A defining feature of REM sleep is paralysis of nearly all muscles. In REM sleep behavior disorder (RBD), the absence of REM atonia permits the appearance of dream enactment. This disorder is strongly associated with neurodegenerative diseases such as Parkinson's disease, and it often appears in early stages when the disease involves the lower brainstem including the pons. Considerable evidence demonstrates that neurons of the sublaterodorsal (SLD) nucleus of the pons, also known as the subcoreuleus, generate muscle atonia during REM sleep. Lesions of this area produce REM without atonia while pharmacological activation triggers a REM-like state. We recently found that glutamatergic REM-active neurons in the SLD directly project to the glycinergic/GABAergic premotorneurons in the spinal cord. Our hypothesis is that these spinal projecting SLD (SLDsp) neurons play a critical role in the generation of muscle atonia during REM sleep. We will examine the electrophysiological actions of the cholinergic, monoaminergic and orexinergic afferents to the SLDsp neurons using patch- clamp recordings in a slice preparation. We will retrogradely prelabel the SLDsp neurons with fluorescent tracers microinjected in the spinal cord, and then use these animals for slice recordings.
In Aim 1, and Aim 2, we will determine the electrophysiological responses to cholinergic and monoaminergic inputs. We will determine their pre- and postsynaptic effects, and we will identify their receptor subtypes and their electrophysiologically-mediated mechanisms.
In Aim 3, we will focus on orexinergic inputs. We have found that SLDsp neurons are not directly affected by orexin, but instead orexin increases GABAergic synaptic input to these neurons. We will identify the source of this GABAergic input with a rescue experiment using inducible orexin receptor Ox1R and Ox2R knock-in mice. These mice are born lacking Ox1R or Ox2R or both. We will place injections of an adeno-associated viral vector containing Cre recombinase into specific brain regions of these mice to induce focal rescue of orexin receptors and to restore the orexinergic modulation of GABAergic synaptic input to the SLDsp neurons. Overall these experiments will help define the physiology underlying the regulation of REM-atonia neurons. In addition, these studies will provide essential insights into the mechanism for orexin effects on REM-atonia neurons, and how their absence results in cataplexy, as well as into the control of the REM-atonia neurons in RBD.

Public Health Relevance

During normal Rapid Eye Movement (REM) sleep, there is loss of muscle tone that prevents people from acting out their dreams. REM sleep behavior disorder (RBD) and cataplexy may be triggered by the dysfunction of the circuitry that controls REM-atonia The goal of our experiments is to define the physiology of REM sleep atonia, to better understand the neurobiology of RBD and cataplexy and to provide essential insights for the development of more effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061863-04
Application #
8197688
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Gnadt, James W
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$364,438
Indirect Cost
$150,063
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Williams, Rhannan H; Chee, Melissa J S; Kroeger, Daniel et al. (2014) Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci 34:6023-9
Anaclet, Christelle; Ferrari, Loris; Arrigoni, Elda et al. (2014) The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat Neurosci 17:1217-24
Arrigoni, Elda; Saper, Clifford B (2014) What optogenetic stimulation is telling us (and failing to tell us) about fast neurotransmitters and neuromodulators in brain circuits for wake-sleep regulation. Curr Opin Neurobiol 29:165-71
Weng, F J; Williams, R H; Hawryluk, J M et al. (2014) Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord. J Physiol 592:1601-17
Oishi, Yo; Williams, Rhiannan H; Agostinelli, Lindsay et al. (2013) Role of the medial prefrontal cortex in cataplexy. J Neurosci 33:9743-51
Hawryluk, J M; Ferrari, L L; Keating, S A et al. (2012) Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons. J Neurophysiol 107:2769-81
Arrigoni, E; Mochizuki, T; Scammell, T E (2010) Activation of the basal forebrain by the orexin/hypocretin neurones. Acta Physiol (Oxf) 198:223-35
Arrigoni, Elda; Lu, Jun; Vetrivelan, Ramalingam et al. (2009) Long-term synaptic plasticity is impaired in rats with lesions of the ventrolateral preoptic nucleus. Eur J Neurosci 30:2112-20