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 (Tb) 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 Tb rhythms. During the daytime feeding schedule, all rats exhibited food anticipatory activity and Tb 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

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Food anticipatory activity (FAA) ratios for each DMH lesioned (A) and intact (B) rat, averaged over the last 5 days of daytime restricted feeding (ZT6-10 meal) and nightime restricted feeding (ZT21-1 mealtime).

<p>Ratios are calculated by dividing total activity during the 3-h immediately preceding mealtime by total activity during the 12-h night plus the first 3-h of the light period, and are expressed as difference scores from the same ratios calculated for the ad-lib food access condition. Data points from individual rats are conncected by lines. The upper and lower red dotted lines denotes the lowest anticipation ratios in the intact rats and the lesion rats, respectively.</p

Total daily activity and nocturnal activity in intact and DMH lesion rats.

<p>A. Group mean daily activity counts in intact rats (solid black bars), low-dose ibotenic acid lesion rats (stripped bars) and high-dose lesion rats (white bars), during adlib food access in LD and constant dark (DD), during 2 days of total food deprivation (FD) prior to daytime restricted feeding, during the last 5-day block of the 20-day daytime restricted feeding (RFL-B4), during total food deprivation after daytime restricted feeding (RFL-FD), during the last 5-day block of nightime restricted feeding (RFD-B4) and during the food deprivation that immediately following nighttime restricted feeding (RFD-FD). B. Nocturnality ratios of activity data from each group under the same 7 food access conditions as in Panel A. Significant differences (p<.05) relative to the intact group within each condition are denoted by a star.</p

Group mean body temperatures in intact rats (black bars), low-dose DMH lesion rats (stripped bars) and high-dose lesion rats (white bars), expressed as A.

<p>dark-light differences during ad-lib food access in LD and DD, and as B. 24-h daily means during each of 7 feeding conditions. Abbreviations: RFL, last 5 days of restricted feeding in the light period; RFD, last 5 days of restricted feeding in the dark period; FD, 3-days of total food deprivation immediately following RFL or RFD.</p

Activity and body temperature rhythms in representative intact and DMH-lesion rats.

<p>Raster plots of locomotor activity (A–D), and average waveforms of locomotor activity (E–H) and body temperature (I–L) from an intact control rat with strong daytime food anticipatory rhythms (A,E,I), an intact rat with the weakest daytime food anticipation (B,F,J; defined by the lowest food anticipation ratio during daytime feeding), the rat with the lowest daytime food anticipation ratio (C,G,K) from the group that received a low-dose ibotenic acid microinjection causing a small partial lesion, and the rat with the lowest daytime food anticipation ratio (C,G,K) from among rats receiving a high-dose lesion that induced a complete DMH lesion (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024187#pone-0024187-g001" target="_blank">Fig. 1C,F</a>). The raster plots illustrate activity summed in 10 min bins. Each line represents 24 h of recording, with time of day plotted from left to right (144 time points/day), and consecutive days aligned vertically. Time bins in which activity counts were registered are represented by a heavy bar, the height of which signifies the amount of activity (1–10 counts, 11–20 counts and >20 counts/10 min). Grey shading denotes lights-off (hours 12–24 of LD, or all day during constant dark tests). Scheduled mealtime during food restriction are denoted by opaque columns labeled ‘4-h meal’, with red signifying a daytime meal (hours 6–10 of the light period) and blue signifying a late nighttime meal (hours 21–01). Small red arrowheads pointing down denote beginning of total food deprivation test, and small green arrowheads pointing up denote the end of food deprivation. Waveforms of activity (E–H) and temperature (I–L) data were creating by averaging across 5 days of ad-lib food access prior to food restriction (grey shaded waveforms), the last 5 days of the daytime feeding schedule (light weighted red lines) and the last 5 days of the nightime feeding schedule (heavy weighted blue lines). 4-h mealtimes are denoted by the translucent columns. The daily lights-on period is denoted by the yellow horizontal bar above the x-axis. To improve the clarity of the waveforms, the data were subjected to a second order smoothing polynomial averaging across 4 neighbouring data points (Prism 5.0 for Mac OS X). Raw (unsmoothed) data were used for the raster plots and statistical analyses.</p