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Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation.

Grace KP, Horner RL - Front Neurol (2015)

Bottom Line: Rapid eye movement (REM) sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system.Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation.We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Toronto , Toronto, ON , Canada.

ABSTRACT
Rapid eye movement (REM) sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system. Initial theories of REM sleep generation posited that induction of the state required activation of the "pontine REM sleep generator" by cholinergic inputs. Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail.

No MeSH data available.


Hypothesized REM sleep control circuits. (A) The original reciprocal interaction hypothesis. (B) Modified reciprocal interaction hypothesis. (C) Flip-flop circuit proposed by Lu et al. (50). (D) Version of flip-flop circuit proposed by Sapin et al. (83), modified by Grace et al. (63). Anatomical abbreviations: DpMe, deep mesencephalic reticular nucleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PTF, pontine tegmental field; vlPAG, ventrolateral periaqueductal gray.
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Figure 2: Hypothesized REM sleep control circuits. (A) The original reciprocal interaction hypothesis. (B) Modified reciprocal interaction hypothesis. (C) Flip-flop circuit proposed by Lu et al. (50). (D) Version of flip-flop circuit proposed by Sapin et al. (83), modified by Grace et al. (63). Anatomical abbreviations: DpMe, deep mesencephalic reticular nucleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PTF, pontine tegmental field; vlPAG, ventrolateral periaqueductal gray.

Mentions: Mapping the neuroanatomical network responsible for REM sleep generation, although necessary, is insufficient for an understanding of the network dynamics that actually give rise to cycling into and out of REM sleep. In 1975, Hobson and McCarley proposed the reciprocal interaction model: a structural/mathematical hypothesis meant to provide an explanation for the cyclical generation of REM sleep. This model posited that a reciprocal interaction between REM sleep-inactive cell groups and REM sleep-active cell groups form a pacemaker circuit that drives oscillations between sleep stages (94) (Figure 2A). Aminergic neurons in the locus coeruleus and dorsal raphe were hypothesized as the REM sleep-inactive cells. REM sleep-active neurons in the PTF innervating the LC were presumed to be cholinergic and excitatory (95). The model proposed that during wakefulness “cholinergic” PTF neurons would be inhibited by activated aminergic neurons. At non-REM sleep onset, waning aminergic neuron activity would disinhibit “cholinergic” PTF neurons. At a critical point, the combination of this disinhibition and auto-excitation within the “cholinergic” cell group would enable the exponential rise in PTF neuron activity that triggers the onset of REM sleep (96). During REM sleep, “cholinergic” PTF neurons would excite aminergic neurons resulting in their own inactivation and the termination of the REM sleep episode.


Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation.

Grace KP, Horner RL - Front Neurol (2015)

Hypothesized REM sleep control circuits. (A) The original reciprocal interaction hypothesis. (B) Modified reciprocal interaction hypothesis. (C) Flip-flop circuit proposed by Lu et al. (50). (D) Version of flip-flop circuit proposed by Sapin et al. (83), modified by Grace et al. (63). Anatomical abbreviations: DpMe, deep mesencephalic reticular nucleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PTF, pontine tegmental field; vlPAG, ventrolateral periaqueductal gray.
© Copyright Policy
Related In: Results  -  Collection

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Figure 2: Hypothesized REM sleep control circuits. (A) The original reciprocal interaction hypothesis. (B) Modified reciprocal interaction hypothesis. (C) Flip-flop circuit proposed by Lu et al. (50). (D) Version of flip-flop circuit proposed by Sapin et al. (83), modified by Grace et al. (63). Anatomical abbreviations: DpMe, deep mesencephalic reticular nucleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PTF, pontine tegmental field; vlPAG, ventrolateral periaqueductal gray.
Mentions: Mapping the neuroanatomical network responsible for REM sleep generation, although necessary, is insufficient for an understanding of the network dynamics that actually give rise to cycling into and out of REM sleep. In 1975, Hobson and McCarley proposed the reciprocal interaction model: a structural/mathematical hypothesis meant to provide an explanation for the cyclical generation of REM sleep. This model posited that a reciprocal interaction between REM sleep-inactive cell groups and REM sleep-active cell groups form a pacemaker circuit that drives oscillations between sleep stages (94) (Figure 2A). Aminergic neurons in the locus coeruleus and dorsal raphe were hypothesized as the REM sleep-inactive cells. REM sleep-active neurons in the PTF innervating the LC were presumed to be cholinergic and excitatory (95). The model proposed that during wakefulness “cholinergic” PTF neurons would be inhibited by activated aminergic neurons. At non-REM sleep onset, waning aminergic neuron activity would disinhibit “cholinergic” PTF neurons. At a critical point, the combination of this disinhibition and auto-excitation within the “cholinergic” cell group would enable the exponential rise in PTF neuron activity that triggers the onset of REM sleep (96). During REM sleep, “cholinergic” PTF neurons would excite aminergic neurons resulting in their own inactivation and the termination of the REM sleep episode.

Bottom Line: Rapid eye movement (REM) sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system.Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation.We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Toronto , Toronto, ON , Canada.

ABSTRACT
Rapid eye movement (REM) sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system. Initial theories of REM sleep generation posited that induction of the state required activation of the "pontine REM sleep generator" by cholinergic inputs. Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail.

No MeSH data available.