A neural circuit for circadian regulation of arousal

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An unknown aspect of behavioral state regulation is how the circadian oscillator of the suprachiasmatic nucleus (SCN) regulates sleep and waking. In this report, we describe the necessary elements for a circuit that provides circadian regulation of arousal. Trans-synaptic retrograde tracing revealed a prominent indirect projection from the SCN to the noradrenergic nucleus locus coeruleus (LC), a brain arousal system. Double-labeling experiments revealed several possible links between the SCN and the LC, including the dorsomedial (DMH) and paraventricular hypothalamic nuclei (PVN), as well as medial and ventrolateral pre-optic areas. Lesion studies confirmed that the DMH is a substantial relay in this circuit. Next, neurophysiology experiments revealed circadian variations in LC impulse activity. Lesions of the DMH eliminated these circadian changes in LC activity, confirming the functionality of the SCN–DMH–LC circuit. These results reveal mechanisms for regulation of circadian and sleep–waking functions.

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Figure 1: PRV injection site in the LC.
Figure 2: Retrograde labeling in the PGi in the rostral ventrolateral medulla at various times of survival following PRV microinjection into the LC.
Figure 3: Retrograde labeling with PRV in the SCN.
Figure 4: Distribution of PRV-labeled neurons in the hypothalamus in an animal perfused 35 h after an injection of the PRV + CTb cocktail into the LC.
Figure 5: Double retrograde labeling in the SCN.
Figure 6: PRV labeling following DMH lesions.
Figure 7: Dual labeling in the DMH for PRV retrogradely transported from the LC and PHA-L anterogradely transported from the SCN.
Figure 8: LC impulse activity during the circadian cycle.


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We thank R. Miselis and J. Druhan for advice and comments on the manuscript. We also thank E. Haggerty for comments as well as for assistance with monitoring locomotor activity. This work was supported by PHS grant NS24698.

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Correspondence to Gary Aston-Jones.

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