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The Mnpo-VLPO Pathway Augustin Walter, Lorijn Van Der Spek, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, Armelle Rancillac

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The Mnpo-VLPO Pathway Augustin Walter, Lorijn Van Der Spek, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, Armelle Rancillac Structural and functional connections between the median and the ventrolateral preoptic nucleus. : The MnPO-VLPO pathway Augustin Walter, Lorijn van der Spek, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, Armelle Rancillac To cite this version: Augustin Walter, Lorijn van der Spek, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, et al.. Structural and functional connections between the median and the ventrolateral preoptic nucleus. : The MnPO-VLPO pathway. Brain Structure and Function, Springer Verlag, 2019, 224 (9), pp.3045 - 3057. 10.1007/s00429-019-01935-4. hal-03230205 HAL Id: hal-03230205 https://hal.archives-ouvertes.fr/hal-03230205 Submitted on 19 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Structural and functional connections between the median and the ventrolateral preoptic nucleus Alexis-Pierre Bemelmans, Augustin Walter, Lorijn van der Spek, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, Armelle Rancillac To cite this version: Alexis-Pierre Bemelmans, Augustin Walter, Lorijn van der Spek, Eléonore Hardy, Alexis Pierre Be- melmans, et al.. Structural and functional connections between the median and the ventrolateral preoptic nucleus: The MnPO-VLPO pathway. Brain Structure and Function, Springer Verlag, 2019, 224 (9), Epub ahead of print. 10.1007/s00429-019-01935-4. inserm-02282038 HAL Id: inserm-02282038 https://www.hal.inserm.fr/inserm-02282038 Submitted on 9 Sep 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Structural and functional connections between the median and the ventrolateral preoptic nucleus Augustin Walter1,#, Lorijn van der Spek1,#, Eléonore Hardy1, Alexis-Pierre Bemelmans2, Nathalie Rouach1 & Armelle Rancillac1,* 1Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Centre National de la Recherche Scientifique UMR 7241, Institut National de la Santé et de la Recherche Médicale U1050, Collège de France, Labex Memolife, PSL-University, Paris, F-75005, France. 2Commissariat à l'Energie Atomique et aux Energies Alternatives, Département de la Recherche Fondamentale, Institut de biologie François Jacob, Molecular Imaging Research Center and Centre National de la Recherche Scientifique UMR9199, Université Paris-Sud, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France. #A. Walter and L. van der Spek contributed equally. Abbreviated title: The MnPO-VLPO pathway. Keywords: Sleep-promoting neuron, field recordings, VLPO, MnPO, NREM sleep, MEA * Correspondence should be addressed to: Dr. Armelle Rancillac Neuroglial Interactions in Cerebral Physiopathology Center for Interdisciplinary Research in Biology Collège de France CNRS UMR 7241, Inserm U1050 11 place Marcelin Berthelot 75005 Paris France E-mail: [email protected] 1 Abstract The median preoptic nucleus (MnPO) and the ventrolateral preoptic nucleus (VLPO) are two brain structures that contain neurons essential for promoting non-rapid eye movement (NREM) sleep. However, their connections are still largely unknown. Here, we describe for the first time a slice preparation with an oblique coronal slicing angle at 70° from the horizontal in which their connectivity is preserved. Using in vivo the iDISCO method following viral infection of the MnPO or ex vivo biocytin crystal deposition in the MnPO of mouse brain slices, we revealed a strong axonal pathway from the MnPO to the VLPO. Then, to further explore the functionality of these projections, acute 70°slices were placed on multielectrode arrays (MEAs) and electrical stimulations were performed near the MnPO. Recordings of the signals propagation throughout the slices revealed a preferential pathway from the MnPO to the VLPO. Finally, we performed an input-output curve of field responses evoked by stimulation of the MnPO and recorded in the VLPO. We found that field responses were inhibited by GABAA receptor antagonist, suggesting that afferent inputs from the MnPO activate VLPO neuronal networks by disinhibition. 2 Introduction Compared to the large number of brain structures involved in arousal, the ventrolateral preoptic nucleus (VLPO) is considered as one of the main brain regions that turns off wake-promoting neurons during non-rapid eye movement sleep (NREM) (Economo 1930; Sherin et al. 1996; Sakai and Crochet 2001; Saper et al. 2010). Sleep neurons in the VLPO are GABAergic and galaninergic. The immunodetection of galanin forms a cluster in the VLPO allowing its localization. Recently, another brain region composed of GABAergic neurons located in the medullary parafacial zone (PZ) was shown to be required for normal NREM sleep (Anaclet et al. 2014). Lesional experiments suggested that the VLPO could regulate NREMS sleep duration, while PZ could be involved in the regulation of the number of NREM episodes. The median pre-optic nucleus (MnPO) is another region involved in sleep regulation. Located along the midline and dorsal compared to the VLPO, this region also contains GABAergic sleep-active neurons that are c-Fos positive following a NREM sleep hypersomnia (Gong et al. 2004). In the VLPO as in the MnPO, the number of c-Fos neurons is proportional to NREM sleep duration prior the sacrifice of the mouse. In good agreement with this distribution of immunoreactive neurons for c-Fos, unitary recordings in the preoptic area revealed in the VLPO the existence of neurons discharging more frequently during the NREM sleep than during wakefulness (Szymusiak et al. 1998; Takahashi et al. 2009). In contrast to VLPO neurons that display an increase in discharge over an individual NREM period, MnPO sleep-active neurons discharge more frequently at the start of the NREM period (Alam et al. 2013). Therefore, the general hypothesis is that MnPO neurons play a more important role in NREM onset, whereas VLPO neurons are important for maintaining sleep. 3 Indeed, retrograde transport experiments identified a set of GABAergic neurons in the VLPO, containing the peptide galanin, which innervate all of the major components of the ascending arousal systems (Sherin et al. 1998; Saper et al. 2005). Retrograde labeling experiments previously revealed that MnPO neurons strongly project towards the VLPO (Chou et al., 2002; Thompson and Swanson, 2003, Uschakov et al., 2006; Uschakov et al., 2007). This pathway is believed to be crucial for NREM regulation, as MnPO neurons are considered to be involved in sleep pressure, whereas VLPO neurons regulate NREM onset and maintenance (Szymusiak et al., 1998; Takahashi et al., 2009; Gvilia et al., 2006), which may allow MnPO neurons to drive VLPO activity. However, the functionality of this pathway remained to be explored. Here, we used the in vivo the iDISCO method to reconstruct the pathway between the MnPO and the VLPO and biocytin crystal deposition into the MnPO of on coronal or 70° slices to validate the preparation. We show functional connectivity between the MnPO and the VLPO with MEA and field recordings. 4 Materials and Methods Animals. Male C57BL/6J mice (Janvier, France) and FVB Gal-GFP mice (Mutant Mouse Regional Resource Center (MMRRC), USA), 30 days old, were used. The Gal-GFP mouse strain STOCK Tg (Gal-EGFP) HX109Gsat/Mmucd (identification number 016342-UCD) was obtained from the MMRRC, a NIH-funded strain repository, and was donated by N. Heintz (Gong et al. 2003) to the MMRRC via the NINDS-funded GENSAT BAC transgenic project. All animals were bred and housed in a temperature-controlled (20-22°C) room under a 12/12 light/dark cycle (7 am/7 pm) with ad libitum access to food and water. Animals used for ex vivo studies were placed in light-tight ventilated cabinets and sacrificed at ZT-0. All animal procedures were conducted in strict compliance with our institutional protocols and were approved by the European Community Council Directive of 1 January 2013 (2010/63/EU) and the local ethics committee (C2EA-59, ‘Paris Centre et Sud’) and local guidelines for the ethical treatment of animal care (Center for Interdisciplinary Research in Biology in College de France, France). The number of animals used in our study was kept to the necessary minimum. AAV production and injection. One GFP cassette was placed under the control of a hSynapsin- specific promoter in an AAV shuttle plasmid containing the inverted terminal repeats (ITR) of AAV2. Pseudotype serotype 9 AAV particles were produced by transient cotransfection of HEK-293T cells. Viral titers were determined by quantitative PCR amplification of the ITR on DNase-resistant particles and expressed as vector genomes per mL (vg/mL). One-month old C57Bl6 mice were anesthetized with a mixture of ketamine (95 mg/kg; Merial) and xylazine (10 mg/kg; Bayer) in 0.9% NaCl and placed on a stereotaxic frame under body temperature monitoring. AAVs were diluted in PBS at a concentration of AAV-hSynapsin-GFP 1.02 × 1013vg/ml, and 0.5 μl of virus was stereotaxically injected unilaterally into the MnPO at 5 a rate of 0.2 μl/min, using a 29-gauge blunt-tip needle linked to a 2-μl Hamilton syringe (Phymep). The stereotaxic coordinates to Bregma were antero-posterior: -0.3 mm; lateral: 0 mm; and dorso-ventral: 4.5 mm. At the end of the injection, the needle was left in place for 5 min before being slowly removed.
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