Optogenetic stimulation of locus ceruleus neurons augments inhibitory transmission to parasympathetic cardiac vagal neurons via activation of brainstem α1 and β1 receptors.
Locus ceruleus (LC) noradrenergic neurons are critical in generating alertness. In addition to inducing cortical arousal, the LC also orchestrates changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Although the association between arousal and increased heart rate is well accepted, the neurobiological link between the LC and parasympathetic neurons that control heart rate has not been identified. In this study, we test directly whether activation of noradrenergic neurons in the LC influences brainstem parasympathetic cardiac vagal neurons (CVNs). CVNs were identified in transgenic mice that express channel-rhodopsin-2 (ChR2) in LC tyrosine hydroxylase neurons. Photoactivation evoked a rapid depolarization, increased firing, and excitatory inward currents in ChR2-expressing neurons in the LC. Photostimulation of LC neurons did not alter excitatory currents, but increased inhibitory neurotransmission to CVNs. Optogenetic activation of LC neurons increased the frequency of isolated glycinergic IPSCs by 27 ± 8% (p = 0.003, n = 26) and augmented GABAergic IPSCs in CVNs by 21 ± 5% (p = 0.001, n = 26). Inhibiting α1, but not α2, receptors blocked the evoked responses. Inhibiting β1 receptors prevented the increase in glycinergic, but not GABAergic, IPSCs in CVNs. This study demonstrates LC noradrenergic neurons inhibit the brainstem CVNs that generate parasympathetic activity to the heart. This inhibition of CVNs would increase heart rate and risks associated with tachycardia. The receptors activated within this pathway, α1 and/or β1 receptors, are targets for clinically prescribed antagonists that promote slower, cardioprotective heart rates during heightened vigilant states.
Department of Pharmacology and Physiology, Department of Anesthesiology and Critical Care Medicine, The George Washington University, Washington, District of Columbia 20037.
Xin
X
Wang
Ramón A
RA
Piñol
Peter
P
Byrne
David
D
Mendelowitz
D018663:Adrenergic Agents / Q000494:pharmacology; D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001933:Brain Stem / Q000166:cytology*; D000075402:Channelrhodopsins; D005998:Glycine / Q000494:pharmacology; D006321:Heart / Q000294:innervation; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008125:Locus Coeruleus / Q000166:cytology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D010775:Photic Stimulation; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D014630:Vagus Nerve / Q000502:physiology*
D018663:Adrenergic Agents; D001426:Bacterial Proteins; D000075402:Channelrhodopsins; D008164:Luminescent Proteins; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; C054562:yellow fluorescent protein, Bacteria; D014446:Tyrosine 3-Monooxygenase; D005998:Glycine
cardiac vagal neurons; locus ceruleus; optogenetic stimulation