) Chemogenetics-A Transformational and Translational Platform. JAMA Neurol 72:1361-6

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