A variety of drugs of abuse, including especially cocaine and amphetamine that inhibit dopamine reuptake, cause a wakeful hypervigilant state, however the location of the dopamlnergic neurons that play this role remains unclear. The ventral tegmental area (VTA) dopaminergic neurons that project to the prefrontal cortex and ventral striatum do not change in firing rate during behavioral wakefulness. In additon, lesion of the VTA does not decrease wakefulness. We hypothesize that the dopaminergic cells in the ventral periaqueductal gray matter (vPAG) are the long-sought group.
In aim 1, we will determine whether vPAG dopaminergic neurons are wake-active by labeing Fos and tyrosine hydroxylase following spontaneous wakefulness or sleep.
In aim 2 and 4, we will apply anterograde and retrograde tracers to define the afferent and efferent connections of the vPAG DA neurons with the sleep-wake control system.
In aim 3, we will examine the effects of dopamine and dopamine receptor agonists on the vPAG dopaminergic projected neurons via patch-clamping technique on in vitro slice.
In aim 5, we will selectively lesion the wake-active dopaminergic neurons by 6-hydroxydopamine and examine baseline sleep-wake behavior and arousal state mediated by dopamine reuptake inhibitor. Our preliminary results suggest that the dopaminergic cells in the vPAG are wake-active, and they project to basal f6rebraih,!,tlialamus, and prefrontal cortex, and reciprocally communicate with laterodorsal tegmental cholinergic cells, perifornical orexin/hypocretin cells, and locus coeruleus as well as the ventrolateral preoptic nucleus Lesion of vPAG dopaminergic cells causes 20% increase in total sleep. The vPAG dopaminergie cells;rriay provide the long sought dopamine waking influence, and they may also play importanfrqles in arousal mechanisms of psychostimulants that inhibit dopamine reuptake and in sleep disorders of'Parkinson's disease that has extensive loss of mesopontine dopaminergic neurons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Mitler, Merrill
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Beth Israel Deaconess Medical Center
United States
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Qiu, Mei Hong; Chen, Michael C; Fuller, Patrick M et al. (2016) Stimulation of the Pontine Parabrachial Nucleus Promotes Wakefulness via Extra-thalamic Forebrain Circuit Nodes. Curr Biol 26:2301-12
Anaclet, Christelle; Lin, Jian-Sheng; Vetrivelan, Ramalingam et al. (2012) Identification and characterization of a sleep-active cell group in the rostral medullary brainstem. J Neurosci 32:17970-6
Thankachan, S; Fuller, P M; Lu, J (2012) Movement- and behavioral state-dependent activity of pontine reticulospinal neurons. Neuroscience 221:125-39
Vetrivelan, R; Chang, C; Lu, J (2011) Muscle tone regulation during REM sleep: neural circuitry and clinical significance. Arch Ital Biol 149:348-66
Krenzer, Martina; Anaclet, Christelle; Vetrivelan, Ramalingam et al. (2011) Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia. PLoS One 6:e24998
Qiu, Mei-Hong; Vetrivelan, Ramalingam; Fuller, Patrick M et al. (2010) Basal ganglia control of sleep-wake behavior and cortical activation. Eur J Neurosci 31:499-507
Anaclet, Christelle; Pedersen, Nigel P; Fuller, Patrick M et al. (2010) Brainstem circuitry regulating phasic activation of trigeminal motoneurons during REM sleep. PLoS One 5:e8788
Gompf, Heinrich S; Mathai, Christine; Fuller, Patrick M et al. (2010) Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci 30:14543-51
Vetrivelan, Ramalingam; Fuller, Patrick M; Tong, Qingchun et al. (2009) Medullary circuitry regulating rapid eye movement sleep and motor atonia. J Neurosci 29:9361-9
Greco, Mary-Ann; Fuller, Patrick M; Jhou, Thomas C et al. (2008) Opioidergic projections to sleep-active neurons in the ventrolateral preoptic nucleus. Brain Res 1245:96-107

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