Abstract

In female rodents, sleep and activity levels fluctuate over the estrous cycle. When estradiol (E2) levels are highest, sleep is reduced whereas locomotion is increased. The preoptic area (POA) is a key site for estrogenic regulation of these functions. However, molecular mechanisms by which E2 acts to reduce sleep and increase activity are unclear. Recently, we demonstrated a twofold reduction in lipocalin-type prostaglandin D synthase (L-PGDS) transcript levels, after E2 treatment, in the ventrolateral POA (VLPO), a putative sleep-active nucleus. Catalytic activity of L-PGDS produces PGD2, an endogenous somnogen. Thus, we hypothesized that decreases in PGD2 in the VLPO may contribute to the generalized arousal mediated by estrogens. To test this, we infused (i) antisense oligonucleotides (oligos), containing locked nucleic acid moieties (an improved technology), targeted to L-PGDS mRNA, (ii) scrambled sequence control oligos, or (iii) saline vehicle into the VLPO of ovariectomized female mice treated with E2 or oil. Arousal states and activity levels were assessed in response to a series of sensory stimuli (vestibular, olfactory, and somatosensory). The vestibular stimulus, which was administered first, resulted in the strongest responses and elicited significantly different responses among the groups: all groups in the E2 cohort demonstrated increases in overall home cage activity and duration of that activity compared with the oil-treated control groups. As predicted from E2 suppression of L-PGDS transcript levels, the responses of the locked nucleic acid antisense oligo-treated animals from the oil cohort did not differ from the E2-treated groups, such that they also demonstrated increases in activity and duration of activity compared with their controls. Thus, reducing L-PGDS in the VLPO of oil-treated females mimicked the effect of E2 on activity and arousal and represents a unique molecular pathway through which E2 may modulate these functions.