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Interaction Between Hypothalamic Dorsomedial Nucleus and the Suprachiasmatic Nucleus Determines Intensity of Food Anticipatory Behavior

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Interaction Between Hypothalamic Dorsomedial Nucleus and the Suprachiasmatic Nucleus Determines Intensity of Food Anticipatory Behavior Interaction between hypothalamic dorsomedial nucleus and the suprachiasmatic nucleus determines intensity of food anticipatory behavior Guadalupe Acosta-Galvana,1, Chun-Xia Yia,1, Jan van der Vlietb,1, Jack H. Jhamandasc, Pertti Panulad, Manuel Angeles- Castellanose, María del Carmen Basualdoa, Carolina Escobare, and Ruud M. Buijsa,2 aDepartamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, DF 04510, Mexico; eDepartamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, DF 04510, Mexico; bTytgat Institute Academisch Medisch Centrum, 1105 BK, Amsterdam, The Netherlands; cDepartment of Medicine (Neurology), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2S2; and dNeuroscience Center, Institute of Biomedicine, University of Helsinki, 00014, Helsinki, Finland Edited by William J. Schwartz, University of Massachusets Medical School, Worcester, MA, and accepted by the Editorial Board February 24, 2011 (received for review October 18, 2010) Food anticipatory behavior (FAA) is induced by limiting access to and redundant neuronal network in which even the participation food for a few hours daily. Animals anticipate this scheduled meal of clock genes does not seem essential (12, 13). In the present event even without the suprachiasmatic nucleus (SCN), the bi- study, we therefore examined the hypothalamic circuitry that is ological clock. Consequently, a food-entrained oscillator has been involved in FAA by using a combination of behavior with neu- proposed to be responsible for meal time estimation. Recent ronal tracing, neuronal activity markers, and specific lesioning studies suggested the dorsomedial hypothalamus (DMH) as the techniques. Because daytime neuronal activity of the SCN and site for this food-entrained oscillator, which has led to considerable light-induced neuronal activity of the SCN are known to inhibit controversy in the literature. Herein we demonstrate by means of locomotor activity in nocturnal rodents (14, 15), we hypothesized c-Fos immunohistochemistry that the neuronal activity of the that during food restriction, to allow FAA during the light phase, suprachiasmatic nucleus (SCN), which signals the rest phase in the activity and influence of the SCN should be reduced. Because nocturnal animals, is reduced when animals anticipate the sched- the DMH is one of the structures with the most c-Fos activity uled food and, simultaneously, neuronal activity within the DMH during FAA (5, 8), we explored the contribution of the DMH– increases. Using retrograde tracing and confocal analysis, we show SCN interaction toward FAA in the rat as nocturnal rodent. We that inhibition of SCN neuronal activity is the consequence of show that the DMH has GABAergic projections to the SCN that activation of GABA-containing neurons in the DMH that project to are active during FAA and reduce the activity of the SCN. We the SCN. Next, we show that DMH lesions result in a loss or show that a lesion of the DMH decreases that inhibition and diminution of FAA, simultaneous with increased activity in the SCN. leads to a highly active SCN, leading to reduction or disap- A subsequent lesion of the SCN restored FAA. We conclude that in pearance of FAA. The disappearance of FAA following a lesion intact animals, FAA may only occur when the DMH inhibits the of the DMH and its reappearance in the same animal following activity of the SCN, thus permitting locomotor activity. As a result, a lesion of the SCN supports the notion that it is indeed the SCN FAA originates from a neuronal network comprising an interaction that inhibits locomotor activity, thereby preventing FAA during between the DMH and SCN. Moreover, this study shows that the the rest phase in DMH-lesioned animals. DMH–SCN interaction may serve as an intrahypothalamic system to Consequently the present results show that FAA is modulated gate activity instead of rest overriding circadian predetermined by the interaction of the SCN and DMH and suggest that FAA is temporal patterns. generated by a neuronal network, of which the SCN and the DMH are two components. hysiology and behavior of all mammals is organized in an al- Pternating pattern of rest and activity cycles, whereby the en- Results and Discussion dogenous and light-induced daily neuronal activity of the DMH–SCN Interaction. We used rats as our experimental animal suprachiasmatic nucleus (SCN) signals rest in nocturnal rodents and initially explored neuronal activation during FAA by means and activity in diurnal primates, such as humans (1, 2). Restricting of c-Fos immunohistochemistry in the hypothalamus. We used c- food access to a short and predictable episode during the rest Fos as a neuronal marker to investigate which brain areas are phase changes this behavioral pattern, such that an animal activated during FAA in a restricted food protocol. C-Fos is becomes active and for up to several hours anticipates the up- generally accepted as a marker for neuronal activity based on the coming feeding event. This food anticipatory activity (FAA) is early experiments of Morgan and Curran (16, 17); the limitation even exhibited without the known circadian oscillator, the SCN of this technique is that certain neuronal systems may not show (3), and thus may rely on a different circadian pacemaker. c-Fos resulting from their activation. We observed, in agreement In search of the location of this so-called “food entrained with earlier studies (18, 19), that together with increased c-Fos in oscillator” (FEO), two recent studies have claimed that its po- sition is within the dorsomedial nucleus of the hypothalamus (DMH) (4, 5). The designation of the DMH as master clock for Author contributions: C.E. and R.M.B. designed research; G.A.-G., C.-X.Y., J.v.d.V., M.A.-C., M.d.C.B., and R.M.B. performed research; J.H.J. and P.P. contributed new reagents/ana- food entrainment is, however, controversial because some lytic tools; G.A.-G., J.v.d.V., and C.E. analyzed data; and G.A.-G., C.-X.Y., C.E., and R.M.B. groups reported unimpaired FAA despite large lesions of the wrote the paper. DMH (6, 7); others have shown that lesions of the DMH disturb The authors declare no conflict of interest. and diminish the intensity of FAA (6). The possible participation This article is a PNAS Direct Submission. W.J.S. is a guest editor invited by the Editorial of other brain structures in FAA is evident from studies that Board. demonstrate modulation of neuronal activity and induction of 1G.A.-G., C.-X.Y., and J.v.d.V. contributed equally to this paper. clock-gene rhythmicity in hypothalamic and limbic structures by 2To whom correspondence should be addressed. E-mail: [email protected]. – NEUROSCIENCE feeding schedules (8 11). Thus, it has been suggested that FAA This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. depends on a multioscillatory system comprised of a complex 1073/pnas.1015551108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1015551108 PNAS | April 5, 2011 | vol. 108 | no. 14 | 5813–5818 Downloaded by guest on September 24, 2021 the ventral DMH, neurons in the ventral part of the SCN de- from the retina (Fig. 1G). Both observations suggest that the creased their activity (Fig. S1). Following our hypothesis that at projections of the DMH to the SCN may interact with light input least one brain structure that is involved in food anticipation that is arriving from the retina and may modulate the activity of needs to interact with the SCN to inhibit its activity, we placed the SCN in that area. the neuronal tracer cholera toxin subunit B (CtB) into the SCN (n = 24). These injections, especially when placed in the ventral DMH Inhibits SCN Neuronal Activity During FAA. In view of the SCN (n =4)(Fig. S2A), revealed retrograde-labeled neurons in projections of the RFRP neurons to the ventral SCN (Fig. 1D), several hypothalamic areas, including the DMH (Fig. 1A). We and in view of the evidence that many neurons of the DMH observed that the CtB-positive neurons were present in the same contain the inhibitory amino acid GABA (23), we examined area of the DMH that showed c-Fos activation during food re- whether the RFRP projections from the DMH to the SCN may striction (Fig. 1 A and B). The next observation was that the contain GABA. Therefore, the presence of the enzyme for the distribution of the neurons within the DMH projecting to the synthesis of GABA, glutamate decarboxylase (GAD), was ex- SCN was similar to those neurons in the DMH that express Arg- amined in RFRP-positive fibers terminating in the SCN. Con- Phe-Amide-related peptide (Fig. 1C), one of the five active focal microscopic analysis revealed that RFRP fibers terminating mammalian restricted-food amide peptides (RFRP). This ob- in the SCN contained GAD, indicating an inhibitory role of this servation was further investigated using injection of the tracer DMH input to the SCN (Fig. 1 H and I). CtB in the SCN, resulting in retrograde-labeled neurons in the To investigate the relevance of this DMH–SCN interaction for DMH containing RFRP (Fig. 1D). Because RFRP peptides are FAA in 30 naive animals, we first established a baseline of FAA postulated to have a feeding-related functionality (20–22), we by a restricted-food protocol. Because naive animals show a large examined and demonstrated by means of double-labeling im- variation in FAA, we only chose 24 animals that showed clear munofluorescence and confocal microscopical analysis that some evidence of FAA. We divided these animals into three groups neurons with c-Fos labeling during FAA are also positive for (n = 24): (i) a control group that received a (sham) lesion of the RFRP (Fig.
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