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Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep.

Sapin E, Lapray D, Bérod A, Goutagny R, Léger L, Ravassard P, Clément O, Hanriot L, Fort P, Luppi PH - PLoS ONE (2009)

Bottom Line: In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS.Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist.From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.

View Article: PubMed Central - PubMed

Affiliation: CNRS, UMR5167, Physiopathologie des réseaux neuronaux du cycle veille-sommeil, Lyon, France.

ABSTRACT
Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.

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Activated GABAergic neurons in the vlPAG/DpMe region after paradoxical sleep deprivation and hypersomnia (Fos immunohistochemistry combined with GAD67 mRNA in situ hybridization).Schematic distribution of Fos+ (small black dots) and Fos-GAD (large red dots) neurons in the vlPAG/dDpMe region in PSD (A) and PSR (B) animals (sections −7.40 from Bregma). Double-labeled neurons in the vlPAG are more abundant in the lateral and ventral portions of the vlPAG in the PSD animal and in its medial part in the PSR animal.
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pone-0004272-g002: Activated GABAergic neurons in the vlPAG/DpMe region after paradoxical sleep deprivation and hypersomnia (Fos immunohistochemistry combined with GAD67 mRNA in situ hybridization).Schematic distribution of Fos+ (small black dots) and Fos-GAD (large red dots) neurons in the vlPAG/dDpMe region in PSD (A) and PSR (B) animals (sections −7.40 from Bregma). Double-labeled neurons in the vlPAG are more abundant in the lateral and ventral portions of the vlPAG in the PSD animal and in its medial part in the PSR animal.

Mentions: The vlPAG contained a very large number of Fos-GAD double-labeled neurons in PSD animals compared to PSC ones (Figures 1A, B, 2A, Table 1 and Figures S1 and S2). The double-labeled neurons constituted 55% of all the Fos-positive (Fos+) neurons observed in this structure. The lateral part of the periaqueductal gray (lPAG), dDpMe (Figures 1A, B, 2A, S1, and S2), the parvicellular (PCRt) and gigantocellular reticular nuclei (Gi) contained a substantial number of double-labeled cells (Table 1 and Figures S3 and S4). Importantly, the dDpMe and the PCRt were the only brainstem structures in which the number of Fos-GAD neurons was significantly higher in PSD condition not only compared to PSC but also to PSR condition (Table 1). In addition, the double-labeled neurons localized in the dDpMe and the most adjacent part of the vlPAG were strongly GAD-positive (GAD+) and mainly located at the level of the caudal oculomotor nucleus and of the trochlear nucleus (Figure 1A, B). The laterodorsal tegmental nucleus (LDTg) and the caudal part of the DPGi (cDPGi) (Figures S2, S3, S4) contained a small number of double-labeled cells in PSD condition but still significantly above that counted in PSC condition (Table 1). Finally, the percentage of Fos+ neurons expressing GAD67 in the cuneiform (CnF), lateral parabrachial nuclei (LPB) and PCRt was similar (34.2% vs 34,9% respectively, see above), with a more substantial number of double-labeled neurons in the PCRt compared to the two other nuclei (Table 1 and Figures S2 and S3).


Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep.

Sapin E, Lapray D, Bérod A, Goutagny R, Léger L, Ravassard P, Clément O, Hanriot L, Fort P, Luppi PH - PLoS ONE (2009)

Activated GABAergic neurons in the vlPAG/DpMe region after paradoxical sleep deprivation and hypersomnia (Fos immunohistochemistry combined with GAD67 mRNA in situ hybridization).Schematic distribution of Fos+ (small black dots) and Fos-GAD (large red dots) neurons in the vlPAG/dDpMe region in PSD (A) and PSR (B) animals (sections −7.40 from Bregma). Double-labeled neurons in the vlPAG are more abundant in the lateral and ventral portions of the vlPAG in the PSD animal and in its medial part in the PSR animal.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2629845&req=5

pone-0004272-g002: Activated GABAergic neurons in the vlPAG/DpMe region after paradoxical sleep deprivation and hypersomnia (Fos immunohistochemistry combined with GAD67 mRNA in situ hybridization).Schematic distribution of Fos+ (small black dots) and Fos-GAD (large red dots) neurons in the vlPAG/dDpMe region in PSD (A) and PSR (B) animals (sections −7.40 from Bregma). Double-labeled neurons in the vlPAG are more abundant in the lateral and ventral portions of the vlPAG in the PSD animal and in its medial part in the PSR animal.
Mentions: The vlPAG contained a very large number of Fos-GAD double-labeled neurons in PSD animals compared to PSC ones (Figures 1A, B, 2A, Table 1 and Figures S1 and S2). The double-labeled neurons constituted 55% of all the Fos-positive (Fos+) neurons observed in this structure. The lateral part of the periaqueductal gray (lPAG), dDpMe (Figures 1A, B, 2A, S1, and S2), the parvicellular (PCRt) and gigantocellular reticular nuclei (Gi) contained a substantial number of double-labeled cells (Table 1 and Figures S3 and S4). Importantly, the dDpMe and the PCRt were the only brainstem structures in which the number of Fos-GAD neurons was significantly higher in PSD condition not only compared to PSC but also to PSR condition (Table 1). In addition, the double-labeled neurons localized in the dDpMe and the most adjacent part of the vlPAG were strongly GAD-positive (GAD+) and mainly located at the level of the caudal oculomotor nucleus and of the trochlear nucleus (Figure 1A, B). The laterodorsal tegmental nucleus (LDTg) and the caudal part of the DPGi (cDPGi) (Figures S2, S3, S4) contained a small number of double-labeled cells in PSD condition but still significantly above that counted in PSC condition (Table 1). Finally, the percentage of Fos+ neurons expressing GAD67 in the cuneiform (CnF), lateral parabrachial nuclei (LPB) and PCRt was similar (34.2% vs 34,9% respectively, see above), with a more substantial number of double-labeled neurons in the PCRt compared to the two other nuclei (Table 1 and Figures S2 and S3).

Bottom Line: In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS.Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist.From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.

View Article: PubMed Central - PubMed

Affiliation: CNRS, UMR5167, Physiopathologie des réseaux neuronaux du cycle veille-sommeil, Lyon, France.

ABSTRACT
Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.

Show MeSH
Related in: MedlinePlus