Knockdown of clock genes in the suprachiasmatic nucleus blocks prolactin surges and alters FRA expression in the locus coeruleus of female rats

Aug 30, 2007American journal of physiology. Endocrinology and metabolism

Reducing internal clock genes in the brain’s daily rhythm center stops prolactin surges and changes gene activity in the brain’s alertness area of female rats

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Abstract

Antisense treatment disrupted 100% of both proestrous and estradiol-induced prolactin surges in female rats.

Disruption of the circadian feedback loop in the suprachiasmatic nucleus (SCN) affects prolactin (PRL) surges.
The locus coeruleus (LC), which receives SCN projections, is linked to PRL regulation.
Antisense cocktails targeting clock genes in the SCN abolished PRL surges and affected neuronal activity in the LC.
Increased expression of Fos-related antigen in LC neurons was not observed following the antisense treatment.
SCN rhythmicity is necessary for both the magnitude of daily PRL surges and the circadian rhythm of LC neurons.

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The nature of the circadian signal from the suprachiasmatic nucleus (SCN) required for prolactin (PRL) surges is unknown. Because the SCN neuronal circadian rhythm is determined by a feedback loop of Period (Per) 1, Per2, and circadian locomotor output cycles kaput (Clock) gene expressions, we investigated the effect of SCN rhythmicity on PRL surges by disrupting this loop. Because lesion of the locus coeruleus (LC) abolishes PRL surges and these neurons receive SCN projections, we investigated the role of SCN rhythmicity in the LC neuronal circadian rhythm as a possible component of the circadian mechanism regulating PRL surges. Cycling rats on proestrous day and estradiol-treated ovariectomized rats received injections of antisense or random-sequence deoxyoligonucleotide cocktails for clock genes (Per1, Per2, and Clock) in the SCN, and blood samples were taken for PRL measurements. The percentage of tyrosine hydroxylase-positive neurons immunoreactive to Fos-related antigen (FRA) was determined in ovariectomized rats submitted to the cocktail injections and in a 12:12-h light:dark (LD) or constant dark (DD) environment. The antisense cocktail abolished both the proestrous and the estradiol-induced PRL surges observed in the afternoon and the increase of FRA expression in the LC neurons at Zeitgeber time 14 in LD and at circadian time 14 in DD. Because SCN afferents and efferents were probably preserved, the SCN rhythmicity is essential for the magnitude of daily PRL surges in female rats as well as for LC neuronal circadian rhythm. SCN neurons therefore determine PRL secretory surges, possibly by modulating LC circadian neuronal activity.

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Knockdown of clock genes in the suprachiasmatic nucleus blocks prolactin surges and alters FRA expression in the locus coeruleus of female rats

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