Abstract
Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.
Highlights
Despite decades of research, there is a persistent debate regarding the localization of GABA/ glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical sleep (PS), resulting in the loss of muscle tone during this sleep state
We recently demonstrated that glutamatergic neurons within the pontine sublaterodorsal tegmental nucleus (SLD) generate muscle atonia during paradoxical (or rapid eye movement (REM)) sleep (PS) and send descending inputs to the ventromedial medullary reticular formation in rats[12]
Combining the use of short-hairpin RNAs against vGAT with innovative behavioral analyses, we demonstrate that impairment of GABA/glycine ventromedial medulla (vmM) neurotransmission in the rat is sufficient to mimic the major symptoms of human REM sleep behavior disorder (RBD)
Summary
There is a persistent debate regarding the localization of GABA/ glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. We demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. Injection of glutamatergic agonists into the vmM induces muscle atonia, whereas neurotoxic lesion within this region produces an increased muscle tone associated with motor behaviors during PS16,17 According to these data, we proposed that GABA/glycine vmM neurons might be responsible for the muscle atonia during PS through the inhibition of somatic motoneurons[18,19]. We validate a pre-clinical RBD model providing new opportunities for clinical research to improve patient treatment and to study mechanisms responsible for medication-induced RBD, as with antidepressants
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