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Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists.

Zhang Z, Ferretti V, Güntan İ, Moro A, Steinberg EA, Ye Z, Zecharia AY, Yu X, Vyssotski AL, Brickley SG, Yustos R, Pillidge ZE, Harding EC, Wisden W, Franks NP - Nat. Neurosci. (2015)

Bottom Line: For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively.Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation.Thus, α2 adrenergic receptor-induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Imperial College London, South Kensington, UK.

ABSTRACT
Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic-induced sedation and loss of righting reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively. Selective knockdown of α2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation. We used TetTag pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases, non-rapid eye movement sleep, with the accompanying drop in body temperature, was recapitulated. Thus, α2 adrenergic receptor-induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.

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Selective knockout of the GABA vesicular transporter gene (vgat) in the PO hypothalamic area (LPO-Δvgat mice) slows the transition to dexmedetomidine-induced sleep. (a) Cre recombinase, produced from an AAV transgene, deletes exon 2 of the vgat gene33 following AAV-Cre-2A-Venus bilateral injection into the LPO area of vgatlox/lox mice. The image on the right shows the extent of AAV expression, as detected by staining with EGFP antisera. (b) EEG power spectra ten minutes after dexmedetomidine (100 μg kg−1 – red line) or saline (black) injection in control mice (n=8) expressing AAV-GFP in the LPO (LPO-GFP mice; n=6). Lighter shaded envelopes indicate the s.e.m. (c) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg/kg; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-GFP control mice. (d) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=7) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=6) in LPO-GFP control mice. (e) EEG power spectra ten minutes after dexmedetomidine (100 μg/kg – red line; n=6) or saline (black) injection in mice (n=8) expressing AAV-Cre-2A-Venus in the LPO (LPO-Δvgat mice). (f) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (n=8) in AAV-Cre-2A-Venus mice. (g) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-Δvgat mice. For all panels the error bars represent s.e.m.
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Figure 7: Selective knockout of the GABA vesicular transporter gene (vgat) in the PO hypothalamic area (LPO-Δvgat mice) slows the transition to dexmedetomidine-induced sleep. (a) Cre recombinase, produced from an AAV transgene, deletes exon 2 of the vgat gene33 following AAV-Cre-2A-Venus bilateral injection into the LPO area of vgatlox/lox mice. The image on the right shows the extent of AAV expression, as detected by staining with EGFP antisera. (b) EEG power spectra ten minutes after dexmedetomidine (100 μg kg−1 – red line) or saline (black) injection in control mice (n=8) expressing AAV-GFP in the LPO (LPO-GFP mice; n=6). Lighter shaded envelopes indicate the s.e.m. (c) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg/kg; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-GFP control mice. (d) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=7) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=6) in LPO-GFP control mice. (e) EEG power spectra ten minutes after dexmedetomidine (100 μg/kg – red line; n=6) or saline (black) injection in mice (n=8) expressing AAV-Cre-2A-Venus in the LPO (LPO-Δvgat mice). (f) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (n=8) in AAV-Cre-2A-Venus mice. (g) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-Δvgat mice. For all panels the error bars represent s.e.m.

Mentions: To test if dexmedetomidine-induced sedation required GABAergic neurons in the LPO area, we deleted the vesicular GABA transporter (vgat) gene by injecting AAV-Cre-2A-Venus bilaterally into the LPO of mice homozygous for a floxed vgat gene33, vgatlox/lox, to give LPO-Δvgat mice (Fig. 7a). Control vgatlox/lox mice were injected with AAV-GFP to give LPO-GFP mice.


Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists.

Zhang Z, Ferretti V, Güntan İ, Moro A, Steinberg EA, Ye Z, Zecharia AY, Yu X, Vyssotski AL, Brickley SG, Yustos R, Pillidge ZE, Harding EC, Wisden W, Franks NP - Nat. Neurosci. (2015)

Selective knockout of the GABA vesicular transporter gene (vgat) in the PO hypothalamic area (LPO-Δvgat mice) slows the transition to dexmedetomidine-induced sleep. (a) Cre recombinase, produced from an AAV transgene, deletes exon 2 of the vgat gene33 following AAV-Cre-2A-Venus bilateral injection into the LPO area of vgatlox/lox mice. The image on the right shows the extent of AAV expression, as detected by staining with EGFP antisera. (b) EEG power spectra ten minutes after dexmedetomidine (100 μg kg−1 – red line) or saline (black) injection in control mice (n=8) expressing AAV-GFP in the LPO (LPO-GFP mice; n=6). Lighter shaded envelopes indicate the s.e.m. (c) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg/kg; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-GFP control mice. (d) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=7) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=6) in LPO-GFP control mice. (e) EEG power spectra ten minutes after dexmedetomidine (100 μg/kg – red line; n=6) or saline (black) injection in mice (n=8) expressing AAV-Cre-2A-Venus in the LPO (LPO-Δvgat mice). (f) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (n=8) in AAV-Cre-2A-Venus mice. (g) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-Δvgat mice. For all panels the error bars represent s.e.m.
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Figure 7: Selective knockout of the GABA vesicular transporter gene (vgat) in the PO hypothalamic area (LPO-Δvgat mice) slows the transition to dexmedetomidine-induced sleep. (a) Cre recombinase, produced from an AAV transgene, deletes exon 2 of the vgat gene33 following AAV-Cre-2A-Venus bilateral injection into the LPO area of vgatlox/lox mice. The image on the right shows the extent of AAV expression, as detected by staining with EGFP antisera. (b) EEG power spectra ten minutes after dexmedetomidine (100 μg kg−1 – red line) or saline (black) injection in control mice (n=8) expressing AAV-GFP in the LPO (LPO-GFP mice; n=6). Lighter shaded envelopes indicate the s.e.m. (c) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg/kg; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-GFP control mice. (d) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=7) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=6) in LPO-GFP control mice. (e) EEG power spectra ten minutes after dexmedetomidine (100 μg/kg – red line; n=6) or saline (black) injection in mice (n=8) expressing AAV-Cre-2A-Venus in the LPO (LPO-Δvgat mice). (f) Percentage of time scored as NREM sleep after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly greater (two-way ANOVA, P<0.0001) than in saline (n=8) in AAV-Cre-2A-Venus mice. (g) Speed in open field 30 min after dexmedetomidine (100 μg kg−1; filled circles, n=6) was significantly less (two-way ANOVA, P<0.0001) than in saline (open circles, n=8) in LPO-Δvgat mice. For all panels the error bars represent s.e.m.
Mentions: To test if dexmedetomidine-induced sedation required GABAergic neurons in the LPO area, we deleted the vesicular GABA transporter (vgat) gene by injecting AAV-Cre-2A-Venus bilaterally into the LPO of mice homozygous for a floxed vgat gene33, vgatlox/lox, to give LPO-Δvgat mice (Fig. 7a). Control vgatlox/lox mice were injected with AAV-GFP to give LPO-GFP mice.

Bottom Line: For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively.Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation.Thus, α2 adrenergic receptor-induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Imperial College London, South Kensington, UK.

ABSTRACT
Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic-induced sedation and loss of righting reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively. Selective knockdown of α2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation. We used TetTag pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases, non-rapid eye movement sleep, with the accompanying drop in body temperature, was recapitulated. Thus, α2 adrenergic receptor-induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.

Show MeSH
Related in: MedlinePlus