All mammals possess a circadian clock that governs daily oscillations with neural, hormonal, and metabolic functions for the organism with a near 24-h period. The suprachiasmatic nucleus (SCN) within the brain's hypothalamus houses this clock. The SCN has neural connections with various regions of the brain. Prominent among these connections are cholinergic projections from regions of the brain responsible for asleep and alerting, namely the basal forebrain (BF) and brainstem. A considerable body of work is available regarding intracellular signal transduction pathways within SCN. Pharmacological studies in vitro have implicated the M1-subtype of the muscarinic acetylcholine receptor (M1AChR) as the receptor mediating the effects of cholinergics on the circadian system. Recently, the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification has questioned the specificity of the drugs used to implicate the M1AChR in the cholinergic signaling cascade. In lieu of specific pharmacology, other methods must be employed to confidently identify the receptor(s) mediating cholinergic circadian signaling. In this proposal, electrophysiological, behavioral and anatomical studies will be carried out in mice devoid of the M1AChR (M1KO). First, the B6129PF1/J mouse, a mouse of similar genetic background to the M1K0, will be tested for sensitivity to the cholinergic agonist, carbachol, both in vitro and in vivo. Second, the M1KO will be tested for decreased sensitivity to carbachol. Finally, double-label fluorescence confocal microscopy will be used to evaluate whether the cholinergic terminals within the SCN are juxtaposed to M1AChR-containing cells and to map their distribution.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH012351-03
Application #
6637566
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (01))
Program Officer
Desmond, Nancy L
Project Start
2002-02-21
Project End
Budget Start
2003-02-21
Budget End
2004-02-20
Support Year
3
Fiscal Year
2003
Total Cost
$35,871
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820