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Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

ABSTRACT: BACKGROUND:Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAGDA cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown. METHODS:This study combined designer receptors exclusively activated by designer drugs (DREADDs), behavioral pharmacology, electrophysiology, and immunoelectron microscopy in male and female mice to elucidate mechanisms in the vPAG that promote arousal. RESULTS:Activation of locus coeruleus projections to the vPAG or vPAGDA neurons induced by DREADDs promoted arousal. Similarly, agonist stimulation of vPAG alpha1-adrenergic receptors (?1ARs) increased latency to fall asleep, whereas ?1AR blockade had the opposite effect. ?1AR stimulation drove vPAGDA activity in a glutamate-dependent, action potential-independent manner. Compared with other dopaminergic brain regions, ?1ARs were enriched on astrocytes in the vPAG, and mimicking ?1AR transmission specifically in vPAG astrocytes via Gq-DREADDS was sufficient to increase arousal. In general, the wake-promoting effects observed were not accompanied by hyperactivity. CONCLUSIONS:These experiments revealed that vPAG ?1ARs increase arousal, promote glutamatergic input onto vPAGDA neurons, and are abundantly expressed on astrocytes. Activation of locus coeruleus inputs, vPAG astrocytes, or vPAGDA neurons increase sleep latency but do not produce hyperactivity. Together, these results support an arousal circuit whereby noradrenergic transmission at astrocytic ?1ARs activates wake-promoting vPAGDA neurons via glutamate transmission.

SUBMITTER: Porter-Stransky KA

PROVIDER: S-EPMC6326840 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

Porter-Stransky Kirsten A KA Centanni Samuel W SW Karne Saumya L SL Odil Lindsay M LM Fekir Sinda S Wong Jennifer C JC Jerome Canaan C Mitchell Heather A HA Escayg Andrew A Pedersen Nigel P NP Winder Danny G DG Mitrano Darlene A DA Weinshenker David D

Biological psychiatry 20180817 3

<h4>Background</h4>Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAG<sup>DA</sup> cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown.<h4>Methods</h4>This study combined designer receptors exclusively activated by designer drugs (DREADDs), behavioral pharmacology, el ...[more]

PMID: 30269865

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Dataset Information

Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

Publications

Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

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