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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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Hypothermia is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following recovery sleep, but only in LPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation. Each panel shows changes in body temperature following: (a) dexmedetomidine sedation (n=10) (red) or saline (n=20) or CNO (n=3) (black), (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=5), (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=5), (d) recovery sleep (n=10), (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=6), and (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=5). The data in panels a) and d) are for LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice combined, because these were indistinguishable.
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Figure 6: Hypothermia is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following recovery sleep, but only in LPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation. Each panel shows changes in body temperature following: (a) dexmedetomidine sedation (n=10) (red) or saline (n=20) or CNO (n=3) (black), (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=5), (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=5), (d) recovery sleep (n=10), (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=6), and (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=5). The data in panels a) and d) are for LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice combined, because these were indistinguishable.

Mentions: Using TetTagging, we examined if the neural circuitries in the LPO and MnPO areas were sufficient to trigger sedative or recovery sleep-induced hypothermia. Before any treatments, we checked that neither saline or CNO injections caused a change in body temperature (Fig. 6a). The body temperature of the mice was higher during the dark period when they were most active (Supplementary Fig. 7c); as for the sedation experiments, all investigations of temperature were done during the dark period. Two days after doxycycline removal, the LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice were given the sedative dose of 100 μg/kg dexmedetomidine. This caused a strong hypothermia (Fig. 6a), consistent with previous reports6,32. Four days later, on a doxycycline diet, they were then injected with CNO. In the LPO-TetTag-hM3Dq animals, CNO reactivation of the dexmedetomidine-induced hypothalamic ensembles largely recapitulated the temperature drop (Fig. 6b). There was, however, little effect in MnPO-TetTag-hM3Dq mice (Fig. 6c). Thus following dexmedetomidine sedation, activated neuronal ensembles in LPO, but not MnPO, are responsible for the hypothermia produced by this drug.


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)

Hypothermia is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following recovery sleep, but only in LPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation. Each panel shows changes in body temperature following: (a) dexmedetomidine sedation (n=10) (red) or saline (n=20) or CNO (n=3) (black), (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=5), (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=5), (d) recovery sleep (n=10), (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=6), and (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=5). The data in panels a) and d) are for LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice combined, because these were indistinguishable.
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Figure 6: Hypothermia is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following recovery sleep, but only in LPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation. Each panel shows changes in body temperature following: (a) dexmedetomidine sedation (n=10) (red) or saline (n=20) or CNO (n=3) (black), (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=5), (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=5), (d) recovery sleep (n=10), (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=6), and (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=5). The data in panels a) and d) are for LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice combined, because these were indistinguishable.
Mentions: Using TetTagging, we examined if the neural circuitries in the LPO and MnPO areas were sufficient to trigger sedative or recovery sleep-induced hypothermia. Before any treatments, we checked that neither saline or CNO injections caused a change in body temperature (Fig. 6a). The body temperature of the mice was higher during the dark period when they were most active (Supplementary Fig. 7c); as for the sedation experiments, all investigations of temperature were done during the dark period. Two days after doxycycline removal, the LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice were given the sedative dose of 100 μg/kg dexmedetomidine. This caused a strong hypothermia (Fig. 6a), consistent with previous reports6,32. Four days later, on a doxycycline diet, they were then injected with CNO. In the LPO-TetTag-hM3Dq animals, CNO reactivation of the dexmedetomidine-induced hypothalamic ensembles largely recapitulated the temperature drop (Fig. 6b). There was, however, little effect in MnPO-TetTag-hM3Dq mice (Fig. 6c). Thus following dexmedetomidine sedation, activated neuronal ensembles in LPO, but not MnPO, are responsible for the hypothermia produced by this drug.

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