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Orexin-Neuromodulated Cerebellar Circuit Controls Redistribution of Arterial Blood flows for Defense Behavior in Rabbits

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Orexin-Neuromodulated Cerebellar Circuit Controls Redistribution of Arterial Blood flows for Defense Behavior in Rabbits Orexin-neuromodulated cerebellar circuit controls redistribution of arterial blood flows for defense behavior in rabbits Naoko Nisimarua,b, Chetan Mittala,c,1, Yoshinori Shiraia,d, Thongchai Sooksawatee,2, Prabu Anandaraja,c,1, Tsutomu Hashikawaa, Soichi Nagaoa, Akiko Arataa,f, Takeshi Sakuraig, Miyuki Yamamotoh, and Masao Itoa,3 aRIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; bDepartment of Physiology, Faculty of Medicine, Oita University,1-1 Idaigaoka, Hasama,Yufu, Oita 879-5593, Japan; cIndian Institute of Technology, Kharagpur 721-302, India; dDepartment of Neuroplasticity, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; eDepartment of Physiology, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok 10330, Thailand; fDepartment of Physiology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan; gDepartment of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; and hComprehensive Human Studies, University of Tsukuba, 1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2007. Contributed by Masao Ito, July 9, 2013 (sent for review April 27, 2012) We investigated a unique microzone of the cerebellum located in A functionally unique feature of fp is that a large portion of folium-p (fp) of rabbit flocculus. In fp, Purkinje cells were potently Purkinje cells in it are excited by stimulation of the classic de- excited by stimulation of the hypothalamus or mesencephalic peri- fense areas in the hypothalamus and mesencephalic periaqu- aqueductal gray, which induced defense reactions. Using multiple eductal gray (PAG) (14). Electrical or chemical stimulation of neuroscience techniques, we determined that this excitation was the defense areas induces complex motor activities for “fight or mediated via beaded axons of orexinergic hypothalamic neurons flight” and associated cardiovascular responses such as rapid passing collaterals through the mesencephalic periaqueductal increase of blood pressure (BP) (15–17). In natural behaving gray. Axonal tracing studies using DiI and biotinylated dextran conditions, harmful stimuli activate the defense areas via the amine evidenced the projection of fp Purkinje cells to the ventro- amygdala (for review, see ref. 18). Involvement of orexins in the lateral corner of the ipsilateral parabrachial nucleus (PBN). Be- cardiovascular defense reactions has been suggested because cause, in defense reactions, arterial blood flow has been known the genetically induced orexin deficiency in mice leads to atten- to redistribute from visceral organs to active muscles, we hypoth- uation of the transient increase of blood pressure evoked from fl esized that, via PBN, fp adaptively controls arterial blood ow defense areas (19, 20). redistribution under orexin-mediated neuromodulation that could We analyzed neuronal circuit connections to and from fp using occur in defense behavior. This hypothesis was supported by our axonal transport tracers. Importantly, we found that Pukinje cells fi fi nding that climbing ber signals to fp Purkinje cells were elicited in fp project their axons to the ventrolateral corner of the ipsi- by stimulation of the aortic nerve, a high arterial blood pressure, lateral parabrachial nucleus (PBN), a major cardiovascular center or a high potassium concentration in muscles, all implying errors in in the brainstem (21, 22). It was previously shown that PBN the control of arterial blood flow. We further examined the arte- receives Purkinje cell axons from the anterior vermis (21) as well rial blood flow redistribution elicited by electric foot shock stimuli as the middle (6) and lateralmost regions (7) of the nodulus- in awake, behaving rabbits. We found that systemic administra- uvula. These observations suggest that PBN acts as a functional tion of an orexin antagonist attenuated the redistribution and that interface between the cerebellum and supraspinal cardiovascular lesioning of fp caused an imbalance in the redistribution between fl active muscles and visceral organs. Lesioning of fp also diminished centers (21). In defense reactions, arterial blood ow is redis- foot shock-induced increases in the mean arterial blood pressure. tributed from visceral organs and resting muscles to active muscles These results collectively support the hypothesis that the fp micro- (17) by the action of the sympathetic nervous system (23). Subtle complex adaptively controls defense reactions under orexin-mediated control of this redistribution is needed to maintain cardiovascular fi neuromodulation. homeostasis while ful lling the high demand for arterial blood supply to muscles actively involved in defense reactions. fi somatosympathetic | vestibulosympathetic | OX-1R antagonist | On the above-introduced backgrounds, we attempted to de ne bicuculline | baroreceptor the role of orexins in fp function and the role of fp in the control of arterial blood flow. We used rabbits because their flocculus he cerebellar cortex consists of numerous microzones, each has discernible regular folial divisions (8, 9), which is not the case Textending 10 mm2 or so (ref. 1; for review, see ref. 2). Each in rats or mice. microzone receives three distinct types of input, that is, mossy fibers, climbing fibers, and beaded fibers. Beaded fibers contain certain amines or neuropeptides (for review, see refs. 3 and 4) A preliminary report of this work was delivered by N.N. and M.I. at the 35th International and distribute diffusely; supposedly, they determine the general Congress of Physiological Sciences, March 31–April 5, 2005, San Diego, CA, abstract 512. activity or the mode of operation of their target neurons, that is, Author contributions: N.N., A.A., M.Y., and M.I. designed research; N.N., C.M., Y.S., neuromodulation, unlike input/output-specific transmission in T. Sooksawate, P.A., T.H., S.N., A.A., M.Y., and M.I. performed research; T. Sakurai con- fi fi tributed new reagents/analytic tools; N.N., C.M., Y.S., T. Sooksawate, A.A., M.Y., and M.I. mossy bers and climbing bers (5). Several microzones have analyzed data; and N.N., T. Sakurai, and M.I. wrote the paper. been analyzed with regard to their circuit mechanisms and spe- The authors declare no conflict of interest. cificreflex functions (not only somatic; some are autonomic) (6, 7), but the actual roles of beaded fibers remain largely unknown. Freely available online through the PNAS open access option. In this study, we focused on a particular microzone located in the 1On leave from: Indian Institute of Technology, Kharagpur 721-302, India. flocculus [folium-p (fp)] (8, 9), which receives beaded fibers 2On leave from: Chulalongkorn University, Bangkok 10330, Thailand. containing orexins (hypocretins) (10). Orexins consist of A and B 3To whom correspondence should be addressed. E-mail: [email protected]. isopeptides containing 33 and 28 amino acids, respectively, and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. have been implicated in sleep and feeding (11–13). 1073/pnas.1312804110/-/DCSupplemental. 14124–14131 | PNAS | August 27, 2013 | vol. 110 | no. 35 www.pnas.org/cgi/doi/10.1073/pnas.1312804110 Downloaded by guest on September 23, 2021 Results Orexin-Immunopositive Beaded Fibers in Rabbit Cerebellum. In rab- INAUGURAL ARTICLE bits, the flocculus lies in the rostroventrolateral corner of the cerebellum (Fig. 1A) and consists of six folia, fm, f1, f2, f3, f4, and fp (8. 9) (Fig. 1B). In coronal sections, a cut face of fp can be identified by its flattened triangular appearance, with the peak pointing ventrolaterally (Fig. 1C). As examined in three com- plete sets of serial coronal sections (60 μm thick) of the left flocculus, the Purkinje cell layer in fp maximally expands dor- soventrally by 3.0 ± 0.1 mm (mean ± SE of mean, throughout this article) and anteroposteriorly by 3.1 ± 0.2 mm, the total area 2 being 7.2 ± 0.9 mm . Fig. 2. Orexinergic axons in flocculus. (A and B) Beaded orexin-immuno- Immunohistochemical data on orexins are abundant in the positive fibers double-stained for calbindin (red) and orexins (green). ML, literature for mice and rats but are scarce for rabbits; therefore, molecular layer; PC, Purkinje cell. we collected our own data for confirmation. Within the cere- bellum, we observed orexin-immunopositive fibers located al- most exclusively in the flocculus, with a rare detection of such hypothalamus (24). Therefore, we injected SAP into the hypo- fibers in the vermis, as similarly observed in rats (10). A fluo- thalamus as a nonspecific lesioning agent. In two rabbits in which rescence microscopy image shows the beaded appearance of SAP-induced lesions covered the hypothalamus defense area these fibers, which lie adjacent to Purkinje cells and ascend to the bilaterally (except for some surviving orexin-immunopositive neu- molecular layer, some running parallel to the Purkinje cell layer rons) (Fig. S1B), orexin-immunopositive fibers in PAG largely di- (Fig. 2 A and B). In one flocculus, we counted 46 such fibers in minished (Fig. S1D); this finding confirms that these fibers are the molecular layer, 74 in the Purkinje cell layer, and 71 in the branches of orexin-immunopositive fibers of hypothalamic origin. granular layer. As summarized for three rabbits (Table S1), the Abnormally low basal BP was reported to prevail in genetically density of orexin-immunopositive fibers in cross-sectional areas orexin-deficient mice (19), but abnormally low basal BP was not of fp is 2.77 times as high as that in all other (non-fp) folia of the case in our two rabbits systemically injected with orexin the flocculus. The common presence of orexin-immunopositive receptor-1 (OX-1R) antagonists; mean BP were 92 and 105 mmHg fibers may justify our classification of fp as part of the rabbit against the control values 98 and 108 mmHg, respectively. In three flocculus whereas Tan et al. (9) deemed fp as part of the ventral SAP-treated rabbits, the average of the mean BP was also normal: NEUROSCIENCE paraflocculus.
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