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Control Mechanisms in Physiological Rhythms 

Our grant was concerned with elucidating the factors which are involved in 
regulating rhythmic phenomena. We attacked this problem from essentially one 
basic premise. This was, that at a particular point in time, any cell normally 
can act in only one of two ways . It can be engaged in either dividing or in 
performing its particular function; a normal cell's energies are usually directed 
in one or the other of these tasks by means of its basic control mechanisms. 

Our working hypothesis was that if we could identify rhythms of cell 
division and of function and determine the mechanisms by which we could alter 
these rhythms we might find: 1) that the rhythms of division and function 
were inversely related and, 2) that the control mechanism were basically similar. 

Because of the necessity of utilizing large numbers of animals we chose 
Rana pipiens as our test animal. The frog is small, easily stored and handled, 
relatively inexpensive, and available in large numbers. We have used literally 
thousands of these vertebrates. 

We chose DNA content and synthesis of dorsal epidermis and corneal epithelium 
and mitotic activity of dorsal epiermis as representing cell division. To 
represent cell function, we chose plasma corticosterone levels. 

We had previously found that corneal epithelium exhibited a rhythm in 
mitotic division. Present studies conducted on DNA synthesis showed that 
DNA exhibited a rhythm with a period of approximately 24 hours which correlated 
well with previous mitotic division rhythms . Our studies also indicated that 
the rhythm of DNA synthesis in corneal epithelia seemed to be regulated by the 
lighting regime to which the animals were exposed (2,6). 

We also investigated rhythms in dorsal epidermis. Both DNA content and 
DNA synthesis showed diurnal variations which were reproducible and had 
periodicities of approximately 2k hours. We also have indications that these 
rhythms are regulated by changes in the lighting regime (1,5). 

Statistically significant rhythms of mitotic division in the same tissue 
were also observed. These rhythms were reproducible and had periodicities of 
18-24 hours depending on the sex of the animal. Although inverting the lighting 
regime for .14 days was not sufficient to completely invert the rhythm of cell 
division, it appears that the lighting regime is important in this phenomena. 
Animals which were either blinded or parapinealectomized (frontal organ or 
parapineal body of the pineal system cauterized) and tested after l4 days in 
controlled conditions showed no evidence of rhythms in cell division (3). 

As a tangential problem we were able to use the same animals to test thd 
role of changes in environment as a possible stimulus for inducing the develop- 
ment of kidney tumors. These studies showed that there was an increased incidence 
of Lucke adenocarcinoma as seen from a histological study them had been observed 
previously from a gross point of view (4 ). Preliminary evidence indicated 
that this was due to stress of a seasonal nature. 

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We have also investigated the effect of constant light and constant dark 
conditions on mitotic division rhythms (lU). 

We were able to observe reproducible rhythms of plasma corticosterone (7, 10). 
These rhythms are synchronized by the lighting regime and appear to be regulated 
through the parapineal-pineal system (7» 13). We were also able to observe 
reproducible rhythms in eosinophils (8,11) as well as seasonal changes in corto- 
costerone level and hematocrit and eosinophil levels (8, 12). 

There seems to be an inverse correlation between the rhythms of cell division 
and cell function that we have studied. Apparently the lighting regime is im- 
portant in regulating these rhythms. The pineal organ system appears to be in- 
volved in our test animal in the perception of the light stimulus. However, 
this has to be studied in more detail. We hope our future work will be able to 
more clearly characterize these phenomena and any correlation between them. 


A. Papers 

1. Morgan, W.W. and S. Mizell, Diurnal fluctuations in DNA content and 
DNA synthesis in the dorsal epidermis of Rana pipiens , Comp. Biochem. 
and Physiol. 38:591-602 (1971). 

2. Morgan, W.W. and S. Mizell, Daily fluctuations of DNA synthesis in the 
corneas of Rana pipiens , Comp. Biochem. and Physiol. 40 :487-493 (1971). 

3. Garcia-Arce, H. and S. Mizell, Mitotic activity in dorsal epidermis' 
of Rana pipiens . Comp. Biochem. & Physiol. 42:501-510 (1972). 

4. Marlow, P.B. and S. Mizell, Incidence of Lucke Renal Adenocarcinoma in 
Rana pipiens as determined hy histological examination, J. Nat. Cancer 
Instit., 48:823-829 (1972). 

B. Abstracts 

5. Morgan, W.W. and S. Mizell, Rhythmic fluctuations in DNA synthesis and 
DNA content in tissues of Rana pipiens , Fed. Proc. 29:837 (1970). 

6. Morgan, W.W. and S. Mizell, Daily and seasonal fluctuations in corneal 
DNA synthesis of adult Rana pipiens , Physiol., 13:264 (1970). 

7. Akin, D.P. and S. Mizell, Control mechanisms in rhythms of plasma 
corticosterone. Fed. Proc. 30:610 (1971). 

8. Akin, D.P. and S. Mizell, Seasonal changes in hematocrit and eosinophil 
and in plasma corticosterone level. Anat. Rec. 169 :266 (1971). 

9. Mizell, S. and D.P. Akin, Daily and seasonal rhythms of plasma corti- 
costerone, Proc. Intern. Union of Physiol. Sci. 9.: 397 (1971). 

C. In Preparation 

10. Mizell, S. and D.P. Akin, Rhythms of plasma corticosterone in Rana 
pipiens . 

11. Mizell, S. and D.P. Akin, Short period rhythms of eosinophil level in 

Rana pipiens . . 

12. Mizell, S. and D.P. Akin, Seasonal rhythm of plasma corticosterone, 
hematocrit and eosinophil level in Rana pipiens . 

13. Mizell, S. and D.P. Akin, The role of light and the pineal gland in 
regulating plasma corticosterone rhythms . 

14. Mizell, S. and H. Garcia-Arce, The effect of constant lighting conditions 
on mitotic division rhythms.