Interaction between hypothalamic dorsomedial nucleus and the suprachiasmatic nucleus determines intensity of food anticipatory behavior

Abstract

Food anticipatory behavior (FAA) is induced by limiting access to food for a few hours daily. Animals anticipate this scheduled meal event even without the suprachiasmatic nucleus (SCN), the biological clock. Consequently, a food-entrained oscillator has been proposed to be responsible for meal time estimation. Recent studies suggested the dorsomedial hypothalamus (DMH) as the site for this food-entrained oscillator, which has led to considerable controversy in the literature. Herein we demonstrate by means of c-Fos immunohistochemistry that the neuronal activity of the suprachiasmatic nucleus (SCN), which signals the rest phase in nocturnal animals, is reduced when animals anticipate the scheduled food and, simultaneously, neuronal activity within the DMH increases. Using retrograde tracing and confocal analysis, we show that inhibition of SCN neuronal activity is the consequence of activation of GABA-containing neurons in the DMH that project to the SCN. Next, we show that DMH lesions result in a loss or diminution of FAA, simultaneous with increased activity in the SCN. A subsequent lesion of the SCN restored FAA. We conclude that in intact animals, FAA may only occur when the DMH inhibits the activity of the SCN, thus permitting locomotor activity. As a result, FAA originates from a neuronal network comprising an interaction between the DMH and SCN. Moreover, this study shows that the DMH-SCN interaction may serve as an intrahypothalamic system to gate activity instead of rest overriding circadian predetermined temporal patterns. P hysiology and behavior of all mammals is organized in an alternating pattern of rest and activity cycles, whereby the endogenous and light-induced daily neuronal activity of the suprachiasmatic nucleus (SCN) signals rest in nocturnal rodents and activity in diurnal primates, such as humans (1, 2). Restricting food access to a short and predictable episode during the rest phase changes this behavioral pattern, such that an animal becomes active and for up to several hours anticipates the upcoming feeding event. This food anticipatory activity (FAA) is even exhibited without the known circadian oscillator, the SCN (3), and thus may rely on a different circadian pacemaker.In search of the location of this so-called "food entrained oscillator" (FEO), two recent studies have claimed that its position is within the dorsomedial nucleus of the hypothalamus (DMH) (4, 5). The designation of the DMH as master clock for food entrainment is, however, controversial because some groups reported unimpaired FAA despite large lesions of the DMH (6, 7); others have shown that lesions of the DMH disturb and diminish the intensity of FAA (6). The possible participation of other brain structures in FAA is evident from studies that demonstrate modulation of neuronal activity and induction of clock-gene rhythmicity in hypothalamic and limbic structures by feeding schedules (8-11). Thus, it has been suggested that FAA depends on a multioscillatory system comprised of a complex and redundant neuronal netwo...

Bmal1in the Nervous System Is Essential for Normal Adaptation of Circadian Locomotor Activity and Food Intake to Periodic Feeding

“…Thus, reciprocal interactions among multiple clocks throughout the body including the SCN seem very important for determining temporal patterns of animals' behavior and physiology. Importantly, suppressive effects of SCN-derived signals on FAA have been suggested (Acosta-Galvan et al, 2011). In Bmal1 Ϫ/ Ϫ mice, the absence of all circadian clocks throughout the body may enhance the emergence of FAA regulated by noncircadian mechanisms.…”

Endocrine regulation of circadian physiology

“…Two neural substrates have been identified to modify FAA rhythms, which are also established targets of leptin and ghrelin: the dopaminergic reward circuitry Gallardo et al 2014 and the mediobasal hypothalamic appetite-regulating circuitries centers (Bechtold & Loudon 2013). The SCN itself has been recognized as a negative regulator of FAA rhythms (Storch & Weitz 2009, Acosta-Galvan et al 2011. Given that both of these two hormones can directly act on the SCN clock, it is plausible that the circadian pacemaker may mediate part of their FAA-regulating effects.…”

“…Given that both of these two hormones can directly act on the SCN clock, it is plausible that the circadian pacemaker may mediate part of their FAA-regulating effects. Alternatively, it has been shown that the DMH is a positive regulator of FAA through suppression of SCN neuronal activity (Acosta-Galvan et al 2011). The DMH receives input from several metabolic state-sensing brain nuclei such as the ARC (Bouret et al 2004), thus acting as a relay mediating the FAA effects of metabolic hormones.…”

Chrono-biology, Chrono-pharmacology, and Chrono-nutrition

“…Several studies have demonstrated that DMH-lesioned mice and rats showed a significant reduction in FAA formation (113 -115). However, the ability to induce FAA was still present in DMH-lesioned mice (116,117). The decisive data provided by Acosta-Galvan et al (117) indicate that DMH-lesioned mice have reduced FAA, whereas both DMH-and SCN-lesioned mice have increased FAA.…”

“…However, the ability to induce FAA was still present in DMH-lesioned mice (116,117). The decisive data provided by Acosta-Galvan et al (117) indicate that DMH-lesioned mice have reduced FAA, whereas both DMH-and SCN-lesioned mice have increased FAA. This result suggests that the DMH is part of the FEO but not a prerequisite for the induction of FAA.…”