Research reportWake-related activity of tuberomammillary neurons in rats
Introduction
Since the 1930s, researchers have hypothesized that the posterior hypothalamus promotes wakefulness as incidental lesions due to encephalitis and experimental lesions of this area increase sleep and disrupt wakefulness [2], [15], [35]. Several neuronal systems are located in this area, including the histaminergic neurons of the tuberomammillary nucleus (TMN). These neurons are clustered in three subnuclei: the dorsomedial TMN (TMNd) sits along the dorsal edge of the mammillary recess of the third ventricle; the ventrolateral TMN (TMNv) rests along the base of the hypothalamus, lateral to the mammillary recess; and the caudal TMN (TMNc) surrounds the mammillary body [22]. Despite their relatively small number, histaminergic TMN neurons project widely throughout the brain, especially to the cerebral cortex, basal forebrain, and hypothalamus [4], [8], [36]. Afferents to the TMN are less well understood [5], but the TMNv is heavily innervated by the core region of the ventrolateral preoptic area (VLPO), a non-rapid eye movement (NREM) sleep-active area. The TMNd also receives input from the VLPO, but mostly from the rapid eye movement (REM) sleep-active, extended VLPO [16], [28], [30]. As these TMN subnuclei have different patterns of inputs, they also may have different patterns of activity.
This pattern of projections suggests that TMN histaminergic neurons may play an important role in behavioral state control, but the functions of this system are incompletely understood. TMNv and TMNc neurons fire most rapidly during wakefulness [29], and the extracellular concentration of histamine is highest during wakefulness [17], [31]. Many anti-histamine drugs cause drowsiness, and mice that cannot synthesize histamine have less wakefulness at the beginning of the dark period and rapidly fall asleep in new environments [23]. These findings suggest that histamine may help initiate or maintain wakefulness.
While these studies generally suggest that histaminergic TMN neurons are active during wakefulness, it remains unknown whether this pattern is due to circadian influences or whether the TMN subnuclei are all wake-active. Drugs that promote wakefulness or sleep are associated with increased or decreased Fos expression in TMNv neurons, respectively [19], [20], [25], [26], but little is known about the activity of TMN neurons in spontaneously behaving animals. Furthermore, few studies have differentiated the TMN subnuclei when examining TMN neuronal activity. To address these questions, we used Fos and adenosine deaminase immunohistochemistry to study the activity of TMN neurons in association with spontaneous variations in sleep/wake behavior.
Section snippets
Experimental design
We performed two experiments to determine whether histamine neuron activity varies with time of day or behavioral state. Rats were instrumented for electroencephalogram (EEG), electromyogram (EMG), and body temperature recordings, as described below. The animals were sacrificed at specific times, and brain sections were immunostained for Fos and adenosine deaminase (ADA), a marker of histaminergic TMN neurons [24], [37]. Each experimental group contained six to eight animals. All experiments
Experiment 1: TMN activity across 24 h
In rats maintained on a 12:12 LD cycle, TMN Fos expression was higher during the dark period than during the light period (Table 1). This increase was most apparent in the percentage of ADA-IR/Fos-IR neurons, with clear variations across the 4 time points in the dorsomedial, ventrolateral, and caudal subdivisions (p=0.001, 0.008, and 0.02, respectively) (Fig. 2). The percentage of ADA-IR neurons containing Fos was higher in either nighttime group compared to either daytime group. The only
Discussion
We used Fos immunohistochemistry to examine the relationship between TMN neuronal activity and behavioral state. Histaminergic neurons in all TMN subnuclei had increased Fos expression after periods of wakefulness, both over the course of 24 h, and after short periods of spontaneous wakefulness, independent of circadian phase. This pattern suggests that many TMN neurons are wake-active and may play an important role in regulating behavior during wakefulness.
Most likely, these variations in TMN
Acknowledgements
This work was supported by NIH grants MH62589 and MH01507. C. Saper and T. Mochizuki provided thoughtful comments on this manuscript.
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