Evidence for time-of-day dependent effect of neurotoxic dorsomedial hypothalamic lesions on food anticipatory circadian rhythms in rats.

The dorsomedial hypothalamus (DMH) is a site of circadian clock gene and immediate early gene expression inducible by daytime restricted feeding schedules that entrain food anticipatory circadian rhythms in rats and mice. The role of the DMH in the expression of anticipatory rhythms has been evaluated using different lesion methods. Partial lesions created with the neurotoxin ibotenic acid (IBO) have been reported to attenuate food anticipatory rhythms, while complete lesions made with radiofrequency current leave anticipatory rhythms largely intact. We tested a hypothesis that the DMH and fibers of passage spared by IBO lesions play a time-of-day dependent role in the expression of food anticipatory rhythms. Rats received intra-DMH microinjections of IBO and activity and body temperature (T(b)) rhythms were recorded by telemetry during ad-lib food access, total food deprivation and scheduled feeding, with food provided for 4-h/day for 20 days in the middle of the light period and then for 20 days late in the dark period. During ad-lib food access, rats with DMH lesions exhibited a lower amplitude and mean level of light-dark entrained activity and T(b) rhythms. During the daytime feeding schedule, all rats exhibited food anticipatory activity and T(b) rhythms that persisted during 2 days without food in constant dark. In some rats with partial or total DMH ablation, the magnitude of the anticipatory rhythm was weak relative to most intact rats. When mealtime was shifted to the late night, the magnitude of the food anticipatory activity rhythms in these cases was restored to levels characteristic of intact rats. These results confirm that rats can anticipate scheduled daytime or nighttime meals without the DMH. Improved anticipation at night suggests a modulatory role for the DMH in the expression of food anticipatory activity rhythms during the daily light period, when nocturnal rodents normally sleep.

Persistence of a behavioral food-anticipatory circadian rhythm following dorsomedial hypothalamic ablation in rats.

Circadian rhythms of behavior in rodents are regulated by a system of circadian oscillators, including a master light-entrainable pacemaker in the suprachiasmatic nucleus that mediates synchrony to the day-night cycle, and food-entrainable oscillators located elsewhere that generate rhythms of food-anticipatory activity (FAA) synchronized to daily feeding schedules. Despite progress in elucidating neural and molecular mechanisms of circadian oscillators, localization of food-entrainable oscillators driving FAA remains an enduring problem. Recent evidence suggests that the dorsomedial hypothalamic nucleus (DMH) may function as a final common output for behavioral rhythms and may be critical for the expression of FAA (Gooley JJ, Schomer A, and Saper CB. Nat Neurosci 9: 398-407, 2006). To determine whether the reported loss of FAA by DMH lesions is specific to one behavioral measure or generalizes to other measures, rats received large radiofrequency lesions aimed at the DMH and were recorded in cages with movement sensors. Total and partial DMH ablation was associated with a significant attenuation of light-dark-entrained activity rhythms during ad libitum food access, because of a selective reduction in nocturnal activity. When food was restricted to a single 3-h daily meal in the middle of the lights-on period, all DMH and intact rats exhibited significant FAA. The rhythm of FAA persisted during a 48-h food deprivation test and reappeared during a 72-h deprivation test after ad libitum food access. The DMH is not the site of oscillators or entrainment pathways necessary for all manifestations of FAA, but may participate on the output side of this circadian function.

Lesions of the dorsomedial hypothalamic nucleus do not influence the daily profile of pineal metabolism in rats.

The present study attempted to characterize the effects of electrolytic lesions of the hypothalamic dorsomedial nucleus on the daily profile of pineal metabolism as well as on the inhibition of pineal melatonin synthesis induced by acute light exposure during the night. Adult male Wistar rats (n = 107, 12:12 h light-dark cycle) were left intact (n = 47) or lesioned (n = 60). Lesioned rats and their respective controls were killed at six time points distributed throughout the light-dark cycle. At ZT (zeitgeber time) 18 the animals were killed either in the dark or after 15 min of light stimulation. Pineal glands were assayed using high-performance liquid chromatography with electrochemical detection (HPLC-ED). There was no difference in the amounts of pineal indoles between lesioned and control rats under any of the experimental situations tested. These results suggest that in rats, the hypothalamic dorsomedial nucleus does not participate in either the neural control of daily pineal metabolism or the nocturnal light-induced inhibition of the pineal metabolism.

Acceleration of mounting behaviors in female rats by ibotenic acid lesions in the ventromedial hypothalamic nucleus.

To clarify the role of the ventromedial (VMH) or dorsomedial (DMH) hypothalamic nucleus in regulating male sexual behavior in female rats, radiofrequency or ibotenic acid lesions were made in ovariectomized rats, and three behavioral tests in total were carried out after implantation of Silastic tubes containing testosterone. As a result, females with radiofrequency or ibotenic acid lesions in the VMH showed higher levels of mounting behavior than those in females with no brain surgery or with sham-operation. The incidence of intromissive pattern in females with ibotenic acid lesions but not in females with radiofrequency lesions was higher than those in other female control groups. In the group of radiofrequency lesions in the DMH, both frequencies of mounting and intromissive pattern were lower than those in control and sham groups. No ejaculatory pattern was seen in any of the female groups. These results indicate that neuronal cell bodies in the VMH, but not in the DMH, exert an inhibitory influence on mounting activity in female rats.

Food efficiency in rats following brain lesions which affect target body size: implications on the set point for target size.

Target size, i.e. body size appropriate for age, may be reset by bilateral lesions of several brain areas. The mechanism for control of target body size is unknown, but some of the loci have marked effects on gustatory behavior and/or energy metabolism. We have tested the possibility that a disturbance in energy metabolism may be a common factor in resetting target size. Food efficiency for body weight gain and for metabolic size (the 0.75 power of body weight) was determined in rats that were experimentally stunted by neonatal head-irradiation or by bilateral electrolytic lesions produced soon after weaning in the dorsomedial hypothalamic nuclei (DMH) or the substantia nigra (SN). The irradiations were carried out in males and females; the surgical lesions were produced only in males. Observations were carried out from weaning through early adulthood. Subgroups of irradiated rats and controls were fasted for 48 hours at 40 days of age. Irradiated rats had reduced food efficiency for weight gain and for metabolic size, more marked in males than in females. DMH or SN lesions did not change food efficiency for weight gain. Food efficiency for metabolic size increased after DMH lesions and declined after SN lesions. During refeeding after a fast, irradiated rats showed a normal transient increase in food efficiency for weight gain, but not for metabolic size. The differences in food efficiency following different lesions tend to exclude altered energy metabolism as a common factor in the reset of target body size.(ABSTRACT TRUNCATED AT 250 WORDS)