Circadian Rhythms, Reproduction, and Seasonal Changes in Brain Function

When we observe the behavior and physiology of living things, we invariably notice that they are rhythmic. The rotation of the earth results in daily periodicity of the environment, and our planet's circuit around the sun imposes seasonal cycles to which organisms must adapt. Thus it is not surprising that plants and animals show daily and annual cycles when we study them in their natural environment. What fascinates me is the finding that such rhythms persist with nearly (but not exactly) the same period even when organisms are placed in constant environmental conditions. Furthermore, the period of these rhythms - and even their persistence - depends upon the expression of specific genes. In addition, these rhythms depend upon particular structures in the central nervous system. My laboratory studies the molecular and neural basis of these endogenous daily (circadian) rhythms in mammals. We focus upon the suprachiasmatic nucleus of the hypothalamus (SCN), a master pacemaker critical not only to general activity rhythms but also to the estrous cycle, the rhythmic secretion of many hormones, and seasonal breeding.

Although the SCN plays a special, central role as a pacemaker, circadian oscillators are found in many organs. In fact, it's possible that every cell expresses the genes critical to circadian rhythmicity. We are studying the links between the SCN and the peripheral oscillators. Using a variety of surgical and molecular techniques, we have gathered evidence for both neural and blood-borne signals. We are now examining the specific nature of these cues. Our work focuses on the way in which multiple oscillators are coupled through a process of internal entrainment. Neurotransplantation and parabiosis have proven to be useful techniques in this line of research.

Retinal input triggers the expression of immediate early genes, including analogs of the Drosophila period gene, Per, in order to shift the phase of the circadian clock. In constant darkness, the oscillation continues due to transcriptional-translational feedback loops involving not only Per, but also cryptochromes, bmal1, and Clock, and their protein products. The rate at which the clock runs is plastic, and we are investigating influences of the environment on the operation of these feedback loops.

The restriction of reproduction to a particular time of year depends upon the discrimination of daylength. The circadian system accomplishes this by SCN-regulated secretion of the hormone melatonin by the pineal gland, and detection of melatonin duration using highly specific cell membrane receptors in the brain.
Nightly secretion of melatonin provides another cue that may reset the clock and allow the detection of daylength by the SCN. We are characterizing specific SCN cell types which participate in generation of the circadian oscillation, its synchronization with the outside world, and communication with the rest of the brain and ultimately the entire animal.

The appropriate timing of ovulation is controlled not only by signals from the ovary, but also by the circadian clock. We find that projections of the SCN contact not only neurons that contain estrogen receptor, but also those which regulate the pituitary. Furthermore, estrogen-responsive cells reciprocate to regulate circadian rhythms through their projections to the SCN.

What seasonal changes in brain function drive fluctuations in reproduction, sexual behavior, and energy metabolism? We find that daylength regulates the incorporation of neurons born in adulthood. This effect is not attributable to changes in the secretion of gonadal hormones. Daylength and testosterone interact to regulate androgen and opiate receptor expression in hamster brain in ways which may explain seasonal changes in sexual behavior and endocrine feedback. We are discovering mechanisms by which the nervous system integrates environmental (photoperiodic) information with internal (hormonal) messages in order to adapt to season.

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