Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus

Abstract

Sleep and feeding rhythms are highly coordinated across the circadian cycle, but the brain sites responsible for this coordination are unknown. We examined the role of neuropeptide Y (NPY) receptor-expressing neurons in the mediobasal hypothalamus (MBH) in this process by injecting the targeted toxin, NPY-saporin (NPY-SAP), into the arcuate nucleus (Arc). NPY-SAP-lesioned rats were initially hyperphagic, became obese, exhibited sustained disruption of circadian feeding patterns, and had abnormal circadian distribution of sleep-wake patterns. Total amounts of rapid eye movement sleep (REMS) and non-REMS (NREMS) were not altered by NPY-SAP lesions, but a peak amount of REMS was permanently displaced to the dark period, and circadian variation in NREMS was eliminated. The phase reversal of REMS to the dark period by the lesion suggests that REMS timing is independently linked to the function of MBH NPY receptor-expressing neurons and is not dependent on NREMS pattern, which was altered but not phase reversed by the lesion. Sleep-wake patterns were altered in controls by restricting feeding to the light period, but were not altered in NPY-SAP rats by restricting feeding to either the light or dark period, indicating that disturbed sleep-wake patterns in lesioned rats were not secondary to changes in food intake. Sleep abnormalities persisted even after hyperphagia abated during the static phase of the lesion. Results suggest that the MBH is required for the essential task of integrating sleep-wake and feeding rhythms, a function that allows animals to accommodate changeable patterns of food availability. NPY receptor-expressing neurons are key components of this integrative function. arcuate nucleus; NPY-saporin; obesity; rapid eye movement sleep FEEDING AND VIGILANCE (sleep-wake) states are rhythmically expressed across the circadian cycle, and their rhythms are highly integrated (3,64,75). Integration of sleep-wake and feeding rhythms is of fundamental importance for survival. Indeed, a wakeful state is an intrinsic requirement for feeding and foraging behavior, and, in a changeable environment, only close communication between these particular rhythms would permit an animal to respond adaptively and opportunistically to changing patterns of food availability. Although the suprachiasmatic nucleus of the hypothalamus (SCN) has an acknowledged role in establishing and maintaining circadian rhythms (47,63,83), including sleep-wake rhythms (15), entrainment of circadian food-anticipatory rhythms does not require the SCN (79,82), supporting the possibility that integration of sleep-wake and feeding also occurs outside the SCN. Furthermore, integration of physiological signals required to derive rhythms compatible with homeostatic requirements is likely to occur outside the SCN (6,48,75), as this arrangement would provide maximum flexibility for responding to varying challenges.Surprisingly few experiments have attempted to determine sites responsible for integration of sleep and feeding rhythms. However, a large body o...

Drosophila Neuropeptide F Signaling Independently Regulates Feeding and Sleep-Wake Behavior

“…Intact sleep-wake behavior is vital for optimum well-being and, in turn, healthy aging across taxa, with changes in NPF/NPY signaling known to alter the circadian timing (Hermann et al, 2012, Wiater et al, 2011), amount (He et al, 2013, Szentirmai and Krueger, 2006), or continuity of sleep behavior. Likewise, manipulating the excitability of Drosophila NPF neurons changes the fly’s state of hunger (Krashes et al, 2009) and feeding behavior following starvation (Hergarden et al, 2012), with similar effects observed when NPY signaling is altered in mammals (Luquet et al, 2005).…”

Neuropeptide Y stimulates autophagy in hypothalamic neurons

“…Recently, it was described that this brain area is critical for the development of whole-body aging and has impact on lifespan (13,14). In the hypothalamus, NPY is involved in the regulation of different physiological functions, such as regulation of food intake, body temperature, circadian rhythms, memory processing, and cognition (15)(16)(17)(18)(19) (20,21), all of which have been reported to be present in the hypothalamus (22).…”

Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction

“…Rats were anesthetized using 1.0 ml/kg body wt of a ketamine-xylazineacepromazine cocktail [5 ml ketamine HCl, 100 mg/ml (Fort Dodge Animal Health, Fort Dodge, IA); 2.5 ml xylazine, 20 mg/ml, (Vedco, St. Joseph, MO); 1 ml acepromazine, 10 mg/ml (Vedco), and 1.5 ml 0.9% saline solution]. Stereotaxic microinjection parameters, modified from previous work using NPY-SAP and Lep-SAP to lesion Arc neurons (59,28), were used to deliver Lep-SAP and control solution. Lep-SAP (24 ng/50 nl; Advanced Targeting Systems, Carlsbad, CA) was dissolved in 0.1 M PBS (pH 7.4) and injected bilaterally into two sites per side into the Arc.…”

“…Receptors for leptin occur densely in the Arc and are often coexpressed with neuropeptide Y (NPY) (3, 52). The mediobasal hypothalamus, including the Arc, contributes to the hypothalamic control of circadian rhythms, including feeding and rest/activity (22,49,59,28). Obese Zucker rats lacking leptin receptors maintain modified light-entrained temperature and locomotor rhythms and enhanced food anticipatory activity (41, 37).…”

“…Lesions targeted to the Arc block the feeding and anorexic effects of exogenous leptin, induce severe hyperphagia and obesification (7,28), produce rest-activity disturbances (59), and result in circadian arrhythmia for ad libitum feeding (28). We hypothesized that leptin-receptive neurons in the Arc area are important in locomotor and temperature rhythms.…”