Loss of atonia is a cardinal sign of REM sleep behavior disorder (RBD) that precedes many neural degenerative diseases such as Parkinson's disease and Alzheimer's disease by a decade. Understanding the neural circuit of atonia provides not only how the motor system operates during sleep but also the locus of neuropathology of RBD. We have previously identified that the glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD) project to the spinal cord inhibitory interneurons, which proposed to suppress the motor activity during REM sleep. We have since confirmed that loss of glutamate function of the SLD results in RBD-like-phenotype. The controversy has been the involvement of the medulla in regulation of atonia. We have revealed that the SLD has trifurcate projections to GABA/glycine reticulospinaneurons in the rostromedial medulla (RVM), glutamatergic reticulospinal neurons in the ventromedial medulla (VMM) and spinal cord GABA/glycine interneurons. Although lesions of the RVM and VMM show disinhibited phasic motor activity during REM sleep, it is far less than that of SLD lesions. We thus propose the SLD controls atonia mostly by activating spinal cord inhibitory interneurons, and the medullary relays play less critical role in atonia. In this grant, we will use a novel technique DREADD in which modified G coupled cholinergic receptors are inserted into the neurons that are only activated by activate clozapine-N-oxide (CNO). We design a series of experiments using DREADD method to activate or inhibit selective neurons in combination of lesions to identify the premotor sites that regulate atonia.
In aim 1, we ask whether the SLD activation by DREADD induces Fos in the ventral medulla and spinal cord interneurons.
In aim 2, we ask whether DREADD activation of the RVM or VMM can reverse RBD-like phenotype.
In aim 3 we ask whether SLD control of atonia depends on the spinal glycine/GABA interneurons (SLD activation and lesions of spinal cord interneurons or deletion of glycine-GABA). Finally in aim 4, we ask whether the motor cortex drives complex behaviors of RBD. Our data support that the direct projections of the SLD to the spinal cord inhibitory interneurons play a dominant role in suppression of motor behaviors driven by the motor cortex during REM sleep.
Dysfunction of atonia during REM (rapid-eye-movement) sleep is a hallmark of human REM sleep behavior disorder (RBD), an earlier sign of many neural degenerative diseases such as Parkinson's disease. We propose to use rat and mouse model to dissect the neural circuit of muscle atonia. We hypothesize that during REM sleep, the sublaterdorsal tegmental nucleus (SLD) in the dorsal pons activates the spinal cord inhibitory premotor neurons directly and indirectly via the ventral medullary glutamatergci neurons as well as SLD activates GABA/glycine premotor neurons in the ventral medulla, which collectively causes motor neuron atonia. Of these controls, the SLD projections to the spinal cord inhibitory interneurons play a dominant role in regulation of atonia.
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