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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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EEG delta power is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation or recovery sleep. Each panel shows Fourier Transform power spectra when the EEG and EMG signals were scored as either sleep (red) or wake (black). The envelopes represent the s.e.m. (a) Dexmedetomidine sedation (n=7). (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=8). (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=6). (d) Recovery sleep (n=7). (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=8). (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=7). Each spectrum is calculated by combining EEG segments totally 20 minutes. The inserts show representative EEG traces, and the accompanying calibration bars represent 100 μV and 500 msec.
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Figure 5: EEG delta power is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation or recovery sleep. Each panel shows Fourier Transform power spectra when the EEG and EMG signals were scored as either sleep (red) or wake (black). The envelopes represent the s.e.m. (a) Dexmedetomidine sedation (n=7). (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=8). (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=6). (d) Recovery sleep (n=7). (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=8). (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=7). Each spectrum is calculated by combining EEG segments totally 20 minutes. The inserts show representative EEG traces, and the accompanying calibration bars represent 100 μV and 500 msec.

Mentions: The following sequence of results is illustrated with LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice first undergoing dexmedetomidine-induced sedation, followed by CNO treatment, then after a one month gap, 4 hours sleep deprivation and recovery sleep followed by CNO treatment (Figs. 4 and 5). Approximately five minutes after dexmedetomidine injection, the EEG of both LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice exhibited prominent and sustained NREM which lasted ~90 minutes relative to the mice given only saline (Figs. 4a and 5a). All dexmedetomidine-injected mice became immobile (Fig. 4b), but still had a righting reflex. Mice were then put back on the doxycycline diet for 4 days to repress the induction of further TetTag-hM3Dq receptors, and after this injected i.p. with CNO or saline and their EEG and behavioral responses recorded (Figs. 4c,d and 5b). (The mice used in our study exhibited maximal periods of NREM sleep during the “lights on” part of the cycle (Supplementary Fig. 7a,b). All CNO injections were therefore carried out during this period when the mice were most active.)


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)

EEG delta power is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation or recovery sleep. Each panel shows Fourier Transform power spectra when the EEG and EMG signals were scored as either sleep (red) or wake (black). The envelopes represent the s.e.m. (a) Dexmedetomidine sedation (n=7). (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=8). (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=6). (d) Recovery sleep (n=7). (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=8). (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=7). Each spectrum is calculated by combining EEG segments totally 20 minutes. The inserts show representative EEG traces, and the accompanying calibration bars represent 100 μV and 500 msec.
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Figure 5: EEG delta power is recapitulated by reactivation of genetically tagged neuronal ensembles in LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice following dexmedetomidine-induced sedation or recovery sleep. Each panel shows Fourier Transform power spectra when the EEG and EMG signals were scored as either sleep (red) or wake (black). The envelopes represent the s.e.m. (a) Dexmedetomidine sedation (n=7). (b) CNO reactivation after dexmedetomidine sedation for LPO-TetTag-hM3Dq mice (n=8). (c) CNO reactivation after dexmedetomidine sedation for MnPO-TetTag-hM3Dq mice (n=6). (d) Recovery sleep (n=7). (e) CNO reactivation after recovery sleep for LPO-TetTag-hM3Dq mice (n=8). (f) CNO reactivation after recovery sleep for MnPO-TetTag-hM3Dq mice (n=7). Each spectrum is calculated by combining EEG segments totally 20 minutes. The inserts show representative EEG traces, and the accompanying calibration bars represent 100 μV and 500 msec.
Mentions: The following sequence of results is illustrated with LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice first undergoing dexmedetomidine-induced sedation, followed by CNO treatment, then after a one month gap, 4 hours sleep deprivation and recovery sleep followed by CNO treatment (Figs. 4 and 5). Approximately five minutes after dexmedetomidine injection, the EEG of both LPO-TetTag-hM3Dq and MnPO-TetTag-hM3Dq mice exhibited prominent and sustained NREM which lasted ~90 minutes relative to the mice given only saline (Figs. 4a and 5a). All dexmedetomidine-injected mice became immobile (Fig. 4b), but still had a righting reflex. Mice were then put back on the doxycycline diet for 4 days to repress the induction of further TetTag-hM3Dq receptors, and after this injected i.p. with CNO or saline and their EEG and behavioral responses recorded (Figs. 4c,d and 5b). (The mice used in our study exhibited maximal periods of NREM sleep during the “lights on” part of the cycle (Supplementary Fig. 7a,b). All CNO injections were therefore carried out during this period when the mice were most active.)

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