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circadian rhythmicity has been observed at all levels of organization, from
the behavior of mammals, flies, and single cells, to the specific activity of
enzymes, the activity of ribosomes, and the transcription of identified gen-
es ... they are driven by some self-sustaining cellular oscillation as pacemaker
of the system”. 1 From its beginnings, our understanding of circadian biology
has expanded rapidly at all levels, frommolecular to behavioral, over the past
40 years with publications in the field increasing rapidly. The essential
localization-of-function questions for circadian neurobiology is summarized
in Fig. 1.1 . As the diagram indicates, the essential features are intrinsic self-
sustaining oscillators with a period ( t ) approximating 24 h, entrainment
pathways, and output from the oscillators to systems under circadian regu-
lation. The experimental
task was
identification and characterization
of each.
My interest in the field began in 1964 when I was introduced to Julius
Axelrod at a Federated American Societies for Experimental Biology
(FASEB) meeting. Axelrod had made important contributions to under-
standing catecholamine neurotransmission leading to the Nobel Prize in
Physiology or Medicine 145 and, in the course of this, discovered
O -methylating enzymes including the pineal melatonin-forming enzyme,
hydroxyindole- O -methyltransferase (HIOMT). One of his postdoctoral
fellows, Richard Wurtman, was interested in the pineal gland and had pub-
lished data with Axelrod showing a diurnal rhythm in pineal HIOMT
content that is dependent on an intact sympathetic innervation. 143 We
had been studying the effects of hypothalamic and brainstem lesions on
monoamines in the brain, 39 and Axelrod asked the question of whether
central monoamine pathways participated in the regulation of pineal
function. This interaction resulted in a collaborative study between Axelrod
and colleagues at the NIH and Alfred Heller and I at the University of
Chicago. In these, we found a loss of HIOMT responses with bilateral
medial forebrain bundle lesions. 146 These data indicated that the information
Clocks
(self-
sustaining
oscillators)
Entraining periodic
environmental
variables: light and
other.
Entrained
rhythms
Figure 1.1 Diagram showing the necessary components of a circadian timing system:
entrainment pathways, endogenous self-sustaining oscillators (ESSO's), output path-
ways. Modified from Ref. 38 .
 
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