Non-human Animals

Research in the area of biological clocks did not begin with humans. Early research was done on a variety of animals including rats, hamsters, sparrows, lizards, marine snails, and fruit flies. The choice of an animal depended on many considerations--size, rate of reproduction, expense to maintain, and availablity--as well as behavioral issues, such as whether it entrained easily and what environmental factors seemed to affect its behavior.

House sparrows were one of the first animals in which the biological clock was anatomically localized [23]. The sparrow's clock is believed to consist of the suprachiasmatic nucleus (SCN), as in humans, and the pineal gland. In this circadian system, photoreceptors are found in the retina as well as in the pineal gland and in the deep brain. Investigators are clarifying the relationship between the sparrow's two clocks and its photoreceptors [24].

Although sparrows are similar to humans, how do they compare with other vertebrates such as reptiles? Reptiles also have photoreceptors in the eye, the pineal and in the deep brain. Most reptiles and some amphibians, however, also have photorecptors in the parietal eye, an unseeing third eye located on the top of the skull with a well-defined retina, lens, and cornea that is known to play a role in thermoregulation and photoperiodism in some species [25]. In reptiles and other lower vertebrates, the pineal gland synthesizes information from the photoreceptors and in turn secretes melatonin in a rhythm which synchronizes other parts of the clock system. The role of the SCN in lower vertebrates is unclear, but it is thought to contain another part of the clock.

One of the most intensively studied invertebrates is Drosophila, the familiar fruit fly. This insect reproduces quickly, is economical to raise, requires very little space, and has an extensively mapped genome. Locomotor activity is difficult to observe in individual flies, but the eclosion rhythm, which is under clock control, can be observed in large numbers of flies [23]. Mutant strains of flies are presently being used to discover more about the molecular basis of the clock.

The biological clock has been found in the optic lobe in other invertebrates, such as cockroaches, crickets and silkmoths [23]. Mollusks seem to have a clock only in the eyes. Two types of mollusks, a marine snail (Bulla gouldiana), pen & ink of Bulla by Donna Bennet
and the sea hare (Aplysia californica), have large neurons that can be individually studied [see review by 23]. Furthermore, isolated retinal neurons can even be placed in vitro , and still exhibit circadian rhythms in their electrical behavior.

The most widely studied mammals are rats, mice, and hamsters. All of these rodents have clearly defined circadian rhythms measured as the onset of their daily locomotor activity. Hamsters, for example, are nocturnal and will become active at a certain time every night. This rhythm can be quantified by recording their activity on a running wheel which is connected to a computer that converts the raw data into an actogram.

The SCN was first identified as a circadian clock in rats. When Richter lesioned the rat SCN, the animals' locomotor activity became arrhythmic. This experiment was soon followed by a series of investigations in other rodents and mammals on how SCN lesions can affect circadian rhythms [23].

Late in the 1980's a spontaneous mutation, later named the tau mutant, was discovered in a colony of golden hamsters. The period of the mutant's rhythm was noticeably shorter than the 24-hour norm: heterozygous tau mutants had approximately 22-hour periods, and homozygous ones had a 20-hour cycle. When normal hamsters who had been made arrhythmic by a SCN lesion were given a transplanted tau SCN, they resumed a circadian rhythmicity that matched that of the donor. This experiment was also repeated in reverse, with the tau hamster showing a normal hamster's 24-hour rhythm after receiving a normal hamster's SCN. These experiments provided the final proof that the SCN is the site of a clock in mammals [26].

Center researcher Mike Menaker observes the behavior of a tau mutant

A similar mutant gene (clock) that causes a longer than normal period of running wheel behavior was recently found in mice. This discovery is exciting because mice have a well-mapped genome. Investigators hope to use hamster and mouse mutants to identify the clock's internal mechanisms and determine at the genetic level what makes it "tick".