The long-term objectives of this work are to understand the mechanisms whereby the mammalian biological clock (the suprachiasmatic nucleus) mediates circadian rhythmicity, and to develop further a model for the functional analysis of neural tissue transplants in the hypothalamic region. To distinguish pacemaker from trophic or permissive effects of transplanted tissue, we will use tau period mutant animals as hosts and wild-type animals for fetal donor tissue. (The free-running period of the biological clock can readily be distinguished in these groups. In the proposed experiments, we will address the following questions: 1) Do grafts of the fetal suprachiasmatic nucleus (SCN) restore circadian rhythmicity via neural and/or diffusible signal(s)? We will test this hypothesis using polymer-encapsulated SCN. grafts. If the results suggest a diffusible signal, we will work towards identifying that signal. If the results suggest a role for neural efferents of the SCN, we will work towards specifying those efferents. 2) How does the site of placement of the SCN graft influence restoration of function? 3) Which part of the graft within the transplanted tissue is the """"""""functional"""""""" SCN?. 4), Do functional SCN 'grafts restore rhythms other than locomotor rhythms, such as rhythms of drinking, hoarding, gnawing and body temperature? In each experiment, immunocytochemical analyses will allow us to correlate the neuropeptide/transmitter organization of each graft with the restoration of circadian function in individual animals. The significance of the present research program derives from its potential to clarify the nature of the coupling signal (neural or humoral) by which SCN determines the phase and period of circadian 'rhythms, the locus (loci) of the endogenous oscillator mechanism(s), and the general contribution of this work to the understanding of potential of neural tissue grafts to restore hypothalamic function following damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS024292-04A2
Application #
3408744
Study Section
Biopsychology Study Section (BPO)
Project Start
1987-04-01
Project End
1994-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Barnard College
Department
Type
Schools of Arts and Sciences
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10027
LeSauter, J; Silver, R (1998) Output signals of the SCN. Chronobiol Int 15:535-50
LeSauter, J; Romero, P; Cascio, M et al. (1997) Attachment site of grafted SCN influences precision of restored circadian rhythm. J Biol Rhythms 12:327-38
Silver, R; Romero, M T; Besmer, H R et al. (1996) Calbindin-D28K cells in the hamster SCN express light-induced Fos. Neuroreport 7:1224-8
LeSauter, J; Lehman, M N; Silver, R (1996) Restoration of circadian rhythmicity by transplants of SCN ""micropunches"". J Biol Rhythms 11:163-71
Lehman, M N; LeSauter, J; Kim, C et al. (1995) How do fetal grafts of the suprachiasmatic nucleus communicate with the host brain? Cell Transplant 4:75-81
Romero, M T; Lehman, M N; Silver, R (1993) Age of donor influences ability of suprachiasmatic nucleus grafts to restore circadian rhythmicity. Brain Res Dev Brain Res 71:45-52
LeSauter, J; Silver, R (1993) Lithium lengthens the period of circadian rhythms in lesioned hamsters bearing SCN grafts. Biol Psychiatry 34:75-83
Lesauter, J; Silver, R (1993) Heavy water lengthens the period of free-running rhythms in lesioned hamsters bearing SCN grafts. Physiol Behav 54:599-604
Norgren Jr, R B; McLean, J H; Bubel, H C et al. (1992) Anterograde transport of HSV-1 and HSV-2 in the visual system. Brain Res Bull 28:393-9
Canbeyli, R S; Lehman, M; Silver, R (1991) Tracing SCN graft efferents with Dil. Brain Res 554:15-21

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