Our long-term objective is to understand how neuromodulation and synaptic integration shape informationprocessing in the olfactory system. This objective is addressed in the main olfactory bulb (MOB), the firstcentral relay station for olfactory information. The endocannabinoid system is an important neuromodulatorysystem, which involves cannabinoid receptors, CB1R, and their endogenous activators, endocannabinoids(eCBs). In the MOB, neurons express high levels of CB1R, but its cellular and network functions areunknown. Our new preliminary data shows that CB1R agonists and antagonists alter the membrane potentialand response to synaptic input of GABAergic interneurons, granule cells, and the membrane potential andfiring pattern of principal neurons, mitral cells. Based on our preliminary data, the hypothesis is that eCBsprominently modulate membrane properties of MOB neurons, change the response to synaptic input, andregulate the neural network of the MOB. Consequently, the overall aim of this proposal is to determine therole of eCBs and CB1R for neural signaling in the MOB.
In Specific Aim 1, the hypothesis will be tested thatCB1R directly regulates the excitability of mitral cells and granule cells in a slice preparation of the mouseMOB. Do eCBs mediate self-inhibition of mitral cells and granule cells, i.e., are eCBs released by a neuronand target CBIRs on the same neuron? In Specific Aim 2, the hypothesis will be tested that CB1R regulatessynaptic responsiveness of mitral cells and granule cells. Do eCBs serve as retrograde signaling moleculesin the MOB between post- and presynaptic neurons to regulate presynaptic transmitter release? Theinteraction of the eCB system with another modulatory system, the metabotropic glutamate receptor (mGluR)system will be investigated to test the hypothesis that both systems are functionally interrelated. Theexperimental approach includes whole-cell patch-clamp recording and intracellular labeling of MOB neuronsvisualized with near infrared differential interference optics, use of mGluR knockout (KO) mice and CB1R KOmice, and characterization of cellular, membrane, pharmacologic and network properties of eCB-modulatedneural processing in the MOB. Our findings help to explain the properties of marijuana at the cellular levelthrough eCB-mediated synaptic processing in the MOB and eventually lead to a better understanding of drugaddiction and could pave the way for new treatment strategies to prevent the use of drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Minority Biomedical Research Support - MBRS (S06)
Project #
2S06GM008016-36
Application #
7163122
Study Section
Minority Programs Review Committee (MPRC)
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2006-09-25
Budget End
2007-07-31
Support Year
36
Fiscal Year
2006
Total Cost
$104,430
Indirect Cost
Name
Howard University
Department
Type
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Faruque, Mezbah U; Chen, Guanjie; Doumatey, Ayo P et al. (2017) Transferability of genome-wide associated loci for asthma in African Americans. J Asthma 54:1-8
Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Liu, Ching-Ti; Raghavan, Sridharan; Maruthur, Nisa et al. (2016) Trans-ethnic Meta-analysis and Functional Annotation Illuminates theĀ Genetic Architecture of Fasting Glucose and Insulin. Am J Hum Genet 99:56-75
Rand, Kristin A; Rohland, Nadin; Tandon, Arti et al. (2016) Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk. Hum Mol Genet 25:371-81
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Ehret, Georg B (see original citation for additional authors) (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48:1171-1184
Kurian, P; Dunston, G; Lindesay, J (2016) How quantum entanglement in DNA synchronizes double-strand breakage by type II restriction endonucleases. J Theor Biol 391:102-12
Ogunjirin, Adebowale E; Fortunak, Joseph M; Brown, LaVerne L et al. (2015) Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen. Neurochem Res 40:2131-42
Winchester, Danyelle; Ricks-Santi, Luisel; Mason, Tshela et al. (2015) SPINK1 Promoter Variants Are Associated with Prostate Cancer Predisposing Alterations in Benign Prostatic Hyperplasia Patients. Anticancer Res 35:3811-9

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